Search Results (15,741)

Background and purpose: Vulvovaginal candidiasis (VVC), caused by Candida albicans (C. albicans), is exacerbated by oxidative stress and uncontrolled inflammation. Pathogens like C. albicans generate reactive oxygen species (ROS) to enhance virulence, while host immune responses further amplify oxidative damage. This study investigates the antioxidant and antifungal properties of Hyssopus cuspidatus Boriss volatile extract (SXC), a traditional Uyghur medicinal herb, against fluconazole-resistant VVC. We hypothesize that SXC’s bioactive volatiles counteract pathogen-induced oxidative stress while inhibiting fungal growth and inflammation. Methods: GC-MS identified SXC’s major bioactive components, while broth microdilution assays determined minimum inhibitory concentrations (MICs) against bacterial/fungal pathogens, and synergistic interactions with amphotericin B (AmB) or fluconazole (FLC) were assessed via time–kill kinetics. Anti-biofilm activity was quantified using crystal violet/XTT assays, and in vitro studies evaluated SXC’s effects on C. albicans-induced cytotoxicity (LDH release in A431 cells) and inflammatory responses (cytokine production in LPS-stimulated RAW264.7 macrophages). A murine VVC model, employing estrogen-mediated pathogenesis and intravaginal C. albicans challenge, confirmed SXC’s in vivo effects. Immune modulation was assessed using ELISA and RT-qPCR targeting inflammatory and antioxidative stress mediators, while UPLC-MS was employed to profile metabolic perturbations in C. albicans. Results: Gas chromatography-mass spectrometry identified 10 key volatile components contributing to SXC’s activity. SXC exhibited broad-spectrum antimicrobial activity with MIC values ranging from 0.125–16 μL/mL against bacterial and fungal pathogens, including fluconazole-resistant Candida strains. Time–kill assays revealed that combinations of AmB-SXC and FLC-SXC achieved sustained synergistic bactericidal activity across all tested strains. Mechanistic studies revealed SXC’s dual antifungal actions: inhibition of C. albicans hyphal development and biofilm formation through downregulation of the Ras1-cAMP-Efg1 signaling pathway, and attenuation of riboflavin-mediated energy metabolism crucial for fungal proliferation. In the VVC model, SXC reduced vaginal fungal burden, alleviated clinical symptoms, and preserved vaginal epithelial integrity. Mechanistically, SXC modulated host immune responses by suppressing oxidative stress and pyroptosis through TLR4/NF-κB/NLRP3 pathway inhibition, evidenced by reduced caspase-1 activation and decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Conclusions: SXC shows promise as a broad-spectrum natural antimicrobial against fungal pathogens. It inhibited C. albicans hyphal growth, adhesion, biofilm formation, and invasion in vitro, while reducing oxidative and preserving vaginal mucosal integrity in vivo. By disrupting fungal metabolic pathways and modulating host immune responses, SXC offers a novel approach to treating recurrent, drug-resistant VVC. Full article

Capsaicin, the major pungent alkaloid in Capsicum species, has been reported to exhibit cytotoxic activity through various mechanisms. In this study, capsaicin and 37 structurally related vanillylamide and ester analogs were synthesized and evaluated for cytotoxic activity and tumor cell/non-tumor cell selectivity in vitro and compared with a Capsicum baccatum (Aji mochero) extract. Seven analogs with superior potency and selectivity compared to capsaicin were identified. Notably, vanillylamides with a C₁₆–C₁₈ chain exhibited IC₅₀ values five-fold lower than capsaicin (15–84 µM), with selectivity indices up to 35. The extract obtained from the dried chili fruit, known to hold capsaicin as its primary component, however, exhibited significantly lower cytotoxic activity against tumor cells than pure capsaicin. These data demonstrate that even minor modifications to the acyl chain (as exemplified for the nonivamide analogs) can enhance the cytotoxicity and selectivity of these derivatives and that isolated compounds are able to offer even greater efficacy than whole-fruit extracts. Full article

Background/Objectives: The growing threat of antibiotic resistance necessitates the development of novel antimicrobial agents that effectively target pathogenic microorganisms while minimizing toxicity. Methods: Two series DABCO-based cationic homopolymers (D-subs 1kDa, D-subs 5kDa, D-subs 15kDa) and DABCO–pyridinium-based copolymers (PyH-subs 5kDa_Dsubs 5kDa, PyH-subs 7kDa_Dsubs 3kDa, PyH-subs 3kDa_Dsubs 7kDa) were synthesized to mimic to host-defense cationic peptides via ring-opening metathesis polymerization (ROMP). The antimicrobial activities of these polymers were determined by their minimum inhibitory concentrations (MICs) against E. coli (Gram-negative bacteria), P. aeruginosa (Gram-negative bacteria), S. aureus (Gram-positive bacteria), and C. albicans (fungus). In vitro cytotoxicity assays revealed selective toxicity towards bacterial cells, with high selectivity indices for several copolymers. To gain insight into the mechanism of action, morphological changes in S. aureus upon exposure to D-subs 1kDa were examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results: The D-subs 15kDa homopolymer demonstrated the highest overall antimicrobial activity, particularly against S. aureus (MIC: 8 µg/mL), with all polymers exhibiting minimal hemolytic activity (HC₅₀ ≥ 1024 µg/mL). SEM and TEM results revealed membrane disruption indicative of polymer–bacteria interactions. Additionally, stability studies confirmed polymer integrity under physiological conditions for at least 28 days. Conclusions: These results support the potential of DABCO-based cationic polymers as a promising platform for next-generation antimicrobial therapeutics. Full article

Background/Objectives: Aristolochia ringens, a medicinal plant widely used in traditional medicine, has shown potential therapeutic applications. This study aimed to investigate the anticancer mechanism of action of its crude extract against human colorectal adenocarcinoma cells (Caco-2 and HT-29). Methods: Cell viability was assessed using the MTT assay to determine IC₅₀ values. Immunofluorescence microscopy was used to examine nuclear morphology and microtubule integrity. Flow cytometry with PI staining was used for cell cycle analysis and Annexin V-FITC/PI staining for apoptosis detection. Mitochondrial membrane potential was evaluated using JC-1 dye. Bioactivity-guided fractionation was performed via HPLC, and GC–MS was used to profile active constituents. Results: The extract exhibited dose-dependent cytotoxicity with IC₅₀ values below 30 µg/mL in colon adenocarcinoma cell lines. Treated Caco-2 cells showed nuclear shrinkage and disrupted microtubules. PI-based flow cytometry revealed G₁ phase arrest, and Annexin V-FITC/PI staining indicated enhanced late apoptosis. JC-1 staining demonstrated mitochondrial depolarization. HPLC fractionation identified fractions 2 and 3 as active, and preliminary GC–MS analysis tentatively annotated the presence of alkaloids, sesquiterpenes/diterpenes, and steroidal compounds. Conclusions: A. ringens exerts anticancer effects through a mitochondria-mediated apoptotic pathway, involving G₁ checkpoint arrest and cytoskeletal disruption. These findings provide the first integrated cellular and mechanistic evidence of its anticancer potential in colorectal cancer, supporting its promise as a source of novel therapeutic lead compounds. Full article

Background/Objectives: Cancer ranks as the second most prevalent cause of death worldwide, according to the World Health Organization. Approximately one in six global deaths is attributed to cancer. Among females, breast cancer stands out as the most frequent type of tumor. Raloxifene (RLX), recognized as a selective estrogen receptor modulator, has been employed as a therapeutic option in treating breast cancer among postmenopausal women. The objective of this study was to investigate the anticancer potential of raloxifene-loaded hexosomes, nanoliposomes, and nanoniosomes to identify the most effective formulation. Methods: The particle size, zeta potential, entrapment efficiency, and structural elucidation of the various nanovesicle formulations was validated; Results: Each nanocarrier exhibited a negative surface charge, nanometric size, and a reasonable encapsulation efficiency. Cytotoxicity of the different raloxifene-loaded nanovesicles on MCF-7 breast cancer cell lines and MCF10 non tumorigenic cells revealed the substantial cytotoxic activity of the hexosomal nanocarrier compared to the other nanovesicles, exhibiting the lowest IC50 = 45.3 ± 1.10 µM. Conclusions: The RLX-loaded hexosomal formulation showed superior cytotoxic activity, indicating its potential as a highly effective therapeutic agent. To fully understand its capabilities and mechanisms, further in vitro characterization studies are necessary. Full article

Sea anemone venoms contain diverse toxins that have significant pharmacological potential, including anticancer, ecticidal, and immunotherapeutic properties. However, critically, the extraction methodology influences venom composition and bioactivity. This study characterized venom from Stichodactyla haddoni obtained via homogenization, electrical stimulation, and milking. Extraction yields varied significantly between methods: the homogenization, electrical stimulation, and milking of healthy sea anemones yielded crude venoms at rates of 17.8%, 3.4%, and 1.5%, respectively. SDS-PAGE revealed distinct protein banding patterns and concentrations, while RP-HPLC demonstrated method-dependent compositional differences. Comprehensive proteomic profiling identified 2370 proteins, encompassing both unique and shared components across extraction techniques. Label-free quantitative analysis confirmed significant variations in protein abundance that was attributable to the extraction method. Cytotoxicity assays against cancer cell lines revealed concentration-dependent inhibition, with milking-derived venom exhibiting the highest potency. Insecticidal activity against Tenebrio molitor was also method-dependent, with milking venom inducing the highest mortality rate. These findings elucidate the profound impact of extraction methodology on the protein composition and functional activities of S. haddoni venom, providing crucial insights for its optimized exploitation in pharmacological development. Full article

Background/Objective: At least 25% of colorectal cancer (CRC) patients develop liver metastases (CRLM), and chemotherapeutic regimens based on the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) provide a survival advantage, but long-term survival is uncommon. The primary molecular target of FP drugs is thymidylate synthase (TS). Methods: A TS/Top1 dual-targeting cytotoxic mechanism for CF10/LV was confirmed by TS ternary complex detection by Western blot and by immunofluorescence detection of Top1 cleavage complexes. CF10/LV activated the ATR/Chk1 pathway consistent with enhanced replication stress and induced apoptosis. In vivo studies showed CF10 and CF10/LV eradicated liver metastasis in a CRLM model without scarring or weight loss, displaying therapeutic advantages relative to legacy FPs. Results: We demonstrated that a nanoscale FP polymer, CF10, displayed greater potency than expected based on FP content in part through more direct conversion to the TS-inhibitory metabolite, FdUMP. In this study, we tested CF10 for potency advantages relative to 5-FU and trifluorothymidine (TFT, the FP component of TAS-102) and confirmed a general potency advantage for CF10 in CRC cell lines in the Broad Institute PRISM screen. We demonstrated that this potency advantage is retained in CRC cells cultured with human-like folate levels and is enhanced by LV co-treatment to a similar extent as that by 5-FU. Our results confirm CF10 development proceeding as a CF10/LV combination. Mechanistically, CF10 cytotoxicity closely correlates with poisons of DNA topoisomerase 1 (Top1) in the PRISM screen relative to 5-FU and TFT. Conclusions: Our pre-clinical data support an early-phase clinical trial for CF10 for treating liver-metastatic CRC. Full article

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age. Full article

Stroke is a leading global cause of mortality and long-term disability, with cerebral edema constituting a major contributor to early neurological deterioration and poor outcomes. Aquaporin-4 (AQP4), the predominant water channel in the central nervous system, plays a paradoxical role in stroke-related brain edema, facilitating both the formation and clearance of excess fluid depending on the pathological context. This review explores the biphasic function of AQP4 across cytotoxic and vasogenic edema, emphasizing its dynamic regulation, subcellular localization, and implications for therapeutic intervention. Evidence from rodent models shows that AQP4 exacerbates cytotoxic edema in acute ischemia by promoting intracellular water influx into astrocytes, whereas in vasogenic edema, it supports fluid reabsorption and glymphatic clearance, thereby alleviating brain swelling. Human studies corroborate AQP4 upregulation in infarcted regions and suggest a potential role for AQP4 polymorphisms and circulating levels as biomarkers of stroke severity and outcome, although larger cohorts and more robust methodological designs are needed. This review also discusses emerging pharmacological strategies to modulate AQP4 activity, including inhibitors, trafficking modulators, and gene-targeted delivery systems, while highlighting challenges in achieving phase-specific modulation. Given its central role in both injury and recovery, AQP4 emerges as a promising yet complex therapeutic target for personalized management of stroke-induced brain edema. Future directions include real-time imaging of AQP4 function, genotype-stratified clinical trials, and integration of AQP4 modulation with current stroke treatment protocols. Full article

Background: Based on our previously reported series of novel 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives, we have now designed, synthesized, and tested a new series of novel restricted and simplified structural analogues of these compounds against Plasmodium falciparum in vitro; i.e., the 1,3-bis[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3-bis[(4-(substituted-aminomethyl)phenoxy)methyl]benzene compounds. Methods & Results: The pharmacological results revealed significant antimalarial activity, with IC₅₀ values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new nitrogen-containing polyphenyl- or -phenoxymethylbenzene compounds was evaluated on human HepG2 cells. The compound 1f, the 1,3-bis[(4-(3-(morpholin-1-yl)propyl)aminomethyl)phenoxy)methyl]benzene derivative, emerged as one of the most potent and promising antimalarial candidates, demonstrating a cytotoxicity/antiprotozoal activity ratio of 594 against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. Additionally, the 1,3-bis[((substituted aminomethyl)phenyl)methyl]benzene compound 1j and the 1,3-bis[((substituted aminomethyl)phenoxy)methyl]benzenes 2p and 2q also showed strong antimalarial potential, with selectivity indexes (SI) of over 303, 280, and 217, respectively, against the 3D7 strain, which has mefloquine-reduced sensitivity. Furthermore, the 1,3-bis[(4-(pyridin-2-ylethylaminomethyl)phenyl)methyl]benzene 2k was identified as the most noteworthy antimalarial compound, exhibiting a selectivity index (SI) that was superior to 178 against the chloroquine-resistant Plasmodium falciparum W2 strain. It has previously been suggested that the telomeres of P. falciparum may serve as potential targets for these polyaromatic compounds; thus, we assessed the ability of our novel derivatives to stabilize parasitic telomeric G-quadruplexes using a FRET melting assay. Conclusions: However, regarding the stabilization of the protozoan G-quadruplex, it was noted that the few substituted derivatives, which showed interesting stabilization profiles, were not necessarily the most effective antimalarial compounds against both Plasmodium strains. Moreover, these new compounds did not show promising stabilizing effects on the different G4 sequences. Therefore, no correlation arises between their antimalarial activity and the selectivity of their binding to G-quadruplexes. Full article

Triple-negative breast cancer (TNBC) urgently requires new therapeutic strategies due to the limited efficacy of conventional treatments. Recently, PANoptosis, an integrated form of apoptosis, necroptosis, and pyroptosis, has emerged as a promising target in cancer therapy, though effective agents remain scarce. Paclitaxel, a Taxus-derived natural product, is often combined with other drugs to enhance efficacy, yet optimal combinations are limited. This study investigates the synergistic antitumor effects of paclitaxel and cephalomannine in TNBC, focusing on oxygen-regulated cell death pathways. Network pharmacology and molecular docking revealed that the combination targets multiple cell death- and inflammation-related proteins, including BCL2L1, MAPK14, SYK, TNF, and ADAM17, suggesting multi-target synergy. In vitro, the combination significantly inhibited MDA-MB-231 cell viability, proliferation, and migration, while inducing apoptosis and necrosis. Mechanistically, co-treatment markedly increased intracellular ROS levels and γ-H2AX expression, indicating oxidative stress and DNA damage, both of which were reversible by ROS inhibition. Further analysis demonstrated that the treatment activated the p38 and p53 pathways, regulated the Bax/Bcl-2 ratio, and initiated mitochondrial apoptosis. It also promoted RIPK1/RIPK3/MLKL phosphorylation and MLKL membrane translocation, triggering necroptosis, as well as upregulated NLRP3, cleaved Caspase-1, and GSDMD, inducing pyroptosis. The use of specific inhibitors partially reversed these effects, confirming the involvement of ROS-mediated PANoptosis. Similar antitumor effects were also observed in BT-549 cells, indicating the broad applicability of this combination in TNBC. MCF-10A cells exhibited mild but acceptable cytotoxicity, reflecting manageable side effects typical of chemotherapeutic agents. In vivo experiments further validated the combination’s antitumor efficacy and safety. In summary, paclitaxel and cephalomannine synergistically induce PANoptosis in TNBC through oxygen-regulated cell death pathways, offering a novel therapeutic strategy based on oxidative stress modulation by natural compounds. Full article

Lactic acid bacteria (LAB) are a promising source of postbiotics with potential applications in the cosmetic industry; however, strains isolated from fermented vegetables are rarely studied. This study aimed to characterize the bioactivity of postbiotics produced by Lactiplantibacillus pentosus B1 isolated from fermented beetroot juice. An organic extract (ELCFS) and a lyophilizate (LLCFS) were prepared from cell free supernatant of B1 and assessed for antimicrobial activity (MIC, MBC), biofilm inhibition and eradication ability against Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes and Cutibacterium acnes. Stability (temperature, time) and cytotoxicity were also examined. Metabolite composition was determined by GC-MS. MIC values were 10 g/L for ELCFS and 10–20 g/L for LLCFS. ELCFS completely inhibited biofilm formation at 10 g/L, and LLCFS at 25 g/L; partial inhibition was observed at lower concentrations (e.g., E. coli—32.99% at 1 g/L ELCFS; S. aureus and S. pyogenes—74.01% and 95.67%, respectively, at 5 g/L). Complete eradication of mature biofilm was obtained at 2.5 g/L (ELCFS) and 12.5 g/L (LLCFS), while a significant partial effect was observed from 0.04 g/L ELCFS for E. coli (29.3%) and 0.2 g/L LLCFS for S. pyogenes (23.2%). C. acnes showed the lowest sensitivity. A reduction in viability of eucaryotic cells was observed at ≥ 5 g/L ELCFS (90.32%) and 12.5—50 g/L LLCFS (55.87—89.20%). Importantly, concentrations causing partial inhibition and eradication of biofilm did not show cytotoxicity towards fibroblasts. The preparations were thermostable and retained activity over time; only incubation of ELCFS at elevated temperature significantly reduced its antimicrobial activity against the C. acnes strain. GC-MS analysis revealed five organic acids, with lactic acid dominating. The results confirm the potential of L. pentosus B1 as a source of stable, effective, and safe postbiotics for cosmetology applications. Full article

Schiff base ligands prepared from salicylaldehyde and 2-, 3- and 4-methoxybenzylamine were used to prepare copper(II) complexes, characterized by spectral methods, elemental analysis and X-ray crystallography in the case of complex 4a derived from 2-methoxybenzylamine. The DNA cleavage activity of the prepared complexes was exceptional, with best activities of over 95% one-strand cleavage for 4c at 3 mM and full double-strand cleavage for complex 4a at 5 mM. Absorption titration studies with ct-DNA revealed good binding constants (at 10⁵ M⁻¹) with a decrease of up to 56% light absorption. Meanwhile, the EB–DNA displacement method and viscosity studies revealed groove binding as a possible binding mode. For BSA binding studies, all three complexes showed K_BSA values in the optimal range for reversible BSA binding (10⁴ M⁻¹). The copper(II) complexes showed significant cytotoxic effects (67–96% at 1 mM) in mitochondrial activity monitoring assays. Cytotoxicity was confirmed against cancer cell lines (A549 and HepG2) and HEL cells. The complexes 4a and 4c exhibited high activity against HepG2 cancer cells (IC50 < 22 μM), comparable to cisplatin. The radical scavenging activity was determined by the INT method with the best IC50 for 4c (189 ± 11 μM). Overall, complexes 4a and 4c with a methoxy group in the ortho and para positions show high potential in most determined activities, but mainly as DNA cleavers and as cytotoxic agents with selectivity against HepG2 cells. Full article

Lung cancer is the leading cause of cancer mortality worldwide, with a poor prognosis driven by late diagnosis, systemic toxicity of existing therapies, and rapid development of multidrug resistance (MDR) to agents such as paclitaxel and cisplatin. MDR arises through multiple mechanisms, including overexpression of efflux transporters, alterations in apoptotic pathways, and tumour microenvironment-mediated resistance. The application of nanotechnology offers a potential solution to the aforementioned challenges by facilitating the enhancement of drug solubility, stability, bioavailability, and tumour-specific delivery. Additionally, it facilitates the co-loading of agents, thereby enabling the attainment of synergistic effects. Halloysite nanotubes (HNTs) are naturally occurring aluminosilicate nanocarriers with unique dual-surface chemistry, allowing hydrophobic drug encapsulation in the positively charged lumen and functionalisation of the negatively charged outer surface with targeting ligands or MDR modulators. This architecture supports dual-delivery strategies, enabling simultaneous administration of phytocannabinoids and chemotherapeutics or efflux pump inhibitors to enhance intracellular retention and cytotoxicity in resistant tumour cells. HNTs offer additional advantages over conventional nanocarriers, including mechanical and chemical stability and low production cost. Phytocannabinoids such as cannabidiol (CBD) and cannabigerol (CBG) show multitarget anticancer activity in lung cancer models, including apoptosis induction, proliferation inhibition, and oxidative stress modulation. However, poor solubility, instability, and extensive first-pass metabolism have limited their clinical use. Encapsulation in HNTs can overcome these barriers, protect against degradation, and enable controlled, tumour-targeted release. This review examined the therapeutic potential of HNT-based phytocannabinoid delivery systems in the treatment of lung cancer, with an emphasis on improving therapeutic selectivity, which represents a promising direction for more effective and patient-friendly treatments for lung cancer. Full article

Green mold formed by Penicillium digitatum is a major disease that limits the yield and overall value of postharvest citrus fruits. The antifungal activity of sodium cuminate (SC) against P. digitatum and the corresponding mechanism were explored in this research. The minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) of SC against P. digitatum were 0.4 and 0.8 g L⁻¹, respectively. SC (8× MFC) reduced the incidence of disease in Ponkan fruits without compromising their quality. The results of CFW staining and extracellular alkaline phosphatase assays revealed that 1/2MIC SC for 30 min had no impact on the cell wall integrity of P. digitatum. In contrast, 1/2MIC SC apparently destroyed cell membrane integrity, as shown by the increase in the content of reactive oxygen species (ROS), malondialdehyde, and H₂O₂. The addition of exogenous cysteine (Cys) or diphenyleneiodonium chloride (DPI) significantly mitigated the cytotoxic effects of SC. At the same time, mitochondrial membrane potential was significantly decreased by 1/2MIC SC, and the addition of exogenous Cys or DPI restored it to normal levels. In summary, the antifungal capacity of SC might be attributable to membrane damage in P. digitatum caused by oxidative stress. Full article