Search Results (1,798)

Background: As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae Dunaliella salina (D. salina, Ds) to load Dio (Ds-Dio), thereby enhancing its efficacy and exploring its therapeutic potential. Methods: We first characterized the physicochemical properties of Ds and Dio, and then Ds-Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. Results: The novel Ds-Dio delivery system has been successfully established. In the AKI model, Ds-Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by Ds carrier. In addition, Ds-Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that Ds-Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. Conclusion: This study successfully developed a microalgae-based drug delivery system, Ds-Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation. Full article

Synthetic cannabinoids (SCs) are a rapidly developing kind of novel psychoactive substance, frequently associated with acute intoxication and public health concerns. This study aimed to elucidate and compare the phase I metabolic pathways of two structurally related SCs, 5F-ADB-PINACA and 5F-ADBICA, using in vitro and in vivo models. Temporal metabolic profiling was performed to identify potential signature metabolites. Temporal abundance patterns and correlation cluster analysis of metabolites were analyzed to determine metabolite biomarkers. The two SCs were incubated with pooled human liver microsomes for 24 h and were also evaluated in vivo in zebrafish. Metabolite profiles were characterized using UHPLC-QE Orbitrap-MS. HLM analysis identified 21 5F-ADB-PINACA metabolites and 28 5F-ADBICA metabolites. Metabolites of 5F-ADBICA were detected for the first time in vitro and in a zebrafish model. Zebrafish studies confirmed the presence of all key metabolites observed in HLM. Comparative analysis of their metabolic pathways revealed differences in metabolism driven by structural differences between the indazole and indole cores. This is the first time that correlation analysis has been used in the temporal metabolic profiling of SCs. This study comprehensively characterized the metabolism of 5F-ADB-PINACA and 5F-ADBICA, identifying M13 (hydrolytic defluorination) as a potential metabolite biomarker for 5F-ADB-PINACA and M19 (hydrolytic defluorination) as a potential metabolite biomarker for 5F-ADBICA. The metabolic reactions of the main metabolites of the two synthetic cannabinoids are consistent. However, their metabolic processes (i.e., the overall metabolic pathways and temporal progression of these reactions) are different, which illustrates the metabolic similarity of structurally similar synthetic cannabinoids and the impact of different structures on the metabolic processes. Full article

Despite the growing role of business incubators in fostering digital startups in emerging economies, the mechanism through which business incubator characteristics, specifically relational capital and structural embeddedness, influence startup innovation performance remains underexplored, particularly in the context of open innovation practices. This study examines how relational capital and structural embeddedness of business incubators affect the innovation performance of digital startups in Indonesia, with open innovation as a moderating variable. Using a cross-sectional survey design, data were collected from 201 startup owners or managers in Jakarta, West Java, and Banten. Partial Least Squares Structural equation modelling (PLS-SEM) was employed to test the hypothesized relationship. The results indicate that relational capital significantly enhances both innovation performance and structural embeddedness. However, structural embeddedness does not directly affect innovation performance nor mediate the link between relational capital and innovation. Notably, open innovation significantly moderates the relationship between structural embeddedness and innovation performance. This study contributes by integrating relational capital, structural embeddedness, and open innovation into a coherent framework within the underexplored context of Indonesian digital startups. The findings reveal that while relational capital is crucial, structural embeddedness alone is insufficient without active open innovation practices, offering nuanced insights for incubator management in emerging economies. Full article

The healthy evolution of an entrepreneurial ecosystem relies on the symbiotic relationships among its diverse internal actors. This study addresses a gap in entrepreneurial ecosystem research, which has predominantly focused on two-agent models, by constructing a tripartite symbiotic evolution model that incorporates entrepreneurial ventures, incubation chains, and customers. Based on the Logistic and Lotka-Volterra models, the research identifies the system’s equilibrium points and their stability conditions. Simulations reveal evolutionary paths from parasitism and commensalism to mutualism. A comparative case study of SenseTime (Shanghai, China) and Lanma Technology (Shanghai, China) validates these findings. The comparison shows that an influx of multiple agents, coupled with the core venture’s ability to strengthen key symbiotic coefficients, drives the ecosystem towards a dynamic multi-agent symbiosis in the post-optimization phase. Conversely, the failure to establish these robust reciprocal value flows leads to ecosystem fragility. The results indicate that: (1) Multi-agent entrepreneurial ecosystems are complex systems where symbiotic units form adaptive relationships for value creation, adhering to market laws. (2) The system’s equilibrium depends on symbiotic coefficients, leading to four modes—independent coexistence, parasitism, commensalism, and mutualism—with mutualism being the optimal state. (3) The contrasting cases further demonstrate that the evolution towards mutualism is not automatic but hinges on the core venture’s strategic agency in constructing and strengthening synergistic pathways with forward and backward linkages. This study provides a theoretical model for understanding the evolutionary mechanisms of entrepreneurial ecosystems and offers practical insights for optimizing ecosystem governance. Full article

Microbial communities associated with animal cadaver decomposition play a crucial role in biogeochemical cycles in both aquatic and terrestrial ecosystems. However, it remains unclear regarding the diversity, succession, and assembly of phosphate-solubilizing microbes during animal cadaver decay. In this study, plateau pikas (Ochotona curzoniae) as mammal degradation models were placed on alpine meadow soils to study diversity, succession and assembly of phosphate-solubilizing microbes using amplicon sequencing of phoC- and phoD-genes during 94 days of incubation. The total phosphorus concentration in the corpse group increased by 8.53% on average. Alpha diversity of both phoC- and phoD-harboring microbes decreased in the experimental group compared to the control group, and the community structure differed between control and experimental groups. Phosphate-solubilizing microbial community turnover time rate (TDR) of the experimental group was higher than that of the control group, indicating corpse decay accelerates the succession of phoC- and phoD-harboring microbial community. Null model revealed that deterministic process dominated phoC microbial community in corpse group, while the stochastic process dominated phoD microbial community. The microbial network in experimental group was more complicated than that in control group of phoC microbial community, while phoD microbial community showed opposite trend. Partial least squares path modeling (PLS-PM) showed that phoC-harboring microbial community was mainly influenced by pH, Total carbon (TC) and Total phosphorus (TP), while the phoD microbial community was only regulated by TP. These findings elucidate the ecological mechanism of phosphorus-solubilizing microbial community changes during animal corpse degradation. Full article

Background. Contributions of tumor-derived extracellular vesicles, TEX, to tumor progression and metastasis involve their crosstalk with immune cells in the tumor microenvironment. This crosstalk results in metabolic reprogramming of immune cells from anti-tumor to pro-tumor activity. Mechanistic underpinnings of the TEX entry and delivery of molecular signals responsible for metabolic reprogramming may be unique for different types of immune cells. Methods. An in vitro model of THP-1 myeloid cells co-incubated with TEX illustrates the role TEX play in polarization of macrophages to TAMs. Results. In THP-1 cells, the dominant signaling pathway of melanoma cell-derived TEX involves HSP-90/TLR2. This leads to activation of the NF-κB and MAP kinase pathways and initiates THP-1 cell polarization from M0 to M2 with strong expression of immunosuppressive PD-L1. TEX may be seen as “danger” by the myeloid cells, which utilize the pattern recognition receptors (PRR), such as PAMPs or DAMPs, for engaging the complementary ligands carried by TEX. The same melanoma TEX signaling to T cells via DAMPs induced mitochondrial stress, resulting in T-cell apoptosis. Conclusions. As the signaling receptors/ligands in TEX are determined by the tumor, it appears that the tumor equips TEX with an address recognizing specific PRRs expressed on different recipient immune cells. Thus, TEX, acting like pathogens, are equipped by the tumor to alter the context of intercellular crosstalk and impose a distinct autophagy-not-apoptosis signature in recipient THP-1 cells. The tumor might endorse TEX to promote tumor progression and metastasis by enabling them to engage the signaling system normally used by immune cells for defense against pathogens. Full article

This paper presents a hybrid knowledge-based expert system (KBES) designed to predict crack incubation and fatigue life in gear design, serving as both a research tool and an educational resource. While crack growth and initiation are well understood, crack incubation remains a challenging area. The presented expert system (KBES) integrates a novel mathematical model for crack incubation based on analogy and defect analysis principles with an optimization algorithm for gear design. The system uses genetic algorithms to optimize gear parameters, demonstrating a 5–10% deviation from experimental values in a specific gear design problem case study. Based on this KBES and a hybrid approach, we developed a learning environment based on an intelligent tutoring system (ITS) which serves older students (MSc and PhD) as a learning environment for the acquisition of knowledge and, above all, for the development of an in-depth understanding of the phenomena that occur both during incubation and initialization and during the further propagation of cracks in the root of the gear tooth, which is the basis for determining the lifespan of gear transmissions. Full article

The budding yeast Saccharomyces cerevisiae has long served as a valuable model for investigating the molecular mechanisms underlying aging. Calorie restriction (CR) is a well-established intervention that extends lifespan across species, yet the underlying molecular mechanisms remain incompletely understood. In this study, we examined the effects of CR on the chronological lifespan, oxidative stress response, and autophagic activity of the Saccharomyces cerevisiae mutant Sclsm4Δ1, which exhibits premature aging and elevated reactive oxygen species (ROS) levels due to defects in mRNA decapping and processing-bodies (PB) dynamics. We found that both moderate (0.1% glucose) and extreme (water incubation) CR significantly extended the lifespan of Sclsm4Δ1 mutants and markedly reduced intracellular ROS accumulation without activating autophagy. These findings indicate that the beneficial effects of CR stem from improved redox homeostasis and metabolic adaptation, rather than from canonical autophagic pathways. Similar protective effects were observed in a chromosomal lsm4Δ1 mutant generated via CRISPR–Cas9, confirming that CR rescues aging-related phenotypes in different genetic backgrounds. These insights reinforce the roles of nutrient signaling, RNA metabolism, and redox balance in lifespan regulation, offering new perspectives on the conserved anti-aging effects of calorie restriction. Full article

Vitamin D deficiency is associated with the risk of atopic diseases and respiratory infections. The activated vitamin D receptor (VDR) forms a dimer with the retinoid X receptor alpha (RXRA) and binds to VDR/RXRA composite elements (CEs) in enhancers of target genes. However, VDR/RXRA CEs are identified in only 11.5% of cases in ChIP-Seq peaks. Our hypothesis was that VDR could form a VDR-Partner complex with transcription factor for which CEs have not yet been identified. We utilized Web-MCOT to search for novel VDR/Partner CEs in regulatory DNA. The potential formation of the VDR-Partner protein complex was assessed using the AlphaFold machine learning model. Through real-time RT-PCR, we measured the expression of immune system genes in a culture of U937 macrophage-like cells incubated with the active metabolite of vitamin D, calcitriol. We have predicted novel VDR/NR2C2 and VDR/PPARG CEs in the regulatory regions of immune system genes. We found potential synergism of VDR/NR2C2 and VDR/RXRA CEs in relation to the IRF5 gene, as well as potential synergism of VDR/PPARG and VDR/RXRA CEs for MAPK13. Predicting new regulatory relationships through the identification of new potential VDR/Partner CEs may provide insight into the deep mechanisms of vitamin D involvement in the pathogenesis of atopic dermatitis, bronchial asthma, allergic rhinitis, and pulmonary infections. Full article

The complement system is crucial for immune defense, linking innate and adaptive immunity. In the classical and lectin pathways, C4 is split into C4b, triggering opsonization, lysis, and the removal of pathogens and damaged cells. Dysregulated activation of C4 and other components of the classical pathway can lead to tissue damage and heightened inflammation, whereas appropriate regulation of C4b activity serves to mitigate excessive inflammation and prevent injury. ELISA analysis demonstrated C4 activation and cleavage during the co-incubation of PRRSV with fresh porcine serum. Immunoelectron microscopy revealed that porcine red blood cells could immunologically adhere to PRRSV, and C4b was involved in this adhesion process. BLAST (NCBI BLAST+ 2.14.1) analysis revealed that porcine CR1-like CCPs 1-3, CR1-like CCPs 12-14, and CR1-like CCPs 19-21 share high similarity with the CCP 1-3 region of human CR1, which mediates C4b binding. Yeast two-hybrid assays confirmed that all three CR1-like fragments bind C4b. To elucidate the interaction mechanism, homology models of C4b and CR1-like fragments were constructed, followed by molecular docking and dynamics simulations, identifying 18 key amino acids in porcine CR1-like involved in C4b binding. Surface plasmon resonance further validated the binding affinity of CR1-like CCPs 1-3, its mutant 118I, and C4b. These results enhance our understanding of complement regulation and provide a foundation for developing therapeutic strategies targeting complement-related diseases. Full article

Remediating cadmium (Cd) contamination in aquatic and terrestrial environments has become an urgent environmental priority. Biochar has been widely employed for heavy metal removal due to its wide availability, strong adsorption capacity, and potential for recycling agricultural waste. In this study, samples of alkali–Fe-modified biochar (Fe@NaOH-SBC, Fe@NaOH-HBC, and Fe@NaOH-MBC) were prepared from agricultural wastes (ginger straw, Sichuan pepper branches, and kiwi leaves) through NaOH and FeCl₃·6H₂O modification. A comprehensive characterization confirmed that the alkali–Fe-modified biochar exhibits a higher specific surface area, richer functional groups, and successful incorporation of the iron oxides Fe₃O₄ and α-FeOOH. The fitting parameter qmax from the Langmuir model indicates that the alkali–Fe modification of carbon significantly enhanced its maximum capacity for Cd²⁺ adsorption. Furthermore, a synergistic effect was observed between iron oxide loading and alkali modification, outperforming alkali modification alone. Furthermore, a 30-day soil incubation experiment revealed that the application of alkali–Fe-modified biochar significantly increased soil pH, SOM, and CEC while reducing the available cadmium content by 13.34–33.94%. The treatment also facilitated the transformation of highly bioavailable cadmium species into more stable, less bioavailable forms, thereby mitigating their potential entry into the food chain and the associated human health risks. Moreover, short-term spinach seed germination experiments confirmed that treatments with varying additions of alkali–Fe-modified biochar mitigated the inhibition of seed physiological processes by high concentrations of available cadmium to varying degrees. Overall, this study provides a sustainable and effective strategy for utilizing agricultural waste in the remediation of cadmium-contaminated water and soil systems. Full article

The vegetative mycelium of Pleurotus ostreatus (oyster mushroom) exhibits the ability to reduce nematode populations. This property may be utilized in integrated management programs targeting harmful nematodes such as Heterodera schachtii, a major pest of sugar beet crops. In addition to sugar beet, many other plant species serve as hosts for this nematode; susceptible plants promote H. schachtii development and population growth. Current control strategies rely on integrated plant protection methods, including the use of tolerant cultivars, fallowing, and trap crops such as oilseed radish and white mustard. This study aimed to determine whether sugar beet cv. Janetka or nematocidal plants—oilseed radish cv. Romesa and white mustard cv. Bardena—affect the nematocidal activity of P. ostreatus mycelium when applied together. Specifically, the influence of root or seed secretions from these plants on the activity of ten P. ostreatus mycelial strains was assessed using the model nematode Caenorhabditis elegans and the target pest H. schachtii. Experiments were conducted under laboratory conditions on water agar media colonized by P. ostreatus mycelium. Seeds or root exudates of the tested plants were applied to the mycelial surface. Following incubation, nematode mobility (C. elegans) and cyst entwining by the mycelium (H. schachtii) were evaluated, along with the ability of the mycelium to produce toxocysts. The results indicate that trap plants did not significantly alter the nematocidal activity of the mycelium. However, certain mycelial strains were slightly stimulated by seed diffusates or root exudates. Oilseed radish moderately influenced the nematocidal activity of four mycelial strains against C. elegans, whereas in the case of H. schachtii, similar effects were observed with white mustard. The mycelial elimination of H. schachtii occurred through cyst entwining, which was generally more effective in the presence of plant exudates. Overall, the findings demonstrate that incorporating trap crops such as oilseed radish cv. Romesa or white mustard cv. Bardena, as green manure in crop rotation systems, does not interfere with the nematocidal activity of P. ostreatus mycelium and simultaneously may enrich the soil with nutrients. The study further confirms that P. ostreatus maintains its ability to effectively entwine and eliminate H. schachtii cysts even in the presence of sugar beet, supporting its potential role as a biological control agent. To our knowledge, this is the first experiment that integrates the activities of trap plants and sugar beet with the nematocidal effects of P. ostreatus mycelium. Full article

Since 2014, a model of the individual response to ionizing radiation (IR), based on the radiation-induced nucleoshuttling of the ATM protein kinase (RIANS), has been developed by our lab: after irradiation, ATM dimers monomerize in cytoplasm and diffuse into the nucleus to trigger both recognition and repair of DNA double-strand breaks (DSB), the key-damage of IR response. Moderate radiosensitivity is generally caused by heterozygous mutations of ATM substrates (called X-proteins) that are over-expressed in cytoplasm and form complexes with ATM monomers, which reduces and/or delays the RIANS and DSB recognition. Here, we asked whether molecules, rather than X-proteins, can also influence RIANS. Caffeine was chosen as a potential “X-molecule” candidate. After incubation of cells with caffeine, cutaneous fibroblasts from an apparently healthy radioresistant donor, a patient suffering from Alzheimer’s disease (AD) and another suffering from neurofibromatosis type 1 (NF1) were exposed to X-rays. The functionality of ATM-dependent DSB repair and signaling was evaluated. We report here that caffeine molecule interaction with ATM leads to the inhibition of DSB recognition. This effect is significant in radioresistant cells. Conversely, in the AD and NF1 cells, the DSB recognition is already so low that caffeine does not provide any additional molecular effect. Full article

Objective: This study aims to engineer a novel nanoparticle formulation for combined tumor therapy, designated as PDA@Mn-siSur-c-NPs, which comprises a polydopamine/manganese dioxide (PDA@MnO₂) core alongside survivin-targeting siRNA and cyclo(RGD-DPhe-K)-targeting moiety. Methods: The PDA@Mn-siSur-c-NPs were constructed and subjected to detailed characterization. Inductively coupled plasma optical emission spectroscopy (ICP-OES) was employed to quantify manganese content. To assess siRNA stability within the system, samples were incubated with 50% fetal bovine serum (FBS) before agarose gel electrophoresis analysis. Additionally, cellular internalization by 4T1 cells and in vitro photothermal conversion efficiency of the formulation were evaluated. ICP-OES was further utilized to investigate the in vivo pharmacokinetics and tissue distribution of manganese. Animal model studies were conducted to assess the anti-breast cancer efficacy of PDA@Mn-siSur-c-NPs in combination with infrared irradiation. Results: The newly developed PDA@Mn-siSur-c-NPs demonstrated superior siRNA protection, reduced toxicity, and high photothermal conversion capacity. When combined with photothermal therapy (PTT), these nanoparticles exerted enhanced synergistic anti-tumor effects. Delivery of survivin siRNA resulted in a significant downregulation of survivin protein expression in tumor tissues. Moreover, magnetic resonance imaging (MRI) confirmed that the nanoparticles possess favorable imaging properties. Conclusions: This research demonstrates that the integration of PDA@Mn-siSur-c-NPs with PTT holds considerable therapeutic promise for improved breast cancer treatment. Full article

Background/Objectives: Candida biofilms exhibit high resistance to antifungal treatment, motivating investigation of adjunctive physical disinfection methods. To quantitatively assess the effect of Er:YAG laser fluence on growth inhibition and viability of single-species Candida biofilms in vitro using a 7 mm full-beam handpiece. Methods: Biofilms of Candida albicans ATCC 10231, C. glabrata ATCC 90030, C. parapsilosis ATCC 22019, and C. krusei ATCC 6258 were grown on Sabouraud agar. In phase 1, growth inhibition zones (GIZs) were evaluated after non-contact Er:YAG irradiation (2 Hz, 300 µs, 10 mm distance, no air or water spray) at fluences from 0.3 to 3.4 J/cm², with incubation for 24 to 96 h. In phase 2, 96 h mature biofilms were irradiated for 120 s at 0.8, 1.0, 1.5, or 2.0 J/cm², and viability was quantified by colony-forming unit (CFU) imprinting. All experimental conditions were tested in quadruplicate. Results: GIZ diameters increased significantly with fluence for all species (p < 0.05) and remained stable up to 96 h. At the highest fluence, mean GIZs reached approximately 8.0 mm for C. albicans, 7.7 mm for C. parapsilosis, 7.0 mm for C. krusei, and 5.2 mm for C. glaxfbrata. In mature biofilms, CFU counts decreased significantly with increasing fluence (p < 0.05). For C. albicans, CFUs were reduced from 164.0 ± 25.1 at 0.8 J/cm² to 16.5 ± 5.2 at 2.0 J/cm², while C. glabrata decreased from 103.5 ± 5.4 to 20.8 ± 1.7. C. parapsilosis and C. krusei showed maximal reductions at 1.0–1.5 J/cm², followed by partial CFU rebound at 2.0 J/cm². Conclusions: Er:YAG irradiation delivered over a large, uniformly illuminated area induces stable, fluence-dependent inhibition and significant reduction of Candida biofilm viability in vitro. Optimal fluence ranges are species specific, underscoring the need for parameter optimization and further evaluation in more complex biofilm models before clinical extrapolation. Full article