Pablo Muriel

Center for Research and Advanced Studies of the National Polytechnic Institute | Cinvestav · Departamento de Farmacología

The antioxidant effect of caffeine, associated with its ability to upregulate the nuclear factor-E2-related factor-2 (Nrf2)-signaling pathway, was explored as a possible mechanism for the attenuation of liver damage. Nonalcoholic steatohepatitis (NASH) was induced in rats by the administration of a high-fat, high-sucrose, high-cholesterol diet (HFS...

The liver performs various biochemical and molecular functions. Its location as a portal to blood arriving from the intestines makes it susceptible to several insults, leading to diverse pathologies, including alcoholic liver disease, viral infections, nonalcoholic steatohepatitis, and hepatocellular carcinoma, which are causes of death worldwide....

Introduction and objectives Administration of carbon tetrachloride (CCl4), along with an hepatopathogenic diet, is widely employed as a chemical inducer to replicate human nonalcoholic steatohepatitis (NASH) in rodents; however, the role of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome...

Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced b...

The extracellular matrix (ECM), formed by proteoglycans and fibrous proteins, is necessary not only as a supportive platform but also for the normal function of any tissue in the body. ECM homeostasis involves the synthesis and degradation of components in a finely regulated manner. Damage to the tissue alters ECM turnover, resulting in qualitative...

Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differe...

Introduction and objectives Caffeine consumption is associated with beneficial effects on hepatic disorders. The objectives of this study were to evaluate the antifibrotic effects of caffeine on experimental nonalcoholic steatohepatitis (NASH) induced with a high-fat, high-sucrose, high-cholesterol diet (HFSCD), as well as to evaluate the ability o...

Obesity and sedentarism may cause fatty liver, leading to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. These frequent and increasing pathologies are reviewed in this chapter with a special focus on the cellular and molecular mechanisms involved. Possible therapeutic targets are highlighted.

Bile acid accumulation due to biliary tree obstruction or injury to biliary epithelial cells may trigger inflammation and fibrosis of the liver. The cellular and molecular mechanisms involved are discussed, and putative antifibrotic targets are highlighted.

Chronic liver diseases are accompanied by alterations in the intestinal microbiota and increased gut permeability. These factors play a causative role during fibrogenesis. Possible antifibrotic targets are highlighted.

Fibrogenesis is tightly regulated. This chapter describes the cells that are most active in producing extracellular matrix, the signaling pathways involved, and the cytokines and factors that participate in the process of scar tissue formation. Possible therapeutic targets are highlighted.

Experimental models of hepatic fibrosis are useful for illuminating the understanding of the fibrogenic mechanisms of human disease and are helpful for discovering new therapeutic targets and noninvasive markers of fibrosis to fight mortality associated with chronic liver diseases. This chapter critically describes the most important models.

Abuse of alcohol consumption, which is a worldwide health problem, leads to liver steatosis, inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. The main metabolite responsible for alcohol-induced liver injury is acetaldehyde, which induces oxidative stress and hepatic stellate cell activation and therefore exacerbates scar tissue depo...

Chronic liver inflammation leads to fibrosis. This chapter provides an in-depth description of the cellular and molecular mechanisms that link these events. Possible antifibrotic targets are highlighted.

Chronic viral hepatitis can evolve to fibrosis, cirrhosis, and hepatocellular carcinoma. The molecular mechanisms and possible therapeutic targets are discussed herein.

This chapter describes the composition of the extracellular matrix (ECM) of the liver under normal conditions and the quantitative and qualitative alterations observed under chronic hepatic damage conditions. This chapter also describes the molecular mechanisms of ECM turnover.

This chapter summarizes the main noninvasive markers available to assess liver fibrosis. These markers help to evaluate the prognosis and therapeutic response of patients.

One of the main causative factors that triggers extracellular matrix deposition is oxidative stress. Moreover, fibrosis produced by diverse stimuli frequently involves free radicals as profibrogenic signals. The role of nitrosative stress is also discussed. Possible therapeutic targets are highlighted.

Hepatic Fibrosis: Mechanisms and Targets is a complete volume of liver extracellular matrix biology, including molecular signaling pathways, cells and factors that modulate fibrogenesis and fibrosis. The book uses an integrated approach toward the molecular and cellular mechanisms involved in the synthesis and degradation of hepatic fibrotic tissue...

Hepatocellular carcinoma (HCC), the most common primary liver cancer, arises after a long period of exposure to etiological factors. Nonalcoholic steatohepatitis (NASH) is ranked as the main risk factor for developing HCC; hence, experimental models of NASH leading to HCC have become key tools both to investigate the molecular mechanisms underlying...

Chronic diseases represent a major challenge in world health. Metabolic syndrome is a constellation of disturbances affecting several organs, and it has been proposed to be a liver-centered condition. Fructose overconsumption may result in insulin resistance, oxidative stress, inflammation, elevated uric acid levels, increased blood pressure, and i...

Activated hepatic stellate cells (HSCs) and myofibroblasts are the main producers of extracellular matrix (ECM) proteins that form the fibrotic tissue that leads to hepatic fibrosis. Reactive oxygen species (ROS) can directly activate HSCs or induce inflammation or programmed cell death, especially pyroptosis, in hepatocytes, which in turn activate...

Introduction and Objectives Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fi...

The liver is one of the most complex organs of the human body and is involved in various metabolic processes. Due to its anatomical proximity to the digestive tract, its blood flow, and its contribution to the detoxification process, the liver is susceptible to a wide variety of disorders. Hepatic diseases can be caused by alcoholism, viral infecti...

There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms...

Oxidative/nitrosative stress is proposed to be a critical factor in various diseases, including liver pathologies. Antioxidants derived from medicinal plants have been studied extensively and are relevant to many illnesses, including liver diseases. Several hepatic disorders, such as viral hepatitis and alcoholic or nonalcoholic steatohepatitis, in...

Introduction and aim: Stevia has exhibited antioxidant, antihyperglycemic, antihypertensive and anti-inflammatory properties in several in vivo and in vitro models. The objective of this study was to investigate the ability of an aqueous extract of stevia (AES) to prevent experimental cirrhosis in rats and to explore its mechanism of action. Mate...

Rebaudioside A (Reb A) is a diterpenoid isolated from the leaves of Stevia rebaudiana (Bertoni) that has been shown to possess pharmacological activity, including anti‐inflammatory and antioxidant properties. However, the ability of Reb A to prevent liver injury has not been evaluated. Therefore, we aimed to study the potential of Reb A (20 mg/kg;...

Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for liver health. Epidemiological and experimental studies have demonstrated the positive effects of coffee on several liver diseases. Coffee consumption is associated with the prevention of hepatic steatosis and...

Liver cirrhosis is associated with increased morbidity and mortality with important health and social consequences; however, an effective treatment has not been found yet. Previous reports have shown some beneficial effects of stevioside (SVT) in different diseases, but the ability of SVT to inhibit liver cirrhosis has not been reported. Therefore,...

Aim The aims of the present study were to investigate the capacity of stevia leaves to prevent experimental cirrhosis induced by chronic administration of carbon tetrachloride (CCl4) in rats and to explore the action mechanism involved. Methods Liver cirrhosis was established by CCl4 administration (400 mg/kg by i.p. 3 times a week for 12 weeks);...

Stevia has been shown to prevent oxidative stress and inflammation in carbon tetrachloride‐induced cirrhosis models. This study aimed to investigate the ability of an aqueous extract of stevia (AES) to prevent thioacetamide (TAA)‐induced cirrhosis in rats and to explore its mechanism of action. Liver cirrhosis was established by administering TAA (...

Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carc...

The effect of stevia on liver cirrhosis has not been previously investigated. In the present study, the antioxidant and anti-inflammatory properties of stevia leaves were studied in male Wistar rats with carbon tetrachloride- (CCl 4 -) induced acute and chronic liver damage. Acute and chronic liver damage induced oxidative stress, necrosis, and cho...

The leaves of Stevia rebaudiana, a natural sweetener, contain more than 30 different steviol glycosides, of which stevioside (STV) and rebaudioside A are found in major proportion. The main chemistry structures of glycosides found in stevia are diterpenes with strong antioxidant and antiinflammatory properties. Most liver diseases involve nitrogen...

The liver is the second largest organ in the body after the skin; it performs several processes that are extremely important to maintain homeostasis, and it is highly irrigated, receiving approximately 25% of the cardiac output. Therefore, the liver is the major organ responsible for the metabolism of various endogenous and exogenous compounds. Dur...

Curcumin, a bioflavonoid obtained from the Curcuma longa plant, possesses several beneficial properties against liver inflammation, cancer, fibrosis, viral infection, heavy metal toxicity, and steatosis. Its antiinflammatory activity is associated with the inhibition of NF-κB activation, thus preventing proinflammatory cytokine production such as T...

Fibrosis frequently leads to cirrhosis, the final stage of liver damage. There are several complications of cirrhosis, of note: portal hypertension (PHT), gastroesophageal varices, ascites, hepatorenal syndrome (HRS), hepatic encephalopathy (HE), hepatopulmonary syndrome, and hepatocellular carcinoma. Understanding the pathogenesis of PHT could be...

Professor Marcos Rojkind considered the liver as an ecosystem that performs a plethora of essential functions for the preservation of homeostasis in the organism. Blood from the portal triad, rich in oxygen and nutrients, enters the sinusoids, where it drains into the central vein. The synthesis of proteins, bile acids, and hormones; the metabolism...

The liver plays an important role in the absorption, metabolism, synthesis, and storage of nutrients. This organ metabolizes macromolecules such as carbohydrates, lipids, and proteins, which, after intake, are broken into smaller molecules such as glucose, fatty acids, and amino acids. Malnutrition is a common consequence of liver diseases, which i...

Naringenin (NAR), a flavanone, occurs almost exclusively in citrus fruits and is the most abundant flavonoid in these vegetables. It has been shown to possess antioxidant, antiproliferative, antitussive, and interesting hepatoprotective properties. Recent studies indicate that NAR possesses several beneficial effects on the liver on carbon tetrachl...

Oxidative stress plays a causative role in many human diseases; hence, animal (usually rodents) models that involve free radicals are very important to emulate the disease in humans and to evaluate new therapies. The most common experimental models to study liver diseases are carbon tetrachloride, which induces acute or chronic liver injury that sh...

Quercetin (Q) is a ubiquitous flavonoid founded in several natural sources, mainly in skin apples and red onions. Q possesses potent antioxidant properties, as well as metal-chelating property, sufficient reasons for years worthy of investigation. Experimental evidence shows that Q possesses anti-inflammatory and antifibrotic capacities, which toge...

Oxidative stress plays an important pathological role in liver damage induction, progression, establishment, and perpetuation. Due to this, there has been an increasing interest in the study and evaluation of different exogenous antioxidants that can help to attenuate the damage generated by free radical insult. N-acetylcysteine (NAC) and resveratr...

Although some articles portray coffee as negative, most evidence points toward a direct association between coffee intake and human health. This chapter describes the composition of coffee and the protective properties associated with various liver diseases. The main active components of coffee are caffeine, chlorogenic acid, diterpenes (cafestol a...

Adverse gastrointestinal (GI) effects caused by nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin, are recognized as the major limitation to their clinical use. NSAID-induced gastric damage is generated by cyclooxygenase inhibition, activation of inflammatory processes, and oxidative stress. Docosahexaenoic acid (DHA), an omega-...

AIM To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS Thirty-two male Wistar rats (120-150 g) were randomly divided into four groups: (1) a control group (n = 8) that received 0.7% carboxy methyl-cellulose (NAR vehicle) 1 mL/daily p.o.; (2)...

Liver Pathophysiology: Therapies and Antioxidants is a complete volume on morphology, physiology, biochemistry, molecular biology and treatment of liver diseases. It uses an integral approach towards the role of free radicals in the pathogenesis of hepatic injury, and how their deleterious effects may be abrogated by the use of antioxidants. Writte...

Fibrosis frequently leads to cirrhosis, the final stage of liver damage. There are several complications of cirrhosis, of note: portal hypertension, gastroesophageal varices, ascites, hepatorenal syndrome, hepatic encephalopathy, hepatopulmonary syndrome, and hepatocellular carcinoma. Understanding the pathogenesis of portal hypertension could be o...

Oxidative stress is importantly involved in the pathophysiology of various liver diseases. The redox state participates on the course of the inflammatory, metabolic and proliferative liver diseases. The main sources of the reactive oxygen species (ROS) are represented by the mitochondria and cytochrome P450 enzymes in the hepatocyte, Kupffer cells...

An in vitro model that simulates some gastrointestinal (GIT) tract conditions was used to select gram-positive and catalase-negative bacilli. Then, their capacity to dissociate bile salts conjugated to taurine and glycine was qualitatively and quantitatively evaluated. The in vivo experiments were performed on male Wistar rats. Lactobacillus strain...

Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce free radicals (FR). However, antioxidants scavenge FR and maintain the oxidative/antioxidative balance in the liver. When the liver oxidative/antioxidative bala...

Here we evaluated the ability of l-theanine in preventing experimental hepatic cirrhosis and investigated the roles of nuclear factor-κB (NF-κB) activation as well as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) regulation. Experimental hepatic cirrhosis was established by the administration of carbon tetrachlorid...

Background/aims: To evaluate the antioxidant, immunomodulatory, antinecrotic and antifibrotic effects of hesperidin on CCl4-induced cirrhosis. Methods: Liver damage was produced by giving CCl4 injections (0.4 g/kg, i.p., 3 times per week for 8 weeks) to rats. Hesperidin (200 mg/kg) was administered using gavage. The expression of nuclear factor-...

Allopurinol is an inhibitor of xanthine oxidase. The aim of this work was to evaluate the efficacy of allopurinol to reverse the experimental cirrhosis induced by CCl4. Rats received CCl4 for 8 weeks, and immediately after allopurinol was administered for 4 weeks more. Allopurinol reversed all markers of liver damage and oxidative stress to normal...

This study was performed to evaluate the antifibrotic properties of coffee in a model of liver damage induced by repeated administration of thioacetamide (TAA) in male Wistar rats. In this study, cirrhosis was induced by chronic TAA administration and the effects of co-administration of conventional caffeinated coffee or decaffeinated coffee (CC, D...

There is a growing body of evidence that caffeine exerts beneficial effects on the liver; however, the molecular mechanisms by which caffeine exerts beneficial effects on the liver are poorly defined. The aim of the present study was to examine the efficacy of caffeine in preventing thioacetamide (TAA)-induced cirrhosis in rats. Cirrhosis was induc...

Allopurinol is an inhibitor of xanthine oxidase (XO), and XO is an enzyme that generates great amounts of reactive oxygen species. The aim of this work was to evaluate the efficacy of allopurinol to prevent experimental cirrhosis. Fibrosis and cirrhosis were induced by common bile duct ligation (BDL) for 4 weeks in rats. Animals were divided into 4...

It has been demonstrated that this sulfasalazine (SF) inhibits the nuclear factor κB (NFκB) pathway, which regulates important genes during inflammation and immune answer. The aim of this work was to evaluate the effects of SF on carbon tetrachloride (CCl(4))-induced liver fibrosis. We formed the following experimental groups of rats: controls, dam...

The liver Epidemiologic studies Coffee, fibrosis, and cirrhosis Coffee and animal models of hepatic fibrosis Cytokines and liver fibrosis Mechanism of coffee's protective effect Adenosine A2A receptors and caffeine Caffeine metabolism and drug interactions Conclusions References

Primary liver cancer is the sixth most common cancer in the world and the third cause of death by cancer due to its bad prognosis. Most primary liver cancers are Hepatocellular Carcinomas (HCC). The major risk factors for HCC are chronic liver diseases (especially cirrhosis) including hepatitis B and C, alcoholic liver disease, non-alcoholic steato...

Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs used primarily to treat inflammation, pain and fever. Their main mechanism of action is cyclooxygenase (COX) inhibition, and this enzyme has been linked to hepatotoxicity. The association of COX and liver injury has been, in part, due to the presence of COX-2 isoform in damaged liver and the...

Several studies suggest that free radicals may play a role in cholestatic liver injury. The aim of this work was to evaluate the role of trolox in chronic bile duct ligation (BDL). Liver injury was induced by 28-day BDL to male Wistar rats. Animals were divided in four groups of six rats. Trolox was administered daily (50 mg/kg, p.o.). Alanine amin...

There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl₄)-induced acute liver damage. To achieve this, CCl₄ (4 g·kg(-1), per os) was administ...

Previous clinical observations suggested that coffee may have beneficial effects on the liver. In fact, an inverse relationship between coffee consumption and liver cirrhosis has been reported in humans. However, the causative role of coffee has not been established; therefore, the aim of this work was to study the effect of coffee in an experiment...

Transforming growth factor-beta (TGF-beta) plays a pivotal role in liver fibrosis, because it activates hepatic stellate cells, stimulating extracellular matrix deposition. Cyclooxygenase-2 (COX-2) has been associated with TGF-beta because its inhibition decreases TGF-beta expression and collagen production in some cultured cell types. The aim of t...

Since 1900 bc, several therapeutic activities have been attributed to the rhizomes of the plant Curcuma longa for a variety of diseases, including liver disorders. Curcumin, the main active compound obtained from this plant, was first isolated two centuries ago and its structure as diferuloylmethane was determined in 1910. Curcumin has shown anti-i...

Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including hu...

Coffee consumption is worldwide spread with few side effects. Interestingly, coffee intake has been inversely related to the serum enzyme activities gamma-glutamyltransferase, and alanine aminotransferase in studies performed in various countries. In addition, epidemiological results, taken together, indicate that coffee consumption is inversely re...

Chronic cholestasis and cholangitis may lead to the last phase known as biliary cirrhosis, characterized by cellular necrosis, apoptosis, tissue damage, local regeneration, inflammation and fibrosis. Such events are mediated by cytokines. Thalidomide and its analogs have shown to be effective immunomodulatory and hepatoprotective agents. The aim of...

Liver cirrhosis is a common cause of death around the world. One of its more severe complications is hepatic encephalopathy. As a consequence of liver impairment, manganese (Mn) and other substances accumulate in the brain. Astrocytic morphological changes have been found in postmortem brains of cirrhotic patients. In this study we used a model of...

N-acetylcysteine (NAC) is an antioxidant, a precursor of reduced glutathione, and an inhibitor of the profibrotic cytokine liver transforming growth factor-beta (TGF-beta). Carbon tetrachloride (CCl4) cirrhosis is characterized by oxidative stress and fibrosis. Therefore, the aim of this work was to study the effect of NAC on experimental cirrhosis...

There are five nuclear factor-kappaB (NF-kappaB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF-kappaB, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, antichole...

Liver fibrosis is characterized by an excess of collagen fiber deposition, and it is known that Kupffer cells play an important role by immunomodulation of the toxic response. Methyl palmitate (MP) is an effective Kupffer cell inhibitor. The aim of this work was to evaluate the effect of MP on experimental liver fibrosis. Four groups were formed: t...

Cirrhosis is a very common disease and its treatment is limited due to lack of effective drugs. Some studies indicate that this disease is associated with oxidative stress. Therefore, we decided to study the effect of trolox, an effective antioxidant, on experimental cirrhosis. Cirrhosis was induced by CCl4 administration (0.4 g/kg, intraperitoneal...

Hepatic glycogen metabolism is altered by nitric oxide (NO) during endotoxic shock. Thalidomide analogs immunomodulate the endotoxin-induced cytokines which regulate the NO release. We analyzed the short-term effects of some thalidomide analogs on the hepatic glycogen store and on the plasma and hepatic NO in an acute model of endotoxic challenge i...

Curcumin is a phytophenolic compound, which is highly efficacious for treating several inflammatory diseases. The aim of this study was to evaluate the efficacy of curcumin in preventing or reversing liver cirrhosis. A 4-week bile duct ligation (BDL) rat model was used to test the ability of curcumin (100 mg/kg, p.o., daily) to prevent cirrhosis. T...

Liver diseases are a major problem of worldwide proportions. However, the number of drugs actually used successfully in humans is very small. In this review some of the most promising/studied drugs utilized for liver diseases were chosen and analysed critically from the basic to the clinical point of view. Antiviral agents are not discussed because...

The importance of hydroxyl groups in the antioxidant and hepatoprotective properties of resveratrol was investigated. To achieve this, resveratrol or its trimethylated analog were administered (10 mg kg(-1), p.o.) to male Wistar rats and liver damage was induced by acute administration of CCl4 (4 g kg(-1), p.o.); appropriate controls were performed...