Bile acids as novel enhancers of CNS targeting antitumor drugs: a comprehensive review.

Despite a relatively low prevalence of primary brain tumors, they continuously attract scientific interest because of the complexity of their treatment due to their location behind the blood-brain barrier. The main challenge in treatment of brain tumors is not the efficacy of the drugs, per se, but the low efficiency of drug delivery to malignant cells. At the core of the problem is the complex structure of the blood-brain barrier. Nowadays, there is evidence supporting the claim that bile acids have the ability to cross the blood-brain barrier. That ability can be exploited by taking a part in novel drug carrier designs. Bile acids represent a drug carrier system as a part of a mixed micelle composition, bilosomes and conjugates with various drugs. This review discusses the current knowledge related to bile acid molecules as drug penetration modifying agents, with the focus on central nervous system antitumor drug delivery.

Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases.

BACKGROUND: The well-known functions of bile acids (BAs) are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases. DATA SOURCES: Detailed and comprehensive search of PubMed and Scopus databases was carried out for original and review articles. RESULTS: Disturbances in BA homeostasis contribute to the development of several hepatobiliary and intestinal disorders, such as non-alcoholic fatty liver disease, liver cirrhosis, cholesterol gallstone disease, intestinal diseases and both hepatocellular and colorectal carcinoma. CONCLUSION: Further efforts made in order to advance the understanding of sophisticated BA signaling network may be promising in developing novel therapeutic strategies related not only to hepatobiliary and gastrointestinal but also systemic diseases.

Different associations of apoE gene polymorphism with metabolic syndrome in the Vojvodina Province (Serbia).

The metabolic syndrome (MetS) is a polygenic multifactorial metabolic disorder with strong socioeconomic influence. MetS has became a worldwide epidemic, that directly increases the risk of cardiovascular diseases and type 2 diabetes mellitus. The human apoE gene, coding Apolipoprotein E, has three common polymorphisms in human population: e2, e3 and e4, which are proved to be associated with impaired lipid metabolism. The contribution of apoE polymorphism to MetS disorders has not been investigated previously in Vojvodina Province, region with the highest number of obese people in Serbia. The aim of this study was to evaluate apoE gene polymorphism in relation to MetS disorders. The healthy control group of 30 individuals and 63 MetS patients were examined for apoE variants in relation to biochemical and anthropometric parameters. The genotypes were determined by PCR-RFLP. Regarding all parameters, significantly higher values were detected in MetS group compared to control. The MetS group of patients had significantly higher frequency of e4 allele. In addition, positive relation was revealed between e4 allele presence and all measured parameters. It was found that the e4 allele was related with a significantly increased OR of MetS disorders according to the International Diabetes Federation definition. These results suggested that e4 allele may act as a one of determinants for development of metabolic syndrome.

Pathogenesis and regulation of cellular proliferation in acute lymphoblastic leukemia - the role of Ikaros.

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia of childhood. Over the last 50 years there have been tremendous scientific advances in understanding the pathogenesis and the mechanisms that control cellular proliferation in ALL. These discoveries led to the development of efficient therapeutic regimens that greatly improved survival of children with ALL. Recently, several genes have been demonstrated to play a key role in tumor suppression and that their deregulation leads to malignant transformation and can affect overall survival. This review summarizes the role of Ikaros (IKZF1) in tumor suppression and regulation of gene expression in leukemia. Deletions and/or mutations of Ikaros have been detected in a large percentage of pediatric and adult ALL and reduced Ikaros function has been associated with poor outcome in ALL. Ikaros function in chromatin remodeling and epigenetic regulation of gene transcription emphasizes the important role of this protein in controlling cellular proliferation. In this review, we particularly focus on the role of signaling pathways in the regulation of Ikaros activity and its transcriptional control in leukemia.

The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders.

TGR5 is the G-protein-coupled bile acid-activated receptor, found in many human and animal tissues. Considering different endocrine and paracrine functions of bile acids, the current review focuses on the role of TGR5 as a novel pharmacological target in the metabolic syndrome and related disorders, such as diabetes, obesity, atherosclerosis, liver diseases and cancer. TGR5 ligands improve insulin sensitivity and glucose homeostasis through the secretion of incretins. The bile acid/TGR5/cAMP signaling pathway increases energy expenditure in brown adipose tissue and skeletal muscle. Activation of TGR5 in macrophages inhibits production of proinflammatory cytokines and attenuates the development of atherosclerosis. This receptor has been detected in many cell types of the liver where it has anti-inflammatory effects, thus reducing liver steatosis and damage. TGR5 also modulates hepatic microcirculation and fluid secretion in the biliary tree. In cell culture models TGR5 has been linked to signaling pathways involved in metabolism, cell survival, proliferation and apoptosis, which suggest a possible role of TGR5 in cancer development. Despite the fact that TGR5 ligands may represent novel drugs for prevention and treatment of different aspects of the metabolic syndrome, clinical studies are awaited with the perspective that they will complete TGR5 biology and identify efficient and safe TGR5 agonists.

Modification of antioxidative and antiapoptotic genes expression in irradiated K562 cells upon fullerenol C60(OH)24 nanoparticle treatment.

Recent data established the prospective applications for fullerenol (C60(OH)24) nanoparticle (FNP) in many fields, such as antioxidants, neuroprotective agents, and potential anti-radiation drugs. Leukemia cell sensitization to apoptosis induced by ionizing radiation is achieved by upregulation of ROS production and/or downregulation of antioxidative enzymes. Therefore, our aim was to analyze the potential role of fullerenol nanoparticle in modulation of the leukemic cellular response to irradiation. We used the qRT-PCR to analyze the expression level of mRNA for 11 genes in irradiated and FNP pre-treated irradiated K562 cells, and compared the gene expression level with the overall cell survival. Our results of the improved cell survival in FNP-treated irradiated cells and significant overexpression of anti-apoptotic Bcl-2 and Bcl-xL and cytoprotective genes such as GSTA4, MnSOD, NOS, CAT and HO-1 genes, may indicate that FNP exerts cytoprotective function in K562 leukemic cells, rendering K562 cells more tolerant to radiotherapy.

Drug interference with biochemical laboratory tests.

Clinical laboratory practice represents an essential part of clinical decision-making, as it influences 60-70% of medical decisions at all levels of health care. Results of biochemical laboratory tests (BLTs) have a key role in establishment of adequate diagnosis as well as in evaluation of treatment progress and outcome. The prevalence of drug-laboratory test interactions (DLTIs) is up to 43% of patients who had laboratory results influenced by drugs. Unrecognized DLTIs may lead to misinterpreted BLTs results, incorrect or delayed diagnosis, extra costs for unnecessary additional tests or inadequate therapy, as all may cause false clinical decisions. The significance of timely and adequate recognition of DLTIs is to prevent common clinical consequences such as incorrectly interpreted test results, delayed or non-treated condition due to erroneous diagnosis or unnecessary extra tests or therapy. Medical professionals should be educated that it is essential to obtain patient data about medications especially for the drugs used in the last 10 days before biological material collection. Our mini-review aims to provide a comprehensive overview of the current state in this important domain of medical biochemistry with detailed analysis of the effect of drugs on BLTs and to give detailed information to medical specialists.

Low-dose nano-gel incorporated with bile acids enhanced pharmacology of surgical implants.

Aim: Major challenges to islet transplantation in Type 1 diabetes include host-inflammation, which results in failure to maintain survival and functions of transplanted islets. Therefore, this study investigated the applications of encapsulating the bile acid ursodeoxycholic acid (UDCA) with transplanted islets within improved nano-gel systems for Type 1 diabetes treatment. Materials & methods: Islets were harvested from healthy mice, encapsulated using UDCA-nano gel and transplanted into the diabetic mice, while the control group was transplanted encapsulated islets without UDCA. The two groups' survival plot, blood glucose, and inflammation and bile acid profiles were analyzed. Results & conclusion: UDCA-nano gel enhanced survival, glycemia and normalized bile acids' profile, which suggests improved islets functions and potential adjunct treatment for insulin therapy.

In this study, we explore the delivery of insulin producing cells that may benefit those with Type 1 diabetes. Cells were delivered to mice in a protective matrix. The matrix contained unique components, such as bile acids, that allowed for sustained reduction in glucose levels. This process may represent a novel diabetes treatment that could be an alternative to traditional insulin therapies.

The impact of farnesoid X receptor activation on intestinal permeability in inflammatory bowel disease.

The most important function of the intestinal mucosa is to form a barrier that separates luminal contents from the intestine. Defects in the intestinal epithelial barrier have been observed in several intestinal disorders such as inflammatory bowel disease (IBD). Recent studies have identified a number of factors that contribute to development of IBD including environmental triggers, genetic factors, immunoregulatory defects and microbial exposure. The current review focuses on the influence of the farnesoid X receptor (FXR) on the inhibition of intestinal inflammation in patients with IBD. The development and investigation of FXR agonists provide strong support for the regulatory role of FXR in mucosal innate immunity. Activation of FXR in the intestinal tract decreases the production of proinflammatory cytokines such as interleukin (IL) 1-beta, IL-2, IL-6, tumour necrosis factor-alpha and interferon-gamma, thus contributing to a reduction in inflammation and epithelial permeability. In addition, intestinal FXR activation induces the transcription of multiple genes involved in enteroprotection and the prevention of bacterial translocation in the intestinal tract. These data suggest that FXR agonists are potential candidates for exploration as a novel therapeutic strategy for IBD in humans.

Effect of simultaneous exposure to benzene and ethanol on urinary thioether excretion.

The toxicity of benzene is not an issue of the past, especially in developing countries. Bone marrow toxicity is demonstrated among workers. In this study, the effect of simultaneous exposure to benzene and ethanol on benzene metabolism in mice was investigated by measuring the excretion of thioethers in urine. Urinary thioether excretion significantly decreased in the mice receiving both benzene and ethanol compared with the animals receiving benzene only. The assay of determining thioethers in urine samples in this study is a simple and low-cost method, thus suitable for routine use, especially in developing countries, not only for benzene, but also for other alkilating agents, which can be found during occupational exposure. Our results suggest that further research is needed to elucidate the mechanisms of decreased urinary excretion of thioether after simultaneous exposure to benzene and ethanol.

Antimetastatic Potential of Quercetin Analogues with Improved Pharmacokinetic Profile: A Pharmacoinformatic Preliminary Study.

BACKGROUND: Urokinase-type plasminogen activator (uPA) system is a crucial pathway for tumor invasion and metastasis. Recently, multiple anticancer effects of quercetin have been described, including inhibitory activity against uPA. However, the clinical use of this flavonoid has been limited due to its low oral bioavailability. OBJECTIVE: The objectives of the study were to assess the antimetastatic potential of quercetin analogues by analyzing their binding affinity for uPA, and to select the compounds with improved pharmacological profiles. METHODS: Binding affinities of structural analogues of quercetin to uPA receptor were determined by molecular docking analysis using Molegro Virtual Docker software, and molecular descriptors relevant for estimating pharmacological profile were calculated from ligand structures using computational models. RESULTS: Among 44 quercetin analogues, only one quercetin analogue (3,6,2',4',5'-pentahydroxyflavone) was found to possess higher aqueous solubility and membrane permeability, and stronger affinity for uPA than quercetin, which makes it a potential lead compound for anticancer drug development. Like quercetin, this compound has five hydroxyl groups, but arranged differently, which contributes to the higher aqueous solubility and higher amphiphilic moment in comparison to quercetin. Since membrane permeability is not recognized as the limiting factor for quercetin absorption, analogues with higher aqueous solubility and retained or stronger uPA inhibitory activity should also be further experimentally validated for potential therapeutic use. CONCLUSION: Identified quercetin analogues with better physicochemical and pharmacological properties have a high potential to succeed in later stages of research in biological systems as potential anticancer agents with antimetastatic activity.

WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.

Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.

Antioxidant properties of fullerenol C60(OH)24 in rat kidneys, testes, and lungs treated with doxorubicin.

Clinical use of doxorubicin continues to be challenged by its undesirable systematic toxicity, caused mainly by oxidative stress. The aim of this study was to investigate the effectiveness of fullerenol C(60)(OH)(24) polyanion nanoparticles, an antioxidant agent, against doxorubicin-induced nephro-, testicular, and pulmonary toxicity. Results obtained in vitro suggest that fullerenol's anti-proliferative property and protective effect against doxorubicin cytotoxicity are mediated by the antioxidative and radical scavenging activity. Male Wistar rats were divided into five treatment groups: the control group (I) received 0.9% NaCl (1 mL/kg, i.p.). Groups II, III, IV, and V received a single dose of doxorubicin (10 mg/kg i.p.), doxorubicin/fullerenol (100 and 50 mg/kg i.p. of fullerenol 30 min prior to 10 mg/kg i.p. of doxorubicin), and fullerenol (100 mg/kg i.p.), respectively. On the 2(nd) and 14(th) days, organ samples were taken for the measurement of lipid peroxidation and activities of superoxide dismutase, catalase, glutathione-peroxidase, -reductase, and -transferase. Doxorubicin induced a significant increase of lipid peroxidation and alterations of antioxidant enzyme activities, while the fullerenol pre-treatment prevented the effects of doxorubicin on investigated parameters. Fullerenol, applied alone, did not alter basal values of the investigated animals. Considering the mechanisms of doxorubicin toxicity, it can be concluded that fullerenol exerts its protective role by acting as a free radical sponge and/or by removing free iron through formation of fullerenol-iron complex. Results of this study support the hypothesis of testicular, pulmo-, and nephroprotective efficacy of fullerenol in preventing oxidative stress induced by doxorubicin.

DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment.

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

Effects of fullerenol C60(OH)24 on the frequency of micronuclei and chromosome aberrations in CHO-K1 cells.

Poly-hydroxylated C(60) fullerenols (C(60)(OH)(n)) have attracted much attention in biomedical research, due to a variety of biological activities. However, the studies investigating the genotoxic effects of fullerenols are still insufficient. The aim of the present study was to analyze the genotoxic and antigenotoxic potential of fullerenol C(60)(OH)(24). The investigation was carried out with mitomycin C (MMC)-treated and control Chinese hamster ovary cells (CHO-K1), using the chromosome aberration (CA) assay and the cytokinesis-block micronucleus (CBMN) test. Cells were treated with fullerenol nanoparticles, which are well known for their antioxidative properties and cytoprotective effects, both in vivo and in vitro. Our study showed the absence of genotoxicity of fullerenol in a wide range of concentrations (11-221 microM). Fullerenol mediated the decrease in the frequency of micronuclei (MN) and chromosome aberrations compared with the controls at all endpoints examined. A dose-dependent decrease of MN frequency was found 24h after treatment with fullerenol, in contrast to the outcome of the CA assay. Cell proliferation was equally influenced by fullerenol. The majority of aberrations were of the chromosome-type. Our results show that fullerenol does not induce genotoxic effects, and that it protects both non-damaged and MMC-damaged CHO-K1 cells.

Activity of antioxidative enzymes in erythrocytes after a single dose administration of doxorubicin in rats pretreated with fullerenol C(60)(OH)(24).

In earlier in vitro investigations, fullerenol was shown to have a strong antioxidative capability. The present study examined the role of fullerenol as a potential antioxidative protector for doxorubicin-induced oxidative stress in the blood of rats through an investigation of the activity of glutathione-dependent enzymes (glutathione-S-transferase and glutathione peroxidase). It also assessed the influence of fullerenol on the number of blood cells (leukocytes and erythrocytes) as well as on the content of hemoglobin after a single dose administration of doxorubicin. Experiments were performed on six groups of adult male Wistar rats, each group containing eight individuals. Doxorubicin was administrated i.v. (tail vein) in a single dose of 10 mg/kg. Fullerenol C(60)(OH)(24) was administrated to the treated animals i.p. (in doses 50, 100, 200 mg/kg) 30 min before the dosing with doxorubicin. The control group animals were given saline (1 ml/kg; i.p.). One group of animals was treated only with fullerenol (100 mg/kg i.p.). The animals were sacrificed 2 and 14 days after the treatment. Each experiment was repeated twice. The results may indicate that fullerenol induces a decrease in the antioxidative capacity of erythrocytes in oxidative stress conditions, whereas, without doxorubicin, the application of fullerenol did not induce any changes in the enzyme activity of erythrocytes. The results of GST activity might indicate that 50 mg/kg are not sufficient to protect from doxorubicin toxicity, while 200 mg/kg might be toxic for animals, judging from the increase in GST activity.

In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders.

BACKGROUND: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. METHODS: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. RESULTS: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. CONCLUSION: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

Fullerenol C60(OH)24 effects on antioxidative enzymes activity in irradiated human erythroleukemia cell line.

Radiotherapy-induced toxicity is a major dose-limiting factor in anti-cancer treatment. Ionizing radiation leads to the formation of reactive oxygen and nitrogen species (ROS/RNS) that are associated with radiation-induced cell death. Investigations of biological effects of fullerenol have provided evidence for its ROS/RNS scavenger properties in vitro and radioprotective efficiency in vivo. Therefore we were interested to evaluate its radioprotective properties in vitro in the human erythroleukemia cell line. Pre-treatment of irradiated cells by fullerenol exerted statistically significant effects on cell numbers and the response of antioxidative enzymes to X-ray irradiation-induced oxidative stress in cells. Our study provides evidence that the pre-treatment with fullerenol enhanced the enzymatic activity of superoxide dismutase and glutathione peroxidase in irradiated K562 cells.

Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles.

Bile acids have received considerable interest in the drug delivery research due to their peculiar physicochemical properties and biocompatibility. The main advantage of bile acids as drug absorption enhancers is their ability to act as both drug solubilizing and permeation-modifying agents. Therefore, bile acids may improve bioavailability of drugs whose absorption-limiting factors include either poor aqueous solubility or low membrane permeability. Besides, bile acids may withstand the gastrointestinal impediments and aid in the transporter-mediated absorption of physically complexed or chemically conjugated drug molecules. These biomolecules may increase the drug bioavailability also at submicellar levels by increasing the solubility and dissolution rate of non-polar drugs or through the partition into the membrane and increase of membrane fluidity and permeability. Most bile acid-induced effects are mediated by the nuclear receptors that activate transcriptional networks, which then affect the expression of a number of target genes, including those for membrane transport proteins, affecting the bioavailability of a number of drugs. Besides micellar solubilization, there are many other types of interactions between bile acids and drug molecules, which can influence the drug transport across the biological membranes. Most common drug-bile salt interaction is ion-pairing and the formed complexes may have either higher or lower polarity compared to the drug molecule itself. Furthermore, the hydroxyl and carboxyl groups of bile acids can be utilized for the covalent conjugation of drugs, which changes their physicochemical and pharmacokinetic properties. Bile acids can be utilized in the formulation of conventional dosage forms, but also of novel micellar, vesicular and polymer-based therapeutic systems. The availability of bile acids, along with their simple derivatization procedures, turn them into attractive building blocks for the design of novel pharmaceutical formulations and systems for the delivery of drugs, biomolecules and vaccines. Although toxic properties of hydrophobic bile acids have been described, their side effects are mostly produced when present in supraphysiological concentrations. Besides, minor structural modifications of natural bile acids may lead to the creation of bile acid derivatives with the reduced toxicity and preserved absorption-enhancing activity.

Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome.

Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.