Search Results (369)

Cancer remains one of the most prominent global health concerns, posing a substantial threat to public health. Millions of people die from cancer each year, and many cancer types remain incurable at present. Conventional cancer treatments, including surgery, chemotherapy, radiotherapy, and immunotherapy, often fail to achieve optimal clinical outcomes and are frequently associated with severe trauma and adverse effects. Consequently, there is an urgent need to develop novel therapeutic strategies to address these limitations. Hydrogels have been widely utilised as platforms for loading drugs, proteins, DNA, and stem cells in biomedical tissue repair and cancer therapy. Through modification of their physicochemical properties and functions, hydrogels can be endowed with responsiveness to multiple stimuli. In recent years, stimuli-responsive hydrogels (also known as smart-responsive hydrogels), as novel drug delivery systems, have demonstrated remarkable efficacy in cancer treatment. Stimuli-responsive hydrogels are capable of altering their mechanical properties, swelling behaviour, hydrophilicity, bioactivity, and molecular permeability in response to endogenous stimuli (including pH, ROS, and temperature) and exogenous stimuli (including light, ultrasound, and magnetic fields). This review highlights recent advances and applications of responsive hydrogels triggered by endogenous stimuli (including pH, ROS, and temperature) and exogenous stimuli (including light, ultrasound, and magnetic force) in cancer drug delivery and treatment. Finally, the current application limitations and future prospects of smart-responsive hydrogels are summarised. Full article

Mesenchymal stem cells (MSCs) are multipotent adult cells that are highly valued for their immunomodulatory potential and intrinsic ability to home to inflamed sites. This study specifically utilized human dental pulp stem cells (hDPSCs), a unique MSC subtype derived from the neural crest, due to their reported superior anti-inflammatory capacity. To rigorously test their efficacy, we employed the AIRmax murine model, which exhibits a genetically determined high-inflammatory phenotype. Acute inflammation was induced by subcutaneous injection of the polyacrylamide suspension Biogel P-100. Two hours post-induction, AIRmax mice were treated intravenously with hDPSCs. Our results demonstrate that hDPSC treatment produced significant anti-inflammatory effects evident at 24 h. The treated group showed a pronounced reduction in leukocyte migration and decreased protein extravasation in the inflammatory exudate. Crucially, hDPSCs also modulated molecular mediators, significantly decreasing the pro-inflammatory cytokine TNF-alpha and reactive oxygen species (ROS) production. Furthermore, while hDPSCs efficiently and rapidly homed to the inflammation site within 2 h, their maximal therapeutic benefits only manifested after 24 h. This suggests that their robust capacity to modulate acute inflammatory responses relies not only on rapid migration but also on a paracrine “hit-and-run” mechanism that suppresses cellular infiltration and oxidative stress over time. This study reinforces the potential of hDPSCs as a powerful, multi-target therapeutic agent for inflammatory conditions, supporting further investigation into their precise mechanisms and clinical application. Full article

The biological effects of radiofrequency electromagnetic fields (RF-EMFs) remain an unresolved scientific issue with important societal relevance, particularly in the context of the global deployment of fifth-generation (5G) wireless technologies. The skin is continuously exposed to both RF-EMFs and ultraviolet (UV) radiation, a well-established inducer of oxidative stress and DNA damage, making it a relevant model for assessing combined environmental exposures. In this study, we investigated whether post-exposure to 5G RF-EMFs (3.5 and 28 GHz) modulates ultraviolet A (UVA)-induced genotoxic stress in human keratinocytes (HaCaT) and murine melanoma (B16) cells. Post-UV RF-EMF exposure significantly reduced DNA damage markers, including phosphorylated histone H2AX (γH2AX) foci formation (by approximately 30–50%) and comet tail moments (by 60–80%), and suppressed intracellular reactive oxygen species (ROS) accumulation (by 56–93%). These effects were accompanied by selective attenuation of p38 mitogen-activated protein kinase (MAPK) phosphorylation (reduced by 55–85%). The magnitude of molecular protection was comparable to that observed with N-acetylcysteine treatment or pharmacological inhibition of p38 MAPK. In contrast, RF-EMF exposure did not reverse UV-induced reductions in cell viability or alterations in cell cycle distribution, indicating that its protective effects are confined to early molecular stress-response pathways rather than downstream survival outcomes. Together, these findings demonstrate that 5G RF-EMFs can facilitate recovery from UVA-induced molecular damage via redox-sensitive and p38-dependent mechanisms, providing mechanistic insight into the interaction between modern telecommunication frequencies and UV-induced skin stress. Full article

Background: Cannabidiol (CBD), the major non-psychotropic cannabinoid derived from Cannabis sativa L., has demonstrated broad anticancer activity across multiple tumor types; however, its effects in renal cell carcinoma (RCC) remain largely undefined. Given the ongoing need for novel therapeutic strategies in RCC, this study provides preliminary mechanistic insights into the cytotoxic, antiproliferative, and redox-modulating properties of CBD in RCC cells and evaluates the influence of serum conditions on its activity. Methods: Human RCC cell lines (Caki-1 and 769-P) and non-tumoral proximal tubular epithelial cells (HK-2) were treated with CBD (1–100 µM) for up to 48 h under serum-free and serum-supplemented (5%) conditions. Cytotoxic and antiproliferative effects were assessed using the MTT assay, and intracellular reactive oxygen/nitrogen species (ROS/RNS) levels were quantified using the H₂DCFDA fluorescence assay. Results: CBD significantly decreased RCC cell viability and proliferation in a concentration-dependent manner and induced time-dependent ROS/RNS accumulation. Comparable sensitivity was observed in non-tumoral HK-2 renal epithelial cells, indicating limited tumor selectivity under the tested in vitro conditions. Notably, these effects were markedly attenuated in the presence of serum, consistent with CBD’s high serum–protein binding and reduced free bioavailability. Conclusions: CBD induces cytotoxic, antiproliferative, and redox-modulating effects in RCC cells in vitro; however, these responses are strongly attenuated by serum, lack tumor selectivity, and require concentrations exceeding clinically achievable plasma levels. Together, these findings delineate major translational limitations for the therapeutic use of CBD in RCC. Full article

Plant root growth and architectural modifications are well-documented responses to phosphorous (P) starvation. The spatiotemporal dynamics of hydrogen peroxide (H₂O₂) in mediating root development under P deficiency, especially in cereal crops like wheat, remain insufficiently understood. A nutrient solution experiment was conducted to grow two varieties of wheat, including SM15 and HG35, with the treatments of 0.005 and 0.25 mmol/L P supply. Exogenous H₂O₂ and its scavenger ascorbic acid (AsA), and a NADPH oxidase inhibitor diphenylene iodonium (DPI) were added. The distribution of reactive oxygen species (ROS) in roots were detected by chemical staining and fluorescent probe technology. Low P supply did not change the root dry weight and total root length, while it decreased the lateral root density. The increase in the primary root and lateral root growth in P-starved wheat coincided with more ROS in the cell wall of the elongation zone. ROS production and oxidative enzyme activity of P-starved roots increased significantly. Low H₂O₂ induced the formation of lateral roots and significantly increased lateral root density under low P conditions. High H₂O₂ significantly reduced lateral root density but stimulated the nodal root formation. Exogenous AsA or DPI addition reversed the promotion of root growth imposed under the low P treatment or H₂O₂ addition. Furthermore, exogenous H₂O₂ treatment reduced the inhibitory effect of the DPI treatment on nodal root formation. It is suggested that the involvement of ROS in the regulation of wheat root system architecture under low P supply. Full article

Soybean (Glycine max L.) is an essential food and economic crop in China, yet its growth and yield are severely constrained by saline–alkali stress. A saline–alkali soil exacerbates root absorption barriers, leading to 30–50% yield losses. Understanding the mechanisms underlying alkali tolerance is therefore crucial for developing stress-resilient soybean varieties and improving the productivity of saline–alkali land. In our previous study, we evaluated 99 soybean germplasms from Northeast China and obtained the alkali-tolerant varieties HN48 and HN69, along with the alkali-sensitive varieties HNWD4 and HN83. In this study, fifteen-day-old soybean seedlings were subjected to (30 mM NaHCO₃) alkali stress for 72 h, and whole plants were sampled to assess their morphology and physiology, while leaf tissues were harvested for biochemical analysis. For transcriptomic analysis, soybean seedlings were exposed to alkali stress (50 mM NaHCO₃, pH 9.0) for 6 h, and leaf and root tissues were harvested for RNA sequencing. The results showed that alkali-tolerant varieties mitigated these effects by suppressing excessive ROS generation by 55–63%, decreasing malondialdehyde (MDA) accumulation by 37–39%, and increasing photosynthetic efficiency by 18.3%, as well as accumulating more osmoprotectants and activating antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) under alkaline stress. Transcriptome analysis showed that the alkali-tolerant variety HN69 exhibited cultivar-specific enrichment of metabolism cytochrome P450, estrogen signaling, and GnRH signaling pathways under alkali stress. These results collectively indicate that alkali-tolerant soybean varieties adapt to alkali stress through coordinated multi-pathway responses, with differential pathway enrichment potentially underlying the variation in alkali tolerance between cultivars. Overall, this study elucidates the physiological and molecular mechanisms of alkali tolerance in soybean, providing a theoretical foundation for breeding stress-tolerant germplasms. Full article

Selenium-Binding Protein 1 (SBP1), involved in selenium metabolism, contributes to plant stress response. However, it is currently unknown whether the SBP1 protein from Liriodendron hybrid (LhSBP1) plays a role in response to cold stress. In this study, transgenic overexpression lines of LhSBP1 in Arabidopsis thaliana and Populus deltoides × P. euramericana cv. ‘Nanlin 895’, were used as materials to conduct phenotypic observations and physiological and biochemical determinations under cold stress. The results showed that the full-length CDS sequence of LhSBP1 gene was cloned, with a length of 1467 bp, encoding 488 amino acids. Under cold stress, physiological and biochemical indexes showed that the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) in transgenic Arabidopsis were lower, with the contents of hydrogen peroxide (H₂O₂) and superoxide anion (O₂⁻) being 0.72 and 0.71 times those of the wild type, respectively, and the MDA content was 0.53 times that of the wild type. Compared with the wild type, the activities of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) increased by 1.2, 1.75, and 1.48 times respectively, and the soluble protein content increased by 1.41 times, which significantly improved the cold tolerance of Arabidopsis. The contents of H₂O₂, O₂⁻, and MDA in LhSBP1 transgenic ‘Nanlin 895’ poplar were 0.63 and 0.67 times and 0.6 times those of wild type, respectively. The activities of SOD, POD and CAT were increased by 1.37, 1.48, and 1.44 times, and the soluble protein was increased by 1.28 times, which significantly improved the cold tolerance of ‘Nanlin 895’ poplar. Taken together, this study utilized two model plant systems to demonstrate the positive and conserved functions of LhSBP1 in plant cold tolerance defense response, which provided valuable genetic resources for the breeding of cold-tolerance woody plants. Full article

Chemotherapy causes primordial follicle apoptosis, resulting in premature ovarian insufficiency (POI) and infertility. In this study, we found that intraperitoneal injection of retinoic acid (RA) and calcitriol partially reversed the cyclophosphamide and doxorubicin treatment-induced decrease in primordial follicles in neonatal mouse ovaries. Furthermore, RA and calcitriol co-treatment reversed cyclophosphamide treatment-induced PI3K/Akt activity and FOXO3a nuclear export in the oocytes within primordial follicles, suggesting that the oocyte transcriptional activity was decreased, which in turn reduced the binding of chemotherapeutic drugs to DNA. Consistent with these findings, RA and calcitriol co-treatment reversed cyclophosphamide treatment-induced changes in reactive oxygen species (ROS), DNA damage response proteins (γH2AX, p-CHK2, p-p53, PUMA, BAX, Cleaved Caspase-3, and cPARP), and antioxidant proteins (NRF2, HO-1, and GPX4). Moreover, RA and calcitriol co-treatment preserved fertility in cyclophosphamide-treated mice without impairing cyclophosphamide’s antitumor efficacy in MCF-7 tumor-bearing mice. Thus, RA and calcitriol protect mouse primordial follicles from cyclophosphamide treatment-induced apoptosis by inhibiting cyclophosphamide treatment-induced oocyte transcriptional activity and enhancing antioxidant capacity. Our results suggest a potential strategy for preserving ovarian reserve during chemotherapy in female cancer patients. Full article

Rheumatoid arthritis (RA) is frequently accompanied by depression, a comorbidity arising from the interplay of chronic systemic inflammation, neuroimmune activation, oxidative stress, and dysregulation of the gut–brain axis. Increasing evidence suggests that nanomedicine offers unique opportunities for the integrated management of RA-associated depression by enabling precise modulation of both peripheral inflammation and central nervous system (CNS) pathology. This review outlines the biological mechanisms linking RA and depression—including cytokine cascades, mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and microbial metabolite imbalance—and highlights recent progress in nanocarrier platforms capable of dual-site intervention. Liposomes, polymeric nanoparticles (NPs), exosomes, inorganic nanozymes, and emerging carbon-based nanomaterials have demonstrated the ability to target inflamed synovium, reprogram macrophage phenotypes, traverse the blood–brain barrier (BBB), suppress microglial overactivation, enhance neuroplasticity, and restore gut microbial homeostasis. Furthermore, stimulus-responsive nanoplatforms activated by ROS, pH, enzymes, or hypoxia provide spatiotemporally controlled drug release, thereby improving therapeutic precision. Finally, we discuss integrative designs such as dual-targeting nanomedicines, co-delivery systems, and microbiota-modulating nano-interventions, which offer promising strategies for the comprehensive treatment of RA-associated depression. This review aims to provide mechanistic insights and design principles to guide the development of next-generation nanomedicine for coordinated systemic-central modulation in RA comorbidity. Full article

This review synthesizes research on nuclear factor erythroid 2-related factor 2 (Nrf2) in intestinal health across human, livestock, and mouse models. The Nrf2 signaling pathway serves as a master regulator of cellular antioxidant defenses and a key therapeutic target for intestinal inflammatory disorders, including ulcerative colitis and Crohn’s disease. The interplay between oxidative stress, Nrf2 signaling, and NF-κB inflammatory cascades represents a critical axis in the pathogenesis and resolution of intestinal inflammation. Under normal physiological conditions, Nrf2 remains sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which facilitates its ubiquitination and proteasomal degradation. However, during oxidative stress, reactive oxygen species (ROS) and electrophilic compounds modify critical cysteine residues on Keap1, disrupting the Keap1-Nrf2 interaction and enabling Nrf2 nuclear translocation. Once in the nucleus, Nrf2 binds to antioxidant response elements (ARE) in the promoter regions of genes encoding phase II detoxifying enzymes and antioxidant proteins, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase. This comprehensive review synthesizes current evidence demonstrating that activation of Nrf2 signaling confers protection against intestinal inflammation through multiple interconnected mechanisms: suppression of NF-κB-mediated pro-inflammatory cascades, enhancement of cellular antioxidant capacity, restoration of intestinal barrier integrity, modulation of immune cell function, and favorable alteration of gut microbiota composition. We systematically examine a diverse array of therapeutic agents targeting Nrf2 signaling, including bioactive peptides, natural polyphenols, flavonoids, terpenoids, alkaloids, polysaccharides, probiotics, and synthetic compounds. The mechanistic insights and therapeutic evidence presented underscore the translational potential of Nrf2 pathway modulation as a multi-targeted strategy for managing intestinal inflammatory conditions and restoring mucosal homeostasis. Full article

Background/Objectives: Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options restricted to benznidazole and nifurtimox, both associated with significant toxicity and reduced efficacy during chronic infection. Seeking novel, safe, and sustainable chemotherapeutic candidates, two new saturated cardanol-derived phospholipid analogs—LDT10 and LDT119—were rationally designed based on the molecular scaffold of miltefosine and biosourced from cashew nut shell liquid (CNSL). This study aimed to evaluate the pharmacokinetic properties of these compounds in silico and assess their antiparasitic activity, cytotoxicity, and morphological and ultrastructural effects on all developmental forms of T. cruzi in vitro. Materials and Methods: In silico ADMET predictions (SwissADME, pkCSM) were performed to determine bioavailability, pharmacokinetic behavior, CYP inhibition, mutagenicity, and hepatotoxicity. Antiproliferative activity was evaluated in epimastigotes, trypomastigotes, and intracellular amastigotes using dose–response assays and flow cytometry. Cytotoxicity was assessed in HEPG2 and HFF-1 cells using resazurin-based viability assays. Morphological and ultrastructural alterations were investigated through scanning (SEM) and transmission (TEM) electron microscopy. Reactive oxygen species (ROS) generation was quantified with H₂DCFDA after 4 h and 24 h of exposure. Results: In silico analyses indicated favorable drug-like profiles, high intestinal absorption (>89%), absence of mutagenicity or hepatotoxicity, and non-penetration of the blood–brain barrier. LDT10 was not a P-gp substrate, and LDT119 acted as a P-gp inhibitor, suggesting reduced efflux and higher intracellular retention. Both compounds inhibited epimastigote proliferation with low IC₅₀ values (LDT10: 0.81 µM; LDT119: 1.2 µM at 48 h) and reduced trypomastigote viability (LD₅₀ LDT10: 2.1 ± 2 µM; LDT119: 1.8 ± 0.8 µM). Intracellular amastigotes were highly susceptible (IC₅₀ LDT10: 0.48 µM; LDT119: 0.3 µM at 72 h), with >90% inhibition at higher concentrations. No cytotoxicity was observed in mammalian cells up to 20 µM. SEM revealed membrane wrinkling, pore-like depressions, rounded cell bodies, and multiple flagella, indicating cell division defects. TEM showed Golgi disorganization, autophagic vacuoles, mitochondrial vesiculation, and abnormal kinetoplast replication, while host cells remained structurally preserved. Both compounds induced significant ROS production in trypomastigotes after 24 h in a dose-dependent manner. Conclusions: LDT10 and LDT119 exhibited potent and selective in vitro activity against all developmental stages of T. cruzi, with low micromolar to submicromolar IC₅₀/LD₅₀ values, minimal mammalian cytotoxicity, and extensive morphological and ultrastructural damage consistent with disruption of phospholipid biosynthesis pathways. Combined with favorable in silico pharmacokinetic predictions, these CNSL-derived phospholipid analogs represent promising candidates for future Chagas disease chemotherapy and warrant further in vivo evaluation. Full article

Rapid alkalinization factor (RALF) peptides represent a central class of signaling molecules in plants, regulating processes ranging from fertilization to immune responses. These diverse functions are largely mediated by a conserved receptor complex centered on FERONIA kinase (FER). This review summarizes recent advances positioning the RALF-FER signaling pathway as a major regulatory hub integrating intrinsic and extrinsic signals to coordinate growth, development, and stress adaptation. We examine how this pathway controls the polar growth of root hairs and pollen tubes, orchestrates reproductive barriers and fertilization, and modulates immune and abiotic stress signaling through mechanisms involving ROS, Ca²⁺, and apoplast pH. By framing this new knowledge within the broader framework of known RALF-FER mechanisms, we demonstrate how this pathway achieves high signaling specificity. Finally, we discuss critical unresolved issues and suggest future research directions in the emerging field of molecular stress physiology, highlighting the potential for manipulating this pathway for agricultural crop improvement. Full article

Background: Osteoblast senescence constitutes one of the major mechanisms in bone degeneration and is under tight regulation by metabolism and oxidative stress. While hypoxia has recently emerged as an important microenvironmental factor influencing the function of bone cells, its role in osteoblast senescence and metabolic regulation has yet to be defined. Methods: The present work entails hypoxia-modulated osteoblast senescence at one level, transcriptomic and metabolomic sequencing, and two levels, in vitro MC3T3-E1 and in vivo AAV-shAtp6v1a mouse models. In transcriptome profiling, hypoxia-responsive genes were identified, whereas non-targeted metabolomics was used to uncover metabolic alterations induced by ATP6V1A knockdown. Oxidative stress and mitochondrial function were assessed by qRT-PCR, Western blotting, SA-β-Gal staining, ROS detection, JC-1 mitochondrial potential, and immunofluorescence. Micro-CT, H&E, Masson, and immunohistochemistry studies were performed to investigate bone structure and protein expression in vivo. Results: Hypoxia markedly mitigated osteoblast senescence, decreasing p53 and p21 expressions and the number of SA-β-Gal-positive cells. It reduced intracellular ROS levels and increased HK2 and LDH expression, decreased ATP, and increased lactate, hinting at a shift toward glycolysis. Transcriptome analysis identified ATP6V1A as one of the major hypoxia-downregulated genes. Knockdown of ATP6V1A reduced ROS levels, inhibited p21 expression, improved mitochondrial function. Metabolomics disclosed remapping pathways in glycolysis, lipid, and amino acid metabolism. Conclusions: This study identifies a “Hypoxia–ATP6V1A–Oxidative Stress–Metabolic Remodeling–Anti-Senescence” axis, demonstrating that hypoxia delays osteoblast senescence by downregulating ATP6V1A, suppressing oxidative stress, and reprogramming metabolism, providing new insights and potential therapeutic targets for bone degenerative diseases. Full article

Background/Objectives: Postbiotics derived from lactic acid bacteria are emerging as promising antimicrobial agents due to their antibacterial, antibiofilm, and immunomodulatory properties. Among their metabolites, lactic acid (LA) is thought to play a major role in antimicrobial activity. This study investigated the proteomic response of Pseudomonas aeruginosa and Staphylococcus aureus to Lacticaseibacillus rhamnosus cell-free supernatant (CFS) and compared it with that elicited by LA alone. Methods: Overnight bacterial cultures were exposed to sub-MIC LA or CFS (1:10 for P. aeruginosa and 1:8 for S. aureus; ~12.5–15.6 mM LA) for 6 h at 37 °C. Intracellular proteins were harvested and subsequently quantified and purified to be analysed by HPLC–MS/MS, for quantitative label-free proteomics. Results: Proteomic analysis revealed clear separation of treated samples from controls, with largely overlapping responses to CFS and LA. Hallmark acid-stress adaptations were observed, including urease-mediated pH buffering, confirming that part of the response was driven by mild organic acid. In P. aeruginosa, treatments suppressed virulence pathways (phenazines, T3SS), while shifting metabolism toward lactate utilisation and reinforcing the outer membrane (lipid A, polyamine). In S. aureus, decreased abundance of the SaeRS-regulated immune-evasion factor Sbi, together with changes in envelope, ROS and translation-related proteins, suggested a bacteriostatic-like state. S. aureus differences between CFS and LA were more pronounced; CFS uniquely increased cell-wall defences, oxidative stress (SodA, SodM) and chaperone expression (GroS, GrpE), suggesting stress beyond acidification alone. Conclusions: These findings shed light on the molecular mechanisms underlying bacterial adaptation to CFS and highlight their potential as a novel antimicrobial approach. Full article

Diabetic wounds remain a major clinical challenge due to impaired angiogenesis, chronic inflammation, oxidative stress, and persistent infection, all of which delay tissue repair. Conventional dressings provide only passive protection and fail to modulate the wound microenvironment effectively. Chitosan (CS) is a naturally derived polysaccharide inspired by biological structures in crustaceans and fungi. It has emerged as a multifunctional biomimetic polymer with excellent biocompatibility, antimicrobial activity, and hemostatic properties. Recent advances in biomimetic materials science have enabled the development of stimuli-responsive CS hydrogels. These systems can sense physiological cues such as pH, temperature, glucose level, light, and reactive oxygen species (ROS). These smart systems emulate natural wound healing mechanisms and adapt to environmental changes. They release bioactive agents on demand and promote tissue homeostasis through controlled angiogenesis and collagen remodeling. This review discusses the biomimetic design rationale, crosslinking mechanism, and emerging strategies underlying single and dual-responsive hydrogel systems. It further emphasizes how nature-inspired structural and functional designs accelerate diabetic wound repair and outlines the current challenges and future prospects for translating these bioinspired intelligent hydrogels into clinical wound care applications. Full article