Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

Inflammasome in ALS Skeletal Muscle: NLRP3 as a Potential Biomarker.

Since NLRP3 inflammasome plays a pivotal role in several neurodegenerative disorders, we hypothesized that levels of inflammasome components could help in diagnosis or prognosis of amyotrophic lateral sclerosis (ALS). Gene and protein expression was assayed by RT-PCR and Western blot. Spearman's correlation coefficient was used to determine the linear correlation of transcriptional expression levels with longevity throughout disease progression in mice models. Kaplan-Meier analysis was performed to evaluate MCC950 effects (NLRP3 inhibitor) on lifespan of SOD1G93A mice. The results showed significant alterations in NLRP3 inflammasome gene and protein levels in the skeletal muscle of SOD1G93A mice. Spearman's correlation coefficient revealed a positive association between Nlrp3 transcriptional levels in skeletal muscle and longevity of SOD1G93A mice (r = 0.506; p = 0.027). Accordingly, NLRP3 inactivation with MCC950 decreased the lifespan of mice. Furthermore, NLRP3 mRNA levels were significantly elevated in the blood of ALS patients compared to healthy controls (p = 0.03). In conclusion, NLRP3 could be involved in skeletal muscle pathogenesis of ALS, either through inflammasome or independently, and may play a dual role during disease progression. NLRP3 gene expression levels could be used as a biomarker to improve diagnosis and prognosis in skeletal muscle from animal models and also to support diagnosis in clinical practice with the blood of ALS patients.

Lack of Delta-Sarcoglycan (Sgcd) Results in Retinal Degeneration.

Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd-/-). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd+/+) and Sgcd-/- mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd-protein complex (α-, ß-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd-/- mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd-/- has a phenotype that is compatible with retinal degeneration.

[Continuous intra arterial nimodipine for vasospasm secondary to subarachnoid hemorrhage. Report of one case]. / Terapia continua intra-arterial selectiva con nimodipino para el tratamiento del vasoespasmo refractario en hemorragia subaracnoidea aneurismática. Caso clínico.

We report a 39-year-old male with an aneurysmal subarachnoid hemorrhage without hydrocephalus, in whom a right choroidal aneurysm was early excluded by endovascular coil insertion. Intracranial pressure (PIC) and cerebral oxygenation (PtiO2) sensors for neuromonitoring were installed due to a persistent comatose state. From the 3rd day, neuromonitoring became altered. CT angiography and cerebral angiography showed severe proximal and distal vasospasm (VE) of the middle (ACM) and anterior (ACA) right cerebral arteries. VE was treated with angioplasty and intravenous nimodipine. Forty eight hours later, despite hemodynamic maximization, neuromonitoring became altered again, mainly explained by a decrease in PtiO2 below 15 mmHg. A severe VE in ACM and right ACA was confirmed by angiography. Given the presence of an early and recurrent VE, which was associated with a decrease in cerebral oxygenation, internal carotid micro-catheters for continuous nimodipine infusion were installed. This therapy maintained a normal neuromonitoring for 15 days. During this period, attempts were done to decrease or discontinue the infusion, but the patient presented parallel falls of cerebral oxygenation or decreased cerebral perfusion observed with perfusion CT, interpreted as persistent VE. Finally, the infusion was stopped at day 15 without significant complication. We conclude that intra-arterial nimodipine continuous infusion in refractory VE can be useful and safe in selected patients. Multimodal neuromonitoring is essential.

Composition of web services using Markov decision processes and dynamic programming.

We propose a Markov decision process model for solving the Web service composition (WSC) problem. Iterative policy evaluation, value iteration, and policy iteration algorithms are used to experimentally validate our approach, with artificial and real data. The experimental results show the reliability of the model and the methods employed, with policy iteration being the best one in terms of the minimum number of iterations needed to estimate an optimal policy, with the highest Quality of Service attributes. Our experimental work shows how the solution of a WSC problem involving a set of 100,000 individual Web services and where a valid composition requiring the selection of 1,000 services from the available set can be computed in the worst case in less than 200 seconds, using an Intel Core i5 computer with 6 GB RAM. Moreover, a real WSC problem involving only 7 individual Web services requires less than 0.08 seconds, using the same computational power. Finally, a comparison with two popular reinforcement learning algorithms, sarsa and Q-learning, shows that these algorithms require one or two orders of magnitude and more time than policy iteration, iterative policy evaluation, and value iteration to handle WSC problems of the same complexity.

Comparison of mutation profiles in the Duchenne muscular dystrophy gene among populations: implications for potential molecular therapies.

Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.

Consumption of ultra-processed food and its association with obesity in Chilean university students: A multi-center studyUltra-processed food and obesity in Chilean university students.

OBJECTIVE: To explore the associations between the consumption of three categories of ultra-processed food (sugary beverages, sweet, and salty snacks) and body mass index (BMI) among Chilean university students. METHODS: We conducted a multi-center, descriptive study among 2,039 students from 6 Chilean universities. Food consumption was surveyed using a validate food survey. That height and body weight were objectively measured to calculate BMI for determining weight status, and also, tobacco use and physical activity were measured. RESULTS: An intake equal to or higher than 1 serving of sugary beverage a day was associated with greater odds of obesity in university students (OR:1.32 [95% CI: 1.00, 1.74]), 2 servings/day (OR: 1.30 [95% CI: 1.04, 1.50]), and 3 servings/day (OR: 1.39 [95% CI: 1.05, 1.80]). Neither consumption of sweet nor salty snacks (≥1 servings/day) related to differential odds of obesity: (OR: 0.83 [95% CI: 0.42, 1.64]) and (OR: 1.79 [95% CI: 0.93, 3.41]), respectively. CONCLUSION: In a sample of Chilean university students, consumption of sugary beverages, and not consumption of sweet or salty snacks, was associated with obesity.

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystemic, progressive, neurodegenerative disorder. Despite it being generally fatal within a period of 2-4 years, it is highly heterogeneous; as a result, survival periods may vary greatly among individual patients. Biomarkers can serve as tools for diagnosis, prognosis, indicators of therapeutic response, and future therapeutics. Free-radical-dependent mitochondrial damage is believed to play a crucial role in neurodegeneration in ALS. Mitochondrial aconitase, which is also known as aconitase 2 (Aco2), is a key Krebs cycle enzyme and is involved in the regulation of cellular metabolism and iron homeostasis. Aco2 is very sensitive to oxidative inactivation and can aggregate and accumulate in the mitochondrial matrix, causing mitochondrial dysfunction. Loss of Aco2 activity may therefore reflect increased levels of mitochondrial dysfunction due to oxidative damage and could be relevant to ALS pathogenesis. The aim of our study was to confirm changes in mitochondrial aconitase activity in peripheral blood and to determine whether such changes are dependent on, or independent of, the patient's condition and to propose the feasibility of using them as possible valid biomarkers to quantify the progression of the disease and as a predictor of individual prognosis in ALS. METHODS: We measured the Aco2 enzymatic activity in the platelets of blood samples taken from 22 controls and 26 ALS patients at different stages of disease development. We then correlated antioxidant activity with clinical and prognostic variables. RESULTS: Aco2 activity was significantly lower in the 26 ALS patients than in the 22 controls (p < 0.05). Patients with higher levels of Aco2 activity survived longer than those with lower levels (p < 0.05). Aco2 activity was also higher in patients with earlier onset (p < 0.05) and in those with predominantly upper motor neuron signs. CONCLUSIONS: Aco2 activity seems to be an independent factor that could be used in the long-term survival prognosis of ALS. Our findings suggest that blood Aco2 could be a leading candidate for use as a biomarker to improve prognosis. More studies are needed to confirm these results.

Impact of gilt immunocastration on weight losses and instrumental and chemical characteristics of Teruel dry-cured ham.

A total of 32 fresh hams intended for the Spanish Protected Designation of Origin "Teruel ham" were used to evaluate the impact of gilt immunocastration (vs. entire gilts) on weight losses during the dry-curing process. After processing, 20 dry-cured hams (10 of each group) were chosen at random to assess instrumental and chemical characteristics. Hams from immunocastrated gilts tended (P = 0.057) to present lower weight losses, they were fattier (P < 0.05) at both subcutaneous and intramuscular levels and had lower (P < 0.05) water activity and volatile compounds that provide unpleasant odors than those from entire gilts. However, immunocastration increased (P < 0.05) slightly sodium chloride and sodium nitrite contents, being normal levels. Fatty acid profile was not significantly affected (P > 0.05). It can be concluded that, in general, immunocastration could be a good strategy in gilts to improve the quality of Teruel dry-cured ham.

Performance of RAPID noncontrast CT stroke platform in large vessel occlusion and intracranial hemorrhage detection.

Background: Noncontrast CT (NCCT) is used to evaluate for intracerebral hemorrhage (ICH) and ischemia in acute ischemic stroke (AIS). Large vessel occlusions (LVOs) are a major cause of AIS, but challenging to detect on NCCT. Aims: The purpose of this study is to evaluate an AI software called RAPID NCCT Stroke (RAPID, iSchemaView, Menlo Park, CA) for ICH and LVO detection compared to expert readers. Methods: In this IRB approved retrospective, multicenter study, stand-alone performance of the software was assessed based on the consensus of 3 neuroradiologists and sensitivity and specificity were determined. The platform's performance was then compared to interpretation by readers comprised of eight general radiologists (GR) and three neuroradiologists (NR) in detecting ICH and hyperdense vessel sign (HVS) indicating LVO. Results: A total of 244 cases were included. Of the 244, 115 were LVOs and 26 were ICHs. One hundred three cases did not have LVO nor ICH. Stand-alone performance of the software demonstrated sensitivities and specificities of 96.2 and 99.5% for ICH and 63.5 and 95.1% for LVO detection. Compared to all 11 readers and eight GR readers only respectively, the software demonstrated superiority, achieving significantly higher sensitivities (63.5% versus 43.6%, p < 0.0001 and 63.5% versus 40.9%, p = 0.001). Conclusion: The RAPID NCCT Stroke platform demonstrates superior performance to radiologists for detecting LVO from a NCCT. Use of this software platform could lead to earlier LVO detection and expedited transfer of these patients to a thrombectomy capable center.

Effect of Castration Type and Diet on Growth Performance, Serum Sex Hormones and Metabolites, and Carcass Quality of Heavy Male Pigs.

A trial was carried out to study the effect of type of castration and diet on pigs destined for Teruel ham production, which is a Spanish protected designation of origin for dry-cured ham. A total of 144 Duroc × (Landrace × Large White) male pigs were used. Half of them were surgically castrated and the other half were immunocastrated with three doses at approximately 25, 58 and 79 kg of body weight. Furthermore, three diets (control vs. high energy vs. low crude protein-CP- and amino acids-AA) were tested from 80 to 137 kg of body weight. Growth performance, serum sex hormones and metabolites, and carcass quality were evaluated. Immunocastrated males grew faster and had better feed conversion ratio than surgically castrated males, but presented lower carcass fatness. Pigs fed the high-energy diet and the low-CP and -AA diet were more efficient at transforming feed into gain than those fed the control diet, but no effect was detected on carcass quality. In conclusion, surgically castrated males are preferable than immunocastrated males for Teruel dry-cured ham elaboration. Besides, a high-energy diet or a low-CP and -AA diet might improve productive performances, but does not provide any benefit in terms of carcass quality.

Pharmacogenetics of taxane-induced neurotoxicity in breast cancer: Systematic review and meta-analysis.

Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

Sex, fiber-type, and age dependent in vitro proliferation of mouse muscle satellite cells.

During postnatal growth and after muscle injury, satellite cells proliferate and differentiate into myotubes to form and repair musculature. Comparison of studies on satellite cell proliferation and differentiation characteristics is confounded by the heterogeneity of the experimental conditions used. To examine the influence of sex, age, and fiber-type origin on in vitro properties of satellite cells derived from postnatal muscles, fast extensor digitorum longus (EDL) and slow soleus (SOL) muscles were extracted from male and female mice of 1 week to 3 months of age. Myoblast proliferation and myogenic regulatory factor (MRF) expression was measured from cultures of freshly isolated satellite cells. Higher proliferation rate and elevated Myod1 expression was found in male EDL and SOL derived cells compared with females at age of 40, 60, and 120 days, whereas inverse tendency for cell proliferation was apparent in EDL of juvenile (7-day-old) pups. Myogenin and Mrf4 transcripts were generally elevated in males of 40 and 60 days of age and in female EDL of juveniles. However, these differentiation markers did not significantly correlate with proliferation rate at all ages. Pax7, whose overexpression can block myogenesis, was up-regulated especially in 40-day-old females where MRF expression was low. These results indicate that gender, postnatal age, and muscle fiber origin affect proliferation and muscle transcription factor expression in vitro. The results also support the view that satellite cells originating from slow and fast muscles are intrinsically different and warrant further studies on the effect of cell origin for therapeutic approaches.

Levels of membrane fluidity in the spinal cord and the brain in an animal model of amyotrophic lateral sclerosis.

A mutant form of the copper/zinc superoxide dismutase (SOD1) protein is found in some patients with amyotrophic lateral sclerosis (ALS). Alteration of the activity of this antioxidant enzyme leads to an oxidative stress imbalance, which damages the structure of lipids and proteins in the CNS. Using fluorescence spectroscopy, we monitored membrane fluidity in the spinal cord and the brain in a widely used animal model of ALS, the SOD(G93A) mouse, which develops symptoms similar to ALS with an accelerated course. Our results show that the membrane fluidity of the spinal cord in this animal model significantly decreased in symptomatic animals compared with age-matched littermate controls. To the best of our knowledge, this is the first report showing that membrane fluidity is affected in the spinal cord of a SOD(G93A) animal model of ALS. Changes in membrane fluidity likely contribute substantially to alterations in cell membrane functions in the nervous tissue from SOD(G93A) mice.

Tobacco consumption in Chilean university students and associations with anthropometry, eating habits and sleep quality multicentric study.

Tobacco Consumption (TC) is one of the main causes of the deterioration of health; however, there are few studies linking its consumption with diet and nutrition among university students. The objective of this study is to test the association of smoking with anthropometry, diet and sleep quality among Chilean university students. Cross-sectional study. University students (n = 1454) from the North, South and Central parts of Chile were evaluated. A self-assessment survey was used to evaluate healthy and unhealthy eating habits. Nutritional status was evaluated by Body Mass Index (BMI). Two surveys were used to assess sleep quality: the Questionnaire of Insomnia and the Epworth Scale. Finally, participants were consulted about Tobacco Consumption: 30% of the students consume tobacco and have a higher score in unhealthy food consumption, less frequent weekly breakfast consumption (< 0.01), lower daily fruit (< 0.01) and vegetables (< 0.05) consumption, higher alcohol consumption (< 0.05) and daily junk food consumption (< 0.05) compared to non-consuming students. Men who consume tobacco present greater insomnia (< 0.001), sleep latency (< 0.001) and daytime sleepiness (< 0.05) compared to non-consumers; and women who consume tobacco have a higher weight (< 0.001) and BMI (< 0.01). When performing logistic regression, tobacco consumption is positively associated with major alcohol consumption (< 0.001), whereas fish (< 0.05) and vegetable (< 0.05) consumption was negatively associated. In conclusion, students of both sexes who smoke have more unfavorable health factors and a poorer quality of life.

Effect of Immunocastration and Diet on Growth Performance, Serum Metabolites and Sex Hormones, Reproductive Organ Development and Carcass Quality of Heavy Gilts.

It is desirable to increase fatness in gilts destined for Teruel dry-cured ham production. A total of 192 Duroc × (Landrace × Large White) gilts of 40.3 ± 4.80 kg body weight (BW) were used to assess the impact of immunocastration and feeding on growth performance, serum metabolites and sex hormones, reproductive organ development, and carcass quality. Six treatments were arranged factorially (2 × 3) with two types of gilt (entire gilts (EG) vs. immunocastrated gilts (IG)) and three experimental diets (control vs. high energy vs. low crude protein and amino acids) provided from 76 to 134 kg BW (n = 4 per treatment, being the replicate the pen with eight pigs). Immunocastration was carried out at 58 and 77 kg BW. The IG grew faster and showed lighter reproductive tracts and greater fatness than EG. The experimental feeds had limited effect on carcass quality, but the high-energy diet improved gain-to-feed ratio and the low-protein and -amino-acids diet did not impair growth performance. In conclusion, immunocastration was a better strategy than the tested diets to increase the fatness of gilts intended for Teruel dry-cured ham, although increasing energy or decreasing crude protein and amino acid levels in the diet could be beneficial strategies for pig farmers.

Influence of Immunocastration and Diet on Meat and Fat Quality of Heavy Female and Male Pigs.

Two experiments were carried out; one with female pigs and the other with male pigs destined for Teruel dry-cured ham production, to evaluate the effect of immunocastration (entire gilts-EG vs. immunocastrated gilts-IG and surgically castrated males vs. immunocastrated males-IM) and diet (control vs. high energy vs. low crude protein and amino acids) on meat quality and fat composition. Fifteen meat samples and eight fat samples of each treatment were analyzed in both experiments. In the case of males, six fat samples per treatment were analyzed to determine boar taint. Immunocastration is a good strategy in gilts intended for dry-cured ham production because improves meat composition; however, in males, immunocastration impairs the results of pork chemical composition compared with surgical castration. The IG presented a lower polyunsaturated/saturated fatty acids ratio than EG, improving fat technological quality. Diets had little effect on pork or fat quality in gilts, but a high-energy level using oilseeds and a low-crude-protein and -amino-acids diet from 80 to 137 kg of body weight could be interesting in IM to maintain or increase fat consistency, respectively. Moreover, in general, immunocastration is effective in avoiding boar taint in males.

Immunocastration in Gilts: A Preliminary Study of the Effect of the Second Dose Administration Time on Growth, Reproductive Tract Development, and Carcass and Meat Quality.

Increasing fatness and avoiding puberty are desirable in gilts intended for high-quality dry-cured ham production. A total of 48 Duroc x (Landrace x Large White) females of 26.5 ± 3.70 kg body weight (BW) were used to evaluate the impact of immunocastration and to find the optimum application time of the second dose for immunocastration on growth; sex hormones; reproductive tract development; and carcass, meat, and fat quality. Gilts were allocated to four experimental treatments (n = 12): control (entire gilts, EG) and immunocastrated gilts (IG), providing the second dose at 12, 9, or 7 weeks before slaughter (with approximately 60, 75, or 90 kg BW, respectively). Mean slaughter BW was 125 kg. Immunocastrated gilts had lighter reproductive tracts and greater fat thickness than EG. Fat from IG was more saturated and less polyunsaturated than that from EG. Numerically, gilts immunocastrated 9 and 12 weeks before slaughter presented higher fatness than those immunocastrated 7 weeks before slaughter. In conclusion, immunocastration is a good strategy to improve the fatness of gilts destined to dry-cured ham elaboration, with the optimum time for the second dose application seemingly between 9 and 12 weeks before slaughter.

Melatonin protects against taurolithocholic-induced oxidative stress in rat liver.

Cholestasis, encountered in a variety of clinical disorders, is characterized by intracellular accumulation of toxic bile acids in the liver. Furthermore, oxidative stress plays an important role in the pathogenesis of bile acids. Taurolithocholic acid (TLC) was revealed in previous studies as the most pro-oxidative bile acid. Melatonin, a well-known antioxidant, is a safe and widely used therapeutic agent. Herein, we investigated the hepatoprotective role of melatonin on lipid and protein oxidation induced by TLC alone and in combination with FeCl(3) and ascorbic acid in rat liver homogenates and hepatic membranes. The lipid peroxidation products, malondialdehyde and 4-hydroxyalkenals (MDA + 4-HDA), and carbonyl levels were quantified as indices of oxidative damage to hepatic lipids and proteins, respectively. In the current study, the rise in MDA + 4-HDA levels induced by TLC was inhibited by melatonin in a concentration-dependent manner in both liver homogenates and in hepatic membranes. Melatonin also had protective effects against structural damage to proteins induced by TLC in membranes. These results suggest that the indoleamine melatonin may potentially act as a protective agent in the therapy of those diseases that involve bile acid toxicity.