A Phase I, Two Parts Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of BAR502 in Healthy Subjects

First-in-human, single centre, two parts, dose-escalation, parallel-group, safety, tolerability, pharmacokinetic and pharmacodynamic Phase I study. Part A: randomised, double-blind, placebo-controlled, single ascending dose study.
Part B: open label, multiple ascending dose study.

Start Date04 Dec 2024

Sponsor / Collaborator

BAR Pharmaceuticals s.r.l.

NCT05203367

/ WithdrawnPhase 1

Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of BAR 502 in Healthy Subjects

This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.

Start Date25 Nov 2022

Sponsor / Collaborator

BAR Pharmaceuticals s.r.l.

100 Clinical Results associated with TGR5 x FXR

100 Translational Medicine associated with TGR5 x FXR

0 Patents (Medical) associated with TGR5 x FXR

458

Literatures (Medical) associated with TGR5 x FXR

01 May 2025·Journal of Ethnopharmacology

Gegen-Qinlian decoction alleviates metabolic dysfunction-associated steatohepatitis by modulating the microbiota-bile acid axis in mice

Article

Author: Cao, Ying ; Chen, Milian ; Wu, Yan ; Shu, Xiangbing ; Zhao, Wenxia ; Ji, Guang ; Zhang, Li

ETHNOPHARMACOLOGICAL RELEVANCEMetabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), and is currently the most prevalent chronic liver disease worldwide. Gegen-Qinlian decoction (GQD), a classical Traditional Chinese Medicine (TCM) formula from Treatise on Febrile Diseases, has been historically used to treat heat-dampness syndromes. Recent studies revealed that GQD is effective in treating MASH, but the underlying mechanisms remain unknown.AIM OF THE STUDYThis study aims to evaluate the therapeutic effect of GQD on MASH and explore the potential mechanisms targeting the gut microbiota-bile acid (BA) axis.MATERIALS AND METHODSPhytochemical profiling of GQD was performed using UPLC-Q-TOF-MS. MASH was induced in mice via a fructose-, palmitate-, and cholesterol-enriched (FPC) diet, followed by treatment with low-, medium-, or high-dose GQD. H&E and oil red O staining were utilized to examine the histological change, and serum lipids and enzymes were biochemically analyzed. 16SrDNA sequencing was applied to analyze the alteration of the gut microbiota, and the gas chromatography-mass spectrometry technique was introduced to investigate the fecal bile acid (BA) profile. Serum lipopolysaccharide (LPS) concentrations were analyzed by enzyme-linked immunosorbent assay. Intestinal tight junction proteins (ZO1, Occludin) and BA receptors (FXR, TGR5, and VDR) were detected by Western blot and immunofluorescence staining.RESULTSThe quality of GQD was confirmed, and GQD treatment improved hepatic steatosis, reduced the content of liver triglyceride (20-40 % reduction, p < 0.01) and cholesterol (20-25 % reduction, p < 0.01) in FPC-induced MASH mice. High-dose GQD further decreased serum TC (3.97 ± 1.00 vs 5.51 ± 1.11, p < 0.05), LDL-c (0.53 ± 0.18 vs 1.07 ± 0.28, p < 0.01), ALT (31.90 ± 6.20 vs 47.90 ± 12.78, p < 0.05) and ALP (90.83 ± 13.46 vs 132.90 ± 23.67, p < 0.05) levels, suggesting the effects of GQD in counteracting metabolic inflammation. GQD treatment restored gut microbiota diversity and reversed gut dysbiosis by decreasing the abundance of pathogenic bacteria, resulting in reduced serum LPS while enhancing intestinal tight junction proteins (ZO1, Occludin). Concurrently, GQD treatment reshaped fecal BA profiles, increased intestinal TGR5/VDR expression, with BA shifts strongly correlating to microbiota changes.CONCLUSIONGQD alleviated hepatic and metabolic disorders in MASH mice, possibly through reversing gut dysbiosis and modulating BA profile. Targeting the microbiota-BA axis represents a promising pattern for TCM prescriptions in treating MASH.

01 May 2025·International Journal of Biological Macromolecules

Salidroside attenuates NASH through regulating bile acid-FXR/TGR5 signaling pathway via targeting gut microbiota

Article

Author: Li, Hongshan ; He, Zheyun ; Wu, Boming ; Xia, Zhanyang ; Zhang, Jun ; Zhou, Jing ; Liu, Hongliang ; Chen, Si ; Wu, Yuan

Nonalcoholic steatohepatitis (NASH) is a significant threat to human health. Our previous study revealed that salidroside attenuated NASH and regulated the gut microbiota. However, whether the therapeutic effect of salidroside depends on gut microbiota remains to be determined. Therefore, we conducted further experiments to elucidate the essential functions of gut microbiota-associated metabolic pathways in the anti-NASH effects of salidroside. Our results showed that salidroside effectively alleviated lipid accumulation and inflammatory injury in NASH mice. 16S rRNA sequencing revealed that salidroside increased the abundance of Bacteroides. Mice receiving fecal microbiota transplantation (FMT) from salidroside-treated also presented less hepatic steatosis and higher abundance of Bacteroides. Antibiotics eliminated the effects of salidroside on hepatic steatosis and the gut microbiota. Mechanistically, salidroside and FMT from salidroside-treated altered the bile acid (BA) profile by decreasing the levels of conjugated BAs and tauro-α/β-muricholic acid and activated downstream farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Furthermore, we found that inhibitors of bile salt hydrolase (BSH) and FXR/TGR5 abolished the effects of salidroside and reduced downstream carnitine palmitoyltransferase 1α and lipoprotein lipase expression. These data demonstrate that salidroside attenuated NASH via gut microbiota-BA-FXR/TGR5 signaling pathway and reveal the underlying mechanism of salidroside on NASH.

01 Apr 2025·American Journal of Physiology-Gastrointestinal and Liver Physiology

Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release

Article

Author: Fonseca Pedro, Patricia ; Marschall, Hanns-Ulrich ; Cox, Helen M ; Tsakmaki, Anastasia ; Bewick, Gavin A ; Lövgren-Sandblom, Anita ; Ovadia, Caroline ; Williamson, Catherine ; Mitchell, Alice L ; Chambers, Jenny ; Fan, Hei Man ; Tough, Iain R

Sulfated progesterone species (PMxSs) increase postprandially in women with intrahepatic cholestasis of pregnancy (ICP) but not in women with uncomplicated pregnancy. PMxS can be enterohepatically recycled via active transport from the gut lumen by apical sodium-dependent bile acid transporter (ASBT) and stimulate gut hormone secretion. Active reabsorption of PMxS may play a role in the pruritus suffered by women with ICP. ASBT inhibition is a plausible therapy for ICP-associated pruritus.

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