Downregulation of SERINC5 expression in buffy coats of HIV-1-infected patients with detectable or undetectable viral load.

Among the host restriction factors against HIV, SERINC5 has been described in vitro, but the mRNA level of SERINC5 in vivo has been little studied. We compare SERINC5 expression in subjects with HIV-1 (highly active antiretroviral treatment (HAART) and HAART-naïve) with and without suppression of viral load. A cross-sectional study was performed with 107 individuals distributed as follows: 24 with HAART-naïve and detectable viral load (> 50 copies/mL), 13 with HAART and detectable viral load (> 50 copies/mL), 50 with HAART and undetectable viral load (≤ 50 copies/mL), and 20 without HIV-1. SERINC5 expression in buffy coats was determined using RT-qPCR. The viral load was determined using real-time PCR and the amount of CD4 + and CD8 + T-lymphocytes was measured using flow cytometry. The data were normalized with the Shapiro-Wilk test and the Kruskal-Wallis test was subsequently performed. The relative expression was compared with a T-test and the remaining data with the Mann-Whitney U-test. ANCOVA multiple linear regression analysis was performed between characteristics of patients with SERINC5 expression. The mean and SD of the SERINC5 expression in the three groups with HIV-1 was 0.9 ± 0.2 and without HIV-1 was 1.7 ± 0.14 (P < 0.001). Multiple linear regression did not show the participation of CD4 +, CD8 + , viral load, infection time, or treatment time. No differences in the SERINC5 expression were found among the studied groups of patients with HIV-1. When comparing the groups with and without HIV-1 infection, SERINC5 was downregulation in the HIV-1 groups.

Mechanisms of action of acetaldehyde in the up-regulation of the human α2(I) collagen gene in hepatic stellate cells: key roles of Ski, SMAD3, SMAD4, and SMAD7.

Alcohol-induced liver fibrosis and eventually cirrhosis is a leading cause of death. Acetaldehyde, the first metabolite of ethanol, up-regulates expression of the human α2(I) collagen gene (COL1A2). Early acetaldehyde-mediated effects involve phosphorylation and nuclear translocation of SMAD3/4-containing complexes that bind to COL1A2 promoter to induce fibrogenesis. We used human and mouse hepatic stellate cells to elucidate the mechanisms whereby acetaldehyde up-regulates COL1A2 by modulating the role of Ski and the expression of SMADs 3, 4, and 7. Acetaldehyde induced up-regulation of COL1A2 by 3.5-fold, with concomitant increases in the mRNA (threefold) and protein (4.2- and 3.5-fold) levels of SMAD3 and SMAD4, respectively. It also caused a 60% decrease in SMAD7 expression. Ski, a member of the Ski/Sno oncogene family, is colocalized in the nucleus with SMAD4. Acetaldehyde induces translocation of Ski and SMAD4 to the cytoplasm, where Ski undergoes proteasomal degradation, as confirmed by the ability of the proteasomal inhibitor lactacystin to blunt up-regulation of acetaldehyde-dependent COL1A2, but not of the nonspecific fibronectin gene (FN1). We conclude that acetaldehyde up-regulates COL1A2 by enhancing expression of the transactivators SMAD3 and SMAD4 while inhibiting the repressor SMAD7, along with promoting Ski translocation from the nucleus to cytoplasm. We speculate that drugs that prevent proteasomal degradation of repressors targeting COL1A2 may have antifibrogenic properties.

MIF and TNFα serum levels in rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs: a cross-sectional study.

Macrophage migration inhibitory factor (MIF) and tumor necrosis factor alpha (TNFα) play a pivotal role in rheumatoid arthritis (RA). MIF is considered a relevant cytokine because it appears before TNFα in the inflammatory cascade thus stimulating TNFα production and MIF's relationship with traditional synthetic disease modifying antirheumatic drugs (sDMARDs) is unknown. In this cross-sectional study, we investigated the association of MIF and TNFα serum levels with methotrexate (MTX) and in combination with chloroquine (CLQ) and sulfasalazine (SSZ) in RA patients classified according to the ACR/EULAR 2010 criteria. Patients were divided into three groups: MTX-monotherapy group (n = 40), MTX combination therapy groups: MTX + CLQ (n = 41), and MTX + CLQ + SSZ (n = 42). MIF and TNFα serum levels were determined by ELISA. We found high levels of ESR, CRP, RF, and anti-CCP in all therapy groups. Furthermore, we subclassified 97 patients with established RA (≥2 years of disease duration) and found that TNFα serum levels were lower in the combination therapy group (MTX + CLQ + SSZ) in comparison with the monotherapy MTX group (16.7 pg/mL versus 13.6 pg/mL, p = 0.02). However, we did not find differences between sDMARD therapies in MIF serum levels. We did find a significant reduction in MIF serum levels in patients treated with oral steroids compared with patients without oral steroids (1.7 ng/mL versus 4.3 ng/mL, p < 0.001). In conclusion, this study supports the role of sDMARDs in modifying TNFα serum levels and oral steroids MIF serum levels. Nevertheless, we found that MIF serum levels are not modified by sDMARD treatment.

Beneficial effects of quercetin on oxidative stress in liver and kidney induced by titanium dioxide (TiO2) nanoparticles in rats.

TiO2 nanoparticles used as vectors for the delivery of drugs have shown greater effectiveness. However, TiO2 nanoparticles can cause oxidative stress in liver and kidney, so we analyzed if a previous or simultaneous quercetin treatment could counteract this in rats. Five groups of male Wistar rats (200-250 g) were included: (1) healthy controls, (2) TiO2 group, (3) quercetin group, (4) preventive group: quercetin for 5 days prior to exposure of TiO2, and (5) therapeutic group: TiO2 (5 mg/kg, i.v.) plus quercetin single dose for 5 days (5 mg/kg/day, i.p.). Hepatic and renal function tests were made. Five animals from each group were sacrificed (0, 14 and 28 days), and liver and kidney tissue were obtained. Malondialdehyde (MDA), reduced/oxidized glutathione, and activity of glutathione peroxidase/reductase were measured, as well as the level of gene expression by q-PCR. There were no significant changes in serum ALT and AST activities. More damage was observed at 14 versus 28 days, because TiO2 was excreted in urine. Quercetin indeed showed a renal protective effect by increasing glutathione reductase and peroxidase levels and reducing MDA levels. On the other hand, TiO2 liver damage was less pronounced with quercetin as therapeutic treatment. TiO2 induces significantly the glutathione reductase expression and it can be down-regulated by quercetin. Biochemical tests in serum and urine showed a better effect of quercetin administered in the therapeutic group. Care should be taken with the dose and time of administration of quercetin, because this antioxidant could also have a pro-oxidant effect.

Downregulation of inducible nitric oxide synthase (iNOS) expression is implicated in the antiviral activity of acetylsalicylic acid in HCV-expressing cells.

Previously, we described that acetylsalicylic acid (ASA) decreases HCV expression, but the mechanisms involved have not been clearly established. We evaluated the participation of inducible nitric oxide synthase (iNOS) in the regulation of HCV-RNA induced by ASA. Huh7 cells expressing non-structural HCV proteins were exposed to 4 mM ASA and incubated at the same times we reported HCV downregulation (24-72 h), and iNOS mRNA and protein levels were then measured by real-time PCR and Western blot, respectively. Nitric oxide levels were measured at the same time. Inhibition of iNOS mRNA by small interfering RNAs (siRNA) and activation of the iNOS gene promoter by ASA treatment were evaluated. In Huh7 replicon cells treated with ASA, we found decreased levels of iNOS mRNA, iNOS protein and nitrosylated protein levels at 48-72 h. ASA exposure also reduced the transactivation of the iNOS promoter in HCV replicon cells at 48 h, and this was partly due to the decrease in the affinity of transcription factor C/EBP-ß for its binding site in the iNOS promoter. siRNA silencing of iNOS decreased HCV-RNA expression (65 %) and potentiated the antiviral effect (80 %) of ASA compared with control cells. ASA reduces iNOS expression by downregulating promoter activity, mRNA and protein levels at the same time that it decreases HCV expression. These findings suggest that the antiviral activity of ASA is mediated partially through the modulation of iNOS.

Use of proteomic analysis tools to identify HCV-proteins down-regulated by acetylsalicylic acid.

Background and aim. Acetylsalicylic acid (ASA) has been shown to downregulate HCV expression; however, the involved mechanisms are unknown. We used proteomic analysis to compare protein expression profiles between human hepatocarcinoma cells (Huh7) and Huh7-HCV cells harboring expression of non-structural HCV proteins, to elucidate the mechanism(s) involved in ASA-mediated downregulation of HCV replication. Material and methods. Both cell lines were treated or untreated with 4 mM ASA and harvested at 0, 24, 48 and 72 h to isolate total proteins, which were resolved by two-dimensional gel electrophoresis (2DE) to separate them by isoelectric point (pI), followed by fractionation by molecular weight (MW). Gels were scanned and analyzed with PD-Quest software V8.0.1, and proteins were elucidated by the specific pI and MW using TAGIDENT software. Statistics analysis included the t-test. esults and Discussion. Different protein patterns among hepatocytes expressing HCV-proteins in ASA treated and untreated cells were found. Among proteins differentially expressed in Huh7-HCV cells, we found proteins related to cell proliferation (MTMR6, FAM22, HDGF and HCF-1) after 24 h of ASA treatment; and upregulation of angiostatin, PI4KA and STAT-1 after 48 h of treatment. Finally, at 72 h of ASA exposure, we identified overexpression of adenylsuccinate synthase, 2'-3'-di-deoxyadenosine, ubiquitin-protein-ligase E6A, adenylosuccinate-lyase and nibrin (NBN). Conclusion. We found that ASA induces different protein patterns in Huh7-HCV cells promoting activation of proteins involved in cell progression, repair of double strand breaks, proliferation, inhibition of apoptosis and growth stimulation at the same time that it decreased HCV expression.

Cu/Zn superoxide dismutase (SOD1) induction is implicated in the antioxidative and antiviral activity of acetylsalicylic acid in HCV-expressing cells.

We evaluated the participation of oxidative stress in the negative regulation of hepatitis C virus (HCV)-RNA induced by acetylsalicylic acid (ASA). We used the HCV subgenomic replicon cell system that stably expresses HCV-nonstructural proteins (Huh7 HCV replicon cells) and the parental cell line. Cells were exposed to 4 mM ASA at different times (12-72 h), and pyrrolidine dithiocarbamate (PDTC) was used as an antioxidant control. Reactive oxygen species (ROS) production, oxidized protein levels, cytosolic superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GPx) activity were measured to evaluate oxidative stress. In addition, viral RNA and prostaglandin (PGE(2)) levels were determined. We observed that ASA treatment decreased ROS production and oxidized protein levels in a time-dependent fashion in both parental and HCV replicon cells with a greater extent in the latter. Similar results were found with PDTC exposure. Average GPx activity was decreased, whereas a striking increase was observed in average cytosolic SOD activity at 48 and 72 h in both cells exposed to ASA, compared with untreated cells. HCV replicon cells showed higher levels of Cu/Zn-SOD expression (mRNA and protein) with ASA treatment (48 and 72 h), whereas NS5A protein levels showed decreased expression. In addition, we found that inhibition of SOD1 expression reversed the effect of ASA. Interestingly, PDTC downregulated HCV-RNA expression (55%) and PGE(2) (60%) levels, imitating ASA exposure. These results suggest that ASA treatment could reduce cellular oxidative stress markers and modify Cu/Zn-SOD expression, a phenomenon that may contribute to the mechanisms involved in HCV downregulation.

Unraveling the Molecular Mechanisms Involved in HCV-Induced Carcinogenesis.

Cancer induced by a viral infection is among the leading causes of cancer. Hepatitis C Virus (HCV) is a hepatotropic oncogenic positive-sense RNA virus that leads to chronic infection, exposing the liver to a continuous process of damage and regeneration and promoting hepatocarcinogenesis. The virus promotes the development of carcinogenesis through indirect and direct molecular mechanisms such as chronic inflammation, oxidative stress, steatosis, genetic alterations, epithelial-mesenchymal transition, proliferation, and apoptosis, among others. Recently, direct-acting antivirals (DAAs) showed sustained virologic response in 95% of cases. Nevertheless, patients treated with DAAs have reported an unexpected increase in the early incidence of Hepatocellular carcinoma (HCC). Studies suggest that HCV induces epigenetic regulation through non-coding RNAs, DNA methylation, and chromatin remodeling, which modify gene expressions and induce genomic instability related to HCC development that persists with the infection's clearance. The need for a better understanding of the molecular mechanisms associated with the development of carcinogenesis is evident. The aim of this review was to unravel the molecular pathways involved in the development of carcinogenesis before, during, and after the viral infection's resolution, and how these pathways were regulated by the virus, to find control points that can be used as potential therapeutic targets.

VNTR (CAG)n polymorphism of the ATXN2 gene and metabolic parameters of cardiovascular risk associated with the degree of obesity in the Amerindian population of Oaxaca.

INTRODUCTION: The ATXN2 gene has a VNTR (CAG)n with locus in exon1. Long alleles within the normal range (22-29 repeats) are associated with severe obesity in people from the United Kingdom, Indonesia and the Caribbean. OBJECTIVE: To analyse the influence of VNTR (CAG)n on metabolic profile in adults with obesity and pre-obesity, as well as to estimate its effect on the risk of developing diabetes. METHODS AND MATERIAL: 255 adults of Chinantec Amerindian ethnic origin were included, who underwent anthropometric and biochemical evaluation. The VNTR was amplified by end-point PCR and by 8% PAGE electrophoresis. RESULTS: Differences were found in the waist/hip circumference index and body mass index in the carriers of genotypes different to the one homozygous for 22 repeats with a Student's t-test value of 0.0041 and 0.0334, respectively. We also found an association with a family history of chronic disease. CONCLUSION: The VNTR of ATXN2 is associated with obesity in Mexican adults of Chinantec ancestry.

The role of dystroglycan in PDGF-BB-dependent migration of activated hepatic stellate cells/myofibroblasts.

Hepatic stellate cells are embedded in the loose connective tissue matrix within the space of Disse. This extracellular matrix contains several basement membrane components including laminin, but its composition changes during liver injury because of the production of extracellular matrix components found in scar tissue. These changes in extracellular matrix composition and in cell-extracellular matrix interactions may play a key role in hepatic stellate cell transdifferentiation. In this communication we used early passages of mouse hepatic stellate cells (activated HSC/myofibroblasts) to study the platelet-derived growth factor BB (PDGF-BB)-dependent expression and regulation of ß-dystroglycan and its role in activated HSC/myofibroblast migration. We used Northern and Western analysis to study dystroglycan expression and confocal microscopy to investigate changes in subcellular distribution of the protein. Activated HSC migration was investigated using an in vitro wound-healing assay. PDGF-BB induced significant changes in dystroglycan regulation and subcellular distribution of the protein. Whereas steady-state levels of dystroglycan mRNA remained constant, PDGF-BB increased dystroglycan transcription but shortened the t(1/2) by 50%. Moreover, PDGF-BB changed dystroglycan and α5-integrin cellular distribution. Cell migration experiments revealed that PDGF-BB-dependent migration of activated HSC/myofibroblasts was completely blocked by neutralizing antibodies to fibronectin, α5-integrin, laminin, and ß-dystroglycan. Overall, these findings suggest that both laminin and fibronectin and their receptors play a key role in PDGF-BB-induced activated HSC migration.

VNTR (CAG)n polymorphism of the ATXN2 gene and metabolic parameters of cardiovascular risk associated with the degree of obesity in the Amerindian population of Oaxaca. / Polimorfismo VNTR (CAG)n del gen ATXN2 y parámetros metabólicos de riesgo cardiovascular asociados con el grado de obesidad en población amerindia de Oaxaca.

INTRODUCTION: The ATXN2 gene has a VNTR (CAG)n with locus in exon1. Long alleles within the normal range (22-29 repeats) are associated with severe obesity in people from the United Kingdom, Indonesia and the Caribbean. OBJECTIVE: To analyse the influence of VNTR (CAG)n on metabolic profile in adults with obesity and pre-obesity, as well as to estimate its effect on the risk of developing diabetes. METHODS AND MATERIAL: 255 adults of Chinantec Amerindian ethnic origin were included, who underwent anthropometric and biochemical evaluation. The VNTR was amplified by end-point PCR and by 8% PAGE electrophoresis. RESULTS: Differences were found in the waist/hip circumference index and body mass index in the carriers of genotypes different to the one homozygous for 22 repeats with a Student's t test value of 0.0041 and 0.0334, respectively. We also found an association with a family history of chronic disease. CONCLUSION: The VNTR of ATXN2 is associated with obesity in Mexican adults of Chinantec ancestry.

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways.

UNLABELLED: It has been reported that salicylates (sodium salicylate and aspirin) inhibit the replication of flaviviruses, such as Japanese encephalitis virus and dengue virus. Therefore, we considered it important to test whether acetylsalicylic acid (ASA) had anti-hepatitis C virus (HCV) activity. To this end, we examined the effects of ASA on viral replication and protein expression, using an HCV subgenomic replicon cell culture system. We incubated Huh7 replicon cells with 2-8 mM ASA for different times and measured HCV-RNA and protein levels by northern blot, real-time polymerase chain reaction, and western analysis, respectively. We found that ASA had a suppressive effect on HCV-RNA and protein levels (nearly 58%). ASA-dependent inhibition of HCV expression was not mediated by the 5'-internal ribosome entry site or 3'-untranslated regions, as determined by transfection assays using bicistronic constructs containing these regulatory regions. However, we found that HCV-induced cyclooxygenase 2 (COX-2) messenger RNA and protein levels and activity and these effects were down-regulated by ASA, possibly by a nuclear factor kappa B-independent mechanism. We also observed that the ASA-dependent inhibition of viral replication was due in part to inhibition of COX-2 and activation of p38 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) mitogen-activated protein kinases (MAPKs). Inhibition of these kinases by SB203580 and U0126, respectively, and by short interfering RNA silencing of p38 and MEK1 MAPK prevented the antiviral effect of ASA. Taken together, our findings suggest that the anti-HCV effect of ASA in the Huh7 replicon cells is due to its inhibitory effect on COX-2 expression, which is mediated in part by the activation of MEK1/2/p38 MAPK. CONCLUSION: These findings suggest the possibility that ASA could be an excellent adjuvant in the treatment of chronic HCV infection.

Acute treatment of constant darkness increases the efficiency of ATP synthase in rat liver mitochondria.

The circadian oscillations of many physiological processes provide an endogenous temporal program for the adaptive synchronization of mammals to the fluctuating external world. The lack of exposure to light causes the circadian system to undergo a process of dark adaptation similar to dark adaptation in the visual system. The aim of the present work was investigate the effect of acute treatment of constant darkness on mitochondrial ATP synthase activities and membrane fluidity in liver from male rat. We found that ATP synthase activity was not changed by the treatment. However ATPase activity and membrane fluidity were significantly diminished and pH gradient driven by ATP hydrolysis was incremented, in comparison from samples from rats kept on normal light/dark cycles. Additionally, the treatment of constant darkness diminishes the passive proton permeability of the inner mitochondrial membrane. In conclusion constant darkness induces a more efficient coupling between proton transport and catalysis, and increment the efficiency of the enzyme because the ratio of ATP synthase/ATPase activity was higher. These results exhibited the physiological adaptation of liver mitochondria to acute treatment of constant darkness in order to satisfy the cellular energy demand.

Expression of the Biologically Active Insulin Analog SCI-57 in Nicotiana Benthamiana.

Diabetes mellitus is a growing problem worldwide; however, only 23% of low-income countries have access to insulin, and ironically it costs higher in such countries than high-income ones. Therefore, new strategies for insulin and insulin analogs production are urgently required to improve low-cost access to therapeutic products, so as to contain the diabetes epidemic. SCI-57 is an insulin analog with a greater affinity for the insulin receptor and lower thermal degradation than native insulin. It also shows native mitogenicity and insulin-like biological activity. In this work, SCI-57 was transiently expressed in the Nicotiana benthamiana (Nb) plant, and we also evaluated some of its relevant biological effects. An expression plasmid was engineered to translate an N-terminal ubiquitin and C-terminal endoplasmic reticulum-targeting signal KDEL, in order to increase protein expression and stability. Likewise, the effect of co-expression of influenza M2 ion channel (M2) on the expression of insulin analog SCI-57 (SCI-57/M2) was evaluated. Although using M2 increases yield, it tends to alter the SCI-57 amino acid sequence, possibly promoting the formation of oligomers. Purification of SCI-57 was achieved by FPLC cation exchange and ultrafiltration of N. benthamiana leaf extract (NLE). SCI-57 exerts its anti-diabetic properties by stimulating glucose uptake in adipocytes, without affecting the lipid accumulation process. Expression of the insulin analog in agroinfiltrated plants was confirmed by SDS-PAGE, RP-HPLC, and MS. Proteome changes related to the expression of heterologous proteins on N. benthamiana were not observed; up-regulated proteins were related to the agroinfiltration process. Our results demonstrate the potential for producing a biologically active insulin analog, SCI-57, by transient expression in Nb.

Aminoguanidine reduces diabetes-associated cardiac fibrosis.

Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE-associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative-associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM). Forty-five male Wistar rats were divided into three groups: Control, T2DM and T2DM+AG. Rats were fed with a high-fat, high-carbohydrate diet (HFCD) for 2 weeks and rendered diabetic using low-dose streptozotocin (STZ) (20 mg/kg), and one group was treated with AG (20 mg/kg) up to 25 weeks. In vitro experiments were performed in primary rat myofibroblasts to confirm the antioxidant and antifibrotic effects of AG and to determine if blocking the receptor for AGEs (RAGE) prevents the fibrogenic response in myofibroblasts. Diabetic rats exhibited an increase in cardiac fibrosis resulting from HFCD and STZ injections. By contrast, AG treatment significantly reduced cardiac fibrosis, α-smooth muscle actin (αSMA) and oxidative-associated Nox4 and Nos2 mRNA expression. In vitro challenge of myofibroblasts with AG under T2DM conditions reduced intra- and extracellular collagen type I expression and Pdgfb, Tgfß1 and Col1a1 mRNAs, albeit with similar expression of Tnfα and Il6 mRNAs. This was accompanied by reduced phosphorylation of ERK1/2 and SMAD2/3 but not of AKT1/2/3 and STAT pathways. RAGE blockade further attenuated collagen type I expression in AG-treated myofibroblasts. Thus, AG reduces oxidative stress-associated cardiac fibrosis by reducing pERK1/2, pSMAD2/3 and collagen type I expression via AGE/RAGE signaling in T2DM.

Acute renal failure induced by carbon tetrachloride in rats with hepatic cirrhosis.

Relationship between cirrhosis and renal dysfunction is not yet fully understood. A model of cirrhosis with acute hepatic and renal damage (RF), produced by CCl4 in rats, with hemodynamic and renal functional alterations, similar to those observed in decompensated cirrhosis (DC) in man, was used to study chemical nephrotoxicity in animals. We performed in male Wistar rats hepatic and renal functional and hemodynamic studies in control, cirrhotic and decompensated cirrhotic (DC) groups. Cirrhosis was induced with carbon tetrachloride by chronic administration. Association between liver and renal functional alterations was detected in rats with decompensated cirrhosis, showing fall in mean arterial pressure and reduction of glomerular filtration rate and filtration fraction. Renal hemodynamics did not change in cirrhotic rats, similarly to what occurs in compensated cirrhotic patients. However, DC rats exhibited increased sodium, glucose and phosphate urinary excretions and decreased ATP in renal cortex. DC animals had severe hypoglycemia. There was an extensive liver fibrosis. Glomeruli had hypercellularity and tubules showed extensive vacuolization in cirrhotic and DC rats. The present study suggests that in this model, damage typical of acute tubular necrosis ensues in cirrhotic rats. We describe functional and morphological damage in liver and kidney in a model of cirrhosis that might predispose to the development of acute renal failure when an individual with hepatic damage is exposed in acute way to chemical toxicants.

Natural Dietary Pigments: Potential Mediators against Hepatic Damage Induced by Over-The-Counter Non-Steroidal Anti-Inflammatory and Analgesic Drugs.

Over-the-counter (OTC) analgesics are among the most widely prescribed and purchased drugs around the world. Most analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are metabolized in the liver. The hepatocytes are responsible for drug metabolism and detoxification. Cytochrome P450 enzymes are phase I enzymes expressed mainly in hepatocytes and they account for ≈75% of the metabolism of clinically used drugs and other xenobiotics. These metabolic reactions eliminate potentially toxic compounds but, paradoxically, also result in the generation of toxic or carcinogenic metabolites. Cumulative or overdoses of OTC analgesic drugs can induce acute liver failure (ALF) either directly or indirectly after their biotransformation. ALF is the result of massive death of hepatocytes induced by oxidative stress. There is an increased interest in the use of natural dietary products as nutritional supplements and/or medications to prevent or cure many diseases. The therapeutic activity of natural products may be associated with their antioxidant capacity, although additional mechanisms may also play a role (e.g., anti-inflammatory actions). Dietary antioxidants such as flavonoids, betalains and carotenoids play a preventive role against OTC analgesics-induced ALF. In this review, we will summarize the pathobiology of OTC analgesic-induced ALF and the use of natural pigments in its prevention and therapy.

Serum levels of P-glycoprotein and persistence of disease activity despite treatment in patients with systemic lupus erythematosus.

Around 25% of patients with systemic lupus erythematosus (SLE) could be refractory to conventional therapies. P-glycoprotein expression on cell surface has been implied on drug resistance, however, to date, it is unknown if P-gp serum levels are associated with SLE disease activity. Evaluate the association of serum P-gp levels and SLE with disease activity despite treatment. A cross-sectional study was conducted on 93 female SLE patients, all receiving glucocorticoids at stable doses for the previous 6 months before to baseline. SLE patients were classified into two groups: (a) patients with active disease [SLE disease activity index (SLEDAI) ≥ 3] despite treatment, and (b) patients with inactive disease (SLEDAI < 3) after treatment. Forty-three healthy females comprised the control group. Serum P-gp, anti-DNA, and both anti-nucleosome antibody levels were measured using ELISA. Active-SLE patients despite treatment had higher P-gp levels compared with inactive-SLE after treatment (78.02 ng/mL ± 114.11 vs. 33.75 ng/mL ± 41.11; p = 0.018) or versus reference group subjects (30.56 ng/mL ± 28.92; p = 0.011). P-gp levels correlated with the scores of SLEDAI (r = 0.26; p = 0.01), Mexican-SLEDAI (MEX-SLEDAI) (r = 0.32; p = 0.002), SLICC/ACR damage index (r = 0.47; p < 0.001), and with prednisone doses (r = 0.33; p = 0.001). In the multivariate model, the high P-gp levels were associated with SLICC/ACR score (p = 0.001), and SLEDAI score (p = 0.014). Our findings support a relationship between serum P-gp levels and SLE with disease activity despite treatment, but it requires further validation in longitudinal studies.

Effect of symbiotic supplementation on fecal calprotectin levels and lactic acid bacteria, Bifidobacteria, Escherichia coli and Salmonella DNA in patients with cervical cancer.

BACKGROUND: patients with cervical cancer (CC) receiving chemotherapy and radiotherapy have several gastrointestinal adverse effects. OBJECTIVE: to evaluate the effect of dietary symbiotic supplementation on fecal calprotectin (FCP), bacterial DNA levels, and gastrointestinal adverse effects in patients with CC. METHODS: clinical, controlled, randomized, double-blind trial. Patients consumed symbiotics or placebo three times a day for seven weeks. FCP was assessed by Elisa method. DNA from probiotic and pathogenic bacteria were determined by quantitative real-time polymerase chain reaction. Diarrheal evacuations were evaluated with the Bristol stool form scale and nausea and vomiting were measured using the scale of the National Institute of Cancerology of the United States. RESULTS: after a seven-week treatment, FCP concentration was lower in the symbiotic group compared to the control group (p < 0.001). Stool consistency in the placebo and symbiotic groups was similar at baseline. A significant improvement in stool consistency was obtained in both groups at the end of the intervention (p < 0.001). The concentrations and total proportions of the probiotic and pathogenic bacteria were similar in both groups. Nausea significantly diminished in both groups (p < 0.001) at the end of the trial. Furthermore, the symbiotic group had a statistically significant decrease in the frequency and intensity of vomiting when compared to the control group (p < 0.001). CONCLUSIONS: the symbiotic treatment decreases significantly the FCP levels and the frequency and intensity of vomiting in patients with CC.