Origanum majorana essential oil improves the rat's sexual behavior and testicular oxidative damage induced by imidacloprid via modulating the steroidogenesis pathways.

The neonicotinoid insecticide imidacloprid has been linked to significant reproductive damage in mammals. Origanum majorana essential oil (OME) is a natural herbal product used in the management of many diseases due to its strong antioxidant effects. The oil was hydrodistilled from O. Majorana and analyzed using GC/MS then its possible protective mechanisms against IMI-induced reprotoxicity in male rats were investigated. 28-adult male Wistar rats were divided into 4 groups as follows: group (1) control group, group (2) OME, group (3) IMI, and group (4) IMI + OME. The treatments were applied daily via oral gavage for 60 days. Remarkable abnormalities in both territorial aggressive and sexual behaviors were observed in IMI-treated rats with a significant elevation of serum FSH and LH as well as altered testicular redox status. Along with inhibition of the testicular expression of StAR and aromatase genes and serum total testosterone in addition to abnormal sperm count, viability, motility, and morphology. Histopathological examination showed severe degeneration and necrosis in both germ cells and Leydig cells with atrophy in most of the seminiferous tubules. Co-administration of OME with IMI notably improved all the above-mentioned studied parameters, and restored rats' spermatogenesis, sexual behavior, and favorably modulates the levels of both testosterone and gonadotropic hormones via its potent antioxidant effect. These findings support the use of OME as a fertility enhancer and suggest that it could be used to manage pesticide-induced male infertility.

Empagliflozin attenuates neurodegeneration through antioxidant, anti-inflammatory, and modulation of α-synuclein and Parkin levels in rotenone-induced Parkinson's disease in rats.

Sodium-glucose co-transporter 2 (SGLT 2) inhibitors are a relatively new antidiabetic drug with antioxidant and anti-inflammatory properties. Therefore, this study aimed to investigate whether SGLT 2 inhibitors have a neuroprotective effect in PD. Twenty-four Wistar rats were randomized into four groups. The first one (control group) received dimethyl sulfoxide (DMSO) as a vehicle (0.2 mL/48 hr, S.C). The second group (positive control) received rotenone (ROT) (2.5 mg/kg/48 hr, S.C) for 20 successive days, whereas the third and fourth groups received empagliflozin (EMP) (1 and 2 mg/kg/day, orally), respectively. The two groups received rotenone (2.5 mg/kg/48 hr S.C) concomitantly with EMP for another 20 days on the fifth day. By the end of the experimental period, behavioral examinations were done. Subsequently, rats were sacrificed, blood samples and brain tissues were collected for analysis. ROT significantly elevated oxidative stress and proinflammatory markers as well as α-synuclein. However, dopamine (DP), antioxidants, tyrosine hydroxylase (TH), and Parkin were significantly decreased. Groups of (EMP + ROT) significantly maintained oxidative stress and inflammatory markers elevation, maintained α-synuclein and Parkin levels, and elevated TH activity and dopamine level. In both low and high doses, EMP produced a neuroprotective effect against the PD rat model, with the high dose inducing a more significant effect.

The potential antiepileptic activity of astaxanthin in epileptic rats treated with valproic acid.

OBJECTIVES: Epilepsy is a neurological disease characterized by sudden, abnormal, and hyper- discharges in the central nervous system (CNS). Valproic acid (VPA) is commonly used as a broad-spectrum antiepileptic therapeutic. However, in many cases, patients develop resistance to VPA treatment due to overwhelming oxidative stress, which in turn might be a major catalyst for disease progression. Therefore, antioxidants can potentially become therapeutic agents by counteracting reactive oxygen species (ROS)-mediated damage. The present study is aimed to evaluate the potential antiepileptic effect of astaxanthin (ASTA) in pentylenetetrazol (PTZ) induced epileptic model rats that are chronically treated with VPA for 8 weeks. METHOD: Fifty-male Wistar rats were randomly divided into five groups: Non-PTZ group, PTZ, PTZ/VPA, PTZ/ASTA, and PTZ/VPA/ASTA treated groups. RESULTS: PTZ/VPA treated group showed a neuroprotective effect with improvement in antioxidant levels, behavioral test, and histopathological changes induced by PTZ. VPA also exhibited an anti-inflammatory effect as its treatment resulted in the reduction of tumor necrosis factor-α (TNF-α). ASTA exhibited an anticonvulsant effect and enhanced anti-inflammatory effect as compared to VPA. During the combined therapy, ASTA potentiated the antiepileptic effect of the VPA by reducing the oxidative stress and TNF-α as well as increased the glutathione (GSH) levels. Also, there were substantial improvements in the behavioral and histopathological changes in the VPA/ASTA treated group as compared to the VPA treated group. CONCLUSION: ASTA could have an antiepileptic and anti-inflammatory effect by reducing ROS generation. Therefore, co-administration of both the therapeutics (VPA/ASTA) has a synergistic effect in treating epilepsy and could potentially minimize recurrence and/or exacerbation of seizures.

Defining the role of CFTR channel blocker and ClC-2 activator in DNBS induced gastrointestinal inflammation.

In the present study, we have investigated and/or compared the role of glibenclamide, G as cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor, and lubiprostone, L as chloride channel-2 (ClC-2) activator in the 2,4-dinitrobenzene sulfonic acid (DNBS)-induced gastrointestinal inflammation. GI inflammation was induced by intrarectal administration of DNBS. Rats were randomly allocated in 5 groups as sham control, distilled water + DNBS, sulfasalazine (S) + DNBS, G + DNBS, and L + DNBS. All the groups were pre-treated successively for five days before the induction of colitis. One day before and the first four days after DNBS administration various parameters were studied. Later, blood chemistry, colon's gross structure, histology, and the antioxidant load was examined. Pre-treatment with G significantly protected the change induced by DNBS concerning the change in body weight, food intake, diarrhea, occult blood in the feces, wet weight of the colon, and spleen. G because of its anti-inflammatory property down-regulated the neutrophil and WBC count and up-regulated the lymphocyte number. Moreover, G efficiently ameliorates the oxidative stress in the colon and declines the level of myeloperoxidase and malondialdehyde and up-regulated the level of superoxide dismutase and glutathione. Lubiprostone has not shown any promising effects, in fact, it causes an increase in diarrheal frequency. Our findings from this study represent that G has good potential to ameliorate GI inflammation induced by DNBS by its multiple actions including CFTR blockage and reducing the release of inflammatory markers from the MCs, anti-inflammatory and free radical scavenging property.

Cinnamomum zeylanicum Blume (Ceylon cinnamon) bark extract attenuates doxorubicin induced cardiotoxicity in Wistar rats.

Anti-tumour efficacy of doxorubicin is hindered by the cumulative dose-dependent cardiotoxicity induced by reactive oxygen species during its metabolism. As Cinnamomum zeylanicum has proven antioxidant potential, objective of this study was to investigate the cardioprotective activity of Cinnamomum bark extract against doxorubicin induced cardiotoxicity in Wistar rats. Physicochemical and phytochemical analysis was carried out and dose response effect and the cardioprotective activity of Cinnamomum were determined in vivo. 180 mg/kg dexrazoxane was used as the positive control. Plant extracts were free of heavy metals and toxic phytoconstituents. In vivo study carried out in Wistar rats revealed a significant increase (p < 0.05) in cardiac troponin I, NT-pro brain natriuretic peptide, AST and LDH concentrations in the doxorubicin control group (18 mg/kg) compared to the normal control. Rats pre-treated with the optimum dosage of Cinnmamomum (2.0 g/kg) showed a significant reduction (p < 0.05) in all above parameters compared to the doxorubicin control. A significant reduction was observed in the total antioxidant capacity, reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase activity while the lipid peroxidation and myeloperoxidase activity were significantly increased in the doxorubicin control group compared to the normal control (p < 0.05). Pre-treatment with Cinnamomum bark showed a significant decrease in lipid peroxidation, myeloperoxidase activity and significant increase in rest of the parameters compared to the doxorubicin control (p < 0.05). Histopathological analysis revealed a preserved appearance of the myocardium and lesser degree of cellular changes of necrosis in rats pre-treated with Cinnamomum extract. In conclusion, Cinnamomum bark extract has the potential to significantly reduce doxorubicin induced oxidative stress and inflammation in Wistar rats.

The potential role of sesquiterpene lactones isolated from medicinal plants in the treatment of the metabolic syndrome - A review.

Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management.

Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition, associated with regulation of Nrf2/HO-1, MAPK/NF-κB, and Bax/Bcl-2 signaling.

BACKGROUND: The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity. METHODS: Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation. RESULTS: Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival. CONCLUSIONS: Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.

Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of IL-6/JAK2/STAT3 signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is accompanied by progressive joint damage and disability. The intolerability of conventional antirheumatic drugs by some patients necessitates the search for effective antirheumatic agents having better tolerability. In the current work, we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren as potential antirheumatic candidates and to explore their modulatory effects on joint destruction, inflammatory response, and intracellular signaling. Arthritis was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. on days 1, 4, and 7. Treated groups received their respective drugs, starting from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which is an anti-inflammatory cytokine. Besides, cartilage and bone destruction biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor-kappa B ligand (RANKL); were significantly reduced after treatment with the test agents, which was further confirmed by histopathological investigation. The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and inducible nitric oxide synthase (iNOS) in articular tissue were markedly attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In addition, oxidative stress and inflammatory markers such as malondialdehyde, nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment with the test agents, while glutathione content was elevated. Furthermore, the renin inhibitor aliskiren produced effects close to those of the normal and methotrexate, the gold standard antirheumatic drug, in most of the measured parameters. Collectively, these findings led to the assumption that the downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic agent for RA, because of its ability to normalize most of the measured parameters after CFA-induced arthritis.

Effects of l-carnitine and/or maize distillers dried grains with solubles in diets of gestating and lactating sows on the intestinal barrier functions of their offspring.

The objective of this study was to investigate the effects of l-carnitine and/or maize distillers dried grains with solubles (DDGS) in diets of gestating and lactating sows on the intestinal barrier functions of their offspring. The experiment was designed as a 2×2 factorial with two dietary treatments (soyabean meal v. DDGS) and two l-carnitine levels (0 v. 100 mg/kg in gestating diets and 0 v. 200 mg/kg in lactating diets). Sows (Landrace×Large White) with an average parity of 4·2 with similar body weight were randomly assigned to four groups of thirty each. Dietary supplementation with l-carnitine increased the total superoxide dismutase activity but decreased the concentration of malondialdehyde of the jejunal mucosa in newborn piglets and weaning piglets on day 21. Dietary supplementation with l-carnitine decreased the concentrations of IL-1ß, IL-12 and TNF-α in the jejunal mucosa of newborn piglets and decreased the concentrations of IL-6 and TNF-α in the jejunal mucosa of weaning piglets on day 21. There was an interaction between dietary treatment and l-carnitine on the bacterial numbers of total eubacteria in the digesta of caecum in weaning piglets on day 21. Bacterial numbers of total eubacteria in weaning piglets on day 21 were significantly increased by l-carnitine only in soyabean meal diet, but there was no significant effect of l-carnitine in DDGS-based diet. Dietary supplementation with l-carnitine increased the bacterial numbers of Lactobacillus spp. and bifidobacteria spp. in the digesta of caecum in weaning piglets on day 21. Dietary supplementation with l-carnitine in sows affected the expression of tight junction proteins (claudin 1, zonula occludens-1 (ZO-1) and occludin) in the jejunal mucosa of their offspring by increasing the expression of ZO-1 mRNA in the jejunal mucosa of newborn piglets, and by increasing the expression of ZO-1 and occludin mRNA in the jejunal mucosa of weaning piglets on day 21. In conclusion, dietary supplementation with l-carnitine in gestating and lactating sows had positive effects on intestinal barrier functions of newborn piglets and weaning piglets on day 21, but it did not have effects on intestinal barrier functions of growing-finishing pigs in the filial generation. There were no effects of dietary treatment of sows on intestinal barrier functions in their offspring.

A new triphenylphosphonium-conjugated amphipathic cationic peptide with improved cell-penetrating and ROS-targeting properties.

We study for the first time whether triphenylphosphonium (TPP) moiety can improve cellular delivery and redox properties of amphipathic cationic peptides based on YRFK/YrFK cell-penetrating and cytoprotective motif. TPP moiety was found to increase reducing activity of both stereoisomeric peptides in solution and on electrode surface in association with TPP-mediated intramolecular interactions. Among TPP-conjugated peptides, newly synthesized TPP3-YrFK featured both increased antioxidant efficacy and proteolytic resistance. TPP-conjugated peptides preferably mitigated endogenic ROS in mitochondria and cytoplasm of model glioblastoma cells with increased oxidative status. This anti-ROS effect was accompanied by mild reversible decrease of reduced glutathione level in the cells with relatively weak change in glutathione redox forms ratio. Such low interference with cell redox status is in accordance with non-cytotoxic nature of the compounds. Intracellular concentrations of label-free peptides were analyzed by LC-MS/MS, which showed substantial TPP-promoted penetration of YrFK motif across cell plasma membrane. However, according to ΔΨm analysis, TPP moiety did not profoundly enhance peptide interaction with mitochondrial inner membrane. Our study clarifies the role of TPP moiety in cellular delivery of amphipathic cationic oligopeptides. The results suggest TPP moiety as a multi-functional modifier for the oligopeptides which is capable of improving cellular pharmacokinetics and antioxidant activity as well as targeting increased ROS levels. The results encourage further investigation of TPP3-YrFK as a peptide antioxidant with multiple benefits.

Evaluation of testicular torsion management in Ogbomoso, South-Western Nigeria and surgical detorsion-augmented treatment with phytochemical fractions of Corchorus olitorius leaf in experimental rats.

Background: There is need to investigate whether phytochemicals along with surgical detorsion could serve as better managements options in TT patients rather than surgical detorsion (SD) alone. Methods: The descriptive cross-sectional part of this study is questionnaire-based addressing sociodemographic characteristics of participants and their experience in management of TT. In the experimental part, male rats (n = 32) were grouped into: sham, Ischemia-reperfusion injury (IRI), dichloromethane (DCM) and ethanol fraction (100 mg/kg) of CO. Evaluation of tissue GPx, total thiol, SOD, MDA and H2O2 was done. Serum estimations of nitrite, TNF-α and IL-6, MPO, sperm motility, count and viability was also carried out. Tissue expression of bax and caspase 3 was assessed. Results: 68.9 % respondents agreed that SD alone is non-effective in the management of TT while 83.6 % reported a need to augment surgery with medications. Oxidative stress markers like H2O2, MDA and nitrite increased by IRI were decreased in post-treatment groups, along with a significant increase in the tissue level of GSH, GST, SOD, GPx, and total thiol. Inflammatory mediators were elevated in IRI while post-treatment rats showed significant decrease. IRI decreased sperm count significantly this was reversed by post-treatment. Bax and caspase 3 was increased in IRI rats and post-treatment with CO fractions reduced them. Conclusions: Quantitative cross-sectional study has revealed through experience of clinicians that surgical detorsion alone is not effective in managing TT. Augmented treatment with CO leaf fractions suppressed testicular IRI through inhibition of pro-apoptotic proteins expression, oxidative stress and inflammation.

Availability of aldo-keto reductase 1C3 and ATP-binding cassette B1 as therapeutic targets for alleviating paclitaxel resistance in breast cancer MCF7 cells.

Paclitaxel (PTX) is frequently utilized for the chemotherapy of breast cancer, but its continuous treatment provokes hyposensitivity. Here, we established a PTX-resistant variant of human breast cancer MCF7 cells and found that acquiring the chemoresistance elicits a remarkable up-regulation of aldo-keto reductase (AKR) 1C3. MCF7 cell sensitivity to PTX toxicity was increased by pretreatment with AKR1C3 inhibitor and knockdown of this enzyme, and decreased by its overexpression, inferring a crucial role of AKR1C3 in the development of PTX resistance. The PTX-resistant cells were much less sensitive to 4-hydroxy-2-nonenal and acrolein, cytotoxic reactive aldehydes derived from ROS-mediated lipid peroxidation, compared with the parental cells. Additionally, the resistant cells lowered levels of 4-hydroxy-2-nonenal formed during PTX treatment, which was mitigated by pretreating with AKR1C3 inhibitor, suggesting that AKR1C3 procures the chemoresistance through facilitating the metabolism of the cytotoxic aldehyde. The gain of PTX resistance additively promoted the aberrant expression of an ATP-binding cassette (ABC) transporter ABCB1 among the ABC transporter isoforms. The combined treatment with AKR1C3 and ABCB1 inhibitors overcame the PTX resistance and cross-resistance to another taxane-based drug docetaxel. Collectively, combined treatment with AKR1C3 and ABCB1 inhibitors may exert an overcoming effect of PTX resistance in breast cancer.

Acute and sub-acute oral toxicity Lagerstroemia speciosa in Sprague-Dawley rats.

Through the boost of the natural medicinal market, individuals began to use a variety of organic materials in the marketed herbal preparation. Lagerstroemia speciosa (LS) leaves are known as banaba. People have been using a decoction of LS leaves as antidiabetic. The study aimed to investigate the acute and sub-acute oral toxicity of LS in Sprague-Dawley rats. The acute toxicity was determined by a single oral dose of LS (2000 mg/kg). Therein animal behaviour and mortality rate were observed for 14 days. The LS (200 mg/kg) was given for 28 days daily in the sub-acute study. The body weight, organ weight, food, water intake, biochemical, haematological parameters, and histopathology were studied. The findings of this study showed no mortality or morbidity was found in acute and sub-acute toxicity studies in rats. Additionally, no significant variations were found in the respective weight of organ, haematological and biochemical parameters of treated groups with reference to the control group. Moreover, no visible histological changes were detected in the liver of treated groups with reference to the control. In conclusion, the oral administration of LS did not fabricate any major toxic effect in rats. No toxic consequences were reported during acute and sub-acute toxicity investigations. Overall, LS is a safe, natural bio-actives as studied. Further investigations of cytotoxicity and genotoxicity of the above drug(s) or their combinations may be executed for appreciative safety.

Evaluation of the antioxidative potential of diisopropyldithiocarbamates sodium salt on diclofenac-induced toxicity in male albino rats.

Diclofenac (DIC) is a non-steroidal anti-inflammatory drug (NSAID) which is known to induce oxidative stress. Dithiocarbamates are compounds with proven antioxidant effect. The aim of the present study was to investigate the antioxidant capacity of diisopropyldithiocarbamates sodium salt (a synthetized compound) (Na(i-Pr2dtc)) against diclofenac-induced toxicity in the testes of male Wistar albino rats. The animals were assigned into six groups of six rats each. Group 1 (control) received corn oil, Groups 2, 3, 4, 5, 6 received DIC (100 mg/kg), DIC and (Na(i-Pr2dtc) (30 mg/kg), DIC and vitamin E (30 mg/kg), (Na(i-Pr2dtc) (30 mg/kg) and vitamin E only respectively. Our findings show that treatment with DIC significantly reduced superoxide dismutase (SOD) activity by 42% compared to normal control (NC) animals. In DIC treated group, Na(i-Pr2dtc) caused a 17% elevation of catalase (CAT) activity compared to DIC only group. Reduced glutathione level was significantly reduced in DIC only treated group when compared with DIC and VIT E treated group. Photomicrographs of testis from Na(i-Pr2dtc) treated rats showed normal seminiferous epithelium with no lesions. In conclusion, Na(i-Pr2dtc) has antioxidant properties.

Time course of changes in inflammatory and oxidative biomarkers in lung tissue of mice induced by exposure to electronic cigarette aerosol.

Significance: Electronic cigarettes (e-cigarettes) have become a popular way to smoke all over the world. Chronic exposure to e-cigarette aerosol may influence lung health. This study uses an animal model to explore the time course of the effect of exposure to e-cigarette aerosols on the lung. Methods: Lung samples were collected after exposure of Balb/c mice to e-cigarette aerosols for 1 h/day (6 times/week) for 1, 2 and 4 weeks and compared to sham-exposed controls. Examined biomarkers including inflammatory cells, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), and Thiobarbituric acid reactive substances (TBARS). Results: Exposure of animals to e-cigarette aerosols induced significant increases (P < 0.05) in total inflammatory cells, eosinophils, macrophages and TNFα in the lung tissue after 1, 2 and 4 weeks of exposure. Furthermore, level of IL-10 significantly decreased, whereas levels of neutrophils and basophils significantly increased (P < 0.05) after 1 week of exposure. Exposure of animals to e-cigarette aerosol also induced significant decreases (P < 0.05) in the GSH/GSSG ratio, and GPx levels after 2 and 4 weeks of exposures. The activity of catalase was also reduced (P < 0.05) after 4 weeks of exposure. Level of TBARS showed a trend of elevation with time and it reached a significant elevation after 4 weeks (P < 0.01). Conclusion: Current results indicate that inhalation of unflavored e-cigarette aerosol might be associated with inflammation in lung tissue that worsen as the duration of exposure increases. Further experiments including more time points, histopathology and pulmonary physiology experiments are needed to confirm the current results.

Migraine in Patients Undergoing PFO Closure: Characterization of a Platelet-Associated Pathophysiological Mechanism: The LEARNER Study.

The association between migraine and patent foramen ovale (PFO) has been documented. We aimed to investigate platelet activation, prothrombotic phenotype, and oxidative stress status of migraineurs with PFO on 100 mg/day aspirin, before and 6 months after PFO closure. Data show that, before PFO closure, expression of the classical platelet activation markers is comparable in patients and aspirin-treated healthy subjects. Conversely, MHA-PFO patients display an increased prothrombotic phenotype (higher tissue factorpos platelets and microvesicles and thrombin-generation potential), sustained by an altered oxidative stress status. This phenotype, which is more controlled by P2Y12-blockade than by aspirin, reverted after PFO closure together with a complete migraine remission. (pLatelEts And MigRaine iN patEnt foRamen Ovale [LEARNER]; NCT03521193).

A hybrid bacterium with tumor-associated macrophage polarization for enhanced photothermal-immunotherapy.

Remodeling the tumor microenvironment through reprogramming tumor-associated macrophages (TAMs) and increasing the immunogenicity of tumors via immunogenic cell death (ICD) have been emerging as promising anticancer immunotherapy strategies. However, the heterogeneous distribution of TAMs in tumor tissues and the heterogeneity of the tumor cells make the immune activation challenging. To overcome these dilemmas, a hybrid bacterium with tumor targeting and penetration, TAM polarization, and photothermal conversion capabilities is developed for improving antitumor immunotherapy in vivo. The hybrid bacteria (B.b@QDs) are prepared by loading Ag2S quantum dots (QDs) on the Bifidobacterium bifidum (B.b) through electrostatic interactions. The hybrid bacteria with hypoxia targeting ability can effectively accumulate and penetrate the tumor tissues, enabling the B.b to fully contact with the TAMs and mediate their polarization toward M1 phenotype to reverse the immunosuppressive tumor microenvironment. It also enables to overcome the intratumoral heterogeneity and obtain abundant tumor-associated antigens by coupling tumor penetration of the B.b with photothermal effect of the QDs, resulting in an enhanced immune effect. This strategy that combines B.b-triggered TAM polarization and QD-induced ICD achieved a remarkable inhibition of tumor growth in orthotopic breast cancer.

A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus.

Background & Aims: High-dose irradiation is an essential tool to help control the growth of hepatic tumors, but it can cause radiation-induced liver disease (RILD). This life-threatening complication manifests itself months following radiation therapy and is characterized by fibrosis of the pericentral sinusoids. In this study, we aimed to establish a mouse model of RILD to investigate the underlying mechanism of radiation-induced liver fibrosis. Methods: Using a small animal image-guided radiation therapy platform, an irradiation scheme delivering 50 Gy as a single dose to a focal point in mouse livers was designed. Tissues were analyzed 1 and 6 days, and 6 and 20 weeks post-irradiation. Irradiated livers were assessed by histology, immunohistochemistry, imaging mass cytometry and RNA sequencing. Mitochondrial function was assessed using high-resolution respirometry. Results: At 6 and 20 weeks post-irradiation, pericentral fibrosis was visible in highly irradiated areas together with immune cell infiltration and extravasation of red blood cells. RNA sequencing analysis showed gene signatures associated with acute DNA damage, p53 activation, senescence and its associated secretory phenotype and fibrosis. Moreover, gene profiles of mitochondrial damage and an increase in mitochondrial DNA heteroplasmy were detected. Respirometry measurements of hepatocytes in vitro confirmed irradiation-induced mitochondrial dysfunction. Finally, the highly irradiated fibrotic areas showed markers of reactive oxygen species such as decreased glutathione and increased lipid peroxides and a senescence-like phenotype. Conclusions: Based on our mouse model of RILD, we propose that irradiation-induced mitochondrial DNA instability contributes to the development of fibrosis via the generation of excessive reactive oxygen species, p53 pathway activation and a senescence-like phenotype. Lay summary: Irradiation is an efficient cancer therapy, however, its applicability to the liver is limited by life-threatening radiation-induced hepatic fibrosis. We have developed a new mouse model of radiation-induced liver fibrosis, that recapitulates the human disease. Our model highlights the role of mitochondrial DNA instability in the development of irradiation-induced liver fibrosis. This new model and subsequent findings will help increase our understanding of the hepatic reaction to irradiation and to find strategies that protect the liver, enabling the expanded use of radiotherapy to treat hepatic tumors.

Comparative study of the antioxidant activity of the essential oils of five plants against the H2O2 induced stress in Saccharomyces cerevisiae.

The purpose of this work was to investigate the protective effect of five essential oils (EOs); Rosmarinus officinalis, Thymus vulgaris, Origanum compactum Benth., Eucalyptus globulus Labill. and Ocimum basilicum L.; against oxidative stress induced by hydrogen peroxide in Saccharomyces cerevisiae. The chemical composition of the EOs was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The in vitro antioxidant activity was evaluated and the protective effect of EOs was investigated. Yeast cells were pretreated with different concentrations of EOs (6.25-25 µg/ml) for an hour then incubated with H2O2 (2 mM) for an additional hour. Cell viability, antioxidants (Catalase, Superoxide dismutase and Glutathione reductase) and metabolic (Succinate dehydrogenase) enzymes, as well as the level of lipid peroxidation (LPO) and protein carbonyl content (PCO) were evaluated. The chemical composition of EOs has shown the difference qualitatively and quantitatively. Indeed, O. compactum mainly contained Carvacrol, O. basilicum was mainly composed of Linalool, T. vulgaris was rich in thymol, R. officinalis had high α-Pinene amount and for E. globulus, eucalyptol was the major compound. The EOs of basil, oregano and thyme were found to possess the highest amount of total phenolic compounds. Moreover, they have shown the best protective effect on yeast cells against oxidative stress induced by H2O2. In addition, in a dose dependent manner of EOs in yeast medium, treated cells had lower levels of LPO, lower antioxidant and metabolic enzymes activity than cells exposed to H2O2 only. The cell viability was also improved. It seems that the studied EOs are efficient natural antioxidants, which can be exploited to protect against damages and serious diseases related to oxidative stress.

Watermelon rind ethanol extract exhibits hepato-renal protection against lead induced-impaired antioxidant defenses in male Wistar rats.

Lead acetate associated tissue injury has been linked to altered antioxidant defenses, hyperuricemia and inflammation. We hypothesized that watermelon rind extract, would ameliorate lead acetate-induced hepato-renal injury. Thirty Male Wistar rats received distilled water, lead acetate (Pb; 5 mg/kg) with or without watermelon rind extract (WM; 400 mg/kg; WM + Pb; 15 days of WM pretreatment); Pb + WM (15 days of WM post treatment) and simultaneous treatment (WM-Pb) for 30 days. Lead toxicity led to elevated serum malondialdehyde, creatinine, urea, uric acid, lactate dehydrogenase, liver injury enzymes, as well as decreased body weight. Decreased serum levels of reduced glutathione, nitric oxide, total protein and glutathione peroxidase activity was also observed. However, these alterations were ameliorated by watermelon rind extract in lead acetate-treated rats. Watermelon rind ethanol extract protects against lead acetate-induced hepato-renal injury through improved antioxidant defenses at least in part, via uric acid/nitric oxide-dependent pathway signifying the health benefits of this agricultural waste and a potential for waste recycling while limiting environmental pollution.