Search Results (12,591)

This work investigates the corrosion behavior of 18%Ni high-strength steel (00Ni18Co-8Mo5TiAl, solution-treated at 820 °C for 3 h and aged at 480 °C for 3 h) in NaCl solutions with 1%, 3.5%, and 6% chloride ions, as well as chloride ions’ effect on passive film properties. The corrosion process was systematically studied via chemical immersion tests (GB/T 17897-1999, 144 h, solution-to-sample contact area ratio 20:1) and electrochemical methods, including EIS (frequency range: 100 kHz–0.01 Hz) and Tafel polarization curves (scan rate: 10 mV/min). Passive film evolution was analyzed via Mott–Schottky curves (fixed frequency: 1000 Hz, scanning potential: −1 V to 1 V vs. SCE). Microstructural observations show the steel exhibits pitting corrosion in chloride environments, with corrosion products transforming from loose outer α-FeOOH/γ-FeOOH to dense inner Fe₃O₄/β-FeOOH. These dense products inhibit anodic reactions. Electrochemical results reveal polarization resistance decreases and corrosion current density rises with increasing chloride concentration. Mott–Schottky curves indicate that flat band potential increases from −0.2177 V to −0.1258 V with rising chloride concentration, increasing point defects in the passive film and weakening its self-healing ability. Full article

The BCL-2 family of proteins plays a central role in the regulation of apoptosis, with BCL-2 and BCL-xL representing two of its most prominent antiapoptotic members. This review explores the molecular regulation of BCL-2 and BCL-xL genes, emphasizing the structural domains that define the functions of the broader BCL-2 family. Beyond their canonical roles in preventing mitochondrial outer membrane permeabilization, both proteins contribute significantly to cancer development. Their overexpression enhances invasiveness and tumor progression, supports angiogenesis, and critically modulates cellular responses to chemotherapy, often conferring drug resistance. Additional non-apoptotic functions, including roles in metabolism, mitochondrial dynamics, and cellular homeostasis, further expand their biological relevance. Clinical trials exploring strategies to inhibit BCL-2 and BCL-xL, including selective BH3 mimetics and combination regimens, are discussed with emphasis on their potential and limitations in oncology. Overall, this review highlights the multifaceted contributions of BCL-2 and BCL-xL to cancer biology and underscores the importance of continued efforts to refine targeted therapeutic approaches. Full article

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified a multi-target small-molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) that effectively reprograms human glioma cells into neuron-like cells by activating endogenous ASCL1 (174.4-fold) and remodeling the transcriptional landscape. This conversion led to the strong upregulation of neuronal markers (e.g., MAP2 and GAD67) and suppression of glial identity. Functionally, DLC79 treatment inhibited glioma malignancy in vitro, impairing proliferation, migration, invasion, and clonogenicity. In a subcutaneous xenograft model, brief pretreatment with DLC79 significantly attenuated the tumorigenic potential of glioma cells, reducing tumor bioluminescence by 56% and tumor mass by 47%. Our study establishes pharmacological reprogramming as a promising anti-glioma strategy that leverages neuronal conversion to reduce oncogenic properties, thereby initiating a novel therapeutic paradigm. Full article

The concentration of extracellular vesicles (EVs) in the peripheral blood of COVID-19 patients is increased. Nevertheless, their potential role in the transmission of infection remains unclear. This study was performed to determine whether EVs produced by the sub-genomic replicon system developed in Baby Hamster Kidney (BHK-21) cells could transfer SARS-CoV-2 replicon RNA, leading to the establishment of a viral replication system in human cells. Purified EVs from the SARS-CoV-2 sub-genomic replicon cell line BHK-21 were cultured with a naive human cell line. The success of EV-mediated transfer of SARS-CoV-2 replicon RNA and its productive replication was assessed using G-418 selection, a luciferase assay, immunostaining, and Western blot. We found that the A549 cell line cultured with EVs isolated from SARS-CoV-2 BHK-21 replicon cells developed G-418-resistant cell colonies. SARS-COV-2 RNA replication in A549 cells was confirmed by nano luciferase, Nsp1 protein. SARS-CoV-2 RNA replication causes massive morphological changes. Treatment of cells with the FDA-approved Paxlovid demonstrated a dose-dependent inhibition of viral replication. We isolated two human epithelial cell lines (gastrointestinal and neuroblastoma) and one vascular endothelial cell line that stably support high-level replication of SARS-CoV-2 sub-genomic RNA. Viral elimination did not revert the abnormal cellular shape, vesicle accumulation, syncytia formation, or EV release. Our study’s findings highlight the potential implications of EV-mediated transfer of replicon RNA to permissive cells. The replicon model is a valuable tool for studying virus-induced reversible and irreversible cellular reprogramming, as well as for testing novel therapeutic strategies for SARS-CoV-2. Full article

The escalating threat of antibiotic resistance, particularly from Staphylococcus aureus (S. aureus), has become a critical challenge in both public health and animal husbandry. The extensive use of conventional antibiotics in livestock production accelerates the emergence of resistant strains, heightening risks to food safety and human health. Although plant-derived bioactive compounds are increasingly recognized as promising alternatives to synthetic antimicrobials, the mechanisms underlying their efficacy—and the potential for synergistic action among different plant parts—remain poorly understood. In particular, the antibacterial interactions among extracts from different tissues of Cyperus esculentus L. (C. esculentus), a plant rich in flavonoids and phenolics, have yet to be systematically evaluated. Here, we investigated the antibacterial properties and mechanisms of ethanol extracts from the tubers, stems–leaves and their mixture of C. esculentus against S. aureus. Using Oxford cup diffusion assays, scanning electron microscopy (SEM), bacterial growth kinetics, and untargeted metabolomics, we assessed both phenotypic inhibition and metabolic disruption. The mixed extract exhibited the strongest antibacterial effect, producing a 26.15 mm inhibition zone—approximately 7% greater than that of single-part extracts—and induced cell wall rupture and disintegration as observed by SEM. Growth curve analyses revealed time-dependent bacterial suppression, while metabolomic profiling identified 845 differential metabolites, indicating disturbances in amino acid, lipid, and nucleotide metabolism. Flavonoids such as acacetin, diosmetin, naringenin, and silybin A were identified as principal active compounds contributing to these effects. Full article

This review highlights the anti-inflammatory and antioxidant effects of probiotics and their complex health-related impacts. The main health areas targeted are gastrointestinal inflammation, neuroinflammation, systemic metabolic disorders, and liver conditions. Probiotics work mechanistically to regulate key inflammatory pathways by suppressing nuclear factor (NF-κb) and mitogen-activated protein kinase (MAPK) pathways and activating antioxidant defenses through nuclear erythroid 2-related factor (Nrf2). They stimulate anti-inflammatory cytokines (including interleukin 10 (IL-10) and inhibit pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), partly through the regulation of T cells. Probiotics also produce antioxidant metabolites (e.g., exopolysaccharides and short-chain fatty acids), which enhance the host’s resistance to oxidative stress. Supplementation with probiotics improves intestinal inflammation and oxidative injury in gut disorders. Clinical trials suggest that probiotic supplements may reduce neuroinflammation and oxidative stress, while improving cognitive or behavioral outcomes in neurodegenerative disorders. Overall, this review underscores that probiotics have potent anti-inflammatory and antioxidant effects within the gut–brain axis and across various organ systems, supporting their use as valuable adjunctive therapies for inflammatory and oxidative stress-related conditions. It further emphasizes that additional mechanistic research and controlled clinical trials are essential to translate these findings into the most effective therapeutic strategies. Full article

Cytokine storm is a critical driver of acute respiratory distress syndrome and multiple organ failure. Human β-defensin 2 (HBD-2) is the first inducible defensin discovered in human body. Defensin can resist pathogenic microorganisms invading the body through direct bactericidal effect and also modulates acquired immune response. Albumin exhibits immunomodulatory properties and can reduce the level of inflammatory cytokines to improve the systemic inflammatory response. We previously engineered a recombinant fusion protein, DF₂-HSA, comprising two HBD-2 molecules linked to human serum albumin. Here, we evaluated its effect on cytokine storm using a lipopolysaccharide (LPS)-induced cytokine storm murine model (BALB/c athymic mice, female). DF₂-HSA reduced the mortality in cytokine storm murine model and prolonged the retention time of HBD-2 in the body. A Luminex assay showed that DF₂-HSA reduced the production of multiple inflammatory cytokines in cytokine storm murine model. Evans blue staining showed that DF₂-HSA reduced vascular leakage. Transmission electron microscopy showed that DF₂-HSA reduced the lung injury of cytokine storm mice. The pathological results showed that DF₂-HSA alleviated the lung and small intestine damage of cytokine storm mice. In summary, DF₂-HSA effectively inhibits cytokine storms and ameliorates associated tissue damage. Full article

KRAS alterations are a hallmark of pancreatic ductal adenocarcinoma (PDAC) found in >90% of tumors. This review examines the historical evolution of the understanding of RAS and its central role in PDAC biology. We summarize the various downstream effectors, feedback loops, and resistance mechanisms that play a pivotal role in PDAC oncogenesis. Our review explores the early development of covalent inhibitors of KRAS G12C and efforts at specific inhibition of other codons and newer approaches of targeted protein degradation. We subsequently summarize the development of panRAS inhibitors and allosteric and switch-region targeting before focusing on rational therapeutic blockade of crosstalk and upstream signaling, with attention to synthetic lethality approaches transitioning from preclinical to early-phase in-human clinical trials. This review elaborates on ongoing KRAS-specific siRNA research and evolving KRAS-directed immunotherapies. We conclude by outlining the current KRAS clinical trial landscape and future areas of investigation. Full article

Pathogens that have developed resistance to antibiotics pose a threat to public health. The primary goal in preventing foodborne infections is to inhibit the growth of and, subsequently, eliminate antibiotic-resistant pathogens at every stage from production to consumption. Escherichia coli, which has acquired resistance to most known antibiotics, is frequently found in chicken meat. In many countries, due to unregulated antibiotic use in poultry farming, poor hygiene in slaughterhouses, or cross-contamination, extended-spectrum beta-lactamase (ESBL)-producing E. coli has been identified as the causative agent in poultry-associated food poisoning. The need for more effective antimicrobial agents against this pathogen, which is resistant to existing antibiotics, has led to increased attention being paid to postbiotics produced by lactic acid bacteria, particularly bacteriocins. This study aimed to determine the antimicrobial effects of postbiotics obtained from kefir-derived Lactiplantibacillus plantarum and Lactococcus lactis against ESBL-positive E. coli. To achieve this, E. coli strains were isolated from raw chicken meat samples collected from the market using culture-based methods, and their antimicrobial resistance profiles were determined using the disk diffusion method. The ESBL positivity of the isolates was assessed using the double-disk synergy test. The antimicrobial activities of the postbiotics against the identified ESBL-positive E. coli strains were tested using the macro-dilution method to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. ESBL-positive E. coli was detected in 48% of raw chicken meat samples. The antimicrobial effects of postbiotics were examined by disk diffusion, and postbiotics produced by 18 Lb. plantarum strains and 20 Lc. lactis strains showed strong antimicrobial activity. Significant differences in the antimicrobial effects of postbiotics were observed between the two species. Lb. plantarum postbiotics exhibited both bacteriostatic (concentration 60%) and bactericidal (concentration 80%) effects on ESBL-positive E. coli strains, whereas Lc. lactis postbiotics showed only bacteriostatic effects (80% concentration). Postbiotics derived from probiotic bacteria offer promising effects against multidrug-resistant E. coli due to their heat resistance, activity across different pH values, strong antimicrobial effects, affordability, and ease of production. Full article

Despite increasing interest in probiotics as antibiotic alternatives in swine production, few studies have directly compared the functional efficacy of different commercial probiotic formulations under controlled conditions. We conducted an in vitro study using porcine intestinal epithelial (IPEC-J2) and macrophage-like (3D4/21) cell models to compare the efficacy of three commercial probiotic consortia (C1: three strains of Bacillus velezensis; C2: B. licheniformis + B. subtilis; C3: Clostridium butyricum). Treatments were evaluated for their ability to inhibit pathogenic Escherichia coli, Clostridium perfringens, and Salmonella spp., enhance epithelial barrier integrity, and modulate immune responses. Experimental endpoints included pathogen inhibition assays, adhesion to IPEC-J2 cells, transepithelial electrical resistance (TEER), tight junction protein expression, and cytokine profiling via RT-qPCR and proteomics. Data were analyzed using the Kruskal–Wallis test with false discovery rate (FDR) control at 5%. C1 cell-free supernatant (CFS) strongly inhibited pathogen growth (84.8 ± 5.3% inhibition of ETEC F4⁺F18⁻ vs. medium control; p < 0.05), whereas C2 had no effect, and C3 inhibited only one isolate. The coculture of IPEC-J2 cells with C1 CFS increased the expression of TJ proteins ZO-1, MUC13, and MUC20 (+12.9–46.6% vs. control; p < 0.001) and anti-inflammatory TGF-β; reduced pro-inflammatory IL-6 in LPS-stimulated 3D4/21 cells. In comparison, C2 and C3 showed minimal impact on epithelial barrier integrity and immune modulation, as indicated by negligible changes in TEER values, tight junction protein expression (ZO-1, MUC13, MUC20), and cytokine profiles relative to the control. In conclusion, C1 demonstrated greater in vitro efficacy than C2 (B. licheniformis + B. subtilis) and C3 (Clostridium butyricum), including pathogen inhibition assays, epithelial adhesion, TEER measurements, and cytokine modulation, suggesting its potential as a leading candidate for functional probiotic applications. Full article

Three new pyrrole alkaloids, streptopyrroles D–F (1–3), along with four known analogs (4–7) were isolated from Sea Anemone-Associated Streptomyces sp. S1502 via an OSMAC (One Strain Many Compounds)-based strategy. Their structures were elucidated through comprehensive spectroscopic analyses, including HRESIMS and 1D/2D NMR experiments (COSY, HSQC, and HMBC), and further confirmed by X-ray crystallography. Biological evaluation identified streptopyrrole (4) as an anti-MRSA (methicillin-resistant Staphylococcus aureus) agent, while 4 and 6 displayed broad-spectrum cytotoxicity and good selectivity against a panel of human cancer cell lines. Notably, 4 and 6 showed particularly potent activity against the lung cancer cell lines H1299, SW1573, and A549, with IC₅₀ values ranging from 5.43 to 16.24 μM. Further mechanistic investigation revealed that both compounds suppress the proliferation of lung cancer cells by inducing cell cycle arrest at the G0/G1 phase and impair metastatic potential by inhibiting migration and invasion. These findings not only expand the structural diversity of marine-derived pyrrole alkaloids but also reveal the anticancer mechanisms of 4 and 6, highlighting their promise as active candidates for further antitumor drug development, particularly in lung cancer. Full article

Background/Objectives: Cutaneous leishmaniasis (CL) remains a major neglected tropical disease, and current chemotherapeutic options are limited by toxicity and emerging resistance. Repurposing azole antifungals is a promising approach, as they target ergosterol biosynthesis, a pathway also essential in Leishmania spp. This study investigated the antileishmanial potential of econazole through in vitro and in vivo assays. Methods: Econazole activity was evaluated against Leishmania amazonensis promastigotes and intracellular amastigotes using MTT and luminescence-based methods. Cytotoxicity in NCTC cells was determined to calculate the selectivity index (SI). Drug interactions with miltefosine were assessed by fixed-ratio isobologram analysis. In vivo efficacy was examined in BALB/c mice infected with L. amazonensis and orally treated with econazole (2.5, 5, or 10 mg/kg/day) for 28 days. Lesion development and parasite burden were monitored. Molecular docking simulations were performed using SwissDock. Results: Econazole showed potent in vitro activity, with EC₅₀ values of 8.9 µM for promastigotes and 11 µM for intracellular amastigotes, and a CC₅₀ of 31 µM. Isobologram analysis revealed additive interactions with miltefosine (ΣFIC 0.5–1.2; mean 0.95). In vivo, econazole reduced lesion size and parasite load, achieving up to 75% reduction at 10 mg/kg/day. Docking results suggested that econazole may inhibit sterol biosynthesis, potentially through interaction with 14α-demethylase. Conclusions: These findings provide the first evidence of econazole activity against L. amazonensis in vitro and in vivo. Its exploratory efficacy and compatibility with miltefosine support further investigation of econazole as a repurposed candidate for CL, including optimization of dosing strategies and combination regimens. Full article

Background: The current rise in multidrug-resistant pathogens highlights the urgent need for the discovery of novel antibacterial agents with potential clinical applications. A considerable proportion of these developed resistances may be attributable to the intrinsic response of bacteria to antibiotic-induced stress conditions in the environment. Consequently, the identification and characterization of genetic alterations in physiological processes in response to antibiotics represent promising strategies for the discovery and characterization of naturally produced novel antibacterial agents. This study investigated the antimicrobial activity of an antimicrobial active isolate Actinomadura coerulea derived from a meerkat fecal sample. Methods: The production of secondary metabolites that potentially compromise bacterial cell wall integrity was confirmed by the induction of promoter activity in whole-cell biosensors in which an antibiotic-inducible promoter was fused to the luciferase cassette. During plate-based biosensor assays, we identified naturally resistant Bacillus subtilis colonies growing in the zone of inhibition around A. coerulea colonies. After these successive rounds of selection, highly resistant spontaneous B. subtilis mutants had evolved that were subjected to whole-genome sequencing. Results: Non-silent mutations were identified in pssA, which encodes a phosphatidylserine synthase; mdtR, as a gene for the repressor of multidrug resistance proteins, and yhbD, whose function is still unknown. A new cinnamycin-like molecule, coerumycin, was discovered based on the physiological role of PssA and comprehensive genomic analysis of A. coerulea. Additional experiments with cell extracts containing coerumycin as well as the cinnamycin-like compound duramycin confirmed that the interaction between coerumycin and the bacterial cell envelope is inhibited by a loss-of-function mutation in pssA. Conclusion: Our approach demonstrates that combining the exploration of niche habitats for actinomycetes with whole-cell biosensor screening and characterization of natural resistance development provides a promising strategy for identifying novel antibiotics. Full article

The frequent and indiscriminate use of all classes of synthetic anthelmintics to deworm small ruminants has decreased their effectiveness in a worldwide problem of anthelmintic resistance. Using active plant metabolites with anthelmintic properties has become a suggested alternative to control parasitic helminths. The present study investigated the ovicidal and larvicidal activity of a fraction (CnF4) containing protocatechuic acid (3,4-dihydroxybenzoic acid) from Chamaecrista nictitans (Fabaceae) and a commercial standard of protocatechuic acid against strains of the parasitic nematode Haemonchus contortus susceptible (HcIVM-S) and resistant (HcIVM-R) to ivermectin, using egg hatch inhibition (EHI) and L3 larval mortality assays. The CnF4 fraction showed an EHI greater than 90% at 0.8 mg/mL against HcIVM-S and an EHI = 88.39% at 1.6 mg/mL against HcIVM-R. The commercial standard of protocatechuic acid displayed an EHI of 97.49% at 0.25 mg/mL against HcIVM-S and an EHI greater than 98% at 0.5 mg/mL. In the larval mortality assays, protocatechuic acid caused 72.4% larval mortality of HcIVM-S at 8 mg/mL and 53.2% mortality of HcIVM-R at 16 mg/mL. These results indicate that protocatechuic acid was more effective in inhibiting egg hatching and causing larval mortality against HcIVM-S compared to HcIVM-R. Full article

GmSRC7 is a broad-spectrum antiviral R gene from soybean, but its downstream and functionally related genes remain unclear. Virus-induced gene silencing (VIGS) assays in Nicotiana benthamiana (Nb) showed that suppression of several gene families—WRKY transcription factors, chaperones, ethylene pathway components, MAPK cascade elements, salicylic acid (SA) signaling genes, calcium-dependent protein kinases, nuclear migration proteins, RNA replication-related genes, and immune regulators—consistently weakened GmSRC7-mediated resistance to Soybean Mosaic Virus (SMV) and Tobacco Mosaic Virus (TMV). Targeted silencing of four regulatory genes—NbEDS1, NbARF1, NbSGT1, and NbCOI1—markedly enhanced GmSRC7-mediated resistance to SMV and TMV in our experiments. Silencing the serine/threonine kinase gene NbPBS1 increased GmSRC7-conferred resistance to SMV but did not significantly alter its resistance to TMV. Transient expression assays showed that NbARF1, NbSGT1, and NbCOI1 antagonize GmSRC7-mediated defense against SMV and TMV, whereas NbPBS1 specifically suppresses anti-SMV activity without affecting TMV resistance. Transient overexpression of SA-degrading enzymes (AtS3H, AtS5H, and NahG) significantly reduced GmSRC7-conferred resistance to SMV, indicating that SA is essential for this R protein-mediated defense. Genes were also grouped by immune pathways and function: co-expression of chaperone family genes inhibited GmSRC7 activity against SMV and TMV, while co-expression of WRKY family genes enhanced anti-SMV activity of GmSRC7. Finally, transient silencing of soybean genes GmEDS1, GmSGT1-1, GmSGT1-2, GmJAR1, and GmSGS3 compromised GmSRC7-mediated resistance to SMV. Full article