Effects of the tetravanadate [V4O12]4- anion on the structural, magnetic, and biological properties of copper/phenanthroline complexes.

The aim to access linked tetravanadate [V4O12]4- anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4'-dimethioxy-2,2'-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4- anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cu⋯O/Cu⋯Cu bridges. Stability studies of water-soluble 3 and 4 by UV-Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium-copper(II) systems.

Edible and medicinal mushrooms (Pleurotus ostreatus, Ustilago maydis, Ganoderma lucidum) reduce endoplasmic reticulum stress and inflammation in adipose tissue of obese Wistar rats fed with a high fat plus saccharose diet.

Obesity is an increasing global public health problem. A strategy to treat obesity is the use of functional foods. Edible and medicinal mushrooms contain diverse bioactive compounds showing important antihyperlipidemic, antioxidant, and prebiotic properties. We analysed the effects of adding (10%) of Pleurotus ostreatus (Po, basidiomata), Ganoderma lucidum (Gl, basidiomata), or Ustilago maydis (Um, galls), milled, to a high fat plus saccharose diet (HFD + S) for 6 months in a model of obesity with Wistar rats. We assessed weight gain, body composition, lipid parameters, endoplasmic reticulum stress (proteins and inflammatory markers: BiP, XBP-1, JNK, p-JNK, TNF-α), and adiponectin in subcutaneous adipose tissue (SAT). The consumption of edible and medicinal mushrooms decreased weight gain (-17.2-30.1%) and fat mass (-23.7-43.1%), maintained fat-free mass, reduced levels of serum biochemical parameters (TC: -40.1-44.1%, TG: -37.7-51.6%, LDL-C: -64.5-71.1%), and prevented adipocyte hypertrophy (-30.9-36.9%) and collagen deposition (-70.9-73.7%) in SAT. Compared with the HFD + S group, mushroom consumption by Wistar rats significantly reduced the expression of proteins associated with endoplasmic reticulum stress and inflammation (BiP: -72.2-88.2%; XBP-1: -71.5-81.8%; JNK: -71.2-90.0%; p-JNK: -37.3-81.0%; TNF-α: -80.7-91.5%), whereas significantly increased adiponectin protein expression (246.4-654.2%) in SAT. These effects outperformed those obtained through the commercial lipid-lowering drug atorvastatin, contributing synergistically to prevent further obesity-related dysfunctions, such as insulin resistance derived from inflammation and ER stress in adipose tissue. Bioactive compounds from edible, functional and medicinal mushrooms represent new emerging therapies for obesity treatments using natural products.

Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer.

Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.

Bis(benzimidazole)amino thio- and selenoether Iron(II) complexes as proton reduction electrocatalysts.

Two novel Iron (II) complexes featuring tetrapodal bis(benzimidazole)amino thio- and selenoether ligands (LS and LSe) were synthesized, characterized, and tested as electrocatalysts for the hydrogen evolution reaction. The bromide complexes [Fe(LS,LSe)Br2] (1-2) are highly insoluble, but their DMSO solvates were characterized by single crystal X-ray diffraction, revealing an octahedral coordination environment that does not feature coordination of the chalcogen atoms. The corresponding triflate derivatives [Fe(LS,LSe)(MeCN)3]OTf2 (1c-2c) were employed for electrocatalytic proton reduction, with 1c exhibiting higher activity, thus suggesting that the thioether may participate as a more competent pendant ligand for proton transfer.

Prevalence of Gastric Preneoplastic Lesions in First-Degree Relatives of Patients with Gastric Cancer: a Cross-Sectional Study.

PURPOSE: Worldwide, gastric cancer (GC) is the 5th cancer with the highest incidence and the 4th in mortality. To reduce it, one strategy is to diagnose preneoplastic lesions (PNL): atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia (DYS); to form risk groups on which to focus surveillance efforts as are first-degree relatives (FDR). The aim of this study was to determine prevalence of gastric PNL in FDR of patients with GC, and to study association with sex, age, and Helicobacter pylorii (Hp) infection. METHODS: Cross-sectional study. One hundred and ten FDR, aged between 50 and 65 years, 54.5 female, obtained through convenience sampling, were studied. Biodemographic data survey and upper gastrointestinal endoscopy with histological study were applied according to Sidney protocol, and focal lesions found. Diagnosis of these lesions and condition of mucosa was carried out by applying OLGA and OLGIM systems. Descriptive statistics, estimation of prevalence, odds ratio (OR), and 95% confidence intervals (95CI) were calculated. RESULTS: Median age of study group was 56.5 years. Prevalence of PNL, AG, IM, and DYS were 86.4%, 82.7%, 54.5%, and 12.7% respectively. Advanced stages of OLGA and OLGIM were verified in 18.0% and 16.3% respectively. No association with sex, age, and Hp infection were found ([OR 3.10; 95CI 1.0; 9.64]; [OR 0.74; 95CI 0.26; 2.14]; [OR 0.58; 95CI 0.12; 2.77]) respectively. CONCLUSION: FDR of patients with GC have a high prevalence of PNL, which makes them a risk group in which endoscopic surveillance should be applied.

Self-assembled nickel cubanes as oxygen evolution catalysts.

Ni4O4 cubanes [(µ3-L1O)NiCl(MeOH)]4 (1) and [(µ3-L2O)NiCl(H2O)]4 (2) (L1OH = 1-H-2-benzimidazolylmethanol, L2OH = 1-methyl-2-benzimidazolylmethanol) self-assemble from commercially available 1-H- and 1-methyl-2-benzimidazolylmethanol and NiCl2·6H2O in high yields under mild conditions. Both complexes were characterised spectroscopically and by X-ray crystallography. The cubanes oxidise water electrocatalytically to dioxygen at neutral pH in aqueous potassium phosphate buffer solutions.

Calidad de vida laboral y desempeño laboral en médicos del Instituto Mexicano del Seguro Social de Bienestar, en el estado de Chiapas / Quality Of Work-Life And Work Performance In Physicians At The Mexican Institute Of Social Security, In The State Of Chiapas

Introducción: Mantener una calidad de vida laboral trae como beneficio una mayor productividad. Objetivo: Conocer si la calidad de vida laboral es predictor significativo del nivel de desempeño laboral autopercibido por los médicos que laboran en el Instituto Mexicano del Seguro Social de Bienestar, en el estado de Chiapas, México. Material y métodos. El estudio tuvo un enfoque cuantitativo, transversal y predictivo. La población estuvo formada por 445 médicos. El tipo de muestreo fue no probabilístico por conveniencia, ya que se seleccionó a los médicos que laboran en el Instituto Mexicano del Seguro Social (IMMSS) Bienestar, en el estado de Chiapas. La muestra fue de 169 médicos que representan el 37.97% de la población. Se realizó un análisis de regresión lineal simple por el método de pasos sucesivos. Resultados. Se encontró que la variable nivel de calidad de vida laboral explicó el 64.9% de la varianza de la variable dependiente nivel de desempeño laboral. De igual manera, se determinó que existe una influencia lineal positiva y significativa entre las variables. Se encontró que la variable calidad de vida laboral es un predictor significativo del desempeño laboral de manera muy importante (ß = .806). Conclusiones. Se encontró que la calidad de vida laboral influye en el desempeño laboral de los médicos que laboran en el Instituto Mexicano del Seguro Social de Bienestar, en el estado de Chiapas de manera muy importante. En la medida que los médicos encuestados mejoren su calidad de vida laboral influirá en su desempeño laboral.

Introduction: Maintaining a quality of working life brings as a benefit a greater productivity. Objective: To know if the quality of work life is a significant predictor of the level of self-perceived work performance by the doctors who work at the Mexican Institute of Social Security of Well-being, in the state of Chiapas. Material and methods: The study had a quantitative, cross-sectional and predictive approach. The population consisted of 445 doctors. The type of sampling was non-probabilistic for convenience, since the doctors who work in the Mexican Institute of Social Security (IMMSS) Bienestar, in the state of Chiapas, were selected. The sample consisted of 169 physicians who represent 37.97% of the population. A simple linear regression analysis was carried out by the method of successive steps. Results: It was found that the variable level of working life described 64.9% of the variance of the dependent variable level of job performance. Similarly, it was determined that there is a positive and significant linear influence between the variables. The quality of work life variable was found to be a significant predictor of work performance in a very important way (ß = .806). Conclusions: It was found that the quality of work life influences the work performance of the doctors who work in the Mexican Institute of Social Security of Well-being, in the state of Chiapas in a very important way. To the extent that the surveyed doctors improve their quality of work life, it will influence their work performance.

Mexican Ganoderma Lucidum Extracts Decrease Lipogenesis Modulating Transcriptional Metabolic Networks and Gut Microbiota in C57BL/6 Mice Fed with a High-Cholesterol Diet.

Prevention of hyperlipidemia and associated diseases is a health priority. Natural products, such as the medicinal mushroom Ganoderma lucidum (Gl), have demonstrated hypocholesterolemic, prebiotic and antidiabetic properties. However, the underlying transcriptomic mechanisms by which Gl exerts bioactivities are not completely understood. We report a comprehensive hepatic and renal transcriptome profiling of C57BL/6 mice under the consumption of a high-cholesterol diet and two standardized Gl extracts obtained from basidiocarps cultivated on conventional substrate (Gl-1) or substrate containing acetylsalicylic acid (ASA; Gl-2). We showed that Gl extracts modulate relevant metabolic pathways involving the restriction of lipid biosynthesis and the enrichment of lipid degradation and secretion. The Gl-2 extract exerts a major modulation over gene expression programs showing the highest similarity with simvastatin druggable-target-genes and these are enriched more in processes related to human obesity alterations in the liver. We further show a subset of Gl-modulated genes correlated with Lactobacillus enrichment and the reduction of circulating cholesterol-derived fats. Moreover, Gl extracts induce a significant decrease of macrophage lipid storage, which occurs concomitantly with the down-modulation of Fasn and Elovl6. Collectively, this evidence suggests a new link between Gl hypocholesterolemic and prebiotic activity, revealing thereby that standardized Mexican Gl extracts are a novel transcriptome modulator to prevent metabolic disorders associated with hypercholesterolemia.

Pro-Resolving Lipid Mediator Resolvin E1 Mitigates the Progress of Diethylnitrosamine-Induced Liver Fibrosis in Sprague-Dawley Rats by Attenuating Fibrogenesis and Restricting Proliferation.

Liver fibrosis is a complex process associated to most types of chronic liver disease, which is characterized by a disturbance of hepatic tissue architecture and the excessive accumulation of extracellular matrix. Resolvin E1 (RvE1) is a representative member of the eicosapentaenoic omega-3 lipid derivatives, and is a drug candidate of the growing family of endogenous resolvins. Considering the aforementioned, the main objective of this study was to analyze the hepatoprotective effect of RvE1 in a rat model of liver fibrosis. Male Sprague-Dawley rats received diethylnitrosamine (DEN, 70 mg/mg body weight intraperitoneally (i.p)) as an inductor of liver fibrosis once weekly and RvE1(100 ng/body weight i.p) twice weekly for four weeks. RvE1 suppressed the alterations induced by DEN, normalizing the levels of alanine aminotransferase (ALT), albumin, and lactate dehydrogenase (LDH), and ameliorated DEN injury by decreasing the architecture distortion, inflammatory infiltration, necrotic areas, and microsteatosis. RvE1 also limited DEN-induced proliferation through a decrease in Ki67-positive cells and cyclin D1 protein expression, which is related to an increase of the levels of cleaved caspase-3. Interestingly, we found that RvE1 promotes higher nuclear translocation of nuclear factor κB (NF-κB)p65 than DEN. RvE1 also increased the levels of nuclear the nuclear factor erythroid 2-related factor 2 (Nrf2), but with no antioxidant effect, measured as an increase in glutathione disulfide (GSSG) and a decrease in the ratio of glutathione (GSH)/GSSG. Taken together, these results suggest that RvE1 modulates the fibrogenesis, steatosis, and cell proliferation in a model of DEN induced fibrosis.

Phytochemical Analysis and Antioxidant and Anti-Inflammatory Capacity of the Extracts of Fruits of the Sechium Hybrid.

In addition to their own antioxidants, human cells feed on external antioxidants, such as the phenolic compounds of fruits and vegetables, which work together to keep oxidative stress in check. Sechium edule, an edible species of chayote, has phenolic compounds with antioxidant activity and antineoplastic activity. A Sechium hybrid shows one thousand times greater antineoplastic activity than edible species, but its antioxidant and anti-inflammatory activities and the content of phenolic compounds are unknown. The aim of this study was to determine the antioxidant and anti-inflammatory capacity of the extract of fruits of the Sechium hybrid in vitro and in vivo. Phytochemical analysis using HPLC showed that the extract of the Sechium hybrid has at least 16 phenolic compounds; galangin, naringenin, phloretin and chlorogenic acid are the most abundant. In an in vitro assay, this extract inhibited 2,2-diphenyl-L-picrylhydrazyl (DPPH) activity and protected the dimyristoylphosphatidylethanolamine (DMPE) phospholipid model cell membrane from oxidation mediated by hypochlorous acid (HClO). In vivo, it was identified that the most abundant metabolites in the extract enter the bloodstream of the treated mice. On the other hand, the extract reduces the levels of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin-6 (IL-6) but increases interleukin-10 (IL-10) and glutathione peroxidase levels. Our findings indicate that intake of the fruits of the Sechium hybrid leads to antioxidant and anti-inflammatory effects in a mouse model. Therefore, these results support the possibility of exploring the clinical effect of this hybrid in humans.

Synthesis, structure, and biological activity of bis(benzimidazole)amino thio- and selenoether nickel complexes.

Four new nickel (II) complexes with bis(benzimidazole)thio- and selenoether-based ligands have been synthesized and characterized in the solid state by elemental analysis, IR, magnetic susceptibility and X-ray crystallography, and in solution by FAB+ mass spectrometry, UV-vis spectroscopy and cyclic voltammetry. Single-crystal X-ray diffraction analysis of the compounds revealed octahedral geometries for all nickel centers. Three of the four complexes are dimers with chloride bridges between the two Ni(II) ions. However, in solution all complexes have a monomeric formulation, based on mass spectrometry and osmometry measurements. The complexes were also screened for their cytotoxic activity on human cell lines (HeLa, SK-LU-1 and HEK-293), and compared with a related Cu(II) complex.

Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats.

Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.

Conformational Effects of [Ni2 (µ-ArS)2 ] Cores on Their Electrocatalytic Activity.

Two nickel complexes supported by tridentate NS2 ligands, [Ni2 (κ-N,S,S,S'-NPh {CH2 (MeC6 H2 R')S}2 )2 ] (1; R'=3,5-(CF3 )2 C6 H3 ) and [Ni2 (κ-N,S,S,S'-NiBu {CH2 C6 H4 S}2 )2 ] (2), were prepared as bioinspired models of the active site of [NiFe] hydrogenases. The solid-state structure of 1 reveals that the [Ni2 (µ-ArS)2 ] core is bent, with the planes of the nickel centers at a hinge angle of 81.3(5)°, whereas 2 shows a coplanar arrangement between both nickel(II) ions in the dimeric structure. Complex 1 electrocatalyzes proton reduction from CF3 COOH at -1.93 (overpotential of 1.04 V, with icat /ip ≈21.8) and -1.47 V (overpotential of 580 mV, with icat /ip ≈5.9) versus the ferrocene/ferrocenium redox couple. The electrochemical behavior of 1 relative to that of 2 may be related to the bent [Ni2 (µ-ArS)2 ] core, which allows proximity of the two Ni⋅⋅⋅Ni centers at 2.730(8) Å; thus possibly favoring H+ reduction. In contrast, the planar [Ni2 (µ-ArS)2 ] core of 2 results in a Ni⋅⋅⋅Ni distance of 3.364(4) Šand is unstable in the presence of acid.

Outstanding reversible H2S capture by an Al(iii)-based MOF.

The MOF-type MIL-53(Al)-TDC was demonstrated to be an optimal adsorbent for H2S capture combining an unprecedented uptake at room temperature, excellent cyclability and low-temperature regeneration.

Easily reduced bis-pincer (NS2)2molybdenum(iv) to (NHS2)2Mo(ii) by alcohols vs. redox-inert (NS2)(NHS2)iron(iii) complexes.

Iron and molybdenum complexes supported by a pincer-type dianionic [NS2]2- donor were prepared to compare their structural, spectroscopic, and electrochemical properties. The versatility of the [NS2]2Mo(iv) complex (2) to access different oxidation states was evidenced in the activation of methanol and isopropanol, oxidising them to formaldehyde or acetone with concomitant reduction and protonation to afford [NHS2]2Mo(ii), complex (3). This redox behaviour contrasts with the null reactivity observed for the analogous ferric complex [NS2][NHS2]Fe(iii) (1). Complex 2 presents a quasi-reversible process at E1/2 = -0.80 V relative to the ferrocenium/ferrocene couple (Fc+/Fc), which is attributed to the Mo(iv)/Mo(v) redox couple. Two irreversible cathodic processes were observed at Ecp = -1.59 and -2.20 V, which are attributed to the Mo(iv)/Mo(iii) and Mo(iii)/Mo(ii) redox couples. Cyclic voltammetry and solid-state structures obtained by X-ray crystallography support a 2H+ and 2e- process, whereby the Mo(iv) centre in 2 is reduced sequentially to Mo(iii), and finally to Mo(ii) in 3. These redox events were observed at Ecp = -1.22 and -2.15 V (vs. Fc+/Fc) in the anodic cyclic voltammograms of 2 in THF in the presence of acid. A new reduction peak was detected under these conditions at Ecp = -2.30 V, consistent with electrocatalytic proton reduction. This was corroborated for 2 as a catalyst precursor in the presence of increasing amounts of p-toluenesulfonic acid, with the addition of 2 to 14 equivs resulting in an increase of the current measured.

Calix[8]arene nanoreactor for Cu(I)-catalysed C-S coupling.

The catalytic activity of Cu(i) confined within a phenanthroline-containing calix[8]arene derivative was tested in C-S cross-coupling reactions. The substrate selectivity, solvent dependence, and catalyst loading differ significantly from those reported for bimetallic molecular systems. The putative monomeric complex represents the first calix[8]arene functionalised for endo-oriented metal chelation used as a nanoreactor.

Thyroid hormone in the frontier of cell protection, survival and functional recovery.

Thyroid hormone (TH) exerts important actions on cellular energy metabolism, accelerating O2 consumption with consequent reactive oxygen species (ROS) generation and redox signalling affording cell protection, a response that is contributed by redox-independent mechanisms. These processes underlie genomic and non-genomic pathways, which are integrated and exhibit hierarchical organisation. ROS production led to the activation of the redox-sensitive transcription factors nuclear factor-κB, signal transducer and activator of transcription 3, activating protein 1 and nuclear factor erythroid 2-related factor 2, promoting cell protection and survival by TH. These features involve enhancement in the homeostatic potential including antioxidant, antiapoptotic, antiinflammatory and cell proliferation responses, besides higher detoxification capabilities and energy supply through AMP-activated protein kinase upregulation. The above aspects constitute the molecular basis for TH-induced preconditioning of the liver that exerts protection against ischemia-reperfusion injury, a strategy also observed in extrahepatic organs of experimental animals and with other types of injury, which awaits application in the clinical setting. Noteworthy, re-adjusting TH to normal levels results in several beneficial effects; for example, it lengthens the cold storage time of organs for transplantation from brain-dead donors; allows a superior neurological outcome in infants of <28 weeks of gestation; reduces the cognitive side-effects of lithium and improves electroconvulsive therapy in patients with bipolar disorders.

Thyroid hormone-induced cytosol-to-nuclear translocation of rat liver Nrf2 is dependent on Kupffer cell functioning.

L-3,3',5-triiodothyronine (T(3)) administration upregulates nuclear factor-E2-related factor 2 (Nrf2) in rat liver, which is redox-sensitive transcription factor mediating cytoprotection. In this work, we studied the role of Kupffer cell respiratory burst activity, a process related to reactive oxygen species generation and liver homeostasis, in Nrf2 activation using the macrophage inactivator gadolinium chloride (GdCl(3); 10 mg/kg i.v. 72 h before T(3) [0.1 mg/kg i.p.]) or NADPH oxidase inhibitor apocynin (1.5 mmol/L added to the drinking water for 7 days before T(3)), and determinations were performed 2 h after T(3). T(3) increased nuclear/cytosolic Nrf2 content ratio and levels of heme oxygenase 1 (HO-1), catalytic subunit of glutamate cysteine ligase, and thioredoxin (Western blot) over control values, proteins whose gene transcription is induced by Nrf2. These changes were suppressed by GdCl(3) treatment prior to T(3), an agent-eliciting Kupffer-cell depletion, inhibition of colloidal carbon phagocytosis, and the associated respiratory burst activity, with enhancement in nuclear inhibitor of Nrf2 kelch-like ECH-associated protein 1 (Keap1)/Nrf2 content ratios suggesting Nrf2 degradation. Under these conditions, T(3)-induced tumor necrosis factor-α (TNF-α) response was eliminated by previous GdCl(3) administration. Similar to GdCl(3), apocynin given before T(3) significantly reduced liver Nrf2 activation and HO-1 expression, a NADPH oxidase inhibitor eliciting abolishment of colloidal carbon-induced respiratory burst activity without altering carbon phagocytosis. It is concluded that Kupffer cell functioning is essential for upregulation of liver Nrf2-signaling pathway by T(3). This contention is supported by suppression of the respiratory burst activity of Kupffer cells and the associated reactive oxygen species production by GdCl(3) or apocynin given prior to T(3), thus hindering Nrf2 activation.

Colloidal carbon stimulation of Kupffer cells triggers Nrf2 activation in the isolated perfused rat liver.

Activation of transcription factor Nrf2 was investigated in the isolated perfused rat liver infused with 0.5 mg of colloidal carbon (CC)/ml for 5-15 min to stimulated Kupffer cell function. Infusion of CC enhanced liver O(2) consumption over basal levels, with a time-dependent increase in CC-induced O(2) uptake, at constant rates of CC phagocytosis by Kupffer cells, as assessed histologically, and adequate viability conditions of the livers, as shown by the marginal (0.34 %) total sinusoidal lactate dehydrogenase (LDH) efflux over intrahepatic LDH activity. Under these conditions, cytosolic protein levels of Nrf2 (Western blot) and inhibitor of Nrf2 Keap1 progressively declined by CC infusion, those of nuclear Nrf2 increased, leading to enhancement in the nuclear/cytosolic Nrf2 ratios. It is concluded that the respiratory burst of CC-stimulated Kupffer cells triggers Nrf2 activation in the perfused liver, a response that may afford cellular protection under pro-oxidant conditions underlying Kupffer cell stimulation.