Search Results (823)

Muco-obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis, are characterized by the accumulation of highly viscoelastic mucus that compromises mucociliary clearance and fosters infection and inflammation. Mucoactive therapy, encompassing both true mucolytics and non-cleaving agents, seeks to restore airway patency by altering mucus structure, hydration, and transport properties, yet its clinical impact remains variable. This narrative review provides a critical reappraisal of the pharmacological actions and therapeutic outcomes of the main mucolytic agents: N-acetylcysteine (NAC), erdosteine, carbocisteine, bromhexine, ambroxol, and dornase alfa. Beyond their classical role in reducing mucus viscosity, these drugs exhibit pleiotropic effects, including antioxidant, anti-inflammatory, and immunomodulatory activities. Specifically, for thiol-based compounds, the action consists of breaking the disulfide bonds that stabilize the mucin network; for carbocisteine, it lies in modulating mucin glycosylation and chloride transport. Ambroxol and bromhexine act by stimulating surfactant secretion and enhancing mucociliary clearance. Finally, dornase alfa exerts an enzymatic effect on extracellular DNA, a key contributor to the tenacity of mucus in cystic fibrosis. Clinical evidence indicates that NAC and erdosteine can reduce exacerbation rates in COPD, carbocisteine shows benefit with prolonged administration, and dornase alfa remains a cornerstone in CF management. However, therapeutic efficacy is constrained by heterogeneous mucus composition, pharmacokinetic limitations, and disease-specific variability. A key interpretative message is that clinical benefit appears greatest when the dominant biophysical determinant of mucus pathology is specifically targeted, supporting a transition from broad disease-label prescribing to mechanism-informed, phenotype-aware mucolytic therapy. Emerging strategies, such as agents targeting mucin–DNA interactions and advanced inhalation delivery systems, promise improved specificity and durability. By integrating mechanistic insights with clinical data, this review underscores the need for personalized mucolytic therapy and innovative approaches to overcome current challenges in managing muco-obstructive lung diseases. Full article

Pirfenidone (PFD) shows therapeutic potential for liver fibrosis, but its molecular mechanisms are not fully elucidated. Activation of hepatic stellate cells (HSCs) is central to liver fibrosis, making their targeted elimination a prime therapeutic strategy. Since amino acid metabolism governs both HSC activation and ferroptosis, we investigated whether PFD acts by reprogramming these metabolic pathways. Analysis of primary rat HSCs revealed that their in vitro activation induced fibrotic markers, including collagen type I and α-smooth muscle actin, as well as key metabolic enzymes. Specifically, we observed upregulation of glutaminase 1, initiating glutaminolysis to produce glutamate; serine hydroxymethyltransferase 2, which generates glycine from serine; and pyrroline-5-carboxylate synthase, the rate-limiting enzyme for de novo proline synthesis. Treatment with PFD suppressed HSC activation by reducing protein levels of these enzymes, an effect consistent with PFD’s inhibition of activating transcription factor 4 nuclear accumulation. This created a dual metabolic vulnerability, limiting amino acid precursors for both collagen synthesis and the master antioxidant glutathione (GSH). Consequently, while PFD alone was not cytotoxic, GSH depletion sensitized activated HSCs to ferroptosis. Co-treatment with the ferroptosis inducer erastin triggered a synergistic increase in reactive oxygen species, labile iron, and lipid peroxidation, culminating in cell death. This synergistic lethality was abrogated by the ferroptosis inhibitor ferrostatin-1 and the antioxidant N-acetylcysteine, confirming ferroptosis as the specific cell death modality. Our study uncovers a dual anti-fibrotic mechanism for PFD: PFD inhibits collagen synthesis by limiting key amino acid precursors and depletes GSH. This compromises antioxidant defenses, creating vulnerability to ferroptosis. Our findings establish a rationale for using PFD in combination therapies designed to eliminate activated HSCs. Full article

Background: There is a growing number of studies suggesting the effectiveness of dietary supplements in preventing and treating endometriosis. It has been suggested that deficiencies in vitamins D and E as well as zinc are associated with the increased risk of endometriosis development. Beneficial effects of magnesium, curcumin, resveratrol and epigallocatechin-3-gallate were found in experimental animal studies. A reduction in pain related to endometriosis was shown in women using omega-3 and alpha-lipoic acid. Meanwhile, decreasing endometriotic lesion size after the supplementation of omega-3, N-acetylcysteine, vitamin C and epigallocatechin-3-gallate was observed in animal and human studies. Thus, the aim of this critical review was to summarize the available data describing the effects of dietary supplements used in the treatment of endometriosis. Material and Methods: The PubMed, Embase, Cochrane, and Web of Science databases were searched for related studies until 15 December 2025. Finally, 34 studies were included in the synthesis. Results: Of these 34 studies, only 23 were randomized, placebo-controlled trials. There have been no RCTs evaluating the effectiveness of vitamin E, zinc, alpha-LA, EGCG and DIM in the treatment of endometriosis. Single studies evaluating the effectiveness of vitamin C, magnesium, resveratrol, NAC and PEA with PLD have not confirmed it. Meanwhile single studies evaluating the effectiveness of selenium, propolis and quercetin have confirmed it. Of the four studies assessing the effectiveness of vitamin D, two confirmed it and two did not; of the two studies assessing probiotics, one confirmed its effectiveness and one did not; of the two studies assessing curcumin, one confirmed its effectiveness and one did not; and of the three studies assessing omega-3, two confirmed its effectiveness and one did not. All four RCTs assessing the combination of vitamins C and E confirmed their effectiveness. Conclusions: Despite encouraging observations from experimental studies, the results of RCTs are less encouraging and do not allow for the formulation of recommendations concerning the use of supplements in the treatment of endometriosis symptoms according to EBM. Full article

Inflammation can promote aggressive phenotypes in prostate cancer, including enhanced migration/EMT-like changes and inflammasome-associated cytokine release. Here, we examined whether curcumin modulates these inflammation-driven responses in androgen-independent prostate cancer cells. PC-3 and DU145 cells were treated with curcumin (10 or 25 μM) or N-acetylcysteine (NAC; 2 mM). Sub-cytotoxic dosing was defined by CCK-8 viability assays. LPS (0.5 μg/mL) was used to induce motility-, invasion-, and EMT-associated responses, assessed by wound-healing assay, Matrigel-coated Transwell invasion assay, and RT–qPCR of SNAI1, CDH1, and VIM. Intracellular ROS was quantified by CM-H₂DCFDA flow cytometry. Inflammasome-associated and EMT-related protein changes were evaluated under LPS priming (24 h) followed by ATP triggering (5 mM, 1 h), with NLRP3, cleaved caspase-1, cleaved IL-1β, vimentin, and E-cadherin assessed by immunoblotting and IL-1β secretion measured by ELISA. Curcumin at 10–25 μM did not cause overt cytotoxicity and significantly reduced LPS-induced wound closure and invasive activity in both cell lines, accompanied by attenuation of EMT-associated transcriptional changes and a decrease in ROS-positive events. Under LPS priming/ATP triggering, inflammasome-associated protein signals and IL-1β secretion were robustly induced; curcumin suppressed IL-1β release and attenuated NLRP3, cleaved caspase-1, and cleaved IL-1β signals, while reversing vimentin/E-cadherin changes. NAC produced similar inhibitory patterns, supporting a redox-linked contribution to these responses. Collectively, curcumin dampens inflammation-driven motility/invasion, EMT-associated changes, and inflammasome-associated responses in androgen-independent prostate cancer cells. Full article

Cysteine is a sulfur-containing amino acid that plays a central role in skin physiology through thiol-mediated redox regulation and glutathione (GSH) synthesis. It critically influences melanogenesis, collagen homeostasis, and wound healing. However, its clinical application is limited by poor stability and bioavailability. In this review, we provide a mechanistic and comparative analysis of cysteine and its derivatives, including N-acetylcysteine (NAC), cysteinamide (C-NH₂), GSH, and related compounds. These derivatives regulate melanogenesis by modulating dopaquinone pathways and tyrosinase activity, maintain collagen balance by preserving redox-sensitive enzymatic processes, and enhance wound healing through antioxidant and anti-inflammatory mechanisms. Importantly, chemical modifications such as acetylation, amidation, and esterification improve pharmacokinetic properties, enabling more effective intracellular delivery. Furthermore, different derivatives exhibit distinct advantages depending on biological context, highlighting the importance of compound selection. Overall, cysteine derivatives emerge as promising therapeutic candidates for dermatological applications, particularly in pigmentation disorders and impaired wound healing. Future studies should focus on in vivo validation and clinical translation. Full article

This study aimed to investigate the effects of resveratrol (RES) and carboplatin (CPT), alone and in combination, on cell viability, apoptosis, cell cycle progression, mitochondrial function, and oxidative stress in Y79 retinoblastoma (RB) cells. Particular emphasis was placed on evaluating the synergistic potential of the combination and elucidating the interconnected molecular mechanisms underlying its anticancer effects. Y79 cells were treated with RES, CPT, and their combinations. Cell viability and synergy were assessed using the MTT assay and combination index (CI) analysis. Apoptosis (annexin V/PI), cell cycle distribution (propidium iodide (PI) staining), intracellular ROS production (DCFH-DA), and mitochondrial membrane potential (JC-1) were evaluated by flow cytometry. ROS dependency was further examined using N-acetylcysteine (NAC) pretreatment. Expression levels of apoptosis- and cell cycle-related genes (BAX, BCL-2, CASP3, CASP9, CCNB1, and CDK1) were analyzed by RT-qPCR. Cytoskeletal alterations were assessed by immunocytochemistry. In addition, the antitumor effects of the combination were validated in a three-dimensional (3D) tumor spheroid model. RES and CPT reduced cell viability in a dose- and time-dependent manner and demonstrated synergistic effects (CI < 1) at selected concentrations. Combination treatment significantly increased apoptosis, induced G2/M phase arrest, enhanced ROS accumulation, and promoted mitochondrial depolarization compared with single-agent treatments. NAC pretreatment attenuated ROS generation and partially restored cell viability, supporting a contributory role of oxidative stress in combination-induced cytotoxicity. At the transcriptional level, the RES + CPT combination significantly increased the BAX/BCL-2 ratio and upregulated CASP3 and CASP9 expression, while downregulating CCNB1 and CDK1, consistent with mitochondrial apoptotic activation and G2/M arrest. Immunocytochemical analysis revealed pronounced cytoskeletal disruption and apoptotic morphology in the combination group. Importantly, in the 3D spheroid model, co-treatment markedly reduced spheroid size and viability and enhanced cell death compared with monotherapies. The combination of RES and CPT exerts a synergistic anticancer effect in Y79 RB cells through coordinated mechanisms involving ROS accumulation, mitochondrial dysfunction, caspase activation, and G2/M phase arrest. The attenuation of cytotoxicity by NAC and the validation of efficacy in a 3D tumor spheroid model strengthen the mechanistic relevance of these findings. These results support further preclinical investigation of this combination strategy in in vivo models and normal retinal cell systems. Full article

Background/Objectives: High-altitude pulmonary edema (HAPE) remains a serious condition with limited preventive options. This study evaluated the prophylactic protective effects of nebulized human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in a rat model of hypobaric hypoxia-induced lung injury and explored potential mechanistic clues, with a focus on oxidative stress and TEK/Tie2 signaling. Methods: Rats were exposed to hypobaric hypoxia (47 kPa; 9.7% O₂) for 72 h and received prophylactic nebulized hUC-MSC-EVs (300 μg/rat). Lung injury was evaluated by histopathology, wet-to-dry ratio, and bronchoalveolar lavage fluid (BALF) protein concentration. Invasive pulmonary function indices were measured using a forced oscillation system. BALF cytokines (TNF-α, IL-6, and IL-10), reactive oxygen species (ROS), and TEK/Tie2 expression in lung tissue were assessed. In addition, transcriptome sequencing (RNA-seq) was performed to characterize global transcriptional changes. N-acetylcysteine (NAC), a classical antioxidant, was included as an auxiliary mechanistic intervention to assess the association of ROS with TEK/Tie2 changes. Results: Compared with hypoxia controls, prophylactic nebulized hUC-MSC-EVs reduced histopathological injury, pulmonary edema, and barrier leakage, and improved pulmonary function indices. hUC-MSC-EV intervention also attenuated inflammatory responses in BALF, with decreased TNF-α and IL-6 and increased IL-10. Hypobaric hypoxia increased ROS accumulation and decreased TEK/Tie2 expression, whereas nebulized hUC-MSC-EVs reduced ROS and partially preserved TEK/Tie2 expression. NAC pretreatment similarly reduced ROS and was accompanied by Tie2 preservation. Conclusions: Prophylactic nebulized hUC-MSC-EVs mitigated hypobaric hypoxia-induced lung injury, accompanied by reduced oxidative stress, improved vascular barrier integrity, and preservation of TEK/Tie2 expression. These findings support nebulized hUC-MSC-EVs as a potential lung-targeted prophylactic strategy for hypobaric hypoxia-induced lung injury and suggest that ROS imbalance may be associated with Tie2 preservation. Full article

Background/Objectives: Oxidative stress plays an important role in the pathophysiology of endometriosis, contributing to inflammation, immune dysregulation, and lesion progression. This has led to growing interest in antioxidant-based strategies as potential supportive interventions. Methods: A literature search was conducted using PubMed, Scopus, and Web of Science databases, covering studies published from database inception until the end of January 2026. The review focused on clinically relevant endpoints, including pain intensity, markers of inflammation and oxidative stress, reproductive parameters, and quality of life. Results: Among the analyzed interventions, the most consistent clinical effects were observed with melatonin, with randomized controlled trials indicating a moderate reduction in pain. N-acetylcysteine shows potentially beneficial effects; however, the available clinical data remain limited and heterogeneous. For other supplements, the evidence is inconsistent or insufficient to support clear clinical conclusions, and in many cases relies on indirect or mechanistic findings rather than well-established clinical outcomes. Conclusions: Current evidence does not support the use of non-mineral antioxidant supplements as standalone therapy for endometriosis. They may be considered as adjunctive strategies, although their clinical effectiveness remains uncertain and requires confirmation in well-designed randomized clinical trials. Full article

Bovine mastitis is a multifactorial inflammatory disease primarily characterized by inflammatory cell infiltration and the destruction of mammary alveoli. It is a major cause of reduced milk yield and quality. The imbalance between antioxidant defenses and the generation of reactive oxygen species (ROS), which occurs due to the high metabolic activity of the mammary gland during the periparturient period, increases the incidence of mastitis. During early lactation, especially in high-yielding dairy cows, the massive synthesis and secretion of milk increase the energy demand of mammary tissue, leading to excessive ROS accumulation. This results in cell membrane disruption and, ultimately, antioxidant dysfunction in the mammary tissue. This study established an in vitro oxidative stress model by treating bovine mammary epithelial cells (BMECs) with 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH). The optimal concentration of 1000 μmol/L AAPH was determined using the CCK-8 assay. Model validation showed that, compared to the control group, ROS levels were significantly elevated (p < 0.001) and mitochondrial membrane potential was significantly decreased (p < 0.001) in the AAPH-treated group. Transmission electron microscopy (TEM) analysis revealed that AAPH treatment caused ultrastructural damage, including reduced microvilli, mitochondrial swelling, disappearance of cristae, and vacuolization. Mechanistic studies demonstrated that AAPH treatment significantly upregulated the mRNA and protein expression of AMPK, HMOX-1, mTOR, NOS, and SOD (p < 0.001), while significantly downregulating CYP1A1 expression (p < 0.001). Pretreatment with N-acetylcysteine (NAC) effectively alleviated the oxidative stress damage caused by AAPH. This study successfully established an in vitro AAPH-induced oxidative stress model in BMECs and revealed its molecular mechanism of cellular damage. The damage occurs through modulation of the AMPK/mTOR signaling pathway and the regulation of antioxidant-related gene expression. Full article

Exercise-derived reactive oxygen species (ROS) are required for mitochondrial and hypertrophic adaptations, creating a practical trade-off: antioxidant strategies may support short-term performance and recovery yet blunt training signals when mis-timed or over-dosed. We performed a structured narrative review informed by transparent database searches of MEDLINE, Scopus, and SPORTDiscus (2000–2025), prioritizing human intervention studies and using mechanistic evidence to interpret plausibility. Evidence was mapped by antioxidant class, dose, timing, training modality, and context. Across trials, chronic high-dose vitamins C/E taken close to key sessions are most consistently associated with attenuation of redox-sensitive signaling, whereas food-first polyphenols and selected bioactives (e.g., tart cherry/anthocyanins, pomegranate, and curcumin) more often support recovery when positioned away from adaptation-critical workouts, without clear evidence of impaired training gains. N-acetylcysteine can acutely improve tolerance to repeated high-intensity exercise, but effects during prolonged training remain uncertain and appear context-dependent. We propose Redox-Adaptive Periodization, aligning antioxidant class, dose, and timing with the primary objective (adaptation vs. immediate readiness) and environmental constraints, and we outline methodological priorities to advance precision redox management. Full article

Mucins are highly glycosylated proteins that form the structural basis of mucus and represent a key component of innate immunity at mucosal surfaces, particularly in the respiratory tract. Beyond their mechanical barrier function, mucins actively participate in pathogen trapping, regulation of mucociliary clearance, modulation of inflammatory responses, and maintenance of epithelial homeostasis. Dysregulation of mucin synthesis, composition, or transport contributes to mucus hypersecretion, impaired airway clearance, and chronic inflammation in respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. This review summarizes current insights into mucin biology, including their biosynthesis, structure, classification, and regulation, with emphasis on the gel-forming mucins MUC5AC and MUC5B. The role of mucins in mechanical protection, host–pathogen interactions, control of inflammation, and coordination of innate immune responses is reviewed. Attention is given to the interplay between mucins, immune cells, and microbial communities in maintaining airway barrier integrity. The article further examines mucoactive therapeutic strategies aimed at restoring mucus barrier function. Expectorants, mucolytics, mucoregulators, and mucokinetic agents are reviewed with respect to their mechanisms of action and clinical relevance. Established drugs, including N-acetylcysteine, carbocysteine, dornase alfa, ambroxol, and hypertonic solutions, are considered alongside emerging molecular targets such as NF-κB-dependent regulation of mucin expression, calcium-activated chloride channels, MARCKS-mediated mucin exocytosis, purinergic signaling pathways, and NO/cGMP signaling. Non-pharmacological approaches, including airway clearance techniques and respiratory rehabilitation, are covered concisely. Conclusions: Overall, this review highlights mucins as dynamic regulators of innate immunity and underscores the need for mechanism-based, personalized mucoactive therapies to improve outcomes in chronic inflammatory airway diseases. Full article

Arsenic induces apoptosis in both cancerous and non-cancerous cells. The mechanism of arsenic-induced apoptosis is complex. We previously demonstrated that the antioxidant acetyl L-carnitine prevented sodium arsenite-induced apoptosis in zebrafish embryos. To gain more insight into the mechanism of arsenic-induced apoptosis, we explored the effect of another antioxidant, N-acetylcysteine (NAC). Co-treatment of sodium arsenite with 1 or 2 mM NAC had no effect on zebrafish development. There was a significant but partial reduction in apoptosis in the embryos co-treated with sodium arsenite and 1 mM NAC, while embryos treated with 1 mM NAC alone showed the loss of normal apoptosis that was observed in the control embryos. Complete abolition of apoptosis occurred in embryos co-treated with sodium arsenite and 2 mM NAC; however, 2 mM NAC alone resulted in 100% mortality, indicating antioxidant toxicity at high doses. NAC (1 mM) did not prevent sodium arsenite-induced increase in motor neurons, suggesting that arsenic-induced apoptosis and supernumerary motor neuron development are mediated via distinct pathways. To determine whether NAC prevented arsenic-induced apoptosis via reactive oxygen species (ROS) signaling, we assessed ROS levels and oxidative modification of proteins (carbonylation) using an OxyBlot assay. Neither sodium arsenite nor NAC altered protein oxidation, ROS levels, or p53, a pro-apoptotic protein, transcript levels. Additionally, dicoumarol, an inducer of p53 protein degradation, did not inhibit sodium arsenite-induced apoptosis. These results indicate that protein oxidation and p53 signaling are not involved in arsenic-induced apoptosis and that NAC prevents arsenic toxicity in zebrafish embryos through a hitherto unknown mechanism. Full article

We report the case of a 58-year-old man who experienced moderate renal and liver impairment after accidental poisoning with Colchicum autumnale, which he confused with wild garlic (Allium ursinum). Colchicum autumnale contains colchicine, a toxic compound that disrupts cell division. The patient received intensive care therapy, intravenous lipid emulsion, vitamin K supplementation, and N-acetylcysteine replacement. After seven days of hospitalisation, he was discharged in good health. This case highlights the importance of patients presenting at the emergency department with uncertain anamnesis, gastrointestinal symptoms or recent consumption of perennial plants before symptom onset, which should raise the suspicion of intoxication. Early diagnosis, organ-specific supportive therapy, and timely initiation of disease-specific therapy are crucial for improving patients’ outcomes. Full article

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition resulting from a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, leading to the accumulation of ultra-large von Willebrand factor (vWF) multimers and widespread microvascular thrombosis. While therapeutic plasma exchange and immunosuppression have significantly improved response, refractory and relapsed disease are significant challenges. N-acetylcysteine (NAC) has emerged as a biologically plausible adjunctive therapy due to its potential to reduce disulfide bonds in vWF multimers. However, its clinical role is unclear. This systematic review aimed to evaluate the clinical evidence regarding the efficacy and safety of N-acetylcysteine in patients with immune-mediated TTP. Methods: We performed a systematic review in accordance with the PRISMA guidelines. PubMed/MEDLINE, Google Scholar, and ClinicalTrials.gov were searched until January 2026. Studies involving patients with immune-mediated TTP treated with NAC were included. Case reports, case series, and observational studies involving patients with immune-mediated TTP treated with NAC were included. Risk of bias was evaluated using adapted quality assessment tools. Results: Sixteen studies encompassing 69 patients met the inclusion criteria. Most reports were case reports or small case series; two were larger observational cohorts. NAC was predominantly used as adjunctive therapy in relapsed or refractory TTP. Dose regimens varied. Platelet recovery following NAC was reported within 1–15 days in responding cases. Predominantly positive haematological responses were observed in small series. Significant heterogeneity in patient populations, timing of initiation, concomitant therapies, and outcome reporting limited causal inference. Conclusions: The current evidence suggests that NAC has a biologically rational and potentially adjunctive value in TTP, particularly in refractory disease or resource-constrained settings. However, current data are largely heterogeneous and derived from low-level evidence. Well-designed prospective studies and randomized controlled trials are needed to determine whether NAC provides significant clinical benefit beyond standard therapy. Full article

This study evaluated the protective effects of lipid emulsion (LE) against bupivacaine-induced cytotoxicity in human rotator cuff fibroblasts (hRCFs). hRCFs were divided into control, bupivacaine alone (Bupivacaine), LE alone (LE), LE-pretreated bupivacaine (LE + Bupivacaine), N-acetylcysteine alone (NAC), and NAC-pretreated bupivacaine (NAC + Bupivacaine). Cell viability was assessed by MTT and Live/Dead assays; ROS production by DCF-DA; apoptosis by Annexin V/PI staining and TUNEL assay; cleaved caspase-3 and PARP expression by Western blot; cell cycle by FACS; cell proliferation by Ki-67 staining; and wound healing. Cell viability decreased in a bupivacaine concentration-dependent manner (p < 0.001). Pretreatment with LE or NAC improved cell viability compared with bupivacaine alone (p < 0.001). ROS levels were elevated by bupivacaine, whereas LE and NAC pretreatments significantly reduced ROS (p < 0.001). Bupivacaine-induced apoptosis was significantly attenuated by LE and NAC, as evidenced by reductions in apoptosis rate, expression levels of cleaved caspase-3 and PARP-1, TUNEL-positive nuclei, and the subG1 population (p < 0.05). Cell proliferation and wound healing were suppressed by bupivacaine but restored by LE and NAC pretreatment. This study demonstrates bupivacaine-induced cytotoxicity in hRCFs and suggests that LE and NAC mitigate these effects by reducing oxidative stress and promoting cell survival and wound healing. Full article