Oxide Levels Research Articles

Oxidative stress and cytotoxicity of co-formulants of glyphosate-based herbicides in HMWB cells

Abstract Background Glyphosate-based herbicides (GBHs) are widely used worldwide because of their effectiveness and low cost. However, there is a growing concern regarding the potential health risks associated with glyphosate exposure. Glyphosate is always marketed in formulations containing ingredients other than the active substance. These co-formulants may have toxic effects on humans and animals. Although several studies have assessed the health risks related to glyphosate, the toxicological effects of the co-formulants must be analysed in more detail to ensure the health and safety of pesticide users and the general population. This study aimed to characterize and compare the cytotoxic effects of co-formulants with those of the active substance and GBH formulations. Methods Human mononuclear white blood (HMWB) cells were exposed to varying concentrations (0.1 µM, 1µM, 10 µM, 100 µM, 1 mM, 10 mM) of glyphosate, three GBHs (Fozat 480, Roundup, and Glyfos), and two co-formulants for 4- and 20-hours. Cytotoxicity was assessed using the CCK-8 assay, and oxidative stress levels in HMWB cells were evaluated using the superoxide dismutase (SOD) assay. Cell viability and SOD activity were analysed using a spectrophotometer at 460 nm absorbance. Results Glyphosate alone did not significantly affect the cell viability. However, notable cytotoxic effects were observed in response to GBHs and adjuvants at concentrations as low as 100 µM. Furthermore, the Oxidative stress levels in cells treated with GBHs or adjuvants were significantly higher than those treated with glyphosate alone. Conclusions These findings suggest that the cytotoxic effects of GBHs are likely attributed to the adjuvants present in the formulations, which promote oxidative stress. Further studies are necessary to evaluate the health risks associated with using glyphosate-based herbicides, and co-formulants should be considered when assessing their safety. Key messages • The safety of GBHs cannot be solely attributed to glyphosate itself but also to the other components in the formulation. • Toxicity evaluation should take into account not only glyphosate but also the co-formulants present in these herbicides when assessing their safety.

Nitric oxide-producing monocyte-myeloid suppressor cells expand and accumulate in the spleen and mesenteric lymph nodes of Yersinia enterocolitica-infected mice

IntroductionYersinia enterocolitica (Ye) is a Gram-negative bacterium that causes gastrointestinal infections. The myeloid-derived suppressor cells (MDSCs) constitute a cellular population with the capacity of inducing the specific suppression of T cells. Although there is evidence supporting the role of MDSCs in controlling the immune responses in several bacterial infections, its role during Ye infection has not yet been reported. Therefore, the purpose of the present work was to analyze MDSCs after oral Ye infection.MethodsC57BL/6 wild-type mice were infected with Ye WAP-314 serotype O:8. The proliferation of splenocytes and mesenteric lymph nodes (MLN) cells was measured as well as the levels of cytokines and nitric oxide (NO) in culture supernatants. The frequency and subsets of MDSCs were analyzed in the intestinal mucosa and spleen by flow cytometry. Furthermore, monocytic-MDSCs (Mo-MDSCs) and polymorphonuclear-MDSCs (PMN-MDSCs) were purified from the spleen of infected mice and their suppressor activity was evaluated in co-cultures with purified T cells.Resultswe observed a marked expansion of CD11b+Gr-1+ cells, a phenotype consistent with MDSCs, in the spleen and intestinal mucosa of Ye-infected mice. Interestingly, a robust proliferation of splenocytes and MLN cells was observed only when the MDSCs were depleted or the NO production was blocked. In addition, we determined that only Mo-MDSCs had the ability to suppress T-cell proliferation.ConclusionOur results highlight a mechanism by which Ye may induce suppression of the immune responses. We suggest that NO-producing Mo-MDSCs expand and accumulate in MLN and spleen of Ye-infected mice. These cells can then suppress the T-cell function without interfering with the anti-bacterial effector response. Instead, these immature myeloid cells may perform an important function in regulating the inflammatory response and protecting affected tissues.

The evolution of endothelial dysfunction according to the length of the implanted stent on the background of nebivolol therapy

Abstract Introduction The development of atherosclerosis is the driving cause for arterial interventions using coronary stents. Long-stent implantation can increase the vascular injury thereby contributing to the progression of endothelial dysfunction (ED) by the degradation and reduction bioavailability of the nitric oxide (NO) - thus increasing the risk of major cardiovascular events. Purpose Evaluation the evolution of endothelial dysfunction biomarker depending on the length of the stent implanted on the background of nebivolol therapy. Methods The study included 100 patients with stable angina pectoris II–III functional class (age 59.72±0.59 years) undergoing PCI with stent implantation who started the treatment with nebivolol 5mg per day tangent to the conventional treatment and were exposed to PCI with stent implantation, depending on the stent’s length they were divided in three groups: I group - 14 patients with implanted stent’s length ≤15 mm, II group - 57 subjects with implanted stent’s length =15-30 mm and the III group -29 cases where the implanted stent’s length was ≥30 mm. In all the groups was appreciated in blood the endothelial dysfunction’s marker - NO. This marker was assessed preprocedural, postprocedural (after 24 hours) and at intervals of one month, 3,6,12 months after coronary angioplasty, the NO level being compared between these groups and the reference pattern consisting of 20 healthy people. Results The circulating level of nitric oxide determined in I group -61,28±6,92 μM/L and in the II group -56.6±3.03 μM/L and the III group52.39±3.35 was compromised at the preprocedural stage versus the reference pattern - 78.67±2.72 μM/L. During the post- PCI period (first 24 hours), the biomarker level’s was reduced in I group -52.35±1.66 μM/ L, II group -53.74±2.77 μM/L and III group - 52.98±2.91 μM/L. After one month after the intervention on the backroung of the treatment with nebivolol, was recorded a gaing of the NO value in I group - 64.97±5.35 μM/L, II group -63.15±3.99 μM /L and the III group-59.38±4.46 μM/L. The NO serum concentration during the period 3 and 6 months continued to increase in all groups vs the reference pattern. At the 12-month period, the NO level remained high in all the studied groups versus the baseline: I group 99.2±1.1 μM / L (p>0.05), II group-97.96±2.2 μM/L (p<0.001) and the III group -97.65±1.9 μM/L (p<0.001). Conclusion The stent’s length = 15-30 mm and ≥30 mm reveals the presence of an expanded atherosclerotic process, the substrate of which is constituted by the endothelial dysfunction, this being confirmed by the low preprocedural level of NO. The stent implantation procedure induced the accentuation of endothelial dysfunction, and the 12-month nebivolol treatment favored the increase of NO serum concentraon in all groups by 24.9% vs the reference pattern and by 73.3% vs baseline.

20 (S)-Protopanaxadiol Alleviates DRP1-Mediated Mitochondrial Dysfunction in a Depressive Model In Vitro and In Vivo via the SIRT1/PGC-1α Signaling Pathway

Depression is a complex and common mental illness affecting physical and psychological health. Panax ginseng C. A. Mey is a traditional Chinese medicine with abundant pharmacological activity and applications in regulating mood disorders. 20 (S)-Protopanaxadiol is the major intestinal metabolite of ginsenoside and one of the active components in ginseng. In this study, we aimed to investigate the therapeutic effects of 20 (S)-Protopanaxadiol on neuronal damage and depression, which may involve mitochondrial dynamics. However, the mechanism underlying the antidepressant effects of 20 (S)-Protopanaxadiol is unelucidated. In the present study, we investigated the potential mechanisms underlying the antidepressant activity of 20 (S)-Protopanaxadiol by employing a corticosterone-induced HT22 cellular model and a chronic unpredicted mild stress (CUMS)-induced animal model in combination with a network pharmacology approach. In vitro, the results showed that 20 (S)-Protopanaxadiol ameliorated the corticosterone (CORT)-induced decrease in HT22 cell viability, decrease in 5-hydroxytryptamine (5-HT) levels, and increase in nitric oxide (NO) and malondialdehyde (MDA) levels. Furthermore, 20 (S)-Protopanaxadiol exerted improvement effects on the CORT-induced increase in HT22 cell mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and apoptosis. In vivo, the results showed that 20 (S)-Protopanaxadiol ameliorated depressive symptoms and hippocampal neuronal damage in CUMS mice, and sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-1-Alpha (PGC-1α) activity were activated in the hippocampus of mice, thereby alleviating mitochondrial dysfunction and promoting the clearance of damaged mitochondria. In both in vivo and in vitro models, after inhibiting SIRT1 expression, the protective effect of 20 (S)-Protopanaxadiol on mitochondria was significantly weakened, and dynamin-related protein 1 (DRP1)-mediated mitochondrial division was significantly reduced. These findings suggest that 20 (S)-Protopanaxadiol may exert neuroprotective and antidepressant effects by attenuating DRP1-mediated mitochondrial dysfunction and apoptosis by modulating the SIRT1/PGC-1α signaling pathway.

Unraveling Neurotoxicity Discrepancies: Comparative In vitro and In vivo Analysis of Colistin and Polymyxin B and the Underlying Mechanisms.

Polymyxins, including colistin and polymyxin B, are the final resort against Gram-negative bacterial infections. However, its clinical application is restricted due to concerns related to neurotoxicity. Despite the similar antibacterial spectrum and mode of action shared between colistin and polymyxin B, there is still a lack of definitive evidence to support the idea that their neurotoxicity profiles are identical. To comprehensively compare the neurotoxicity between colistin and polymyxin B both in vivo and in vitro and establish a theoretical foundation to guide the rational use of polymyxins within clinical settings. in vitro experiments simulated nerve damage by exposing N2a and RSC96 cells to colistin and polymyxin B. The evaluation of nerve injury included assessments of cell viability and apoptosis. To discern the variance in the mechanisms of nerve injury between colistin and polymyxin B, oxidative stress levels were examined, such as SOD, CAT, GSH, and malondialdehyde (MDA). In in vivo experiments, a rat nerve injury model was created by intraventricular injections of colistin and polymyxin B, respectively. The impact of these drugs on brain injury in rats, particularly within the hippocampus and medulla oblongata, was measured using HE and Nissl staining. The potential influence of polymyxins on the ferroptosis pathway was evaluated by assessing LPO and Fe2+ levels and the degree of mitochondrial impairment. At equivalent doses, colistin demonstrated a reduced level of neurotoxicity compared to polymyxin B, both in vitro and in vivo. in vitro experiments revealed greater cell viability and a lower apoptosis rate after colistin treatment than after polymyxin B treatment. This variance in outcomes could be attributed to the comparatively lower levels of oxidative stress associated with colistin administration.In a rat model, nerve injury resulted in observable damage to both the hippocampus and the medulla oblongata. A comprehensive assessment of the extent of damage in the CA1 to CA4 regions of the hippocampus, and the solitary tract nucleus of the medulla oblongata underscored that the neurotoxic effects of colistin remained milder compared to those elicited by polymyxin B. Even when evaluated at equivalent multiples of clinically recommended doses, colistin exhibited lower neurotoxicity in vivo than polymyxin B. For the first time, this study demonstrated the role of ferroptosis in polymyxin B-induced nerve damage. The activation levels observed within the ferroptosis pathway due to polymyxin B exceeded those triggered by colistin. Colistin exhibited a marked reduction in neurotoxicity compared to polymyxin B, evident in both the equivalent and clinically recommended doses. These findings suggest that, from the perspective of neurotoxicity, colistin presents a more favorable option for clinical use.

Camel Whey Protein Attenuates Acute Heat Stress-Induced Kidney Injury in Rats by Up-Regulating CYP2J Activity and Activating PI3K/AKT/eNOS to Inhibit Oxidative Stress

Camel whey protein (CWP) is a potent natural antioxidant, noted for its abundance of antioxidant amino acids. Despite its promising properties, the precise mechanisms underlying its effects remain inadequately explored. This study aims to investigate the impact of CWP on kidney damage induced by acute heat stress in rats, as well as to elucidate its mechanism of action. We assessed CWP’s influence on cytochrome P450 2J (CYP2J) activity during heat stress, measured oxidative stress levels, and evaluated renal injury using CYP2J knockout rats. Our findings indicate that acute heat stress reduces CYP2J expression, while CWP administration restores CYP2J activity and enhances PI3K/Akt signaling. However, CWP did not mitigate oxidative stress-induced kidney damage in CYP2J−/− rats, suggesting the necessity of CYP2J for its protective effects.

Impact of MaNu dietary counselling on Oxidative Stress and Gestational Weight Gain during pregnancy

Abstract According to the WHO guidelines, to counteract the excessive weight gain during pregnancy and to mitigate the increase in oxidative stress (OS) which naturally increases during pregnancy, a healthy lifestyle and a correct diet are crucial as preventive measures to promote health. The MaNu project was conceived precisely to control these factors through dietary counselling. We expect that pregnant women who voluntarily undergo an educational program consisting of specific and accurate dietary advice will be able to emphasize weight control and contain the increase in OS. Our randomized controlled trial (RCT) has a parallel group design and takes place in the Obstetrics and Clinical Nutrition Departments of Michele and Pietro Ferrero Hospital (Verduno, north-western Italy), where physiological pregnant women are enrolled between 12-17 gestational weeks (GWs). The educational intervention takes place between 12-24 GWs. Dietary habits were collected with a questionnaire and urine samples were analysed to quantify the OS using 15-F2t-isoprostane, malondialdehyde and total antioxidant power. The descriptive analyses are based on paired t-tests. Preliminary analyses on 76 women who completed two out of three time points (T0 and T1) indicate that, of women who received the intervention, 35% experienced excessive weight gain (based on guidelines), compared to 39% shown by controls. Following the counselling, the 15-F2t-isoprostane decreased significantly (mean T0=5.1 ng/ml vs. mean T1=3.5 ng/ml, p = 0.02). Concerning nutrient intake, a statistically significant reduction in sugar consumption has been found in the intervention group (mean T0=92.2 g vs. mean T1=83.3 g, p = 0.03). Conversely, no correlations have been detected between OS and the main pro and anti-oxidant macronutrients. Although promising, our findings need further verification since the RCT is still ongoing, and it is imperative to attain the anticipated sample size before drawing any definitive conclusions. Key messages • Dietary counselling during pregnancy should be implemented as a preventive strategy used to counteract potential pregnancy complications and ensure the well-being of both the mother and the baby. • Healthy diet is essential to control the increase in oxidative stress levels during pregnancy and to prevent excessive weight gain, factors that can lead to the onset of pregnancy complications.

Lactiplantibacillus plantarum NMGL2 exopolysaccharide ameliorates DSS-induced IBD in mice mainly by regulation of intestinal tight junction and NF-κB p65 protein expression

Treatment of inflammatory bowel disease (IBD), a common chronic intestinal disease, by exopolysaccharides (EPSs) produced by lactic acid bacteria has raised increasing concerns. Here, the EPS produced by Lactiplantibacillus plantarum NMGL2 was evaluated for its ameliorating effect on dextran sodium sulfate (DSS)-induced IBD in mice. Administration of the EPS was shown to decrease the body weight loss and the values of disease activity index (DAI) and alleviate the colon damage as evidenced by an improvement in colonic length shortening, a reduction in colonic coefficient, and a reduction in colonic mucosal architecture and inflammatory infiltration. Cytokine assay of the blood and colon tissue samples showed that the EPS could decrease the levels of pro-inflammatory TNF-α and IL-1β, and increase anti-inflammatory IL-10. Oxidative stress assay of the colon tissue showed that the nitric oxide (NO) and malondialdehyde (MDA) levels decreased significantly (p < 0.05), while superoxide dismutase (SOD) and glutathione (GSH) levels increased significantly (p < 0.05) after the EPS intervention. These results were further confirmed by the significantly (p < 0.05) down-regulated levels of NF-κB p65, p-IKKβ, and p-IκBα, and significantly (p < 0.05) enhanced expression of ZO-1 and occludin, as evaluated by Western-blot analysis of these proteins expressed in colonic tissue. The EPS produced by L. plantarum NMGL2 alleviated IBD by suppressing the NF-κB signaling pathway, suggesting its potential as a functional food agent in the prevention of IBD.

Enhancing wound healing through innovative technologies: microneedle patches and iontophoresis

IntroductionWound healing is a complex process involving multiple stages, including inflammation, proliferation, and remodeling. Effective wound management strategies are essential for accelerating healing and improving outcomes. The CELLADEEP patch, incorporating iontophoresis therapy and microneedle technology, was evaluated for its potential to enhance the wound healing process.MethodsThis study utilized a full-thickness skin defect model in Sprague-Dawley rats, researchers compared wound healing outcomes between rats treated with the CELLADEEP Patch and those left untreated. Various histological staining techniques were employed to examine and assess the wound healing process, such as H&E, MT and immunofluorescence staining. Furthermore, the anti-inflammatory and proliferative capabilities were further investigated using biochemical assays.ResultsMacroscopic and microscopic analyses revealed that the CELLADEEP patch significantly accelerated wound closure, reduced wound width, and increased epidermal thickness and collagen deposition compared to an untreated group. The CELLADEEP patch decreased nitric oxide and reactive oxygen species levels, as well as pro-inflammatory cytokines IL-6 and TNF-α, indicating effective modulation of the inflammatory response. Immunofluorescence staining showed reduced markers of macrophage activity (CD68, F4/80, MCP-1) in the patch group, suggesting a controlled inflammation process. Increased levels of vimentin, α-SMA, VEGF, collagen I, and TGF-β1 were observed, indicating enhanced fibroblast activity, angiogenesis, and extracellular matrix production.DiscussionThe CELLADEEP patch demonstrated potential in promoting effective wound healing by accelerating wound closure, modulating the inflammatory response, and enhancing tissue proliferation and remodeling. The CELLADEEP patch offers a promising non-invasive treatment option for improving wound healing outcomes.

Targeting BRD4-HK2 reverses the meta-inflammatory shift in perivascular adipose tissue and rescues cardiometabolic vascular dysfunction

Abstract Background/Introduction Reducing vascular inflammation is crucial to halt and reverse cardiometabolic damage. BRD4, an epigenetic pan-inflammatory activator whose inhibition has shown promising results in cancer, may play an important role in this context. However, its role in cardiometabolic disease remains unclear. Purpose To investigate BRD4-related transcriptional programmes and therapeutic modulation in translational models of cardiometabolic disease. Methods We dissected small arteries (100-300 μM) from visceral fat biopsies in healthy volunteers (n=16) and patients with obesity and hypertension (n=16), a highly prevalent cardiometabolic phenotype. We assessed the ex vivo effects of BRD4 inhibition on vascular function by pressure myography in the presence or absence of perivascular adipose tissue (PVAT), at baseline and after incubation with the BRD4 inhibitor RVX-208 or with anti-inflammatory/anti-metabolic drugs. We used a cardiometabolic mouse model (high-fat diet+L-NAME supplementation) that mirrored our human phenotype and orally administered RVX-208 (150 mg/kg) or vehicle for 5 days (n=6 per group) to confirm the in vivo effect of chronic BRD4 inhibition. Finally, we investigated the molecular pathways involved in the perivascular cross-talk in an in vitro model of human adipocytes (hADSCs) and endothelial cells (HAECs) using gene overexpression/silencing strategies. We assessed ROS and nitric oxide levels (confocal microscopy), protein and gene expressions (Western blot; qPCR), transcriptional (custom qPCR array; chromatin immunoprecipitation (ChIP)) and metabolic changes (metabolomics, lipidomics, mitochondrial swelling). Results Vascular inflammation, remodeling and function were altered in cardiometabolic patients/mice. RVX-208 attenuated ex vivo vascular dysfunction to a greater extent than anti-IL-1β, anti-IL-6 receptor and anti-TNF-α. In vessels with intact PVAT we observed a stronger effect, due to the restoration of healthy PVAT phenotype (Figure 1). In PVAT, Hexokinase-2 (Hk2) - a glycolytic enzyme implicated in mitochondrial dysfunction and inflammation - was the top downregulated gene by RVX-208 treatment; ChIP confirmed increased binding of BRD4 to the Hk2 promoter. In line, metabolomics and lipidomics assays revealed a PVAT glycolytic shift with increased fatty acid storage in disease states, which was reversed by BRD4 inhibition. The in vitro study showed that: i) healthy adipocytes overexpressing HK2 shift to an inflammatory phenotype; ii) their secretome induces an inflammatory phenotype in HAECs; iii) ex vivo PVAT-selective inhibition of HK2 ameliorates vascular dysfunction (Figure 2). Conclusions We identified BRD4-HK2 interaction at the PVAT level as a novel mediator of cardiometabolic damage. Its targeting rescues vascular dysfunction by reversing the PVAT meta-inflammatory shift. Epigenetic modulators of meta-inflammation may represent a promising strategy in patients with obesity and hypertension.

Odoratin balances ROS/NO through EZH2/PPARγ signalling to improve myocardial fibrosis.

Myocardial fibrosis is a critical concern in clinical medicine. This study explores the potential of odoratin as a treatment for myocardial fibrosis and investigates its underlying mechanisms. In vitro experiments involved stimulating primary mouse cardiomyocytes with TGF-β1, followed by odoratin treatment, to assess levels of reactive oxygen species (ROS) and nitric oxide (NO). In vivo, a mouse model of myocardial fibrosis was established using abdominal aortic constriction (AAC) and treated with odoratin. ROS and NO levels in myocardial tissue were then evaluated. Immunofluorescence and Western blotting analysis showed that odoratin reduced excess ROS, enhanced NO production and decreased fibrosis-related protein expression in vitro. In vivo, odoratin significantly improved cardiac function, reduced ROS, increased NO levels and mitigated fibrosis in AAC-induced mice. Both in vitro and in vivo, odoratin inhibited the expression of NADPH oxidase 4 and EZH2, while promoting the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) and PPARγ. The anti-fibrotic effects of odoratin were reversed by PPARγ antagonism, and EZH2 overexpression diminished PPARγ activation by odoratin. These findings suggest that odoratin may combat myocardial fibrosis by balancing ROS and NO through PPARγ activation, with EZH2 inhibition likely playing a key regulatory role.

Zinc signaling controls astrocyte-dependent synapse modulation via the PAF receptor pathway.

Astrocytes are important regulators of neuronal development and activity. Their activation plays a key role in the response to many central nervous system (CNS) pathologies. However, reactive astrocytes are a double-edged sword as their chronic or excessive activation may negatively impact CNS physiology, for example, via abnormal modulation of synaptogenesis and synapse function. Accordingly, astrocyte activation has been linked to neurodegenerative and neurodevelopmental disorders. Therefore, the attenuation of astrocyte activation may be an important approach for preventing and treating these disorders. Since zinc deficiency has been consistently linked to increased pro-inflammatory signaling, we aimed to identify cellular zinc-dependent signaling pathways that may lead to astrocyte activation using techniques such as immunocytochemistry and protein biochemistry to detect astrocyte GFAP expression, fluorescent imaging to detect oxidative stress levels in activated astrocytes, cytokine profiling, and analysis of primary neurons subjected to astrocyte secretomes. Our results reveal a so far not well-described pathway in astrocytes, the platelet activation factor receptor (PAFR) pathway, as a critical zinc-dependent signaling pathway that is sufficient to control astrocyte reactivity. Low zinc levels activate PAFR signaling-driven crosstalk between astrocytes and neurons, which alters excitatory synapse formation during development in a PAFR-dependent manner. We conclude that zinc is a crucial signaling ion involved in astrocyte activation and an important dietary factor that controls astrocytic pro-inflammatory processes. Thus, targeting zinc homeostasis may be an important approach in several neuroinflammatory conditions.

Oxidative Phosphorylation as a Predictive Biomarker of Oxaliplatin Response in Colorectal Cancer

Oxaliplatin is successfully used on advanced colorectal cancer to eradicate micro-metastasis, whereas its benefits in the early stages of colorectal cancer remains controversial since approximately 30% of patients experience unexpected relapses. Herein, we evaluate the efficacy of oxidative phosphorylation as a predictive biomarker of oxaliplatin response in colorectal cancer. We found that non-responding patients exhibit low oxidative phosphorylation activity, suggesting a poor prognosis. To reach this conclusion, we analyzed patient samples of individuals treated with oxaliplatin from the GSE83129 dataset, and a set of datasets validated using ROCplotter, selecting them based on their response to the drug. By analyzing multiple oxaliplatin-resistant and -sensitive cell lines, we identified oxidative phosphorylation KEGG pathways as a valuable predictive biomarker of oxaliplatin response with a high area under the curve (AUC = 0.843). Additionally, some oxidative phosphorylation-related biomarkers were validated in primary- and metastatic-derived tumorspheres, confirming the results obtained in silico. The low expression of these biomarkers is clinically relevant, indicating poor prognosis with decreased overall and relapse-free survival. This study proposes using oxidative phosphorylation-related protein expression levels as a predictor of responses to oxaliplatin-based treatments to prevent relapse and enable a more personalized therapy approach. Our results underscore the value of oxidative phosphorylation as a reliable marker for predicting the response to oxaliplatin treatment in colorectal cancer.

Chitosan biomineralized with ions-doped nano-hydroxyapatite tunes osteoblasts metabolism and DNA damage

Hydroxyapatite (HA) is a bioceramic material widely used as a bone biomimetic substitute and can be synthesized by biomineralization, according to which HA nanoparticles are formed on a polymer template. Nevertheless, little is known about the effect of ion doping and biomineralization on cell metabolism, oxidative stress, and DNA damage. In the present contribution, we report on synthesizing and characterizing biomineralized chitosan as a polymer template with HA nanoparticles doped with magnesium (MgHA) and iron ions (FeHA). The physical-chemical and morphological characterization confirmed the successful synthesis of low crystalline ions-doped HA nanoparticles on the chitosan template, whereas the biochemical activity of the resulting nanoparticles towards human osteoblasts-like cells (MG63 and HOBIT) was investigated considering their effect on cell metabolism, proliferation, colony formation, redox status, and DNA damage extent. Data obtained suggest that particles enhance cell metabolism but partially limit cell proliferation. The redox status of cells was measured suggesting a slight increase in Reactive Oxygen Species production with chitosan biomineralized with iron-doped HA, whereas no effect with magnesium-doped HA and no effect of all formulations on the oxidation level of Peroxiredoxin. On the other hand, DNA damage was investigated by COMET assay, and expression and foci γH2AX. These latter tests indicated that HA-based nanoparticles promote DNA damage which is enhanced by chitosan thus suggesting that chitosan favors the nanoparticles’ internalization by cells and modulates their biological activity. The potential DNA damage should be considered – and potentially exploited for instance in anticancer treatment – when HA-based particles are used to devise biomaterials.

Staphylea bumalda Alleviates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice by Regulating Inflammatory Cytokines, Oxidative Stress, and Maintaining Gut Homeostasis

Staphylea bumalda is a rare medicine and edible shrub native to the temperate regions of Asia, possessing significant medicinal potential. In this study, the components of S. bumalda tender leaves and buds extract (SBE) were analyzed and identified by HPLC and LC/MS method, and the safety of SBE was evaluated through mouse acute toxicity models. The protective effects of SBE on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice were investigated in terms of inflammatory factor levels, oxidative stress, and gut microorganisms. Results showed that hyperoside, kaempferol-3-O-rutinoside, isorhoifolin, and rutin were the main components of the extract, and SBE demonstrated good safety in experimental mice. SBE could alleviate weight losing, disease activity index (DAI) raising, and colon shortening in mice. Pathological section results showed that the inflammatory cell infiltration decreased significantly, and the number of goblet cells increased significantly in the SBE group. After SBE treatment, interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in serum were significantly decreased, and the levels of myeloperoxidase (MPO) and nitric oxide (NO) in colon tissues were significantly decreased. SBE inhibited gut inflammation by increasing Lactobacillus. In summary, SBE played a therapeutic role in UC mice by relieving colon injury, reducing inflammatory factor levels, and maintaining gut flora homeostasis. SBE is expected to become an auxiliary means to participate in the prevention and treatment of UC.

Characteristics of Nocturnal Boundary Layer over a Subtropical Forest: Implications for the Dispersion and Fate of Atmospheric Species.

The nocturnal boundary layer (NBL) significantly influences the dispersion and fate of atmospheric species at night. Subtropical forests are crucial in carbon and water exchange between the biosphere and the atmosphere. However, the NBL characteristics and their impact on atmospheric species over these forests remain unknown. This study conducted vertical measurements of atmospheric species such as O3 and volatile organic compounds (VOCs), along with meteorological variables, over a national forest reserve in Southern China. Results reveal that the NBL height ranged from 180 to 300 m in the summer and from 80 to 160 m in the winter. The vertical distribution of chemical species varied by time and season, with greater concentration gradients observed in the summer. Over 90% of VOCs above the NBL were anthropogenic, while biogenic VOCs were mainly found within the NBL. Higher O3 concentration and VOC product-to-reactant ratios were observed in the residual layer, suggesting enhanced oxidation levels. This unique vertical distribution of atmospheric species at night is driven by factors, such as emission, deposition, turbulence, and atmospheric chemistry, potentially affecting ecosystem functions. Results from this study highlight the importance of incorporating NBL dynamics into atmospheric models to better understand the evolution of chemical species and their ecological effects over forests.

Investigation of the Cyclohexene Oxidation Mechanism Through the Direct Measurement of Organic Peroxy Radicals.

Monoterpenes, the second most abundant biogenic volatile organic compounds globally, are crucial in forming secondary organic aerosols, making their oxidation mechanisms vital for addressing climate change and air pollution. This study utilized cyclohexene as a surrogate to explore first-generation products from its ozonolysis through laboratory experiments and mechanistic modeling. We employed proton transfer reaction mass spectrometry with NH4+ ion sources (NH4+-CIMS) and a custom-built OH calibration source to quantify organic peroxy radicals (RO2) and closed-shell species. Under near-real atmospheric conditions in a Potential Aerosol Mass-Oxidation Flow Reactor, we identified 30 ozonolysis products, expanding previous data sets of low-oxygen compounds. Combined with simulations based on the Generator for Explicit Chemistry and Kinetics of Organics in the Atmosphere and relevant literature, our results revealed that OH dominates over ozone in cyclohexene oxidation at typical atmospheric oxidant levels with H-abstraction contributing 30% of initial RO2 radicals. Highly oxidized molecules primarily arise from RO2 autoxidation initiated by ozone, and at least 15% of ozone oxidation products follow the overlooked nonvinyl hydroperoxides pathway. Gaps remain especially in understanding RO2 cross-reactions, and the structural complexity of monoterpenes further complicates research. As emissions decrease and afforestation increases, understanding these mechanisms becomes increasingly critical.

Impact of oxidized low-density lipoprotein on rat liver sinusoidal endothelial cell morphology and function

Atherogenesis is associated with elevated plasma levels of oxidized low-density lipoproteins (oxLDL). In vivo, oxLDL causes liver endothelial swelling, and disrupts liver sinusoidal endothelial cell (LSECs) fenestrations. We mapped the nanoscale kinetics of these changes in vitro in isolated rat LSECs challenged with oxLDL and monitored viability with endocytosis and cytotoxicity assays. OxLDL disrupted LSEC ultrastructure – increasing oxLDL concentrations and oxidation levels caused sieve plate loss, fenestration fusion, and gap formation. Importantly, these effects were not uniform across all LSECs. LSECs retained the ability to endocytose ligands irrespective of the presence of oxLDL. However, increasing oxidation levels and concentrations of oxLDL inhibited LSEC mediated degradation of endocytosed ligands. Viability was unaffected by any oxLDL challenge. In conclusion, oxLDL disrupts LSEC ultrastructural morphology in vitro but LSECs remain viable and mostly maintain the scavenging function during oxLDL challenge.

Administration of melatonin nanoparticles improves testicular blood flow, echotexture of testicular parenchyma, scrotal circumference, and levels of estradiol and nitric oxide in prepubertal ossimi rams under summer heat stress.

Environmental heat stress (HS) impairs reproductive efficiency in farm animals. This study investigated, for the first time, how the melatonin and melatonin nanoparticles treatment affected the testicular hemodynamics, testicular volume, echotexture [Pixel intensity (PIX) and integrated density (IND)], scrotal circumference, serum concentration of testosterone (T), estradiol (E2), nitric oxide (NO), and total antioxidant capacity (TAC) in prepubertal Ossimi ram lambs in hot climatic conditions. The lambs undergoing examination had a temperature humidity index (THI) of 87.05 ± 1.70, indicating severe HS condition. Fifteen prepubertal Ossimi ram lambs were exposed to a single s.c injection of either nano melatonin (nano melatonin group; 20mg/ram; n = 5) or melatonin suspended in two ml of corn oil (melatonin group; 40mg/ram; n = 5) or two ml of corn oil (control group; n = 5). Blood collection and ultrasonographic assessment of the testes and supratesticular arteries (STAs) were conducted immediately before treatment (W0) and once weekly for six successive weeks after nano melatonin and melatonin injection (W1-W6). Results revealed decreases (P < 0.05) in the Doppler indices (resistive index; RI and pulsatility index; PI) of the testicular arteries at most time points of the study in the nano melatonin and melatonin groups. PIX of testicular parenchyma was significantly increased (P ˂ 0.05) in the treated groups compared to the control one. IND of testicular parenchyma increased significantly in the nano melatonin group compared to the melatonin and control groups. Testicular volume and scrotal circumference significantly increased (P < 0.05) in nano melatonin and melatonin groups compared to the control one. T concentration did not significantly (P > 0.05) change in the treated groups compared to the control group. E2, NO, and TAC concentrations increased (P < 0.05) in the treated groups compared to the control one. In conclusion, this study extrapolated that administrations of melatonin or nano melatonin can ameliorate the effects of environmental HS in prepubertal Ossimi ram lambs with a more protective effect and lower dose of nano melatonin.

Pyroptosis: An Accomplice in the Induction of Multisystem Complications Triggered by Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a common respiratory disorder, primarily characterized by two pathological features: chronic intermittent hypoxia (CIH) and sleep deprivation (SD). OSA has been identified as a risk factor for numerous diseases, and the inflammatory response related to programmed cell necrosis is believed to play a significant role in the occurrence and progression of multisystem damage induced by OSA, with increasing attention being paid to pyroptosis. Recent studies have indicated that OSA can elevate oxidative stress levels in the body, activating the process of pyroptosis within different tissues, ultimately accelerating organ dysfunction. However, the molecular mechanisms of pyroptosis in the multisystem damage induced by OSA remain unclear. Therefore, this review focuses on four major systems that have received concentrated attention in existing research in order to explore the role of pyroptosis in promoting renal diseases, cardiovascular diseases, neurocognitive diseases, and skin diseases in OSA patients. Furthermore, we provide a comprehensive overview of methods for inhibiting pyroptosis at different molecular levels, with the goal of identifying viable targets and therapeutic strategies for addressing OSA-related complications.