Search Results (25,454)

The species Psychotria densicostata Müll.Arg. is a shrub belonging to the Rubiaceae family, endemic to Brazil. So far, there are reports neither of phytochemical work on nor of biological evaluation of it. This study investigated its alkaloid profile and evaluated the inhibitory effects of extracts, alkaloid-enriched fractions and one of its major constituents on human neutrophil elastase (HNE). The monoterpene indole alkaloids (MIAs) strictosidine (1), (3α,5α)-5-carboxystrictosidine (2), strictosidine lactam (3), lyaloside (4), lyalosidic acid (5), 5-carboxystrictosamide (6), 3,4-dehydrostrictosidinic acid (7), and N-glucopyranosyl vincosamide (8) were characterized in mixture, in its leaves, and/or stems by using an integrated approach combining nuclear magnetic resonance (NMR) techniques, high performance liquid chromatography coupled to a tandem mass spectrometer with an electrospray ionization source (HPLC-ESI-MS/MS), and molecular networks. The crude leaf extract and an alkaloid-enriched fraction derived from it showed inhibitory activity against HNE. These results contribute to the chemical knowledge of the species and suggest its potential biological property. Full article

Background/Objectives: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) necessitates innovative strategies to overcome conventional resistance mechanisms. This study investigated the potential of the natural flavonolignan silibinin (SIL) as an antivirulence agent against S. aureus, with a particular emphasis on its putative multi-target antibacterial activity and its capacity to potentiate the effects of ciprofloxacin (CIP). Methods: The antibacterial and antivirulence properties of SIL were assessed using both in vitro and in silico approaches. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined, and its synergistic interaction with CIP was evaluated using checkerboard assays. Inhibition of biofilm formation, as well as disruption of established biofilms, was assessed using an MTT-based viability assay. Staphyloxanthin (STX) inhibition was examined through pigment extraction and spectrophotometric quantification of pathway intermediates. Molecular docking studies were conducted to predict the binding affinities of the compounds to key bacterial targets, while safety was evaluated through haemolytic and cytotoxicity assays. Results: SIL exhibited weak to moderate direct antibacterial activity (MICs of 256–512 µg/mL), which is characteristic of many natural product scaffolds. Notably, SIL potentiated the activity of CIP, reducing its MIC by up to fourfold against selected resistant strains of S. aureus. SIL significantly inhibited biofilm formation and disrupted established mature biofilms in a strain-dependent manner. In vitro metabolic profiling and in silico analyses provided mechanistic insights into the effects of SIL on STX biosynthesis. Precursor accumulation data suggest inhibition at the diapophytoene desaturase (CrtN) catalytic step, representing a potential mechanism not previously reported for flavonolignans. Molecular docking studies further predicted favourable binding affinities for CrtM and other key targets. Importantly, SIL exhibited no haemolytic activity and low cytotoxicity in macrophages at synergistic concentrations. Conclusions: This study provides evidence that SIL functions as a dual-action agent, potentiating ciprofloxacin efficacy while reducing STX production and inhibiting biofilm formation, thereby impairing key virulence mechanisms of S. aureus. These findings, together with its favourable safety profile, provide a strong rationale for the development of silibinin-based topical adjuvants to combat drug-resistant Staphylococcus infections in humans. Full article

Background/Objectives: To address the limitations of natural curcumin, this study focuses on the functional evaluation of structurally optimized derivatives. We aimed to elucidate structure–activity relationships (SAR) and the stage-specific molecular mechanisms of adipogenesis inhibition using an in vitro cellular assay. Methods: Four novel curcuminoids were synthesized and evaluated in 3T3-L1 preadipocytes against natural curcumin (Curcuminoid I). Efficacy and mechanisms were assessed via cell viability assays, quantitative Oil Red O staining, and time-dependent transcriptional profiling (qPCR/Western blotting) of the KLF family and master regulators. Results: SAR analysis identified Curcuminoid III (symmetric 3,5-dimethoxy-4-hydroxy) as the most potent and safe candidate, whereas Curcuminoid IV exhibited cytotoxicity. Time-course analysis revealed a distinct step-wise inhibition mechanism wherein Curcuminoid III significantly upregulated the differentiation repressor KLF2 at the immediate-early phase. This rapid modulation effectively prevented the subsequent induction of pro-adipogenic factors, including KLF9, KLF15, PPARγ, and C/EBPα, in the mid-stage (3–5 d). Consequently, the expression of the maturation marker aP2 was robustly suppressed by the late stage (5–7 d). Conclusions: The symmetric 3,5-dimethoxy-4-hydroxy substitution pattern appears to confer strong anti-adipogenic activity to Curcuminoid III. Early modulation of the KLF2–PPARγ axis at the onset of differentiation may initiate a cascading inhibitory effect throughout the adipogenic program. These findings highlight the potential of structurally optimized plant-derived bioactive compounds as regulators of metabolic cell fate. Full article

Chronic myeloid leukaemia (CML) is driven by the t(9;22) forming the BCR::ABL1 fusion gene, leading to the development of hyper-myeloid proliferation. This led to development of tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, and Ponatinib. However, resistance or intolerance to ATP-competitive TKIs remains a challenge for some patients. asciminib (ABL001), a novel TKI, targets the myristoyl pocket of ABL1 instead of the ATP-binding site, reducing resistance to mutations. As asciminib is linked to thrombocytopenia, its effects on platelet activation, endothelial function, and inflammation must be studied to assess its potential to promote thrombosis. The main objective of this study is to determine the potential of asciminib as a monotherapy in inducing pathological responses to platelets and endothelium over time within the vasculature. This study assessed the effects of TKIs including asciminib on platelets and thrombotic biomarkers. Washed platelets were used to measure granule secretion, thrombus formation, surface expression of glycoproteins, apoptosis, and viability. Plasma from chronically Asciminib-treated CML patients was analysed using sandwich ELISA for inflammatory and platelet–endothelial biomarkers, and thrombin generation assays were performed to study coagulation. This approach combined in vitro and ex vivo methods to explore the impact of asciminib on platelet function and thrombotic potential. The study shows that acute treatment with asciminib does not promote platelet activation or thrombus formation. Instead, it exhibits an inhibitory effect on thrombus formation in vitro and is associated with reduced thrombo-inflammatory biomarkers ex vivo in chronically treated CML patients. Asciminib was associated with increased thrombin generation over time, suggesting an effect on secondary haemostasis. Asciminib does not appear to induce a prothrombotic or proinflammatory state under the conditions studied, which may be advantageous for CML patients. However, the observed increase in thrombin generation over time suggests a potential effect on secondary haemostasis that warrants further investigation in controlled studies. Full article

The escalating prevalence of antimicrobial resistance (AMR) in Gram-negative uropathogens represents a critical bottleneck in global clinical management. This study evaluated shifting resistance phenotypes and patient risk profiles to identify independent predictors of multidrug resistance (MDR). A comprehensive retrospective analysis was conducted on a cohort of 318 patients, utilizing statistical modeling to evaluate the impact of demographics, prolonged hospitalization, and comorbidities on MDR. Findings revealed a significant longitudinal exacerbation of resistance since 2012. A majority of Klebsiella pneumoniae strains and nearly all Myroides and Providencia species exhibited high-level resistance to cephalosporin/beta-lactamase inhibitor combinations. While high-dose piperacillin-tazobactam remains a therapeutic alternative, its utility is increasingly constrained by escalating Minimum Inhibitory Concentrations (MICs) for Klebsiella and Escherichia coli (E. coli). Statistical modeling identified advanced age as the primary independent driver, with MDR risk increasing linearly with every additional year of age. Furthermore, indwelling catheterization was strongly associated with resistant infections, while human immunodeficiency virus (HIV) status emerged as a significant cofactor in the selection of highly resistant strains. These findings underscore the need for a critical recalibration of therapeutic frameworks, prioritizing precision-guided stewardship. Pharmacodynamic optimization, through extended or continuous infusion regimens and individualized loading doses, is essential to mitigate the clinical burden of resistant pathogens within vulnerable geriatric cohorts. Full article

Carbapenems comprise a class of β-lactam antibiotics with broad-spectrum hydrolytic activity and are often reserved as last-line agents for the treatment of serious multidrug-resistant (MDR) bacterial infections. Clinically important nosocomial MDR Gram-negative bacteria (GNB) include Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Carbapenem resistance among these organisms is predominantly mediated by the production of β-lactamases called carbapenemases, such as K. pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-β-lactamase (VIM), and selected oxacillinase (OXA)-type carbapenemases. These enzymes degrade carbapenems, significantly compromising their clinical efficacy. To address escalating antimicrobial resistance, novel next-generation β-lactamase inhibitors (BLIs), partnered with established β-lactams (BLs), have been approved or are currently under development to inhibit carbapenemase activity. The present narrative review aims to synthesize the most current information on the major carbapenemases and discusses recently approved and investigational BL/BLI combination therapies in terms of their mechanisms of action, spectrum of activity, gaps in coverage, and available clinical and in vitro evidence. Development of resistance to novel BL/BLI combinations is also examined. Comparative analysis of inhibitory spectra and microbiological coverage indicates a continued need for metallo-β-lactamase inhibitors with direct pan-inhibitory activity, pathogen-specific BL/BLI regimens for carbapenem-resistant A. baumannii, and carbapenemase-targeted agents effective in the context of non-enzymatic resistance mechanisms. Treatment-emergent resistance to novel BL/BLIs and limitations in activity profiles underscore the critical need for continued innovation in pipeline development, vigilant global and local surveillance of carbapenemase epidemiology, and robust antimicrobial stewardship strategies to aid in preserving the efficacy of the antibacterial drug armamentarium. Full article

Background/Objectives: Stress experienced by families of individuals with illnesses or disabilities is shaped through the interaction of multiple complex influencing factors. This study aimed to elucidate the factors influencing stress in families of young/adult children with illnesses or disabilities, using Family System Unit Stress Theory (FSUST) as the guiding theoretical framework. Methods: Semi-structured interviews were conducted with 10 families of young/adult children with illnesses or disabilities. Data were analyzed using qualitative content analysis following the approach of Graneheim and Lundman. In line with FSUST, the identified influencing factors were categorized into negative factors (risk/causal/promoting) and positive factors (preventive/inhibitory/suppressive). Results: A total of six categories and 18 subcategories were extracted for the risk/causal/promoting factors, including “accumulation of unshared burdens within the family leading to role overload” and “concerns about the future of the young/adult child.” For the preventive/inhibitory/suppressive factors, five categories and 13 subcategories were extracted, including “receiving a diagnosis of the young/adult child’s illness or disability” and “family maintaining a positive attitude.” Conclusions: Family stress in families of young/adult children with illnesses or disabilities varies through the interaction of multilayered influencing factors, including persistent emotions carried over from the past, difficulties faced in the present, and anticipatory concerns regarding the future. Therefore, nursing practice requires a life course-oriented understanding of family stress and an integrated approach that concurrently reduces risk/causal/promoting factors while enhancing preventive/inhibitory/suppressive factors. Full article

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and an established therapeutic target in diseases such as cancer and ocular disorders. However, long-term use of most current anti-VEGF agents is often limited by their associated side effects, including hypertension, bleeding, and gastrointestinal complications. These limitations have stimulated interest in naturally occurring VEGF inhibitors derived from dietary sources, which may offer safer alternatives due to their favorable safety profiles. In this study, we investigated shared structural features of potent VEGFR2 inhibitors, focusing on naturally derived polyphenols. Polyphenols representing multiple structural subclasses were evaluated for their ability to inhibit VEGFR2 kinase activity using an in vitro kinase assay, to suppress VEGF-induced phosphorylation of VEGFR2 and downstream MAPK signaling in endothelial cells by Western blot, and to reduce VEGF-stimulated endothelial cell proliferation. Across all assays, flavonoids with strong VEGFR2 inhibitory activity displayed consistent structural characteristics, including the number and specific positioning of hydroxyl groups on the A- and B-rings, as well as specific structural elements of the C-ring. Our findings provide a strong foundation for further structure–activity relationship (SAR) studies and facilitate identification of key molecular determinants required for VEGFR2 inhibition. Elucidation of these structural patterns may contribute to the development of more effective and safer angiogenesis inhibitors with reduced adverse effects. Full article

As a crucial national ecological barrier, China’s Southern Collective Forest Region (SCFR) plays an essential role in maintaining regional ecological security and promoting sustainable development. Understanding the mechanisms driving the evolution of its ecosystem service value (ESV) is of great significance. Based on county-level data from 2000 to 2023, this study integrated the equivalent factor method, spatial autocorrelation analysis, the XGBoost-SHAP model, geographically and temporally weighted regression (GTWR), and partial least squares structural equation modeling (PLS-SEM) to examine the spatio-temporal evolution patterns and driving mechanisms of ESV in the SCFR. The results showed that ESV in the SCFR exhibited an overall downward trend, with a cumulative loss of 1973.77 × 10⁸ CNY. This was primarily due to marked reductions in hydrological and climate regulation services. The spatial distribution of ESV exhibited a significant heterogeneity—higher in the southwestern and southeastern mountainous regions, and lower in the northern plains and coastal zones, with the center of gravity shifting first to the northeast and then to the southwest. Local spatial autocorrelation revealed relatively stable “High–High” and “Low–Low” clustering characteristics, where high-value clusters were consistently distributed in core forest zones, while low-value clusters overlapped highly with urban agglomerations. Socio-economic factors exerted a significantly stronger influence on ESV than natural factors. Population density (POP), land use intensity (LUI), and gross domestic product (GDP) were identified as the dominant drivers, exhibiting distinct non-linear threshold effects and significant spatio-temporal heterogeneity. PLS-SEM analysis further quantified LUI as the dominant direct inhibitory pathway on ESV, highlighting urbanization’s indirect negative effect mediated through intensified LUI. Meanwhile, terrain effects were confirmed to positively influence ESV indirectly by constraining LUI and modulating local climate. The analytical framework of “threshold identification–spatio-temporal heterogeneity–causal pathway analysis” proposed in this study elucidated the complex driving mechanisms of ESV evolution, providing valuable guidance for ecological restoration evaluation and differentiated environmental governance. Full article

Background: Lavandula stoechas has attracted increasing attention for its potential anticancer properties; however, evidence regarding its effects on apoptotic signaling across different tumor types remains limited. Methods: In this study, the effects of dry and fresh ethanol extracts of Lavandula stoechas L. subsp. stoechas (LsDE and LsFE) were investigated in MDA-MB-231 triple-negative breast cancer, RT4 bladder carcinoma, and T98G glioblastoma cell lines, providing a comparative evaluation of their apoptotic effects. Long-term proliferative capacity was assessed using clonogenic survival assays, while apoptosis-related responses were evaluated by Annexin V–FITC/propidium iodide staining, quantitative RT-PCR of BAX and BCL2 and Western blot analysis of Bax, Bcl-2, and cleaved PARP1. Results: Both extracts significantly reduced clonogenic survival in all tested cancer cell lines, with LsDE showing stronger inhibitory effects in RT4 and T98G cells. Annexin V/PI analysis revealed cell type-dependent response patterns. In MDA-MB-231 cells, both extracts increased the proportion of PI-positive cells, suggesting a loss of membrane integrity, whereas RT4 cells exhibited increased early apoptotic and membrane-compromised populations. In contrast, T98G cells showed comparatively limited changes associated with apoptosis. Transcriptional analysis demonstrated extract- and cell line-specific modulation of the BAX/BCL2 ratio. Western blot analysis further demonstrated activation of mitochondrial apoptotic signaling through coordinated regulation of Bax and Bcl-2 and increased PARP1 cleavage. LsFE showed the strongest apoptosis-associated changes in MDA-MB-231 cells, whereas LsDE showed stronger effects in T98G cells, while both extracts were effective in modulating these proteins in RT4 cells. Conclusions: These findings indicate that ethanol extracts of L. stoechas impair long-term proliferative capacity and induce tumor type-dependent modulation of apoptosis-related markers. This study provides an integrated experimental framework that combines clonogenic survival assays, apoptosis analyses, gene expression, and protein-level measurements, supporting further investigation of L. stoechas extracts in cancer research. Full article

In this study, the rank of multifaceted activity of catechin (C), epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG) and epigallocatechin-3-gallate (EGCG) was addressed. Their antioxidant activity was determined by the differential pulse voltammetry (DPV), whereas their ability to inhibit angiotensin-converting enzyme (ACE) activity, acetylcholinesterase activity (AChE), and formation of the advanced glycation end-products (AGEs) was performed in a model system to show their importance against hypertension, Alzheimer-type dementia, and diabetic’s complication, respectively. The order of the antioxidant potential of catechins in comparision to gallic acid (GA) was EGCG > ECG > EC > EGC ≈ C > GA, whereas the order of the ACE inhibitory activity was EGCG > ECG > EGC > EC > C, thus indicating the importance of the structure–activity relationship. The correlation between IC₅₀ for ACE inhibition of catechins and their antioxidant activity had the value r = −0.60. The order of the AChE enzyme inhibitory activity was EGCG ≈ EGC > ECG > EC > C, and the weak positive correlation between IC₅₀ and the first anodic peak potential (E_pa1) values was noted (r = 0.67). The ranking of the anti-AGE activities was EGCG ≈ ECG > EGC > EC > C, and a negative correlation between the inhibitory activity of catechins against AGE formation and their antioxidant activity was r = −0.82, whereas a positive correlation (r = 0.88) was noted between their first anodic peak potential (E_pa1) values. The provided results expand our knowledge on the multifaceted activity of catechins, indicating EGCG and ECG as the most active antioxidants against inhibition of ACE and AChE as well as towards AGE formation. Full article

In order to enhance the value and stability of vegetable oils, they may be enriched with essential oils and plant extracts with strong antioxidant activity, yielding innovative formulations with potential applications in skincare. The present research aims to investigate the bioactive properties of an Usnea barbata extract in Jojoba oil (JO) enriched with 5% Peppermint oil (PEO), and 10% vitamin E (PJO). The oil extract (UBPJO) was obtained through cold maceration. The UBPJO antioxidant activity was investigated using ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) and DPPH (2,2-diphenyl-1-picrylhydrazyl)-based methods. The sunscreen capacity of UBPJO was evaluated by measuring their sun protection factor (SPF) values. The antimicrobial potential was investigated against S. aureus, E. coli, and C. albicans. The antioxidant activity of UBPJO was 1.5 times higher than that of PJO. Consequently, the sunscreen efficacy (assessed by SPF measurements) indicated satisfactory UVB protection abilities against S. aureus (UBPJO vs. PJO: 32.41 vs. 30.58). UBPJO exhibited significantly greater inhibitory effects compared to PJO against S. aureus (MIC = 18.75 ± 6.25 vs. 37.50 ± 0.00, p < 0.05). and C. albicans (9.62 ± 2.87 vs. 37.5 ± 12.5, p < 0.05). The bioactive properties investigated in the present study support the inclusion of UBPJO in various skin protective formulations with antiaging, antibacterial, and antifungal effects. Full article

Oxidative stress and inflammation are interconnected pathological processes involved in the progression of neurodegenerative, cardiovascular, and metabolic diseases, highlighting the need for multifunctional therapeutic agents targeting multiple pathways. In this study, two novel hybrid compounds were designed and synthesized in three steps by conjugating butylated phenolic moieties derived from butylated hydroxytoluene and p-coumaric acid with proline and γ-aminobutyric acid (GABA). The aim was the combination of antioxidant, anti-inflammatory, and cytoprotective properties within a single molecular framework. The compounds were evaluated using a comprehensive panel of in vitro and in vivo assays to assess antioxidant, metal-reducing, iron-chelating, antiglycation, anti-inflammatory, and acetylcholinesterase inhibitory activities. Both compounds exhibited significant antioxidant activity, with compound 2 demonstrating superior radical scavenging ability against DPPH, ABTS·⁺ and hydrogen peroxide (IC₅₀ 86 μM, 25 μM and 104 μM, respectively), enhanced ferric-reducing capacity (up to 91% of trolox activity), and strong iron-chelating activity (61.3%). Compound 2 also showed potent inhibition of lipid peroxidation (IC₅₀ 17.5 μM) and moderate antiglycation effects (44%), indicating substantial cytoprotective potential. Furthermore, both compounds selectively inhibited COX-2 over COX-1 and demonstrated moderate lipoxygenase inhibition, while compound 2 exhibited significant in vivo anti-inflammatory activity (53%), exceeding that of ibuprofen. Moderate acetylcholinesterase inhibition was also observed. In summary, the results confirm the design rationale, indicating that compound 2 could be further optimized as a multi-targeting molecule directed against oxidative stress- and inflammation-mediated conditions. Full article

Background: Gastric cancer (GC) is characterized by aggressive invasion and early peritoneal dissemination, which are strongly driven by chronic inflammation and epithelial–mesenchymal transition (EMT). c-Jun N-terminal kinase (JNK), a stress-responsive serine/threonine kinase within the mitogen-activated protein kinase (MAPK) family, integrates inflammatory cues to promote EMT and metastasis. Huangjin Shuangshen granules (HJSS) is a multi-component traditional Chinese medicine (TCM) formula derived from Simiao Yong’an Decoction and clinically used as an adjuvant therapy for GC. However, whether HJSS restrains inflammation-driven metastasis through modulation of JNK-associated EMT signaling remains unclear. Methods: The anti-metastatic efficacy of HJSS was evaluated using integrated in vivo and in vitro models, combined with transcriptomics, network pharmacology and molecular validation. Results: HJSS markedly attenuated LPS-induced metastatic behavior and inflammatory activation. Multilevel analyses converged on MAPK8/JNK as a central regulatory node. HJSS reversed EMT progression and inhibited nuclear phosphorylation of JNK without affecting its upstream kinases. Thermal-shift assays and molecular docking supported potential target engagement of HJSS-derived constituents, including possible interactions with JNK-related signaling targets. Pharmacologic reactivation of JNK partially abrogated the inhibitory effects of HJSS, confirming JNK-dependent action. Conclusions: HJSS suppresses inflammation-driven GC metastasis primarily by attenuating JNK-associated EMT, potentially through modulation of JNK activation by its bioactive constituents. These findings provide mechanistic insight into HJSS as a low-toxicity anti-metastatic strategy and support further exploration of its active constituents. Full article

The global burden of hypertension continues to rise, highlighting an urgent need for effective therapeutic strategies. Angiotensin-converting enzyme (ACE) is central to blood pressure regulation, but commonly used synthetic ACE inhibitors often have adverse side effects, spurring the search for safer natural alternatives. The aim of this study was to investigate Yanbian cattle hemoglobin as a novel precursor for ACE inhibitory peptides. The <1 kDa fraction was identified as exhibiting the highest inhibitory activity through the systematic screening of hydrolysates across multiple molecular weight ranges. LC-MS/MS analysis identified 1980 peptides, of which four were selected for further experiments. Solid-phase synthesis confirmed that NFGYDL exhibited the strongest ACE inhibition (IC₅₀ = 54.95 μM). Inhibition kinetics showed FHDYL acted as a mixed-type inhibitor, DLGHF and NFGYDL as competitive inhibitors and GFHLD as a non-competitive inhibitor. Molecular dynamics simulations validated the stable binding of these bovine blood-derived peptides to the ACE complex. HUVEC functional assays demonstrated that four peptides significantly increased angiotensin II-induced nitric oxide production and endothelin-1 levels, suggesting their potential antihypertensive activity. These findings suggested that bovine blood is a promising natural source of ACE-inhibitory peptides and holds potential for application as a functional component in functional foods targeting hypertension management. Full article