Search Results (21,022)

Musculoskeletal pain is a major cause of disability and long-term analgesic use, increasing interest in safe non-pharmacological interventions. This focused narrative review examines light-emitting diode (LED)-based photobiomodulation (PBM) for musculoskeletal pain, integrating molecular, mechanistic, clinical, and translational evidence. Red and near-infrared LED-PBM may act through mitochondrial and non-mitochondrial photoacceptors, modulation of ATP production, reactive oxygen species, nitric oxide, calcium signaling, inflammatory pathways, oxidative stress responses, and extracellular matrix repair. Clinical evidence suggests a potential benefit in selected conditions, particularly temporomandibular disorders, fibromyalgia, cervical and myofascial pain, tendon and plantar fascia disorders, knee osteoarthritis, and mild-to-moderate peripheral nerve compression, while findings for non-specific low back pain remain inconsistent. The reviewed literature indicates that therapeutic response depends less on emitter identity alone than on wavelength, irradiance, radiant exposure, treatment geometry, target depth, timing, disease phenotype, and protocol quality. LED-based PBM appears generally well tolerated and clinically promising as an adjunct to rehabilitation, but current evidence is limited by heterogeneous devices, incomplete dosimetry, variable comparators, and short follow-up. Future studies should prioritize standardized reporting, depth-aware dosing, phenotype-based recruitment, biomarker-linked outcomes, and direct laser–LED comparisons under dosimetrically matched conditions. Full article

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. Curcumin (CUR) is a polyphenol with several biological properties, including antimicrobial effects. However, its low bioavailability remains a challenge, and nanoencapsulation may represent a useful strategy to overcome this limitation. This study aimed to evaluate, in vitro, the antipromastigote activity of free CUR and the antiamastigote effect of CUR nanoparticles and their association with antimoniate, as well as to elucidate possible mechanisms of action. Free CUR directly inhibited promastigote proliferation, with an IC₅₀ of 25 µM at 24 h. CUR induced mitochondrial hyperpolarization, increased the production of reactive oxygen species (ROS) and nitric oxide (NO), and enhanced lipid peroxidation and the accumulation of lipid droplets in promastigotes. These alterations were associated with autophagic and apoptotic processes, morphological and ultrastructural changes, DNA fragmentation, and cell cycle arrest. Free CUR also reduced the viability of BALB/c peritoneal macrophages, and this effect was attenuated after nanoencapsulation. Free CUR, CUR nanoparticles, and their association with antimoniate (AM) reduced both the percentage of infected macrophages and the number of intracellular amastigotes at all tested concentrations, with increased NO production observed at the highest concentrations of free CUR. Altogether, our findings suggest that CUR exerts leishmanicidal activity against promastigotes by disrupting oxidative metabolism and triggering autophagic and apoptotic pathways, while amastigote elimination appears to occur through mechanisms independent of oxidative stress. Full article

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths, while its resistance to treatment continues to represent a major therapeutic challenge. In the present study, a series of phenothiazine derivatives, including hybrids containing a 1,2,3-triazole linker and the zidovudine (AZT) fragment, were synthesized and evaluated for their anticancer activity against colorectal cancer cell lines HCT116 and HT-29 as well as non-cancerous BEAS-2B cells. Cytotoxic activity was determined using the Alamar Blue assay, while the mechanisms of action were investigated by flow cytometric analysis of apoptosis, cell cycle progression, and reactive oxygen species (ROS) generation. Additionally, changes in the expression of genes associated with apoptosis, oxidative stress, and DNA damage response were analyzed by RT-qPCR. The obtained results demonstrated that AZT-containing derivatives exhibited stronger anticancer activity than non-conjugated phenothiazine analogs. Compounds A9–A12 induced pronounced apoptosis and significant disturbances in cell cycle progression, particularly in HCT116 cells. Among the analyzed derivatives, compound A9 displayed the most favorable overall biological profile, combining strong proapoptotic and cytotoxic activity with relatively high selectivity toward cancer cells and moderate effects on non-cancerous cells. The results indicate that molecular hybridization of phenothiazine derivatives with the AZT scaffold represents a promising strategy for the development of novel anticancer agents targeting colorectal cancer. Full article

Identifying cold-resistance genes is essential for improving the ability of apples (Malus × domestica) to tolerate low temperatures, as cold stress significantly limits their growth and productivity. The MdWRKY31 gene was cloned from apple, and its sequence characteristics, expression pattern, and biological function were systematically investigated. Bioinformatic analysis indicated that MdWRKY31 belongs to the group II WRKY transcription factors and is localized in the nucleus. Expression analysis revealed that MdWRKY31 transcript levels were markedly upregulated under low-temperature stress. To further explore its function, MdWRKY31 was heterologously overexpressed in tomato (Solanum lycopersicum). Following low-temperature treatment, transgenic tomato plants exhibited significantly reduced accumulation of reactive oxygen species, markedly enhanced activities of antioxidant enzymes (SOD, POD, and CAT), increased contents of proline and soluble protein, and a notable decrease in malondialdehyde levels. Additionally, transcript levels of SlCBF1, SlCBF2, SlCBF3, SlICE1, along with the ABA signaling-related genes SlNCED1 and SlABI5, were markedly elevated. Further molecular docking showed that the MdWRKY31 protein has strong binding affinity to the W-box elements in the promoters of SlCBF1 suggesting that it may regulate the expression of these genes through direct protein–DNA interactions. These findings indicate that MdWRKY31 improves plant cold tolerance by CBF-dependent pathways to modulate antioxidant defenses and osmotic balance. These findings identify candidate genetic resources for breeding cold-resistant apple cultivation. Full article

The skin serves as the body’s first line of defense against environmental threats, acting as a barrier between external aggressors and internal systems. Current evidence regarding the roles of sulfur dioxide (SO₂) in biology and medicine is limited. Environmental pollutants, including SO₂, can increase the production of reactive oxygen species in the skin, leading to oxidative damage that may worsen various dermatological conditions. Endogenous SO₂, proposed as the fourth member of the gasotransmitter family, functions as a biological signaling molecule. It is generated in various human skin cells, including vascular smooth muscle cells, endothelial cells, mast cells, keratinocytes, macrophages, adipocytes, fibroblasts, dermal immune cell population, etc, where it performs multiple functions at physiologically relevant concentrations. Endogenous SO₂ plays a crucial role in regulating cell signaling and maintaining skin homeostasis through its antioxidant, anti-inflammatory, and cytoprotective effects. Abnormal generation and metabolism of SO₂ are linked to several critical processes in the skin, including vascular biology, immune response, cell proliferation, pigmentation, malignancy, protective barriers, senescence, and resistance to stress. This paper provides a narrative review of the significant roles of SO₂ in skin health and disease. A comprehensive understanding of the complex molecular effects and mechanisms mediated by SO₂ in human skin, along with the development of gas therapy, will be essential for translating fundamental research into clinical applications. Full article

The roots of Baphicacanthus cusia (Nees) Bremek, commonly known as Nan-Ban-Lan-Gen, have been used for a long time in traditional Chinese medicine to manage inflammatory and infectious diseases. However, the structural features and bioactive potential of its polysaccharides have not been extensively studied. In the present study, a novel homogeneous polysaccharide (BcP-b2) was isolated from the roots of B. cusia, and its bioactivity was evaluated using an activity-guided purification strategy. Multi-dimensional structural analysis identified BcP-b2 as a highly branched galactoarabinan with a molecular weight of ~38.1 kDa, featuring a well-defined backbone and a variety of side chains. In vitro and in vivo assays demonstrated that BcP-b2 attenuated the accumulation of reactive oxygen species (ROS) and enhanced the activities of endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Additionally, BcP-b2 activated macrophages under basal conditions and alleviated lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory mediator release. Transcriptomic and Western blot analyses revealed that these dual effects were achieved through the simultaneous suppression of the PI3K/Akt inflammatory axis and activation of the Nrf2/HO-1 antioxidant pathway, concomitant with enhanced nuclear translocation of Nrf2. These findings provide a molecular basis for the ethno-pharmacological use of Nan-Ban-Lan-Gen and identify BcP-b2 as a promising candidate for further investigation as a potential therapeutic agent. Full article

Fragaria vesca is a highly adaptable diploid model species. Although bHLH transcription factors (TFs) have been widely reported to regulate plant development and stress responses, the bHLH gene family has not been systematically characterized in Fragaria vesca. In this study, we conducted a genome-wide analysis of the bHLH TF family based on the Fragaria vesca v6 genome assembly. A total of 117 FvbHLH genes were identified, and promoter analysis revealed the presence of numerous cis-regulatory elements associated with plant development, hormone signaling, and stress responses. Transcriptome analysis showed that several FvbHLH genes were differentially expressed in leaves and stems under low-temperature stress. The low-temperature expression patterns of selected genes were further validated by reverse transcription quantitative PCR (RT-qPCR). Moreover, heterologous overexpression of FvbHLH86 in Arabidopsis thaliana enhanced cold tolerance by improving reactive oxygen species (ROS) scavenging capacity. These findings provide a valuable foundation for future functional studies of FvbHLH genes and contribute to a better understanding of the molecular mechanisms underlying cold stress responses in Fragaria vesca. Full article

Background: Effective root canal disinfection is essential for successful nonsurgical root canal treatment (RCT). Although sodium hypochlorite (NaOCl) remains the standard irrigant, it carries a risk of chemical tissue injury if extruded beyond the root canal system and may have limited penetration into anatomically complex regions. Underwater discharge plasma (UDP) generates reactive oxygen and nitrogen species (RONS) through high-frequency, high-voltage electrical discharge in aqueous media, and preclinical and in vitro studies have reported broad-spectrum antimicrobial activity. This study evaluated the clinical and radiographic outcomes of nonsurgical RCT performed using physiological saline-based UDP irrigation without NaOCl in a heterogeneous real-world clinical cohort. Methods: This single-center retrospective cohort study included 186 teeth from 134 patients treated with the PLAZEN RCT^® UDP device and physiological saline irrigation, without NaOCl. The median follow-up period was 16 months. Radiographic outcomes were assessed using the Periapical Index (PAI) system, and treatment success was evaluated according to prespecified Strict and Loose criteria incorporating both radiographic and clinical findings. Stratified analysis was performed according to preoperative PAI score: Group A (PAI 1–2) and Group B (PAI 3–5). UDP-related adverse events, defined as thermal tissue injury caused by discharge heat, were ascertained through retrospective review of clinical records, operative notes, and serial periapical radiographs. Results: Among the 186 treated teeth, radiographic outcomes were classified as Healed (85.5%), Healing (3.8%), and Unhealed (10.8%). Overall Strict and Loose success rates were 79.6% and 82.3%, respectively. Initial treatment showed numerically higher success rates than retreatment. In the stratified analysis, Group A showed an 84.1% success rate with 100% tooth survival, whereas Group B demonstrated Strict and Loose success rates of 68.5% and 83.3%, respectively. Exploratory multivariable analysis showed that periodontal pocket depth > 3 mm was the most consistent factor associated with lower odds of treatment success, whereas associations involving canal obliteration and higher preoperative PAI score were less stable across sensitivity analyses and should be interpreted with caution. No UDP-related adverse events were recorded during follow-up. Attrition sensitivity analyses were performed, and the outcome estimates should be interpreted with caution, given the retrospective design and substantial loss to follow-up. Conclusions: In this preliminary observational cohort, physiological saline-based UDP irrigation without NaOCl was associated with favorable observed periapical healing outcomes and no recorded UDP-related adverse events over a median follow-up of 16 months. However, loss to follow-up was substantial; when all 116 teeth lost to follow-up were classified as treatment failures, the worst-case Strict success rate decreased to 49.0%. Therefore, these findings should be interpreted as preliminary descriptive evidence of clinical feasibility rather than as evidence of comparative efficacy or definitive clinical safety. Adequately powered randomized controlled trials with concurrent NaOCl control arms and long-term follow-up are warranted to evaluate the comparative effectiveness, safety, and reproducibility of physiological saline-based UDP irrigation protocols. Full article

Cigarette smoke is a major inducer of oxidative stress, promoting reactive oxygen species (ROS) accumulation and contributing to the pathogenesis of chronic obstructive pulmonary disease (COPD) and lung cancer. Heated tobacco products (HTP) and e-cigarettes are promoted as reduced-risk alternatives; however, their impact on cellular redox regulation remains unclear. Here, we investigated the effects of conventional cigarette smoke extract (CSE), HTP, and e-cigarette extracts on hydrogen peroxide (H₂O₂) permeability mediated by aquaporins (peroxiporins) and on the activity of key antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in ATII-like cells. Eight aquaporins were detected at the mRNA level, and seven were confirmed at the protein level. CSE markedly inhibited H₂O₂ permeability across plasma, mitochondrial, and nuclear membranes. HTP extract impaired H₂O₂ transport across the plasma membrane and nuclear envelope, while mitochondrial permeability was preserved. Both CSE and HTP extract reduced superoxide dismutase and glutathione peroxidase activities. In contrast, e-cigarette extract exerted minimal effects on membrane H₂O₂ permeability and selectively decreased superoxide dismutase activity. Overall, our findings identify a graded pattern of oxidative toxicity (CSE > HTP > e-cigarette) and highlight peroxiporins as critical regulators of intracellular redox homeostasis. Although less harmful than cigarettes, alternative nicotine delivery systems are not biologically inert. Full article

Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated “redox-dead” DRP1-C631A knock-in mutant (Drp1^C/A) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1-like macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1^C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD. Full article

Background: Gentamicin-induced nephrotoxicity limits clinical pharmacotherapy and involves multiple converging stress-response pathways. Ellagic acid (EA) has renoprotective potential, yet its role in coordinating endoplasmic reticulum (ER) stress-mediated apoptosis, autophagy, and inflammation remains unclear. We hypothesized that EA co-treatment would protect the kidney by modulating ER stress-dependent pathways and associated inflammatory and adaptive signaling. Methods: For an integrated mechanistic analysis in a rat model of gentamicin nephrotoxicity, 40 male Sprague-Dawley rats were assigned to control, gentamicin (100 mg/kg), EA (100 mg/kg), and gentamicin + EA groups for 14 days. Renal function, oxidative stress, inflammatory mediators, ER stress markers, apoptosis, autophagy, tubular injury markers, and histopathological changes were assessed. Results: Gentamicin induced renal dysfunction, tubular injury, and ER stress across all unfolded protein response (UPR) branches (IRE1α, PERK, ATF6), C/EBP homologous protein (CHOP)-associated apoptosis, dysregulated autophagy, and upregulated kidney injury molecule-1 (KIM-1). A selective inflammatory signature was observed, with increased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), whereas tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) remained unchanged. Co-administration of ellagic acid with gentamicin significantly improved renal function markers compared to the gentamicin group. In contrast, ellagic acid alone did not show significant differences compared to the control group. Notably, gentamicin induced compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression, while ellagic acid co-treatment attenuated this compensatory upregulation, likely secondary to reduced oxidative stress burden. Conclusions: This study provides integrated evidence that ER stress is closely associated with gentamicin nephrotoxicity. The key novel findings include selective suppression of IL-6, modulation of the apoptosis-autophagy balance, and attenuation of Nrf2/HO-1 signaling without direct reactive oxygen species (ROS) scavenging, demonstrating a multi-target framework for EA’s renoprotective effects. These findings suggest that ellagic acid mitigates renal injury in a context-dependent manner rather than confirming a direct causal mechanism. Full article

Polyethylene microplastics (PE-MPs) are ubiquitous constituents of waste activated sludge (WAS), acting as a major land-based source threatening coastal environmental integrity. However, how particle size and dose govern the methanogenic outcome during WAS digestion remains poorly defined. This study evaluated two particle sizes (50 vs. 300 µm) and doses (100 vs. 200 particles/gTS) to elucidate the differential effects of PE-MPs on methane yield and the underlying biological mechanisms. The results show that, while low-dose treatments either slightly inhibited methane yield (RS1) or had no significant effect (RL1), high-dose treatments (RS2 and RL2) achieved a net positive effect, with significant increases of 10.2% (p < 0.05) and 9.0% (p < 0.05) relative to the control, respectively. Nevertheless, RS2 and RL2 achieved methanogenic enhancement via distinctly different biological pathways. RS2 harnessed the stress of reactive oxygen species (ROS) (110.5% of the control) to drive community restructuring and biomass accrual (positive correlation between ROS intensity and total VS, Pearson’s r = 0.99). Key syntrophic and electrogenic taxa (e.g., Syntrophales, Bacteroidetes vadinHA17) exhibited a fully interconnected, decentralized network, thereby achieving tight coupling between hydrolysis and methanogenesis. RL2 leveraged the physical carrier effect to promote granulation and biomass growth, enriching Syntrophobacter to enhance propionate degradation. This culminated in a highly modular, sparse network characterized by localized competitive interactions. Together, dosage governs the net methanogenic effect of PE MPs, whereas particle size dictates the mechanistic routes of action. This work offers a mechanistic framework to optimize energy recovery from PE-MP-contaminated sludge while mitigating secondary environmental risks, providing a science-based strategy for the sustainable management of plastic-laden sludge that reconciles renewable energy recovery with pollution control. Full article

Oxidative stress is a major contributor to the development of age-related macular degeneration (AMD), and excessive oxidative stress can induce retinal pigment epithelium (RPE) dysfunction, apoptosis, and retinal degeneration. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) is a major enzymatic source of reactive oxygen species (ROS); however, its mechanistic role in sodium iodate (NaIO₃)-induced oxidative injury remains unclear. Tetrahydrocurcumin (THC), the major metabolite of curcumin, exhibits potent antioxidant and cytoprotective activities, but its protective effects against AMD-associated retinal degeneration have not been fully elucidated. In the present study, we investigated whether THC protects against NaIO₃-induced ROS-mediated apoptosis in RPE cells through regulation of NOX2 signaling. In vitro, THC significantly attenuated NaIO₃-induced cytotoxicity and prevented apoptosis by suppressing hydrogen peroxide (H₂O₂) production and intracellular ROS accumulation in ARPE-19 cells. THC also preserved mitochondrial membrane potential by inhibiting the Src/p47^phox/NOX2 signaling pathway and subsequently attenuated mitochondria-mediated apoptotic signaling. Furthermore, THC markedly reduced the expression of apoptotic proteins, including Bax, cleaved caspase-3, and cleaved PARP, concomitantly with suppression of Ras/Raf/MEK/ERK signaling. Mechanistically, treatment with the selective NOX2 inhibitor GSK2795039 significantly attenuated NaIO₃-induced ROS accumulation and mitochondrial depolarization, while co-treatment with THC further enhanced these protective effects. In vivo, THC ameliorated NaIO₃-induced retinal structural abnormalities by preserving the outer nuclear layer (ONL), reducing caspase-3 expression, and improving pupillary light responses in mice. Collectively, these findings demonstrate that THC protects against NaIO₃-induced retinal degeneration through suppressing NOX2-dependent oxidative stress and downstream Ras/Raf/MEK/ERK-mediated apoptotic signaling, highlighting its potential as a therapeutic candidate for AMD and other oxidative stress-related retinal disorders. Full article

Andean berry (Vaccinium meridionale Swartz) is an underutilized fruit that could serve as a source of bioactive compounds with biological properties associated with apoptosis and cytotoxicity in colorectal cancer cells. This study aimed to evaluate the cytotoxic and proapoptotic effects of Andean berry juice (ABJ) in human SW480 and SW620 colon cancer cell lines, which represent early-stage and metastatic colorectal cancer, respectively. The juice was prepared from freeze-dried fruits, and several concentrations were assayed in cells. Bioactive compounds in ABJ showed the strongest reductions in metabolic activity and proliferation observed in SW620 cells. ABJ treatments promoted early apoptosis while inducing cell cycle arrest in the S phase (SW480) and in the G2/M (SW620). Mild mitochondrial depolarization was observed, while increased reactive oxygen species (ROS) accumulation was detected in both cell lines. More proteins involved in the apoptotic process were modulated in SW620 cells, whereas SW480 displayed greater fold changes in regulatory and stress-response proteins. Proteomics and bioinformatics analyses suggested that extrinsic apoptosis predominated in SW480 cells, whereas intrinsic apoptosis was observed in SW620 cells. These results highlighted the cytotoxic and pro-apoptotic potential of the combined activity of polyphenolic compounds from ABJ, demonstrating distinct mechanisms in vitro. Full article

An undescribed seco-kaurane diterpenoid, benincaside A (BA), was isolated from the seeds of Benincasa hispida. The seeds of B. hispida have been traditionally used in folk medicine and previous studies have reported anti-tumor potential in B. hispida seed extracts. Accordingly, we investigated the cytotoxicity and underlying mechanisms of BA in colorectal cancer cells. BA inhibited growth in HT29, Colo205, HCT116, and CT26 colorectal cancer cells, as determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while showing no toxicity toward normal human umbilical vein endothelial cells (HUVEC) and human fibroblast WS-1 cells. In HCT116 cells, BA-induced deoxyribonucleic acid (DNA) damage and apoptosis, as evidenced by morphological changes, 4,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining, and assays of caspase-8 and caspase-3 activities. BA triggered apoptotic cell death via the extrinsic pathway, as indicated by elevated caspase-8 and caspase-3 activities. Intracellular reactive oxygen species (ROS) generation was observed in BA-treated HCT116 cells. The growth-inhibitory effects were significantly attenuated by pretreatment with N-acetylcysteine (NAC, an antioxidant), caffeine (an ATM kinase inhibitor), z-VAD-fmk (pan-caspase inhibitor), or z-IETD-fmk (caspase-8-specific inhibitor). Colorimetric assays confirmed increased caspase-8 and caspase-3 activities in BA-treated cells. This study is the first to report ROS-dependent signaling as a key mechanism underlying BA-induced cell death in HCT116 human colorectal cancer cells. Full article