BACKGROUND: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. METHODS: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. RESULTS: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. CONCLUSIONS: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.

• MeSH
• játra metabolismus   MeSH
• lidé MeSH
• receptory cytoplazmatické a nukleární * metabolismus   MeSH
• receptory spřažené s G-proteiny * metabolismus   MeSH
• transkripční faktory MeSH
• žluč chemie   MeSH
• žlučové kyseliny a soli * farmakologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem MeSH
• Názvy látek
• farnesoid X-activated receptor MeSH Prohlížeč
• GPBAR1 protein, human MeSH Prohlížeč
• receptory cytoplazmatické a nukleární * MeSH
• receptory spřažené s G-proteiny * MeSH
• transkripční faktory MeSH
• žlučové kyseliny a soli * MeSH

Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs' properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.

• Klíčová slova
• ASBT, IBABP, MDR, MRP, NTCP, OATP, bile acid, bile salt, drug delivery, enterohepatic circulation, transport protein,
• MeSH
• enterohepatická cirkulace * MeSH
• játra metabolismus   MeSH
• transportní proteiny metabolismus   MeSH
• žlučové cesty MeSH
• žlučové kyseliny a soli * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• transportní proteiny MeSH
• žlučové kyseliny a soli * MeSH

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.

• Klíčová slova
• Adipocyte differentiation, Endocrine disruptor, Obesity, Obesogen, Weight gain,
• MeSH
• adipogeneze MeSH
• endokrinní disruptory * toxicita   MeSH
• lidé MeSH
• obezita etiologie   MeSH
• předškolní dítě MeSH
• tuková tkáň MeSH
• vystavení vlivu životního prostředí škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• endokrinní disruptory * MeSH

Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system's components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.

• Klíčová slova
• cytokines, flame retardants, interferon, metabolic disruption, metabolism-disrupting chemicals, nonalcoholic fatty liver disease,
• MeSH
• biologické markery MeSH
• cílená molekulární terapie MeSH
• cytokiny metabolismus   MeSH
• interferony metabolismus   MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• náchylnost k nemoci * MeSH
• nealkoholová steatóza jater etiologie   metabolismus   patologie   MeSH
• objevování léků MeSH
• retardanty hoření škodlivé účinky   MeSH
• signální transdukce * MeSH
• zánět etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• cytokiny MeSH
• interferony MeSH
• mediátory zánětu MeSH
• retardanty hoření MeSH

A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity.

• Klíčová slova
• bile acids, cholic acid, deoxycholic acid, hyodeoxycholic acid, lithocholic acid, platinum(II) complexes, steroidal diamines,
• MeSH
• cisplatina analogy a deriváty   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• HeLa buňky MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• proliferace buněk účinky léků   MeSH
• racionální návrh léčiv MeSH
• sloučeniny platiny chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• žlučové kyseliny a soli chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• sloučeniny platiny MeSH
• žlučové kyseliny a soli MeSH