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The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 μM and are known to block the growth of Clostridium difficile 1 , promote hepatocellular carcinoma 2 and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref. 3 ). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids 4 ; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A–B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe–S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes , conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool. The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice—an important proof-of-principle for the engineering of gut microbial pathways.

Cannabidiol (CBD) confers therapeutic effects in some neurological disorders via modulation of inflammatory, oxidative and cell-signalling pathways. However, CBD is lipophilic and highly photooxidative with low oral bioavailability in plasma and brain. In this study, we aimed to design and test a CBD microencapsulation method as a drug delivery strategy to improve the absorption of CBD. Additionally, we evaluated the brain uptake of CBD capsules when administered alongside capsules containing a permeation-modifying bile acid, deoxycholic acid (DCA). Microcapsules containing either CBD or DCA were formed using the ionic gelation method with 1.5% sodium alginate formulations and 100 mM calcium chloride. C57BL/6J wild type mice randomly assigned to three treatment groups (3-4 mice per group) were administered CBD in the following preparations: 1) CBD capsules, 2) CBD capsules + DCA capsules and 3) naked CBD oil (control). To assess the short-term bioavailability of CBD, plasma and brain samples were collected at 0.3, 1 and 3 hours post administration and CBD levels were analysed with liquid chromatography mass spectrometer. We produced spherical capsules at 400 ± 50 μm in size. The CBD capsules were calculated to have a drug loading of 2% and an encapsulation efficiency of 23%. Mice that received CBD capsules + DCA capsules showed a 40% and 47% increase in CBD plasma concentration compared to mice on CBD capsules and naked CBD oil, respectively. Furthermore, the CBD capsules + DCA capsules group showed a 48% and 25% increase in CBD brain concentration compared to mice on CBD capsules and naked CBD oil, respectively. In mice treated with CBD capsules + DCA capsules, the brain CBD concentration peaked at 0.3 hours with a 300% increased availability compared to CBD capsules and naked CBD oil groups, which peaked at 1 hour after administration. The microencapsulation method combined with a permeation enhancer, DCA increased the short-term bioavailability of CBD in plasma and brain.

Obesity is shown in a mouse model of liver cancer to strongly enhance tumorigenesis; a high fat diet alters the composition of intestinal bacteria, leading to more production of the metabolite DCA which, probably together with other factors, induces senescence and the secretion of various senescence-associated cytokines in hepatic stellate cells, thus promoting cancer. Bile acid metabolite links diet and cancer Epidemiological data have demonstrated a link between obesity and cancer. This study shows that in a mouse model of liver cancer, a high-fat diet strongly enhances tumorigenesis by provoking a senescence-associated secretory phenotype (SASP), a recently identified senescent phenotype associated with the secretion of various tumour-promoting factors. Antibiotic and other interventions show that the fatty diet altered the composition of intestinal bacteria leading to more production of deoxycholic acid (DCA), a by-product of microbial bile acid metabolism that is known to cause DNA damage. The authors suggest that DCA, acting with other as-yet unknown factors, induces senescence and the secretion of various senescence-associated cytokines in hepatic stellate cells. These cytokines in turn act to promote the development of liver cancer. These findings highlight the complex mechanistic links between diet, the microbiota and cancer and suggest novel therapeutic approaches. Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer 1 . As the worldwide obesity epidemic has shown no signs of abating 2 , better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer 1 , 3 , the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) 4 , 5 has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage 6 . The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs) 7 , which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer 8 or depleted of senescent HSCs, indicating that the DCA–SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis 3 , indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

BackgroundA Western diet is a risk factor for the development of inflammatory bowel disease (IBD). High levels of fecal deoxycholic acid (DCA) in response to a Western diet contribute to bowel inflammatory injury. However, the mechanism of DCA in the natural course of IBD development remains unanswered.AimsThe aim of this study is to investigate the effect of DCA on the induction of gut dysbiosis and its roles in the development of intestinal inflammation.MethodsWild-type C57BL/6J mice were fed an AIN-93G diet, either supplemented with or without 0.2% DCA, and killed at 24 weeks. Distal ileum and colon tissues were assessed by histopathological analysis. Hepatic and ileal gene expression was examined by qPCR, and the gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. HPLC–MS was used for fecal bile acid quantification.ResultsMice fed the DCA-supplemented diet developed focal areas of ileal and colonic inflammation, accompanied by alteration of the composition of the intestinal microbiota and accumulation of fecal bile acids. DCA-induced dysbiosis decreased the deconjugation of bile acids, and this regulation was associated with the repressed expression of target genes in the enterohepatic farnesoid X receptor–fibroblast growth factor (FXR–FGF15) axis, leading to upregulation of hepatic de novo bile acid synthesis.ConclusionsThese results suggest that DCA-induced gut dysbiosis may act as a key etiologic factor in intestinal inflammation, associated with bile acid metabolic disturbance and downregulation of the FXR–FGF15 axis.

Liposomal amphotericin B (AmBisome ® ; LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.

A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.

ABSTRACT Background Deoxycholic acid (DCA) at a concentration of 10 mg/mL is commonly used for localized fat reduction, but its application in larger areas like the upper arm can lead to higher costs and discomfort. Diluting DCA may provide a cost‐effective solution with reduced pain while still maintaining efficacy. Objective This case series aims to evaluate the efficacy, safety, and overall cost‐effectiveness of diluted DCA injections at concentrations of 5 mg/mL and 2.5 mg/mL for upper arm fat reduction. Methods Four healthy adult females received subcutaneous injections of either 5 mg/mL or 2.5 mg/mL DCA, administered three times at four‐week intervals. Arm circumference and subcutaneous fat thickness were measured at baseline and at 4, 8, 12, and 20 weeks using tape measures and ultrasonography. Pain levels and patient satisfaction were also assessed to gauge the overall balance between treatment efficacy, side effects, and costs. Results Both 5 mg/mL and 2.5 mg/mL concentrations led to significant reductions in subcutaneous fat thickness, with the 5 mg/mL group showing slightly greater reductions. However, changes in arm circumference were minimal across both groups. Pain levels were higher in the 5 mg/mL group, while the 2.5 mg/mL group experienced less discomfort. Importantly, both concentrations demonstrated a balance between efficacy and treatment cost, with the diluted solutions providing a less invasive alternative to the standard 10 mg/mL concentration. Conclusion This case series represents diluted DCA injections, both at 5 mg/mL and 2.5 mg/mL, offering viable minimally invasive options for upper arm fat reduction. While the 5 mg/mL concentration shows slightly greater efficacy, the 2.5 mg/mL option may offer a more comfortable treatment experience. The choice of concentration can be tailored to patient priorities, balancing fat reduction, pain tolerance, and cost considerations.

The treatment of visceral leishmaniasis (kala-azar) often requires prolonged therapy. In this open-label, randomized study involving more than 400 patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. In patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. Some 90% of patients with visceral leishmaniasis (kala-azar) in India and nearly 50% of patients worldwide live in the northeastern Indian state of Bihar. 1 In Bihar, treatment with liposomal amphotericin B is effective in regimens as brief as 5 days, 1 – 3 offering a remedy for the principal drawback of all other antileishmanial agents: a prolonged duration of treatment. 1 , 4 However, when such a regimen of liposomal amphotericin B was abbreviated still further, to a single infusion of 5 or 7.5 mg per kilogram of body weight, the efficacy of the drug (90 to 91% 4 – 6 ) did not reach the . . .

Commensal and pathogenic bacteria must deal with many different stress conditions to survive in and colonize the human gastrointestinal tract. One major challenge that bacteria encounter in the gut is the high concentration of bile salts, which not only aid in food absorption but also act as effective physiological antimicrobials. The mechanism by which bile salts limit bacterial growth is still largely unknown. Here, we show that bile salts cause widespread protein unfolding and aggregation, affecting many essential proteins. Simultaneously, the bacterial cytosol becomes highly oxidizing, indicative of disulfide stress. Strains defective in reducing oxidative thiol modifications, restoring redox homeostasis, or preventing irreversible protein aggregation under disulfide stress conditions are sensitive to bile salt treatment. Surprisingly, cholate and deoxycholate, two of the most abundant and very closely related physiological bile salts, vary substantially in their destabilizing effects on proteins in vitro and cause protein unfolding of different subsets of proteins in vivo. Our results provide a potential mechanistic explanation for the antimicrobial effects of bile salts, help explain the beneficial effects of bile salt mixtures, and suggest that we have identified a physiological source of protein-unfolding disulfide stress conditions in bacteria.