Chemical constituents and pharmacological action of bile acids from animal:a review / 中国中药杂志

Bile of animal(mainly chicken, pig, snake, cow, and bear) has long been used as medicine. As the major active components of bile, bile acids mainly include cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and taurochenodeoxycholic acid. They interact with intestinal microorganisms in enterohepatic circulation, thereby playing an important part in nutrient absorption and allocation, metabolism regulation, and dynamic balance. Bile acids have pharmacological effects such as protecting liver, kidney, heart, brain, and nerves, promoting bile secretion, dissolving gallstones, anti-cancer, relieving cough and dyspnea, dispelling phlegm, treating eye diseases, and regulating intestinal function and blood glucose, which are widely used in clinical practice. This study summarized and analyzed the research on the chemical constituents and pharmacological effects of bile acids from medicinal animals, in a bid to provide scientific basis and reference for the further development and utilization of bile acids.

The diversity of ursodeoxycholic acid precursors from bile waste of commercially available fishes, poultry and livestock in Indonesia

Ursodeoxycholic acid (UDCA), a secondary bile acid (BA), has been used as a drug to treat various liver diseases. UDCA is synthesised from cholic or chenodeoxycholic acid (CA/CDCA), two primary BAs frequently used as the starting materials. Nowadays, swine, cattle, and poultry bile are the main sources of those BAs. However, other commercial animals could be promising sources as well. We identified two livestock, two poultries, and eight fishes that are commercially cultivated in Indonesia. Four free BAs including CA, CDCA, deoxycholic acid (DCA), and lithocholic acid (LA) were identified for their occurrences using thin-layer chromatography and high-performance liquid chromatography. CA was detected in cow, duck, red tilapia, gourami, the common carp, and grouper, whereas CDCA was only detected in two poultries and the common carp. The occurrence of DCA was common and abundant in most tested animals. In contrast, the presence of LA was found to be very low in all samples. The biliary bile of tilapia has been found to contain a high abundance of free CA (43% of the total bile). A simple extraction was able to purify CA from biliary bile of tilapia. This is a new promising and competitive source of CA.

Bile acids regulate anorexigenic neuropeptide through p-STAT3-SOCS3 signaling in mouse hypothalamic cells / 南方医科大学学报

OBJECTIVE@#To explore the effects of taurolithocholic acid (tLCA) and chenodeoxycholic acid (CDCA) on the expression of aorexigenic neuropeptide in mouse hypothalamus GT1-7 cells.@*METHODS@#Mouse hypothalamic GT1-7 cells were treated with culture medium containing 10% FBS (control group, =3) or with 10 nmol/L, 100 nmol/L, 1 μmol/L and 10 μmol/L tLCA (tLCA group, =3) or CDCA (CDCA group, =3) for 12, 24 or 48 h. Real-time PCR was performed to determine the expression levels of proopiomelanocortin (POMC) mRNA in the cells, and the production levels of α-melanocyte-stimulating hormone (α-MSH) were assessed using an ELISA kit. Signal transduction and activator of transcription 3 phosphorylation (p-STAT3), threonine kinase phosphorylation (p-AKT), suppressor of cytokine signaling 3 (SOCS3), G protein-coupled bile acid receptor-1 (TGR5) and farnesoid X receptor (FXR) protein were detected by Western blotting.@*RESULTS@#Western blotting results showed that mouse hypothalamic GT1-7 cells expressed two bile acid receptors, TGR5 and FXR, whose expressions were regulated by bile acids. Real-time PCR showed that the expression of POMC mRNA was significantly increased in the cells after treatment with 10 μmol/L tLCA or CDCA for 24 h. POMC-derived anorexigenic peptide α-MSH increased significantly in GT1-7 cells after treatment with 10 μmol/L tLCA or CDCA for 24 h. Treatment of the cells with tLCA or CDCA significantly increased the expressions of intracellular signaling proteins including p-STAT3, p-AKT and SOCS3.@*CONCLUSIONS@#Mouse hypothalamic GT1-7 cells express bile acid receptors TGR5 and FXR. Bile acids tLCA or CDCA can promote the expression of POMC mRNA and increase the production of the anorexigenic peptide α-MSH. The intracellular signaling proteins p-AKT, p-STAT3 and SOCS3 are likely involved in bile acid-induced anorexigenic peptide production.

Bile acids regulate anorexigenic neuropeptide through p-STAT3-SOCS3 signaling in mouse hypothalamic cells / 浙江大学学报·医学版

OBJECTIVE@#To explore the effects of taurolithocholic acid (tLCA) and chenodeoxycholic acid (CDCA) on the expression of aorexigenic neuropeptide in mouse hypothalamus GT1-7 cells.@*METHODS@#Mouse hypothalamic GT1-7 cells were treated with culture medium containing 10% FBS (control group, =3) or with 10 nmol/L, 100 nmol/L, 1 μmol/L and 10 μmol/L tLCA (tLCA group, =3) or CDCA (CDCA group, =3) for 12, 24 or 48 h. Real-time PCR was performed to determine the expression levels of proopiomelanocortin (POMC) mRNA in the cells, and the production levels of α-melanocyte-stimulating hormone (α-MSH) were assessed using an ELISA kit. Signal transduction and activator of transcription 3 phosphorylation (p-STAT3), threonine kinase phosphorylation (p-AKT), suppressor of cytokine signaling 3 (SOCS3), G protein-coupled bile acid receptor-1 (TGR5) and farnesoid X receptor (FXR) protein were detected by Western blotting.@*RESULTS@#Western blotting results showed that mouse hypothalamic GT1-7 cells expressed two bile acid receptors, TGR5 and FXR, whose expressions were regulated by bile acids. Real-time PCR showed that the expression of POMC mRNA was significantly increased in the cells after treatment with 10 μmol/L tLCA or CDCA for 24 h. POMC-derived anorexigenic peptide α-MSH increased significantly in GT1-7 cells after treatment with 10 μmol/L tLCA or CDCA for 24 h. Treatment of the cells with tLCA or CDCA significantly increased the expressions of intracellular signaling proteins including p-STAT3, p-AKT and SOCS3.@*CONCLUSIONS@#Mouse hypothalamic GT1-7 cells express bile acid receptors TGR5 and FXR. Bile acids tLCA or CDCA can promote the expression of POMC mRNA and increase the production of the anorexigenic peptide α-MSH. The intracellular signaling proteins p-AKT, p-STAT3 and SOCS3 are likely involved in bile acid-induced anorexigenic peptide production.

Xantomatosis cerebrotendinosa sin xantomas tendíneos: caso clínico / Cerebrotendinous xanthomatosis: report of one case

Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by deficiency of 27-sterol-hydroxylase that results in an accumulation of cholestanol in the central nervous system, eyes, tendons, and blood vessels. We report a 22-year-old woman with a history of cataract surgery at the age of 14, cholecystectomy due to cholelithiasis at the age of 17 and chronic diarrhea, who presented with a six months period of gait instability and frequent falls. Physical examination revealed a bilateral pyramidal and cerebellar syndrome, with no visible tendon xanthomas. Cerebral magnetic resonance imaging showed an increase of the signal intensity on the T2-weighted images in periventricular cerebral white matter, dentate nuclei and spinal cord. With a high suspicion of CXT, a genetic study was conducted identifying a pathogenic variant in the CYP27A1 gene. There is considerable variation in clinical characteristics and age of onset of this disease, including absence of tendon xanthomas, delaying the diagnosis. Early recognition and chronic chenodeoxycholic acid therapy can improve outcome and quality of life.

Current management of non-alcoholic fatty liver disease / Atualidades no tratamento da doença hepática gordurosa não alcoólica

SUMMARY Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipid in patients who do not consume alcohol in amounts generally considered harmful to the liver. NAFLD is becoming a major liver disease in Eastern countries and it is related to insulin resistance and metabolic syndrome. Treatment has focused on improving insulin sensitivity, protecting the liver from oxidative stress, decreasing obesity and improving diabetes mellitus, dyslipidemia, hepatic inflammation and fibrosis. Lifestyle modification involving diet and enhanced physical activity associated with the treatment of underlying metabolic are the main stain in the current management of NAFLD. Insulin-sensitizing agents and antioxidants, especially thiazolidinediones and vitamin E, seem to be the most promising pharmacologic treatment for non-alcoholic steatohepatitis, but further long-term multicenter studies to assess safety are recommended.

RESUMO A doença hepática gordurosa não alcoólica (DHGNA) é caracterizada pela deposição significativa de lipídios nos hepatócitos de pacientes que não apresentam história de ingestão alcoólica significativa. É a doença do fígado mais prevalente em populações ocidentais e existe forte associação da DHGNA com a resistência à insulina (RI) e com a síndrome metabólica. O tratamento objetiva reduzir a RI, o estresse oxidativo, a obesidade, a dislipidemia bem como a inflamação e a fibrose hepáticas. O tratamento atual baseia-se principalmente em modificações do estilo de vida, que incluem dieta e prática regular de exercícios físicos, associadas ao tratamento de todos os componentes da síndrome metabólica. Quanto ao tratamento medicamentoso da esteato-hepatite não alcoólica, os agentes insulino-sensibilizantes e os antioxidantes parecem os mais promissores, especialmente as tiazolidinodionas e a vitamina E, mas faltam estudos multicêntricos avaliando sua segurança a longo prazo.

Nuevas estrategias farmacológicas para el tratamiento del hígado graso no alcohólico / New pharmacological strategies for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents an increasing health problem in Chile and worldwide. In some cases NAFLD presents with a progressive form that can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current pharmacological therapies (pioglitazone and vitamin E) show limited response and are associated to significant adverse effects. During recent years several novel and promising pharmacological therapies have been developed to prevent fibrosis, liver cirrhosis and reduce liver related deaths. The present article summarizes some of these promising strategies, including reported efficacy in clinical trials and associated adverse effects. Hopefully in the near future these new therapies will help to improve NAFLD management and reduce liver related complications.

El hígado graso no alcohólico (HGNA) es un creciente problema de salud pública en Chile y el mundo. En un subgrupo de sujetos, el HGNA puede presentarse con un fenotipo de daño hepático progresivo que puede evolucionar a fibrosis progresiva, cirrosis y carcinoma hepatocelular. Las estrategias farmacológicas actuales (pioglitazona y vitamina E) presentan eficacia limitada y no están exentas de efectos adversos. Durante los últimos años se han desarrollado múltiples estrategias farmacológicas novedosas y promisorias que buscan evitar la progresión hacia cirrosis y reducir la mortalidad de causa hepática. El presente artículo resume los principales nuevos fármacos, los efectos beneficiosos reportados y sus efectos adversos. Es de esperar que en un futuro próximo estas terapias permitan cambiar el pronóstico de nuestros pacientes con HGNA.

Non-alcoholic fatty liver diseases: update on the challenge of diagnosis and treatment

The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be 25-30% of the population, and is the most common cause of elevated liver enzymes in Korea. NAFLD is a "hot potato" for pharmaceutical companies. Many clinical trials are underway to develop a first-in-class drug to treat NAFLD. However, there are several challenging issues regarding the diagnosis of NAFLD. Currently, liver biopsy is the gold standard method for the diagnosis of NAFLD and steatohepatitis. Ideally, globally recognized standards for histological diagnosis and methods to optimize observer agreement on biopsy interpretation should be developed. Liver biopsy is the best method rather than a perfect one. Recently, multi-parametric magnetic resonance imagery can estimate the amount of intrahepatic fat successfully and is widely used in clinical trials. But no diagnostic method can discriminate between steatohepatitis and simple steatosis. The other unresolved issue in regard to NAFLD is the absence of satisfactory treatment options. Vitamin E and obeticholic acid have shown protective effects in randomized controlled trials, but this drug has not been approved for use in Korea. This study will provide a description of diagnostic methods and treatments that are currently recommended for NAFLD.

Epidemiological characteristics of norovirus variant of GII.4 Sydney and the outbreaks caused by norovirus variant of GII.4 Sydney in Guangdong province, 2012-2014 / 中华预防医学杂志

<p><b>OBJECTIVE</b>To analyze epidemiological characteristics of norovirus variant of GII.4 Sydney from January 2012 to June 2014 in sentinel hospitals of Guangdong province, as well as the outbreaks caused by norovirus variant of GII.4 Sydney.</p><p><b>METHODS</b>During January 2012 to June 2014, a total of 10 750 fecal samples were obtained from 22 hospitals of surveillance sites in Guangdong province. Those samples were sent to the local municipal CDCs for extracting and detecting norovirus nucleic acid. Then, all the positive samples were delivered to Guangdong provincial CDC that used Random Number Method to draw 855 positive samples for norovirus genotyping, and 690 samples were successfully sequenced. Chi-square tests were used to compare norovirus infection status of diarrhea cases in different age groups as well as during different periods. Epidemiological data of 13 outbreaks which were caused by norovirus variant of GII.4 Sydney from January 2012 to June 2014 were collected from the Public Health Emergency Management Information System of Guangdong Province, and the epidemiological characteristics were analyzed.</p><p><b>RESULTS</b>The norovirus variant of GII.4 Sydney was first detected in August 2012 and the detection rate was 13/15 in November 2012. During November 2012 to January 2013 (period T1), the norovirus positive rate of each month was 23.8% (100/421), 15.9% (61/383) and 19.2% (95/495), respectively. During November 2013 to January 2014 (period T2), the norovirus positive rate of each month was 17.0% (90/529), 8.7% (37/426) and 11.2% (46/409), respectively which were significantly lower than that of period T1 (χ² alue was 6.65, 9.93 and 10.74. P value was 0.010, 0.002, and 0.001, respectively). In period T1, the norovirus positive rate of people ages 15 and older was 26.3% (143/543) and the rate of people under 15 was 14.9% (113/756) (χ² = 2.90, P < 0.001). In period T2, the norovirus positive rate of people ages 15 and older was 10.1% (52/516) and the rate of people under 15 (14.3% (121/848)) (χ²= 5.09, P = 0.024). The foodborne transmission was the infection source for ten of thirteen outbreaks.</p><p><b>CONCLUSION</b>The norovirus variant of GII.4 Sydney was first detected in August 2012. The epidemic began to occur in the community since November 2012, and the strength of the epidemic declined 1 year later. The foodborne transmission was the main infection sources for the outbreaks caused by norovirus variant of GII.4 Sydney.</p>

Efficacy of Magnesium Trihydrate of Ursodeoxycholic Acid and Chenodeoxycholic Acid for Gallstone Dissolution: A Prospective Multicenter Trial

BACKGROUND/AIMS: Cholecystectomy is necessary for the treatment of symptomatic or complicated gallbladder (GB) stones, but oral litholysis with bile acids is an attractive alternative therapeutic option for asymptomatic or mildly symptomatic patients. This study was conducted to evaluate the efficacy of magnesium trihydrate of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on gallstone dissolution and to investigate improvements in gallstone-related symptoms. METHODS: A prospective, multicenter, phase 4 clinical study to determine the efficacy of orally administered magnesium trihydrate of UDCA and CDCA was performed from January 2011 to June 2013. The inclusion criteria were GB stone diameter or =50%, radiolucency on plain X-ray, and asymptomatic/mildly symptomatic patients. The patients were prescribed one capsule of magnesium trihydrate of UDCA and CDCA at breakfast and two capsules at bedtime for 6 months. The dissolution rate, response rate, and change in symptom score were evaluated. RESULTS: A total of 237 subjects were enrolled, and 195 subjects completed the treatment. The dissolution rate was 45.1% and the response rate was 47.2% (92/195) after 6 months of administration of magnesium trihydrate of UDCA and CDCA. Only the stone diameter was significantly associated with the response rate. Both the symptom score and the number of patients with symptoms significantly decreased regardless of stone dissolution. Adverse events necessitating discontinuation of the drug, surgery, or endoscopic management occurred in 2.5% (6/237) of patients. CONCLUSIONS: Magnesium trihydrate of UDCA and CDCA is a well-tolerated bile acid that showed similar efficacy for gallstone dissolution and improvement of gallstone-related symptoms as that shown in previous studies.

Xantomatosis cerebrotendinosa: aspectos fisiopatológicos, clínicos y genéticos / Cerebrotendinous xanthomatosis: physiopathology, clinical manifestations and genetics

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.

The Role of HS-1200 Induced Autophagy in Oral Cancer Cells

Bile acids and synthetic bile acid derivatives induce apoptosis in various kinds of cancer cells and thus have anticancer properties. Recently, it has been suggested that autophagy may play an important role in cancer therapy. However, few data are available regarding the role of autophagy in oral cancers and there have been no reports of autophagic cell death in OSCCs (oral squamous cell carcinoma cells) induced by HS-1200, a synthetic bile acid derivative. We thus examine whether HS-1200 modulates autophagy in OSCCs. Our findings indicate that HS-1200 has anticancer effects in OSCCs, and we observed in these cells that autophagic vacuoles were visible by monodansylcadaverine (MDC)and acridine orange staining. When we analyzed HS-1200-treated OSCC cells for the presence of biochemical markers, we observed that this treatment directly affects the conversion of LC-3II, degradation of p62/SQSTM1 and full-length beclin-1, cleavage of ATG5-12 and the activation of caspase. An autophagy inhibitor suppressed HS-1200-induced cell death in OSCCs, confirming that autophagy acts as a pro-death signal in these cells. Furthermore, HS-1200 shows anticancer activity against OSCCs via both autophagy and apoptosis. Our current findings suggest that HS-1200 may potentially contribute to oral cancer treatment and thus provide useful information for the future development of a new therapeutic agent.

Two Siblings with Cerebrotendinous Xanthomatosis / 대한피부과학회지

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by sterol 27-hydroxylase (CYP27) deficiency. We report two CTX siblings that were presented with typical manifestations such as achilles tendon xanthomas, mental retardation, progressive gait ataxia, and upper motor signs. Their parents and other three sisters were healthy. Serum cholesterol level was within normal limits for both siblings. The older brother has been treated conservatively with muscle relaxant and dopamine agonist because the disease was so progressive, but the younger sister has been treated with 250 mg/day chenodeoxycholic acid (CDCA) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (simvastatin 40 mg/day) to prevent the progressive neurologic dysfunction.

Clinical features of a Chinese infant with inborn error of bile acid metabolism-3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency and review of the literature / 中华儿科杂志

<p><b>OBJECTIVE</b>To study the clinical features of children with 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency and review the literature.</p><p><b>METHOD</b>Clinical features and treatment of one Chinese infant with 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency confirmed by HSD3B7 gene mutation analysis were retrospectively reviewed, and 51 cases of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency who were internationally reported since 2000 were also reviewed in this paper.</p><p><b>RESULT</b>(1) A 3-month-old infant with neonatal cholestasis was admitted to our hospital because of hyperbilirubinemia and abnormal liver dysfunction (total bilirubin 110.7 µmol/L, direct bilirubin 74.5 µmol/L, γ-glutamyltransferase 24.4 IU/L, total bile acid 0.1 µmol/L).His jaundice disappeared within a few weeks, serum liver biochemistries improved and his growth in weight and height was excellent after oral cholic acid therapy.HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patient identified compound heterozygous mutations. This child was confirmed as the most common inborn error of bile acid metabolism-3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency by molecular analysis.(2) Retrospective review of the literature showed that the clinical features of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency included neonatal cholestasis, some patients progressed to severe liver disease and needed liver transplantation without effective therapy; however, serum biochemical characteristics of normal γ-glutamyltransferase activity, normal or low total bile acid concentrations were not consistent with cholestasis, the replacement treatment with cholic acid produced a dramatic improvements in symptoms, biochemical markers of liver injury; 31 cases were diagnosed by HSD3B7 gene mutation analysis.</p><p><b>CONCLUSION</b>The clinical characteristics of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency include neonatal cholestasis, normal serum γ-glutamyltransferase activity, and normal or low serum total bile acid concentration.Oral cholic acid replacement is an effective therapy; definitive diagnosis of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency can be identified by molecular genetic testing technology.</p>

HS-1200 Overcomes the Resistance Conferred by Bcl-2 in Human Leukemic U937 Cells

Bcl-2 protects tumor cells from the apoptotic effects of various anti-neoplastic agents. Increased expression of Bcl-2 has been associated with a poor response to chemotherapy in various malignancies, including leukemia. Hence, bypassing the resistance conferred by anti-apoptotic factors such as Bcl-2 represents an attractive therapeutic strategy against cancer cells, including leukemic cells. This study was undertaken to examine whether the anticancer drug, cisplatin and the synthetic chenodeoxycholic acid (CDCA) derivative, HS-1200 show anti-tumor activity in U937 and U937/Bcl-2 cells. Viability assays revealed that HS-1200 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Various apoptosis assessment assays further demonstrated that HS-1200 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells by inducing apoptosis. In addition HS-1200, but not cisplatin, overcomes the anti-apoptotic effects of Bcl-2 in Bcl-2 over-expressing human leukemic cells (U937/Bcl-2 cells). Notably, we observed that the HS-1200-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with a suppression of the anti-apoptotic effects of Bcl-2 in human leukemic cells over-expressing this protein (U937/Bcl-2 cells). Furthermore, HS-1200 was found to induce the association between PML and SUMO-1, Daxx, Sp100, p53 or CBP in the aggregated PML-NBs of U937/Bcl-2 cells. Thus, PML protein and the formation of mature PML-NBs could be considered as therapeutic targets that may help to bypass the resistance to apoptosis conferred by Bcl-2. Elucidating the exact mechanism by which PML regulates Bcl-2 will require further work.

A Case of Cri du Chat Syndrome with Developmental Delay Misdiagnosed as Fetal Alcohol Syndrome

Cri du Chat syndrome (CdCS) is a chromosomal disease resulting from a deletion on the short arm of chromosome 5. Characteristic features include high pitched cat-like cry, distinguishing facial features, and mental retardation. Some cases have been reported in the Korean literature, but no case reports about the concrete aspects of developmental delay in CdCS patients have been published. Therefore, we report a CdCS patient with developmental delay who was misdiagnosed as fetal alcohol syndrome. The result of the Korean-Child Development Review and Sequenced Language Scale for Infants showed severe developmental retardation, especially in expressive language.

Progress in the ligands and their complex structures of farnesoid X receptor / 药学学报

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily. It is highly related to the formation of metabolic syndrome and the glucose homeostasis, and therefore represents an important drug target against metabolic diseases and diabetes. In recent years, great progress has been made in the agonists, antagonists, and crystal structures of FXR. The diverse FXR ligands and their structure-activity relationship are reviewed in this article. The advances in the crystal structures of FXR in complex with different ligands are also introduced.

Xantomatosis cerebrotendinosa. A Propósito de un Caso / Cerebrotendinous xanthomatosis. A case report

La xantomatosis cerebrotendinosa (XCT) es un raro desorden del almacenamiento de los lípidos, que se transmite en forma autosómica recesiva y se caracteriza por el depósito de colesterol y colestanol en diferentes tejidos, con preferencia por los tendones, los cristalinos y el sistema nervioso central. El diagnóstico de la enfermedad se confirma con la presencia de β–colestanol en sangre y de alcoholes biliares en orina. Obedece a una mutación del gen CYP27A1 (responsable de la síntesis de la enzima esterol 27-hidrolasa) que mapea en el brazo largo del cromosoma 2. Se manifiesta clínicamente por un deterioro neurológico progresivo, además de la presencia de xantomas tendinosos, cataratas juveniles, arterioesclerosis y diarrea crónica. Las alteraciones aparecen en las primeras dos décadas de la vida, pero el diagnóstico definitivo suele hacerse tardíamente (entre la tercera y la cuarta décadas). La terapéutica consiste en la administración de ácido quenodesoxicólico asociado a pravastatina o simvastatina. El tratamiento temprano y prolongado podría detener la progresión de la enfermedad. Se presenta un paciente de 40 años con esta enfermedad y se hace una descripción actualizada de la misma.

Apoptotic Effect of Co-treatment with Chios Gum Mastic and HS-1200 on G361 Human Melanoma Cell Line / 대한해부학회지

Chios gum mastic (CGM) is a resinous exudate obtained from the stem and the main leaves of Pistacia lenticulus tree native to Mediterranean areas. Recently it reported that CGM induce apoptosis in a few cancer cells in vitro. Bile acids and their synthetic derivatives induced apoptosis in various kinds of cancer cells and anticancer effects. It has been reported that the synthetic chenodeoxycholic acid (CDCA) derivatives showed apoptosis-inducing activity on various cancer cells in vitro. This study was undertaken to investigate the synergistic apoptotic effect of cotreatment with a natural product, CGM and a CDCA derivative, HS-1200 on G361 human melanoma cells. To investigate whether the co-treatment of CGM and HS-1200 compared with each single treatment efficiently reduced the viability of G361 cells, MTT assay was conducted. To investigate augmentation of apoptosis in G631 cells co-treated with CGM and HS-1200, DNA electrophoresis, Hoechst staining, proteasome activity assay, flow cytometry, Westen blot analyses, immunofluorescent staining and confocal microscopy were performed. In this study, G361 cells co-treated with CGM and HS-1200 showed several lines of apoptotic manifestation such as nuclear condensations, DNA fragmentation, the reduction of MMP and proteasome activity, the decrease of DNA content, the release of cytochrome c into cytosol, the translocation of AIF and DFF40 (CAD) onto nuclei, activation of caspase-9, caspase-3, PARP and DFF45 (ICAD), and up-regulation of Bax whereas each single treated G361 cells did not. Although the single treatment of 40 micro/mL CGM or 25 micro HS-1200 for 24 hrs did not induce apoptosis, the co-treatment of them induced prominently apoptosis. Therefore, combination therapy of CGM and HS-1200 could be considered, in the future, as an alternative therapeutic strategy for human melanoma.