Assessment of the Relationship between Clinical Variants of Psoriasis and Killer Immunoglobulin-like Receptor (KIR) Genes: A Systematic Review with Meta-analysis.

BACKGROUND: Psoriasis (Ps) is an autoimmune dermatosis. Previous studies have shown an association between KIR genes and susceptibility to some clinical variants of Ps. Therefore, we conducted an exhaustive systematic review with meta-analysis to evaluate the relationship between KIR genes and susceptibility to clinical variants of Ps in the overall population and according to ethnicity. METHODS: According to PRISMA guidelines, we performed a systematic review through PubMed and Web of Science to identify relevant available scientific publications about KIR genes and Ps. The quality of the studies was evaluated using the Newcastle-Ottawa scale. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using random and fixed effect models for the analyzed genes. Heterogeneity was tested using Cochran's Q-Statistic and I2, and the risk of bias was tested using the Begg test and Egger linear regression. RESULTS: A total of 10 case-control studies were included, comprising a variable number of KIR typified genes and psoriasis vulgaris (PsV) as the main clinical variant studied. In the total pooled results, the KIR2DS1 gene (OR = 1.518, p = .010, 95%CI: 1.105 to 2.086) was related to higher susceptibility to PsV, while the KIR2DS4 (OR = 0.563, p = .005, 95%CI: 0.376 to 0.842) and KIR3DL1 (OR = 0.602, p = .040, 95%CI: 0.370 to 0.977) genes were related to protection against PsV. CONCLUSION: This meta-analysis demonstrates that subjects that carry the KIR2DS1 gene could have a potential risk factor for the development of PsV. Conversely, KIR2DS4 and 3DL1 genes appear to confer protection against PsV.

Association between IL-17A, IL-17F and IL-17RA gene polymorphisms and susceptibility to psoriasis and psoriatic arthritis: a meta-analysis.

BACKGROUND: Psoriasis (Ps) is a chronic dermatosis characterized by erythematous-squamous plaques derived from an inflammatory response. The effect of polymorphisms in the genes that encode the members of the IL-17 family and their receptors has been studied to find an association with the susceptibility to Ps. However, the findings have not been conclusive. OBJECTIVES: To describe the association between IL-17A, IL-17F and IL-17RA gene polymorphisms and susceptibility to Ps. METHOD: A systematic review was conducted using the PubMed and Scopus databases to identify studies that evaluated the association between IL-17A, IL-17F, and IL-17RA gene polymorphisms and Ps susceptibility. This meta-analysis included reports published until June 2021. Heterogeneity was assessed using Cochran's Q-statistic test and I2 statistics. The associations between polymorphisms and Ps susceptibility were determined by pooled OR with a 95% CI. RESULTS: Fifteen studies were included. The frequency of the T allele of the IL-17F rs763780 polymorphism was significantly lower in patients with vulgar Ps (OR = 0.732, p = 0.026). The TT genotype of the IL-17F rs763780 polymorphism was significantly associated with a decreased frequency in individuals with Ps and psoriatic arthritis (PsA) (TT:TC + CC OR = 0.664, p = 0.046). Regarding IL-17RA polymorphisms, the AG genotype of the rs4819554 polymorphism showed a near-significant decrease in psoriasis risk compared to the GG genotype (AG:GG OR = 0.604, p = 0.050). Other polymorphisms in IL-17A, IL-17F and IL-17RA showed no association with Ps. CONCLUSIONS: The T allele and TT genotype of the IL-17F rs763780 polymorphism may be associated with a decreased risk of psoriasis. Therefore, the implications of this variant on psoriasis pathogenesis and treatment require further investigation.

Association Study between Psoriatic Arthritis and Killer Immunoglobulin-Like Receptor (KIR) Genes: A Meta-Analysis.

Background: Psoriatic Arthritis (PsA) is a seronegative spondyloarthropathy frequently associated with psoriasis. Studies have shown different members of the KIR (Killer Immunoglobulin-like Receptor) gene family may act as potential susceptibility factors; however, data have been inconsistent or with a reduced sample size. Therefore, the objective of this investigation was to determine associations between KIR genes and PsA susceptibility a meta-analysis approach. Methods: We performed a systemic search on PubMed, Scopus, and Web of Science to identify association studies linking KIR genes with PsA susceptibility. The search cut-off was May 2019. Odds Ratio (OR), 95% Confidence Intervals (95% CI), and forest plots were obtained for each KIR gene. Publication bias was evaluated by Begg and Egger linear regression tests. Results: Five articles were included in this meta-analysis. The KIR2DL2, 2DS1, 2DS2, and 2DS3 genes were positively associated with susceptibility to PsA (OR = 1.269, p = .003; OR = 1.392, p < .001; OR = 1.279, p = .002; and OR = 1.230, p = .038, respectively). In Caucasians, positive association with susceptibility to PsA were maintained by KIR2DL2, 2DS1, and 2DS2 genes (OR = 1.257, p = .005; OR = 1.535, p = .003; and OR = 1.267, p = .004, respectively). Conclusion: These associations suggest that KIR2DL2, 2DS1, 2DS2, and 2DS3 genes are susceptibility factors for PsA.

Interaction between 17ß-estradiol, prolactin and human papillomavirus induce E6/E7 transcript and modulate the expression and localization of hormonal receptors.

BACKGROUND: Cervical cancer (CC) is the second most common cancer in less developed countries and the second leading cause of death by cancer in women worldwide. The 99% of CC patients are infected with the Human Papilloma Virus (HPV), being HPV16 and HPV18 infection the most frequent. Even though HPV is considered to be a necessary factor for the development of CC, it is not enough, as it requires the participation of other factors such as the hormonal ones. Several studies have demonstrated the requirement of estrogen and its receptors (ERα, ERß, and GPER) in the precursor lesions progress towards CC. Also, prolactin (PRL) and its receptor (PRLR) have been associated with CC. The molecular mechanisms underlying the cooperation of these hormones with the viral oncoproteins are not well elucidated. For this reason, this study focused on analyzing the contribution of 17ß-estradiol (E2), PRL, and HPV on the expression and localization of hormone receptors, as well as to evaluate whether these hormones may promote greater expression of HPV oncogenes and contribute to tumor progression. METHODS: qPCR was used to evaluate the effect of E2 and PRL on the expression of E6 and E7 oncoproteins in HeLa and SiHa cervical cancer cells lines. HaCaT cells were transduced with the viral oncogenes E6 and E7 from HPV 16 and 18. ERα, ERß, GPER, and PRLR expression and localization were evaluated by qPCR, Western blot and immunofluorescence. RESULTS: E2 and PRL induce E6/E7 oncogenes expression in HeLa and SiHa cells. E6 and E7 oncogenes of HPV16/18 significantly increased the protein expression of ERα, GPER, and PRLR. ERß was positively regulated only by E6 oncogenes of HPV16/18. Besides, some of these oncogenes modify the location of PRLR toward cytoplasm, and ERα, ERß, and GPER mainly to the nucleus. CONCLUSION: Our studies suggest that the mutual regulation between E2, PRL, and HPV oncogenes could cooperate with the carcinogenesis process in CC.

IL10 haplotypes are associated with diabetic nephropathy susceptibility in patients from western Mexico.

INTRODUCTION: Diabetic Nephropathy (DN) is the main cause of chronic kidney disease (CKD) in diabetic patients. An IL-10 imbalance could be related to renal hypertrophy and trigger to nephropathy. Three promoter polymorphisms (-1082G>A, -819C>T, and -592C>A) at IL10 gene have been associated with changes in the IL-10 expression and DN susceptibility. Therefore, the aim of this study was to analyze this association in Mexican patients with DN. METHODS: We conducted a case-control study on 128 patients with DN and 150 control subjects (CS) from western Mexico. All patients were tested for IL10 polymorphisms by PCR-RFLP. Allele frequencies, genotypes, and haplotypes were compared between groups. The significant haplotypes were correlated with patient clinical features. RESULTS: IL10 gene ATC haplotype (-1082A/-819T/-592C) was found significantly more frequent in DN patients than in CS (P < 0.001; OR = 3.6, 95% CI: 1.7-7.4). Similarly GTA (-1082G/-819T/-592A) haplotype was more frequent in DN patients than CS with significant differences (P < 0.05; OR = 4.02, 95% CI: 1.10-14.78). There were no correlations between IL10 haplotypes and clinical parameters in patients with DN. However, that there is a trend of higher serum urea levels and lower eGFR in ATC haplotype carriers compared to carriers of the other haplotypes (P < 0.05). CONCLUSIONS: These results indicate that IL10 promoter haplotypes ATC and GTA carriers have a higher risk factor to develop DN in the western Mexican population.

Role and New Insights of Pirfenidone in Fibrotic Diseases.

Pirfenidone (PFD) is a non-peptide synthetic molecule issued as a broad-spectrum anti-fibrotic drug with the ability to decrease TGF-ß1, TNF-α, PDGF and COL1A1 expression, which is highly related to prevent or remove excessive deposition of scar tissue in several organs. Basic and clinical evidence suggests that PFD may safely slow or inhibit the progressive fibrosis swelling after tissue injuries. Furthermore, a number of evidence suggests that this molecule will have positive effects in the treatment of other inflammatory diseases. This review contains current research in which PFD has been used as the treatment of several diseases, and focus mainly in the outcomes related to improve inflammation and fibrogenesis. Therefore, the main goal of this review is to focus on the novel findings of PFD efficacy rather than deepen in the chemical aspects of the molecule.

[Effects of alpha lipoic acid and pirfenidone on liver cells antioxidant modulation against oxidative damage]. / Efecto del ácido alfa lipoico y la pirfenidona en la modulación antioxidante celular contra el daño oxidativo.

BACKGROUND: Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. AIM: To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). MATERIAL AND METHODS: HepG2 cells and primary HSC cultures were exposed to menadione 0.1 µM (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 µM, 100 µM y 1000 µM). RESULTS: In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-ß1, TIMP1, IL6, TNFα and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. CONCLUSION: Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes.

Establishment of the upstream processing for renewable production of hydrogen using vermicomposting-tea and molasses as substrate.

This study aimed to establish the optimal operational conditions for hydrogen production using vermicomposting-tea and sugarcane molasses as substrate. The experiments were carried out by triplicate in 110 ml serological bottles, a Box-Behnken design of experiments was performed in anaerobic dark conditions. The maximal hydrogen production (HP), hydrogen production rate (HPR), and hydrogen yield (HY) attained were 1021.0 mlL-1, 5.32 mlL-1h-1, and 60.3 mlLH2-1/gTCC, respectively. The statistical model showed that the optimal operational conditions for pH, molasses concentration, and temperature were 6.5; 30 % (v/v) and 25 °C. The bioreactor run showed 17.202 L of hydrogen, 0.58 Lh-1, and 77.2 mlH2gTCC-1 For HP, HPR, and HY. Chemometric analysis for the volatile fatty acids obtained at the fermentation showed that only two principal components are required to explain 90 % of the variance. The representative pathways for hydrogen production were acetic and butyric acids. This study established the operational conditions for the upstream processing amenable to pilot and industrial-scale operations. Our results add value to molasses within the circular economy for hydrogen production using a novel consortium from vermicompost.

Multisystem Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Role of Oxidative Stress.

With the appearance of the SARS-CoV-2 virus in December 2019, all countries in the world have implemented different strategies to prevent its spread and to intensively search for effective treatments. Initially, severe cases of the disease were considered in adult patients; however, cases of older school-age children and adolescents who presented fever, hypotension, severe abdominal pain and cardiac dysfunction, positive for SARS-CoV-2 infection, have been reported, with increased pro-inflammatory cytokines and tissue damage, condition denominated multisystemic inflammatory syndrome (MIS-C); The emerging data from patients with MIS-C have suggested unique characteristics in the immunological response and also clinical similarities with other inflammatory syndromes, which can support as a reference in the search for molecular mechanisms involved in MIS-C. We here in propose that oxidative stress (OE) may play a very important role in the pathophysiology of MIS-C, such as occurs in Kawasaki disease (KD), severe COVID-19 in adults and other processes with characteristics of vascular damage similar to MIS- C, for which we review the available information that can be correlated with possible redox mechanisms.

Myostatin regulates the fibrogenic phenotype of hepatic stellate cells via c-jun N-terminal kinase activation.

BACKGROUND & AIMS: Myostatin is mainly expressed in skeletal muscle, where it negatively regulates trophism. This myokine is implicated in the pathophysiology of nonalcoholic steatohepatitis, an emerging cause of liver fibrosis. In this study we explored the effects of myostatin on the biology of hepatic stellate cells. METHODS: The effects of myostatin were assessed both in LX-2 and in human primary stellate cells. Cell migration was determined in Boyden chambers. Activation of intracellular pathways was evaluated by Western blotting. Procollagen type 1 secretion was measured by enzyme immunoassay. The role of c-Jun N-terminal kinase was assessed by pharmacologic and genetic inhibition. RESULTS: Activin receptor-2B was up-regulated in livers of mice with experimental fibrosis, and detectable in human stellate cells. Serum myostatin levels increased in a model of acute liver injury. Myostatin reduced HSC proliferation, induced cell migration, and increased expression of procollagen type1, tissue inhibitor of metalloproteinase-1, and transforming growth factor-ß1. Myostatin activated different signaling pathways, including c-Jun N-terminal kinase and Smad3. Genetic and/or pharmacologic inhibition of c-Jun N-terminal kinase activity significantly reduced cell migration and procollagen secretion in response to myostatin. CONCLUSIONS: Activation of activin receptor-2B by myostatin modulates the fibrogenic phenotype of human stellate cells, indicating that a myokine may be implicated in the pathogenesis of hepatic fibrosis.

GPER Overexpression in Cervical Cancer Versus Premalignant Lesions: Its Activation Induces Different Forms of Cell Death.

BACKGROUND: The effect of estrogen has been traditionally studied through the modulation of its alpha and beta nuclear receptors; however, the G Protein-Coupled Estrogen Receptor (GPER) has been recently involved in the pathology of numerous tumors. Although the study of GPER in cervical cancer has begun, its contribution still remains to be completely evaluated. OBJECTIVE: The purpose of this work was to determine the expression of this receptor in different degrees of cervical lesions and whether the stimulation with its specific agonist (G-1) modulated mechanisms of cell survival or cell death in cervical cancer cells. METHODS: Sections of 44 formalin-fixed paraffin-embedded blocks from patients were analyzed by automated immunohistochemistry. After the stimulation with G-1, proliferation was evaluated by the xCELLigence technology, the integrity of the mitochondrial membrane permeability by MitoCaptureTM fluorescence staining, apoptosis by flow cytometry, and senescence by the senescence-associated ß-galactosidase kit. RESULTS: GPER was widely expressed in cervical cancer but not in its precursor lesions. The staining was predominantly cytoplasmic, although it was also important in the nucleus of the epithelial cells. G-1 inhibited proliferation, decreased the mitochondrial permeability, and increased the percentage of apoptosis in SiHa, HeLa, and C-33A. Only in C-33A, an increase of the cells in necrosis was observed, whereas SiHa was the only cell line in which senescence was evidenced. CONCLUSION: GPER is a receptor associated with cervical cancer that inhibits the growth and induces different mechanisms of death in cells derived from uterine cervical cancer. It suggests that GPER can be considered a pharmacological target that prevents the development of cervical carcinogenesis.

Diet switch and omega-3 hydroxy-fatty acids display differential hepatoprotective effects in an obesity/nonalcoholic fatty liver disease model in mice.

AIM: To study the effect of 18-hydroxy-eicosapentaenoic acid (18-HEPE) and 17-hydroxy-docosahexaenoic acid (17-HDHA) in a murine model of obesity/nonalcoholic fatty liver disease. METHODS: C57BL/6 mice were fed with standard chow diet (CD) or high-fat, fructose-enriched diet (HFD) for 16 wk. Then, three groups were treated for 14 d with either, diet switch (HFD for CD), 18-HEPE, or 17-HDHA. Weight and fasting glucose were recorded on a weekly basis. Insulin tolerance test was performed at the end of treatment. Histological analysis (HE and Masson's trichrome stain) and determination of serum insulin, glucagon, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, adiponectin and resistin were carried out as well as liver proteins by western blot. RESULTS: Mice treated with hydroxy-fatty acids 18-HEPE and 17-HDHA displayed no weight loss or improved insulin sensitivity. However, these mice groups showed a significant amelioration on serum GLP-1, adiponectin and resistin levels. Also, a significant reduction on inflammatory infiltrate was observed at both portal and lobular zones. Furthermore, up-regulation of PPARα/γ protein levels was observed in liver tissue and it was associated with decreased levels of NF-κB also determined by western blot analysis. On the other hand, diet switch regimen resulted in a marked improvement in most parameters including: weight loss, increased insulin sensitivity, decreased steatosis, restored levels of insulin, glucagon, leptin, adiponectin and resistin. However, no significant changes were observed regarding inflammatory infiltrate in this last group. CONCLUSION: 18-HEPE and 17-HDHA differentially exert hepatoprotective effects through up-regulation of nuclear receptors PPARα/γ and amelioration of serum adipokines profile.

Effects of 60 kDa prolactin and estradiol on metabolism and cell survival in cervical cancer: Co­expression of their hormonal receptors during cancer progression.

Estrogens and estrogen receptors (ERs), such as ERα and ERß, prolactin (PRL) and prolactin receptor (PRLR) have been reported to be involved in the physiopathology of uterine cervical cancer (UCC). The 60 kDa PRL is an isoform of PRL, which is produced by UCC­derived cells. The present study aimed to evaluate the expression of hormonal receptors in different degrees of cervical lesions, and to determine whether 60 kDa PRL and 17ß­estradiol (E2) modulated cell survival and metabolism in UCC cells, and in HaCaT cells transduced with human papillomavirus (HPV) 16 and 18 E6/E7 oncogenes. ERα, ERß, PRLR, Ki67 and B­cell lymphoma 2 expression levels were analyzed in biopsies of precursor lesions and UCC using immunohistochemistry. In addition, HeLa, SiHa and C33A cells, and transduced HaCaT cells, were stimulated with 60 kDa PRL, E2 or a combination of both. Proliferation was evaluated using the xCELLigence platform, apoptosis was analyzed by flow cytometry and cell metabolism was determined using the MTT assay. The results revealed that ERα, ERß, PRLR and Ki67 expression levels were increased during the progression of cancer. In vitro, 60 kDa PRL alone significantly increased proliferation of SiHa cells. Furthermore, E2 alone or in combination with 60 kDa PRL increased the sensitivity of SiHa cells to cisplatin and increased the percentage of apoptosis; in HaCaT cells, these treatment strategies had the opposite effect on cisplatin sensitivity. Treatment with E2 increased mitochondrial activity in HeLa and SiHa cells, and in HaCaT cells transduced with HPV 16 E6/E7 and HPV 18 E6 oncogenes. PRL had a similar effect on HeLa cells, and on HaCaT cells transduced with HPV 18 E6 and HPV 16 E7. The co­expression of these receptors demonstrated the hormonal dependence of UCC. In addition, E2 and the 60 kDa PRL significantly impacted the metabolism, but not the survival, of cells.

A 60 kDa prolactin variant secreted by cervical cancer cells modulates apoptosis and cytokine production.

Prolactin (PRL) is associated with different types of cancer, such as cervical cancer. Recombinant PRL has antiapoptotic effect on cervical cancer cells, and it can also induce cytokine production on macrophages. A 60 kDa variant of PRL is produced by cervical cancer cells. The aim of the present study was to evaluate this variant's bioactivity, to test its effect on cervical cancer cell apoptosis, and to assess its ability to induce cytokine production on THP-1 macrophages. First, 60 kDa PRL was isolated and used to stimulate Nb2 cells. Later, apoptosis was measured after exposure to 60 kDa PRL. Finally, cytokines were measured on THP-1 stimulated supernatants. Our results show that 60 kDa PRL increased Nb2 cell proliferation. Apoptosis was decreased after stimuli with 60 kDa PRL in cervical cancer cells. IL-1ß and TNF-α are produced by THP-1 macrophages after stimuli. These results suggest that 60 kDa PRL produced by cervical cancer cells is able to reduce apoptosis in HeLa, SiHa and C-33A cells and induce IL-1ß and TNF-α production by THP-1 macrophages.

Cadmium and α-lipoic acid activate similar de novo synthesis and recycling pathways for glutathione balance.

Glutathione (GSH) protects cells against oxidative stress. Redox modifiers induce GSH biosynthesis and recycling to maintain reduced environment inside cells. Cadmium (Cd2+) is a heavy metal that activates redox-sensitive transcriptional factors. The antioxidant α-lipoic acid (ALA) has shown to modulate GSH pathways. This study aimed to investigate de novo synthesis and recycling pathways for GSH balance by different Cd2+ concentrations and ALA in HepG2 cells. ALA activates Nrf2 pathway leading to GSH increment. Pre-treatment with 1µM Cd2+ or ALA produces tolerance to 5µM Cd2+ toxic effects. 5µM Cd2+ exposure significantly augmented nuclear Nrf2, GSH and GCLC, GCLM, HMOX1, TNFα and IL-6 mRNA expression but not GSR, however these upsurges were significantly abrogated by ALA or 1µM Cd2+ pre-treatments. Exposure to low Cd2+ concentration generate timely protective responses, similar to that elicited by ALA, maintaining a normal redox balance inside the cell due to GSH replenishment.

Update on the pathophysiology of liver fibrosis.

Fibrogenesis represents the main pathophysiological consequence of chronic liver disease and leads to life-threatening clinical consequences. The knowledge in this field has grown exponentially in the past 20 years and, currently, evaluation and treatment of liver fibrosis are central issues in hepatology. Classic mechanisms of liver fibrogenesis have been expanded and consolidated over the past few years. Concomitantly, novel mechanisms have been suggested and demonstrated. The aim of this article is to provide an update on these mechanisms with an attempt to integrate classic and novel pathways responsible for the evolution of the fibrogenic process and, potentially, for its regression.

The multifaceted role of pirfenidone and its novel targets.

BACKGROUND: Pirfenidone (PFD) is a molecule that exhibits antifibrotic properties in a variety of in vitro and animal models of lung, liver and renal fibrosis. These pathologies share many fibrogenic pathways with an abnormal fibrous wound-healing process; consequently, tissue repair and tissue regeneration-regulating mechanisms are altered. OBJECTIVE: To investigate the usefulness of PFD as an antifibrotic agent in clinical and experimental models of fibrotic disease. CONCLUSIONS: There is a growing understanding of the molecular effects of PFD on the wound healing mechanism, leading to novel approaches for the management of fibrosis in lung, liver and renal tissues. Although the optimum treatment for fibrosis remains undefined, it is possible that combined therapeutic regimens that include this wide-application molecule, pirfenidone, could offer a useful treatment for fibrotic disease.

Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells.

Oxidative stress is a known mechanism induced, among other things, by arsenic toxicity. As a response, the cell triggers the synthesis of antioxidant and stress response elements like glutathione and heme oxygenase. Alpha-lipoic acid (ALA) is a well-known antioxidant that confers protection to oxidative stress conditions. We analyzed the effect of ALA pretreatment on Nrf2-responsive gene expression of HepG2 cells exposed to As(3+). Cells were treated with 5mM ALA and 8h later exposed to 50µM As(3+) for 24h, analyzing MTT-activity, glutathione content, Nrf2 induction and antioxidant gene expression. As(3+) increased glutathione (154%), heme oxygenase, glutamate cystein ligase, modifier subunit and metallothionein (35-fold, 10-fold and 9-fold, respectively). ALA prevented the strong expression of heme oxygenase by As(3+) exposure (from 35- to 5-times of control cells), which correlated with the reduction of Nrf2 observed in As(3+) group. ALA pretreatment can down-modulate the response mediated by Nrf2 and provide protection to As(3+) exposed HepG2 cells.

Efecto del ácido alfa lipoico y la pirfenidona en la modulación antioxidante celular contra el daño oxidativo / Effects of alpha lipoic acid and pirfenidone on liver cells antioxidant modulation against oxidative damage

Background: Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. Aim: To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). Material and Methods: HepG2 cells and primary HSC cultures were exposed to menadione 0.1 μM (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 μM, 100 μM y 1000 μM). Results: In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-β1, TIMP1, IL6, TNFα and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. Conclusion: Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes.