Search Results (1,973)

Chronic diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, oxidative stress, and defective tissue remodeling, leading to delayed healing. Cordyceps militaris, a medicinal fungus with known anti-inflammatory and antioxidant properties, has shown therapeutic potential in metabolic disorders; however, its role in diabetic wound repair remains unclear. In this study, we evaluated the wound-healing effects of an aqueous extract of C. militaris using in vitro keratinocyte models and a streptozotocin-induced diabetic mouse model. C. militaris treatment significantly accelerated wound closure, improved epidermal regeneration, and enhanced skin barrier integrity. Mechanistically, C. militaris restored HIF-1α and TGF-β1 expression, promoted cell proliferation and fibroblast activation, and increased the expression of matrix metalloproteinases MMP-1 and MMP-2, indicating enhanced extracellular matrix remodeling. In parallel, excessive inflammatory responses were attenuated, as evidenced by reduced IL-6 and TNF-α levels, along with activation of SIRT1/Nrf2/HO-1 antioxidant signaling pathways. Collectively, these findings demonstrate that C. militaris promotes a balanced wound-healing microenvironment and represents a promising natural therapeutic candidate for the treatment of diabetic wounds. Full article

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

For the past decade, cell-based therapies have been the focus of research to investigate their potential to treat ischemic heart disease. The translation to human clinical studies depends on the demonstration of therapeutic efficacy and safety, particularly when transplanted in the subacute and chronic post-MI phase. A number of studies were identified that reported the effect of hiPSC-CMs on cardiac outcomes when transplanted at least 7 days post-myocardial infarction. The mean sample size of the published studies was 30 (±17) animals with a mean follow-up duration of 51 (±37) days. hiPSC-CM transplantation enhanced systolic function through augmented myocardial contractility, decreased infarct size, attenuated ventricular remodeling, and enhanced angiogenesis in the infarct and border zones in both small and large animal models. This effect was enhanced by co-transplantation with cells of vascular or adipose origin and is associated with high expression of VEGF in most studies. Despite this effect, transplanted hiPSC-CMs were structurally immature with limited survival at the endpoint. Epicardial delivery was associated with better efficacy outcomes and lower rates of arrhythmia. No study reported teratoma formation or immune rejection. From the current literature, there appears to be no consensus on the extent to which hiPSC-CMs improved systolic function, nor the degree to which this arises directly from integration of the new myocardium or from a paracrine-mediated mechanism. The nature of this paracrine mechanism and ways to improve the maturity and survival of implanted cardiomyocytes are issues that have yet to be resolved. In summary, while therapeutic benefit from cell therapy is clear, further research is required to establish whether the key mechanisms require a cellular component. Full article

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of action via the CK2α/SMO interaction. In a rat model established with a methionine-choline-deficient diet, orally administered miR-55 markedly improved liver injury, lipid dysregulation, oxidative stress, and pathological collagen deposition. The anti-fibrotic efficacy was quantitatively confirmed by a significant reduction in hepatic hydroxyproline content and downregulation of key fibrogenic genes (Col1a1, Col3a1, TIMP-1, TGF-β1, CTGF) and pro-inflammatory cytokines (TNF-α, IL-6), achieving effects comparable to the full Ge Xia Zhu Yu Decoction. Mechanistically, both bioinformatic prediction and in vivo validation indicated that miR-55 is predicted to target CK2α. This targeting suppressed CK2α expression and disrupted the endogenous CK2α-SMO complex, thereby promoting the ubiquitin-mediated degradation of SMO—a previously unreported mechanism. This cascade inhibited the downstream Gli1 pathway and downregulated pro-fibrotic and pro-angiogenic factors (VEGF, PDGF), thereby providing a comprehensive mechanistic basis for the therapeutic effects. This study is the first to provide evidence that orally delivered, plant-derived miR-55 may act as a natural modulator that potentially through disrupting the CK2α/SMO interaction via a unique complex disruption-promoted degradation mechanism, attenuating Hedgehog signaling and alleviating liver fibrosis. These findings offer important insights into cross-kingdom regulation and highlight miR-55 as a potential targeted therapeutic candidate. Full article

The coal-fired Plomin Thermal Power Plant (Plomin TPP) in Croatia is located in the center of the east coast of the Istrian peninsula (northern Adriatic) and is considered the main source of historical air pollution in the region. Between 1970 and 2000, sulfur-rich coal from the local Raša coal mine was primarily used. In this study, a screening of content and fate of TPP-derived sulfur in soil around the power plant was made two decades after the S-rich coal was banned from use. Soil samples were collected at varying distances from the TPP in the prevailing wind direction (NE), along with a control sample taken more than 10 km away. The samples were analyzed for total sulfur, sulfate, organic sulfur (humic and fulvic), and the stable isotope composition of total sulfur (δ³⁴S). Additionally, coal and coal ash were analyzed for total sulfur, sulfate and δ³⁴S. Soil sampling along the prevailing wind direction from the Plomin TPP revealed markedly elevated sulfur content, with levels at 100 m downwind reaching up to 4 wt.%, which is over 100 times higher than the 0.04 wt.% measured at the control site located upwind. Sulfur content decreases sharply with increasing distance from the TPP, reflecting the deposition gradient along the prevailing wind path. Speciation analysis showed that over 95% of the sulfur in the soil is now present in organic form, mainly bound to humic acids. The δ³⁴S_VCDT values of the bulk coal used in the TPP ranged from −10.0 to −5.0‰. In most soil samples, the bulk δ³⁴S values were positive (+7.0 to +20.0‰). The values of sulfate in soil range from +1.0 to +5.5‰, while those in organic sulfur range from −3.5 to +6.0‰. This indicates that atmospheric deposition of ³⁴S-depleted fly ash and sulfate from coal are the most important sulfur sources, while some of the sulfur in the soil is also of marine origin. Finally, we showed that natural attenuation was a significant and efficient process within the sustainable management of the site historically contaminated by anthropogenic atmospheric sulfur deposition. Full article

Immunodeficiency presents a significant clinical challenge in contexts such as tumour radiotherapy, chemotherapy, and organ transplantation. Current therapeutic interventions are constrained by single-target approaches and substantial adverse effects. As natural bioactive compounds, the immunomodulatory activities of Lactobacillus exopolysaccharides (EPS) are intimately linked to their monosaccharide composition. Mannose and fucose, two rare functional monosaccharides, fulfil critical roles in physiological processes including immune recognition and inflammatory regulation. However, the functional optimisation of EPS through mannose and fucose enrichment remains incompletely characterised. This study established a cyclophosphamide (CTX)-induced immunodeficient mouse model to investigate the immunomodulatory effects of mannose-enriched and fucose-enriched EPS derived from Lactobacillus helveticus. Intervention efficacy was evaluated through a comprehensive assessment of immune organ indices, cytokine profiles, histopathological alterations, and gut microbiota composition. Both mannose-enriched and fucose-enriched EPS significantly elevated splenic indices and ameliorated white pulp atrophy. Furthermore, these EPS variants restored cytokine homeostasis in serum and small intestinal tissues, attenuated hepatic steatosis, and restructured the gut microbiota by enhancing microbial diversity, increasing Firmicutes abundance, and elevating the relative proportions of Bacteroides, Faecalibacterium, and Bifidobacterium. Collectively, mannose-enriched and fucose-enriched EPS from Lactobacillus helveticus alleviated CTX-induced immunodeficiency through multiple mechanisms, including restoration of immune organ integrity, modulation of cytokine networks, and re-establishment of gut microbiota homeostasis. This study provides a theoretical foundation for developing immunomodulatory functional foods and offers novel insights into the microbiota-immunity axis in immune regulation. Full article

Lightweight, lead-free polymer–mineral composites have attracted increasing interest as radiation-attenuating materials for applications where reduced mass and environmental compatibility are required. In this work, the $\gamma$-ray attenuation behavior of poly(ether ether ketone) (PEEK) reinforced with natural palygorskite and pumice was evaluated at filler concentrations of 10–40 wt%. Photon interaction parameters, including the linear attenuation coefficient ($\mu$), half-value layer (HVL), mean free path ($\lambda$), and effective atomic number ($Z_{\mathrm{eff}}$), were computed over the energy range 15 keV–15 MeV using the Phy-X/PSD platform and validated through full Geant4 Monte Carlo transmission simulations. At 15 keV, $\mu$ increased from $1.46{\mathrm{cm}}^{-1}$ for pure PEEK to $4.21{\mathrm{cm}}^{-1}$ and $8.499{\mathrm{cm}}^{-1}$ for the 40 wt% palygorskite- and pumice-filled composites, respectively, reducing the HVL from 0.69 cm to 0.24 cm and 0.11 cm. The corresponding $Z_{\mathrm{eff}}$ values increased from 6.5 (pure PEEK) to 9.4 (40 wt% palygorskite) and 15.3 (40 wt% pumice), reflecting the influence of higher-Z oxide constituents in pumice. At higher photon energies, the attenuation curves converged as Compton scattering became dominant, although pumice-filled PEEK retained marginally higher $\mu$ and shorter $\lambda$ up to the MeV region. These findings demonstrate that natural mineral fillers can enhance the photon attenuation behavior of PEEK while retaining the known thermal stability and mechanical performance of the polymer matrix as reported in the literature, indicating their potential use as lightweight, secondary radiation-attenuating components in medical, industrial, and aerospace applications. Full article

The vibration compaction behavior of fully graded fresh concrete differs fundamentally from that of conventional two-graded concrete. Based on measured vibration responses of an internal vibrator and sinking-ball tests, an energy transfer model for fully graded concrete was established by incorporating the effects of aggregate-specific surface area, paste–aggregate ratio, dynamic damping, and natural frequency, and the spatiotemporal attenuation of vibration energy in fresh concrete was systematically analyzed. Experimental results indicate that fully graded concrete exhibits a higher energy absorption capacity during the early stage of vibration, with a maximum energy absorption rate of 423 W and a peak energy transfer efficiency of 76.3%, both of which are significantly higher than those of two-graded concrete at the same slump. However, as a dense aggregate skeleton rapidly forms, the energy absorption efficiency of fully graded concrete decreases more rapidly during the middle and later stages of vibration, showing a characteristic pattern of “high initial absorption followed by rapid attenuation.” Through segregation assessment and porosity analysis, a safe vibration energy range for fully graded concrete was quantitatively determined, with lower and upper energy thresholds of 159.7 J·kg⁻¹ and 538.5 J·kg⁻¹, respectively. In addition, the experiments identified recommended vibration durations of 30–65 s and effective vibration influence radii of 22–85 mm for fully graded concrete under different slump conditions. These findings provide a quantitative basis for the control of vibration parameters and energy-oriented construction of fully graded concrete. Full article

The enteric nervous system (ENS) constitutes a highly organized and intricate neuronal network comprising two principal plexuses: myenteric and submucosal. These plexuses consist of neurons and enteric glial cells (EGCs). Neurons ensure innervation throughout the intestinal wall, whereas EGCs, distributed within the mucosa, contribute to epithelial barrier integrity and modulation of local inflammatory responses. The ENS orchestrates essential gastrointestinal functions, including motility, secretion, absorption, vascular regulation, and immune interactions with gut microbiota. Under physiological conditions, intestinal homeostasis involves moderate generation of reactive oxygen species (ROS) through endogenous processes such as mitochondrial oxidative phosphorylation. Cellular antioxidant systems maintain redox equilibrium; however, excessive ROS production induces oxidative stress, promoting EGCs activation toward a reactive phenotype characterized by pro-inflammatory cytokine release. This disrupts neuron–glia communication, predisposing to enteric neuroinflammation and neurodegeneration. Obesity, associated with hyperglycemia, hyperlipidemia, and micronutrient deficiencies, enhances ROS generation and inflammatory cascades, thereby impairing ENS integrity. Nevertheless, non-pharmacological strategies—including synthetic and natural antioxidants, bioactive dietary compounds, probiotics, and prebiotics—attenuate oxidative and inflammatory damage. This review summarizes preclinical and clinical evidence elucidating the interplay among the ENS, obesity-induced oxidative stress, inflammation, and the modulatory effects of antioxidant interventions. Full article

Bovine viral diarrhea virus (BVDV) causes severe mucosal inflammation in cattle, and effective treatment options remain limited. Dysregulated activation of the NLRP3 inflammasome, driven by NF-κB and STAT3 signaling, may exacerbate disease pathogenesis, highlighting this axis as a potential therapeutic target. Although traditional Chinese medicine has shown promise in antiviral and anti-inflammatory applications, it remains unclear whether it can inhibit BVDV replication via the NF-κB/STAT3-NLRP3 pathway. The present study aimed to clarify the inhibitory effect of luteolin on bovine viral diarrhea virus (BVDV) replication, and to elucidate its underlying mechanisms from two perspectives: interference with viral internalization and replication processes, as well as regulation of the NF-κB/STAT3-NLRP3 inflammasome pathway. Collectively, this work intended to provide experimental evidence and theoretical support for the development of luteolin as a natural anti-BVDV agent. To this end, BVDV-infected MDBK cells were treated with gradient concentrations of luteolin, followed by quantification of viral load using qRT-PCR and Western blot assays. Meanwhile, the activation status of the NF-κB/STAT3-NLRP3 signaling pathway was evaluated via immunofluorescence staining and luciferase reporter gene assays. Our results demonstrate that luteolin exhibits potent dual antiviral activity against cytopathic BVDV-1m in MDBK (Madin-Darby Bovine Kidney) cells, effectively suppressing both viral replication and inflammatory responses. At non-cytotoxic concentrations, luteolin specifically inhibited the internalization and replication stages of the viral lifecycle, accompanied by reduced NS5B polymerase activity. Importantly, luteolin disrupted the NF-κB/STAT3-NLRP3 axis by suppressing phosphorylation of p65 (Ser536) and STAT3 (Ser727), downregulating NLRP3 and pro-caspase-1 expression, and inhibiting caspase-1 cleavage (p20) as well as maturation of IL-1β and IL-18. Consequently, it attenuated the overexpression of TNF-α and IL-8. To our knowledge, this is the first report of a single compound simultaneously targeting multiple stages of the BVDV lifecycle and counteracting NLRP3-mediated immunopathology, offering a strategic basis for developing flavonoid-based therapies against Flavivirus infections. Full article

This study investigated the influence of groundwater flux and temperature on denitrification in a steep coastal agricultural Island in western Japan. Push–pull tests (PPTs) were conducted at depths of 3 m, 15 m, and 30 m, during winter, spring, and summer to assess denitrification under varying hydrogeological and seasonal conditions. The 3 m layer is silty loam, 15 m is granitic weathered soil, and 30 m is granitic weathered rock, each with distinct hydraulic conductivities and fluxes. The objectives were to assess denitrification rates and fluxes, assess depth- and season-related variability, and determine the relative roles of hydraulic flux and temperature on denitrification. Denitrification was higher at shallow (3 m) and deep (30 m) boreholes during low-flux periods, while low at the intermediate depth (15 m) where fluxes were highest. Temperature variation had weak correlations compared to hydraulic flux, which showed a strong inverse correlation with denitrification. These findings demonstrate that residence time, controlled by groundwater flux, is the dominant factor influencing nitrate attenuation in this steep coastal aquifer. The PPTs results indicate that denitrification rates derived from PPTs decrease under higher hydraulic fluxes, as these conditions promote more oxic conditions. The study highlights the potential for natural denitrification to mitigate nitrate contamination during low-flux periods, providing insights for sustainable groundwater management in agricultural island environments. Full article

To improve the seismic performance of buildings and reduce earthquake-related disaster risks, this study employs the MIDAS finite element analysis platform to establish a numerical model of a 15-story concrete-filled steel tube frame-shear wall structure. Recorded natural ground motion data are used as the primary input, and a main shock-aftershock sequence is constructed using an attenuation-based method. On this basis, a seismic fragility analysis framework is adopted to derive structural fragility curves, which are subsequently assembled into a comprehensive seismic fragility matrix. The results indicate that, under identical main shock-aftershock sequences, aftershock effects increase the collapse probability of the unretrofitted structure by approximately 17–37%. Furthermore, when buckling-restrained braces are introduced, the structural strength at the same damage state increases by about 8% under the action of the main shock alone and by nearly 24% when both the main shock and aftershocks are considered. Full article

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins as a wound-healing response to chronic liver injury, leading to tissue scarring and organ dysfunction. Natural compounds, including phytonutrients and polyphenols, have been shown to exert protective effects by reducing profibrotic biomarkers in vitro and in vivo models. Here, we provide the first evidence that the polyphenol hesperidin (HE) can counteract the onset of fibrotic responses in an ex vivo mouse liver fibrosis model induced by Transforming Growth Factor-β1 (TGF-β1) (5 ng/mL). Notably, HE drives early ECM remodeling in the fibrotic mouse liver tissue. Fibrosis-related parameters were assessed at both the transcriptional and translational levels after treatment with HE at increasing concentrations of 50, 75, and 100 µg/mL. Interestingly, HE at 75 µg/mL exerted the strongest beneficial effect, significantly decreasing the gene expression of α-SMA, SERPINH-1, FN-1, VIM and COL1A1 and counteracting the TGF-β1-induced upregulation of key fibrotic markers, including α-SMA, COL1A2, and VIM, reflecting its capacity to attenuate myofibroblast activation and ECM production and modulating membrane lipid peroxidation. Furthermore, HE inhibited SMAD2 phosphorylation, suggesting that its antifibrotic activity may involve the modulation of the TGF-β/SMAD signaling pathway. Moreover, it promoted an anti-inflammatory response, due to a decrease in IL-1β and IL-6 expression. Our study highlights the potential of the ex vivo model as a platform for evaluating the antifibrotic efficacy of natural molecules, and it suggests significant translational implications and new opportunities for developing innovative therapeutic strategies. Full article

Sarcopenia, an age-related muscle atrophy disease, is a major health concern in aging societies and is closely associated with severe chronic diseases. Its primary pathogenesis involves oxidative stress-induced apoptosis in muscle cells and an imbalance in protein metabolism. This study evaluated the potential of Rhododendron mucronulatum branch extract (RMB) and its major flavonoids, taxifolin-3-O-arabinopyranoside (Tax-G) and taxifolin (Tax-A), as natural therapeutic agents for sarcopenia. Phytochemical analyses were performed using TLC, HPLC, LC-MS/MS, and NMR, and Tax-G and Tax-A were isolated from RMB. In vitro models of apoptosis and muscle atrophy were established in C2C12 cells using H₂O₂ and dexamethasone (DEX), respectively. Cell viability, myotube diameter, and protein expression related to apoptosis and muscle differentiation were assessed. All three substances reduced H₂O₂-induced apoptosis by increasing Bcl-2 and inhibiting cleaved caspase-3 and PARP. They also attenuated DEX-induced muscle atrophy by suppressing Atrogin-1, MuRF1, and FoxO3α while promoting MyoD, Myogenin, Akt, and mTOR. Although Tax-A showed the highest activity, Tax-G exhibited comparable effects with lower cytotoxicity. These findings demonstrate that RMB and its active compounds protect muscle cells by regulating apoptosis and muscle metabolism, suggesting their potential as safe and functional natural materials for the prevention of sarcopenia. Full article

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that strongly suppress immunity and expand during tumor progression. Various antitumor chemotherapy agents can induce MDSC accumulation, reducing treatment effectiveness. We investigated the impact of the CHOP regimen and its components (cyclophosphamide (CTX), doxorubicin, vincristine, and prednisolone) on the dynamics of MDSC accumulation and the associated changes in immune cell profiles in the peripheral blood and spleen of healthy and lymphosarcoma RLS₄₀-bearing CBA mice. CHOP induced significant thymic atrophy and splenomegaly, T-cell depletion, and robust accumulation of MDSCs, primarily polymorphonuclear MDSCs. Kinetic analysis in healthy mice revealed splenic MDSC expansion and T-cell depletion peaked 10-day post-CHOP, driven mainly by CTX; whereas doxorubicin, vincristine, and prednisolone exerted minimal immunological effects. To mitigate CTX-induced MDSCs, glycyrrhizic acid (GLZ), a natural triterpenoid with known immunomodulatory properties, and febroxolone methyl (FM), its novel cyano enone derivative, were administered to CTX-treated mice. GLZ significantly attenuated splenic MDSC accumulation, partially restored T-cell function, and improved immune organ morphology. Conversely, FM exacerbated immunosuppression by expanding MDSCs, enhancing their function by upregulation of Nos1 and Ido1 in vivo, and promoting the generation of highly immunosuppressive bone marrow-derived MDSCs in vitro. Thus, our results highlight CTX’s central role in CHOP-induced MDSC expansion. The structure-dependent duality of triterpenoids, countering (GLZ) or promoting (FM) MDSC expansion, offers therapeutic potential for pathologies ranging from chemotherapy-induced side effects to autoimmunity. Full article