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PloS One 2024Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and oxidative stress plays a crucial role in its development. Juglone, a naturally...
Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and oxidative stress plays a crucial role in its development. Juglone, a naturally occurring naphthoquinone in J. mandshurica, exhibits significant cytotoxic activity against various cancer cell lines. However, whether the anticancer activity of juglone is associated with oxidative stress remains unexplored. In this study, mouse Lewis lung cancer (LLC) and human non-small cell lung cancer A549 cells were used to explore the anticancer mechanisms of juglone. Juglone inhibited LLC and A549 cells viability, with IC50 values of 10.78 μM and 9.47 μM, respectively, for 24 h, and substantially suppressed the migration and invasion of these two lung cancer cells. Additionally, juglone arrested the cell cycle, induced apoptosis, increased the cleavage of caspase 3 and the protein expression of Bax and Cyt c, and decreased the protein expression of Bcl-2 and caspase-3. Furthermore, juglone treatment considerably increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, but suppressed glutathione peroxidase 4 (GPX4) and superoxide dismutase (SOD) activities. It also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which was attenuated by 1,3-diCQA (an activator of PI3K/Akt). Moreover, N-acetylcysteine (a ROS scavenger) partially reversed the positive effects of juglone in terms of migration, invasion, ROS production, apoptosis, and PI3K/Akt pathway-associated protein expression. Finally, in tumor-bearing nude mouse models, juglone inhibited tumor growth without any apparent toxicity and significantly induced apoptosis in NSCLC cells. Collectively, our findings suggest that juglone triggers apoptosis via the ROS-mediated PI3K/Akt pathway. Therefore, juglone may serve as a potential therapeutic agent for the treatment of NSCLC.
Topics: Naphthoquinones; Carcinoma, Non-Small-Cell Lung; Reactive Oxygen Species; Humans; Animals; Apoptosis; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Lung Neoplasms; Mice; Signal Transduction; A549 Cells; Cell Movement; Carcinoma, Lewis Lung; Cell Line, Tumor
PubMed: 38814975
DOI: 10.1371/journal.pone.0299921 -
Frontiers in Public Health 2024To assess leukemia risk in occupational populations exposed to low levels of benzene.
OBJECTIVES
To assess leukemia risk in occupational populations exposed to low levels of benzene.
METHODS
Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model.
RESULTS
The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10, respectively; < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary -MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10.
CONCLUSION
This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m·year.
Topics: Benzene; Humans; Occupational Exposure; Risk Assessment; Leukemia; China; Male; Adult; Sorbic Acid; Middle Aged; Acetylcysteine; Female; Cohort Studies; Incidence
PubMed: 38807987
DOI: 10.3389/fpubh.2024.1355739 -
Heliyon May 2024Antioxidant therapy is gaining traction in managing sepsis and septic shock, owing to its perceived positive impact on patient outcomes. This study sought to compare the...
BACKGROUND
Antioxidant therapy is gaining traction in managing sepsis and septic shock, owing to its perceived positive impact on patient outcomes. This study sought to compare the efficacy of five antioxidant therapies (melatonin, vitamin C, vitamin E, selenium, and -acetylcysteine, both individually and in combination with other compounds such as vitamin B1, hydrocortisone, propolis, and glutamine) in treating sepsis or septic shock in the intensive care unit (ICU).
METHODS
The study involved randomized and multi-arm trials with sepsis or septic shock patients using melatonin, vitamin C, vitamin E, selenium, or -acetylcysteine. Studies were sourced from PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and WHO - Clinical Trials Registry Platform for the frequentist network meta-analysis on 28-day mortality and Sequential Organ Failure Assessment (SOFA) scores. The risk of bias was assessed using the Physiotherapy Evidence Database scale. Therapies were compared directly and indirectly using R software.
RESULTS
The study of 56 trials involving 9,366 patients was included. Bias assessment revealed that 89.3 % of trials achieved excellent or good quality. Based on treatment ranking and pairwise comparisons, melatonin with propolis (SUCRA = 93.29 %) is effective in improving SOFA scores, statistically significant, with no publication bias ( 0.73). High-dose vitamin C (SUCRA = 83.97 %), vitamin C with vitamin B1 (SUCRA = 78.72 %), and melatonin (SUCRA = 67.03 %) are potential therapies for organ dysfunction. Melatonin (SUCRA = 88.22 %) and high-dose vitamin C (SUCRA = 80.75 %) were the most effective in reducing 28-day mortality rates. However, analysis indicated that the results for 28-day mortality rates were not statistically significant. Also, these results contained publication bias ( 0.02).
CONCLUSION
The study offers fresh perspectives on antioxidant therapy treatments for sepsis or septic shock in ICU, emphasizing the combination of melatonin and propolis notably reduces SOFA scores for those patients.
PubMed: 38807867
DOI: 10.1016/j.heliyon.2024.e31447 -
Frontiers in Oncology 2024Cancer is a global health problem accounting for nearly one in six deaths worldwide. Conventional treatments together with new therapies have increased survival to this...
BACKGROUND
Cancer is a global health problem accounting for nearly one in six deaths worldwide. Conventional treatments together with new therapies have increased survival to this devastating disease. However, the persistent challenges of treatment resistance and the limited therapeutic arsenal available for specific cancer types still make research in new therapeutic strategies an urgent need.
METHODS
Chloroquine was tested in combination with different drugs (Panobinostat, KU-57788 and NU-7026) in 8 human-derived cancer cells lines (colorectal: HCT116 and HT29; breast: MDA-MB-231 and HCC1937; glioblastoma: A-172 and LN-18; head and neck: CAL-33 and 32816). Drug´s effect on proliferation was tested by MTT assays and cell death was assessed by Anexin V-PI apoptosis assays. The presence of DNA double-strand breaks was analyzed by phospho-H2AX fluorescent staining. To measure homologous recombination efficiency the HR-GFP reporter was used, which allows flow cytometry-based detection of HR stimulated by I-SceI endonuclease-induced DSBs.
RESULTS
The combination of chloroquine with any of the drugs employed displayed potent synergistic effects on apoptosis induction, with particularly pronounced efficacy observed in glioblastoma and head and neck cancer cell lines. We found that chloroquine produced DNA double strand breaks that depended on reactive oxygen species formation, whereas Panobinostat inhibited DNA double-strand breaks repair by homologous recombination. Cell death caused by chloroquine/Panobinostat combination were significantly reduced by N-Acetylcysteine, a reactive oxygen species scavenger, underscoring the pivotal role of DSB generation in CQ/LBH-induced lethality. Based on these data, we also explored the combination of CQ with KU-57788 and NU-7026, two inhibitors of the other main DSB repair pathway, nonhomologous end joining (NHEJ), and again synergistic effects on apoptosis induction were observed.
CONCLUSION
Our data provide a rationale for the clinical investigation of CQ in combination with DSB inhibitors for the treatment of different solid tumors.
PubMed: 38803536
DOI: 10.3389/fonc.2024.1390518 -
Iranian Journal of Basic Medical... 2024Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the...
Evaluation of the influence of N-acetylcysteine and broccoli extract on systemic paraquat poisoning: Implications for biochemical, physiological, and histopathological parameters in rats.
OBJECTIVES
Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) and broccoli extract, individually and in combination, in alleviating PQ poisoning in rats, leveraging the exceptional anti-oxidant, anti-inflammatory, and anti-apoptotic properties of broccoli.
MATERIALS AND METHODS
Seventy Wistar rats were categorized into seven groups: C (control, vehicle), PQ (paraquat at 40 mg/kg), BC (broccoli extract at 300 mg/kg), NC (N-acetylcysteine at the same dose of 300 mg/kg), and combined groups PQ+BC, PQ+NC, and NC+PQ+BC, all administered equivalent doses. After 42 days, blood samples were collected to evaluate liver and kidney parameters, proinflammatory biomarkers, caspase-3, and caspase-9. Lung tissues were excised, with one part preserved for hydroxyproline and oxidative stress parameter measurement and another sectioned and stained for histopathological analysis.
RESULTS
The PQ group exhibited the highest lung-to-body weight (LW/BW) ratio, while the PQ+BC+NC group demonstrated the lowest ratio. Results indicated an elevated lung hydroxyproline concentration and a significant reduction in anti-oxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase, and total anti-oxidant capacity) (<0.001). The PQ+BC group showed modified malondialdehyde levels, reaching a peak in the PQ group. Additionally, a significant decrease in tumor necrosis factor, interleukin-1, caspase-3, and caspase-9 was observed in the PQ+BC+NC group (<0.01). Pulmonary edema, hyperemia, and severe hemorrhage observed in the PQ group were notably reduced in the PQ+BC+NC group.
CONCLUSION
The combination of active compounds from broccoli and NAC demonstrated significant systemic and pulmonary effects in mitigating PQ-induced toxicity.
PubMed: 38800031
DOI: 10.22038/IJBMS.2024.75258.16311 -
Iranian Journal of Basic Medical... 2024To investigate the protective effect of N-acetylcysteine (NAC) on septic acute kidney injury (SAKI) via regulating Sirtuin3 (SIRT3)-mediated mitochondrial dysfunction...
OBJECTIVES
To investigate the protective effect of N-acetylcysteine (NAC) on septic acute kidney injury (SAKI) via regulating Sirtuin3 (SIRT3)-mediated mitochondrial dysfunction and apoptosis.
MATERIALS AND METHODS
By constructing SIRT3 knockout mice and culturing kidney tubular epithelial cells (KTECs), we assessed the changes of renal function and detected the protein expression of adenine nucleotide translocator (ANT), cyclophilin (CypD) and voltage-dependent anion channel (VDAC) using western-blotting, and simultaneously detected toll-like receptor 4 (TLR4), inhibitor of kappa B kinase (IKKβ), inhibitor of Kappa Bα (IκBα), and p65 protein expression. We observed mitochondrial damage of KTECs using a transmission electron microscope and assessed apoptosis by TdT-mediated dUTP Nick-End Labeling and flow cytometry.
RESULTS
SIRT3 deficiency led to the deterioration of renal function, and caused a significant increase in inducible nitric oxide synthase production, a decrease in mitochondrial volume, up-regulation of TLR4, IκBα, IKKβ, and p65 proteins, and up-regulation of ANT, CypD and VDAC proteins. However, NAC significantly improved renal function and down-regulated the expression of TLR4, IκBα, IKKβ, and p65 proteins. Furthermore, SIRT3 deficiency led to a significant increase in KTEC apoptosis, while NAC up-regulated the expression of SIRT3 and inhibited apoptosis.
CONCLUSION
NAC has a significant protective effect on SAKI by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis of KTECs.
PubMed: 38800015
DOI: 10.22038/IJBMS.2024.72882.15853 -
MedRxiv : the Preprint Server For... May 2024N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through...
N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. There were no between-group differences in risk of AEs. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.
PubMed: 38798604
DOI: 10.1101/2024.05.13.24306839 -
BioRxiv : the Preprint Server For... May 2024The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic...
The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-β expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-β induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-β, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-β mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-β via mitochondrial dsDNA release.
PubMed: 38798499
DOI: 10.1101/2024.05.10.593557 -
Journal of Clinical Medicine May 2024: Crystallization experiments of renal-calculi-forming compounds (calcium oxalate, calcium phosphates, uric acid) are normally performed by monitoring these processes...
: Crystallization experiments of renal-calculi-forming compounds (calcium oxalate, calcium phosphates, uric acid) are normally performed by monitoring these processes during periods of time similar to the residence of urine inside the kidney. Nevertheless, cystine requires high supersaturation for its crystallization, and most experiments last for longer periods. It must be considered that at high supersaturation, the inhibitors of crystalline development have poor effects. : The induction time of crystallization (t) of cystine in experimental conditions similar to those of the formation of cystine renal calculi and the effect of different cystine-binding thiol agents was determined through turbidimetric measurements. We also studied the macro- and microstructure of 30 cystine kidney stones through stereoscopic microscopy and scanning electron microscopy. : Under the studied conditions, the t in absence of crystallization inhibitors was 15 min, and the presence of 9 mM of penicillamine, tiopronin, or N-acetylcysteine totally inhibited crystallization, as their effects relate to the formation of complexes with cystine, although N-acetylcysteine also delayed cystine crystalline development and modified cystine crystal morphology. Cystine stones have traditionally been classified as smooth and rough. The study of their structure shows that all of them begin their formation from a few crystals that generate a compact radial structure. Their subsequent growth, depending on the renal cavity where they are located, gives rise to the rough structure in the form of large blocks of cystine crystals or the smooth structure with small crystals. : To prevent the development of cystine renal stones, the formation of small crystals must be avoided by reducing urinary cystine supersaturation, with N-acetylcysteine being the most effective among the studied cystine-binding thiol agents. Also, the removal of cystine crystals through increased water intake and physical activity can be a very important preventive measure.
PubMed: 38792383
DOI: 10.3390/jcm13102837 -
International Journal of Molecular... May 2024The objective of this study was to investigate if delivering multiple doses of N-acetylcysteine (NAC) post-surgery in addition to pre-incisional administration...
The objective of this study was to investigate if delivering multiple doses of N-acetylcysteine (NAC) post-surgery in addition to pre-incisional administration significantly impacts the wound healing process in a rat model. Full-thickness skin incisions were carried out on the dorsum of 24 Sprague-Dawley rats in six locations. Fifteen minutes prior to the incision, half of the sites were treated with a control solution, with the wounds on the contralateral side treated with solutions containing 0.015%, 0.03% and 0.045% of NAC. In the case of the NAC treated group, further injections were given every 8 h for three days. On days 3, 7, 14 and 60 post-op, rats were sacrificed to gather material for the histological analysis, which included histomorphometry, collagen fiber organization analysis, immunohistochemistry and Abramov scale scoring. It was determined that scars treated with 0.015% NAC had significantly lower reepithelization than the control at day 60 post-op ( = 0.0018). Scars treated with 0.045% NAC had a significantly lower collagen fiber variance compared to 0.015% NAC at day 14 post-op ( = 0.02 and = 0.04) and a lower mean scar width than the control at day 60 post-op ( = 0.0354 and = 0.0224). No significant differences in the recruitment of immune cells and histological parameters were found. The results point to a limited efficacy of multiple NAC injections post-surgery in wound healing.
Topics: Animals; Wound Healing; Acetylcysteine; Rats; Rats, Sprague-Dawley; Injections, Intradermal; Disease Models, Animal; Skin; Male; Surgical Wound; Collagen; Cicatrix
PubMed: 38791242
DOI: 10.3390/ijms25105200