Результаты поиска

Discovery and optimization of 1,3,4-trisubstituted-pyrazolone derivatives as novel, potent, and nonsteroidal farnesoid X receptor (FXR) selective antagonists.

LBVS of 12480 in-house compounds, followed by HTRF assay, resulted in one nonsteroidal compound (11) with antagonistic activity against FXR (69.01 ± 11.75 μM). On the basis of 11, 26 new derivatives (12a-z) were designed and synthesized accordingly. Five derivatives (12f-g, 12p, 12u, and 12y) showed better antagonistic activities against FXR than compound 11. Remarkably, the most potent derivative, 12u (8.96 ± 3.62 μM), showed antagonistic capability approximately 10 times and 8-fold higher than that of the control (GS) and the starting compound 11, respectively. 12u was further confirmed to h

Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice.

Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, a

SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis.

Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing

Work in Progress: Drugs in Development.

Primary biliary cholangitis is an archetypal autoimmune disease that causes cholestasis, fibrosis, and liver failure. Ursodeoxycholic acid and obeticholic acid are approved for its treatment. Not all patients respond, some are intolerant, many have ongoing symptoms, and new therapies are required. Herein we describe drugs in development and potential future biological targets. We consider compounds acting on the farnesoid X receptor/fibroblast growth factor 19 pathway, fibrates and other agonists of the peroxisome proliferator-activated receptor family, transmembrane-G-protein-receptor-5 agoni

Nigakinone enhances FXR expression to synergize with irinotecan in suppressing colorectal cancer cells and xenografts.

The use of irinotecan (CPT-11), a first-line chemotherapeutic agent for colorectal cancer (CRC), is limited by acquired drug resistance and severe adverse effects. It has been found that activation of farnesoid X receptor (FXR) signaling reduced the growth of CRC. Here, we investigated the combination of obeticholic acid (OCA), a well-characterized FXR agonist, with CPT-11 as a potential therapeutic combination for CRC. In vitro experiments demonstrated that the OCA-CPT-11 synergistically inhibited proliferation and migration in FXR-high HT-29 and SW620 cells, but exhibited minimal synergy in

Current therapies and therapeutic decision making for childhood-onset movement disorders.

Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early-onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. Th

FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis.

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro

Bile Acid Malabsorption as a Consequence of Cancer Treatment: Prevalence and Management in the National Leading Centre.

The aim was to establish prevalence of bile acid malabsorption (BAM) and management in patients who underwent treatment for malignancy. Retrospective evaluation of data in patients seen within six months (August 2019-January 2020) was carried out. Demographic, nuclear medicine (Selenium Homocholic Acid Taurine (SeHCAT) scan result), clinical (previous malignancy, type of intervention (medication, diet), response to intervention) and laboratory (vitamin D, vitamin B12 serum levels) data were searched. In total, 265 consecutive patients were reviewed. Out of those, 87/265 (33%) patients (57 fema

Совпадение в полном тексте источника
… Primary biliary acids (cholic and chenodeoxycholic acids) are synthesized in 90–95% via the classic pathway in the liver from cholesterol. The synthesis involves 17 different enzymes, the rate-limiting enzyme is 7α-hydroxylase which converts cholesterol in 7α hydroxycholesterol. … Production of chenodeoxycholic acid requires CYP27A1 enzyme. Therefore, CYP8B1 expression decides about the ratio of cholic acid to chenodeoxycholic acid and CYP7A1 enzyme determines the size of the bile acid pool. …

Метаболизм желчной кислоты в множестве склероза поражается и связан с риском подтвержденного ухудшения состояния здоровья.

КОЛИЧЕСТВО: Подлые кислоты (БА) стали важными посредниками в нейроинфламмации и нейродегенерации, которые являются важными особенностями множественного склероза (МС). Цель этого исследования состояла в изучении уровней сыворотки БА у недавно диагностировавшихся людей с MS (PwMS) и изучении их связи с ухудшением положения инвалидов. МЕТОДЫ: Исследование включало 907 ПТМС и 907 Сопоставимый контроль со стороны шведской группы ЭИМС, основанной на населении, с клиническими последующими данными шведского регистра MS. Уровни сыворотки BA были проанализированы с использованием масс-спектрометрии жидк

Совпадение в аннотации оригинала
BACKGROUND: Bile acids (BAs) have emerged as important mediators in neuroinflammation and neurodegeneration, important features of multiple … milestones 4.0 and 6.0. RESULTS: PwMS had lower concentrations of the primary conjugated BA, glycochenodeoxycholic acid (GCDCA, log2 FC - 0.29, p = 0.009) compared to controls. In relapsing-remitting MS compared to controls, lower concentrations of primary conjugated BAs (log2 FC - 0.30, p = 8.40E - 5), secondary conjugated BAs (log2 FC - 0.18, p = 0.007), and total …

Anaplastic thyroid carcinoma.

Thyroid cancers represent about 1% of all human cancers. Differentiate thyroid carcinomas (DTCs), papillary and follicular cancers, are the most frequent forms, instead Anaplastic Thyroid Carcinoma (ATC) is estimated to comprise 1-2% of thyroid malignancies and it accounts for 14-39% of thyroid cancer deaths. The annual incidence of ATC is about one to two cases/million, with the overall incidence being higher in Europe (and area of endemic goiter) than in USA. ATC has a more complex genotype than DTCs, with chromosomal aberrations present in 85-100% of cases. A small number of gene mutations

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… Efficacy on anaplastic thyroid carcinoma of valproic acid alone or in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative, or lactacystin. Int. J. Oncol. 34, 1353–1362 10.3892/ijo_00000288 Kim T. Y., Kim K. W., Jung T. S. (2007). …

Googling the Guggul (Commiphora and Boswellia) for Prevention of Chronic Diseases.

Extensive research during last 2 decades has revealed that most drugs discovered today, although costs billions of dollars for discovery, and yet they are highly ineffective in their clinical response. For instance, the European Medicines Agency has approved 68 anti-cancer drugs, and out of which 39 has reached the market level with no indication of increased survival nor betterment of quality of life. Even when drugs did improve survival rate compared to available treatment strategies, most of these were found to be clinically insignificant. This is a fundamental problem with modern drug disc

Совпадение в полном тексте источника
… Different bile acids and chenodeoxycholic acids act as natural ligand for FXR, whose expression is elevated in the liver and intestine. When FXR binds to its ligand, it gets activated and reaches the cell nucleus, where it forms a heterodimer with RXR. … GS eliminated the effect of chenodeoxycholic acid (CDCA), an FXR agonist on the expression of Cdx2 and MUC2 and thus prevented bile acid induced gastric intestinal metaplasia and carcinogenesis (Xu et al., 2010 ). …

Association between bile area in the duodenal bulb and abdominal symptoms: Quantitative analysis using blue laser imaging.

Bile acids are strongly associated with the pathogenesis of functional gastrointestinal diseases. In recent years, blue laser imaging (BLI) endoscopy has emerged as a novel image-enhanced endoscopic method, which illustrates bile as a reddish hue. The present study investigated the factors that affect the area of bile in duodenal bulbs using BLI. For this purpose, patients (356 cases) who underwent upper endoscopy with BLI between April, 2017 and December, 2019, and completed patient background and symptom questionnaires [Constipation Scoring System (CSS), Bristol Stool Form Scale (BSFS) and F

Совпадение в полном тексте источника
… The administration of chenodeoxycholic acid increases the frequency of defecation and the BSFS score ( 28 ). However, a high level of bile acids is a contributing factor to diarrhea, which is predominant in IBS ( 29 ). …

Update on cutaneous calciphylaxis.

Calciphylaxis is a devastating disorder with a mortality rate of 80% due to sepsis and organ failure. Hallmarks of this rare disease are arteriolar media calcification, thrombotic cutaneous ischemia, and necrotic ulcerations. Different mechanisms of vascular calcification can lead to calciphylaxis. Early diagnosis by deep cutaneous ulcer biopsy is most important for prognosis. Here, dermatologists play a significant role although treatment usually needs an interdisciplinary approach. Surgical procedures had been the cornerstone of treatment in the past including parathyroidectomy, but recently

Совпадение в полном тексте источника
… In cell culture and animal studies, FXR agonist, 6α-ethyl-chenodeoxycholic acid inhibits phosphate-induced mineralization of cells and ameliorate renal vascular calcification.[ 46 ] In the future, FXR agonist may represent a new class of drugs for medical treatment of calciphylaxis. …

Регулирование питания иммунной системы кишечного мозга происходит на протяжении всей жизни.

Иммунная ось кишечника объединяет микробные, иммунные и нейронные сигналы для регулирования нейроразвития, гомеостаза и подверженности болезням. Раннее питание, в частности молочные олигозакариды, формирует благотворный микробиотический состав, повышает гиппокампальную пластичность, способствует антивоспалительной микроглианской поляризации и поощряет иммунную терпимость. Микробиота - метаболиты гута, включая короткоцепные жирные кислоты, производные триптофана и вторичные желчные кислоты, регулируют микроглиатическое созревание, функцию астроцита, дифференциацию клеток Т, производство нейротр

Совпадение в полном тексте источника
… Microbial products of host molecules Primary bile acids (e.g., cholic acid, chenodeoxycholic acid) are synthesized from cholesterols in the liver and are then converted by gut bacteria into secondary bile acids, which signal through farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor …

Производимые микробиотой иммунные регуляционные метаболиты желчных кислот контролируют автонепроницаемость центральной нервной системы.

Микробиота комменсового кишечника играет определенную роль в патогенезе внекишечных аутоиммунных заболеваний, таких как множественный склероз (MS) с неизвестными механизмами. Деоксихоловая кислота (DCA) и литохолическая кислота (LCA) представляют собой вторичные метаболиты желчных кислот (BAM), получаемые из первичных желчных кислот кишечными микробиотами, которые играют ключевые функции по регулированию иммунной системы путем поощрения дифференциации клеток FOXP3+, регулируемой Т (Treg), за счет клеток TH17. Здесь мы показываем, что бактерии, выделяющие ферменты, ответственные за вторичное пр

Совпадение в полном тексте источника
… Our metabolomic analysis by ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) revealed no differences in the fecal concentration of primary BAs such as cholic acid, glycocholic acid, tauricholic acid, chenodeoxycholic acid, and glycochenodeoxycholic acid between the two cohorts ( Figure …

Терапия клеток CAR-T и модуляция микробиоты в мультислерозе: новые терапевтические стратегии и текущие ограничения.

Множественный склероз (MS) — хроническое аутоиммунное воспалительное заболевание центральной нервной системы (CNS), характеризующееся разрушением миелиновой оболочки вокруг нервных клеток. Широкое распространение и серьезные последствия НР свидетельствуют о недостатках существующих методов лечения и о важности разработки новаторских терапевтических подходов. На основе успешных экспериментальных исследований среди пациентов и экспериментальной модели мышью аутоиммунного энцефаломиелита (EAE) клетки CAR-T предлагают новый терапевтический механизм путем непосредственной адресации и ликвидации кле

Совпадение в полном тексте источника
… Among BAs, primary BAs such as cholic acid and chenodeoxycholic acid, and secondary BAs, such as lithocholic acid and ursodeoxycholic acid (UDCA), enter the bloodstream from the intestine and are involved in various metabolic processes [ 133 , 134 ]. …

Influence of gut microbial metabolites on tumor immunotherapy: mechanisms and potential natural products.

In recent years, tumor immunotherapy has made significant breakthroughs in the treatment of malignant tumors. However, individual differences in efficacy have been observed in clinical practice. There is increasing evidence that gut microbial metabolites influence the efficacy of distal tumor immunotherapy via the gut-liver axis, the gut-brain axis and the gut-breast axis, a process that may involve modulating the expression of immune cells and cytokines in the tumor microenvironment (TME). In this review, we systematically explore the relationship between gut microbial metabolites and tumor i

Совпадение в полном тексте источника
… . | ( 212 ) Qiang-Gan formula | Bile acids (Cholic Acid, Chenodeoxycholic Acid, DCA and LCA) | Decreased hepatic and serum bile acid concentrations, increased fecal lithobionic acid production, improved the structure of intestinal flora, promoted TGR5 expression, and inhibited NF-κB activation. | ( 213 …

Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives.

Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell meta

Совпадение в полном тексте источника
… Human bile acids (BAs), including primary BAs (cholic acid, chenodeoxycholic acid) and secondary BAs (deoxycholic acid, lithocholic acid), are oxidative metabolites of cholesterol in hepatocytes that form amphipathic derivatives with detergent-like, steroidal structures [ 169 ]. …

RESEARCH COMMUNICATIONS OF THE 34th ECVIM-CA CONGRESS.

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Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.

Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate the expression of a wide range of target genes in response to endogenous and exogenous ligands, including steroid hormones, thyroid hormone, vitamin D, retinoic acid, fatty acids, and oxidative steroids. Upon ligand binding, nuclear receptors form dimer complexes with transcriptional cofactors, which interact with specific DNA sequences in the promoter or enhancer regions of target genes to modulate gene expression. This process plays a crucial role in many physiological processes such as reprodu