Transplantation of probiotics to the intestine can positively regulate the gut microbiota,thereby promoting the immune system and treating various diseases.However,the harsh gastrointestinal environment and short rete...Transplantation of probiotics to the intestine can positively regulate the gut microbiota,thereby promoting the immune system and treating various diseases.However,the harsh gastrointestinal environment and short retention time in the gastrointestinal tract significantly limit the bioavailability and intestinal colonization of probiotics.Herein,we present a double-layer polysaccharide hydrogel(DPH)in the form of a double-layer structure composed of a carboxymethyl cellulose(CMCL)supramolecular inner layer and a dialdehyde alginate(DAA)cross-linked carboxymethyl chitosan(CMCS)outer layer.This doublelayer structure allows DPH to encapsulate and deliver probiotics in a targeted manner within the body.In the stomach,the cage structure of the DPH is closed,and the outer layer absorbs surrounding liquids to form a barrier to protect the probiotics from gastric fluids.In the intestine,the cage structure opens and disintegrates,releasing the probiotics.Thus,DPH endows probiotics with excellent intestine-targeted delivery,improved oral bioavailability,enhanced gastrointestinal tract tolerance,and robust mucoadhesion capacity.The encapsulated probiotics exhibit almost unchanged bioactivity in the gastrointestinal tract before release,as well as improved oral delivery.In particular,probiotics encapsulated by DPH exhibit 100.1 times higher bioavailability and 10.6 times higher mucoadhesion than free probiotics in an animal model 48 h post-treatment.In addition,with a remarkable ability to survive and be retained in the intestine,probiotics encapsulated by DPH show excellent in vitro and in vivo competition with pathogens.Notably,DAA-mediated dynamic crosslinking not only maintains the overall integrity of the hydrogels but also controls the release timing of the probiotics.Thus,it is expected that encapsulated substances(probiotics,proteins,etc.)can be delivered to specific sites of the intestinal tract by means of DPH,by controlling the dynamic covalent crosslinking.展开更多
Intestinal farnesoid X receptor(FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis(MASH). All the...Intestinal farnesoid X receptor(FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis(MASH). All the reported FXR antagonists target to the ligand-binding pocket(LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor(NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1(GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.展开更多
基金supported by the National Natural Science Foundation of China (U21A20271)the China Agriculture Research System of the MOF and MARA (CARS-48)+2 种基金the Natural Science Foundation of Shandong Province (ZR2020JQ15)the Taishan Scholar Project of Shandong Province (tsqn201812020)the Fundamental Research Funds for the Central Universities (201941002).
文摘Transplantation of probiotics to the intestine can positively regulate the gut microbiota,thereby promoting the immune system and treating various diseases.However,the harsh gastrointestinal environment and short retention time in the gastrointestinal tract significantly limit the bioavailability and intestinal colonization of probiotics.Herein,we present a double-layer polysaccharide hydrogel(DPH)in the form of a double-layer structure composed of a carboxymethyl cellulose(CMCL)supramolecular inner layer and a dialdehyde alginate(DAA)cross-linked carboxymethyl chitosan(CMCS)outer layer.This doublelayer structure allows DPH to encapsulate and deliver probiotics in a targeted manner within the body.In the stomach,the cage structure of the DPH is closed,and the outer layer absorbs surrounding liquids to form a barrier to protect the probiotics from gastric fluids.In the intestine,the cage structure opens and disintegrates,releasing the probiotics.Thus,DPH endows probiotics with excellent intestine-targeted delivery,improved oral bioavailability,enhanced gastrointestinal tract tolerance,and robust mucoadhesion capacity.The encapsulated probiotics exhibit almost unchanged bioactivity in the gastrointestinal tract before release,as well as improved oral delivery.In particular,probiotics encapsulated by DPH exhibit 100.1 times higher bioavailability and 10.6 times higher mucoadhesion than free probiotics in an animal model 48 h post-treatment.In addition,with a remarkable ability to survive and be retained in the intestine,probiotics encapsulated by DPH show excellent in vitro and in vivo competition with pathogens.Notably,DAA-mediated dynamic crosslinking not only maintains the overall integrity of the hydrogels but also controls the release timing of the probiotics.Thus,it is expected that encapsulated substances(probiotics,proteins,etc.)can be delivered to specific sites of the intestinal tract by means of DPH,by controlling the dynamic covalent crosslinking.
基金We are grateful to the National Key Research and Development Program of China(2021YFA1301200 to C.X.and 2021YFA1301900 to X.C.)the National Natural Science Foundation of China(82130105,92253305,and 82121005 to H.L.+4 种基金82173873 and 82222071 to C.X.82322063 and 22177124 to Jiang Wang)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0830402 to C.X.and XDB0830000 to X.C.)the Program of Shanghai Academic Research Leader(23XD1460300 to Jiang Wang)the Fund of Youth Innovation Promotion Association(2022077 to X.C.).
文摘Intestinal farnesoid X receptor(FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis(MASH). All the reported FXR antagonists target to the ligand-binding pocket(LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor(NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1(GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.
