Since its discovery, small interfering RNA (siRNA) has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA) not easily accessed by conventional drugs. Hence, RNA interference (RNAi) therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs). This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF), an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP), showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases.

Aim: To evaluate the efficacy of locally delivered nanomedicine, vasoactive intestinal peptide in sterically stabilized micelles (VIP-SSM) to the colon and conduct in vitro release studies of a pot...

Serotonin transporter (SERT) deficiency has been implicated in metabolic syndrome, intestinal inflammation, and microbial dysbiosis. Interestingly, changes in microbiome metabolic capacity and several alterations in host gene expression, including lipid metabolism, were previously observed in SERT^−/− mice ileal mucosa. However, the precise host or microbial metabolites altered by SERT deficiency that may contribute to the pleiotropic phenotype of SERT KO mice are not yet understood. This study investigated the hypothesis that SERT deficiency impacts lipid and microbial metabolite abundances in the ileal mucosa, where SERT is highly expressed. Ileal mucosal metabolomics was performed by Metabolon on wild-type (WT) and homozygous SERT knockout (KO) mice. Fluorescent-activated cell sorting (FACS) was utilized to measure immune cell populations in ileal lamina propria to assess immunomodulatory effects caused by SERT deficiency. SERT KO mice exhibited a unique ileal mucosal metabolomic signature, with the most differentially altered metabolites being lipids. Such changes included increased diacylglycerols and decreased monoacylglycerols in the ileal mucosa of SERT KO mice compared to WT mice. Further, the ileal mucosa of SERT KO mice exhibited several changes in microbial-related metabolites known to play roles in intestinal inflammation and insulin resistance. SERT KO mice also had a significant reduction in the abundance of ileal group 3 innate lymphoid cells (ILC3). In conclusion, SERT deficiency induces complex alterations in the ileal mucosal environment, indicating potential links between serotonergic signaling, gut microbiota, mucosal immunity, intestinal inflammation, and metabolic syndrome.

Symbiotic bacteria have many positive effects on the regenerative capacity of the intestine {1}. In this regard, lactate producing bacteria (LAB) including Lactobacillus sp. (key ingredients in the clinically used VSL#3 probiotic mixture), are the most widely studied probiotics. Although, VSL#3 is known to alleviate diarrhea and inflammation associated with many gastrointestinal diseases, the exact mechanisms by which these effects are mediated are unknown. The work by Lee et al. for the first time describes in detail the potential mechanism by which LAB affect the stem cells of the intestine. The authors very systematically identify that administering VSL#3 mixture to mice increased luminal lactate, a key metabolite produced by bacteria. Increased lactate resulted in hyper-proliferation of the intestinal epithelium with an upregulation of many cell types including stem cells, Paneth cells and goblet cells. Recent studies have shown that lactate mediates many biological functions via its specific cell surface receptor GPR81 {2}. Therefore, the authors sought to determine the presence of GPR81 on the Lgr5⁺ stem cells. However, in contrast, these receptors were found on Paneth cells and the mesenchymal or stromal cells (which are located in close proximity to the crypts in the intestine) instead. Activation of GPR81 by lactate increased the secretion of Wnt3a (an important regulator of stemness), which in turn activated the Wnt/b-Catenin pathway, to increase the stem cell population. In addition to the effects observed in vivo with both probiotics and lactate, the authors demonstrated similar activity ex vivo in intestinal organoid culture. The efficacy of administering probiotics or lactate as a therapeutic modality to prevent radiation and anticancer drug induced epithelial damage was also tested. Finally, administering a mutant form of Lactobacillus plantarum devoid of lactate dehydrogenase activity (which prevents the production of lactate) completely abrogated the beneficial effects on stemness, corroborating their findings. Therefore, the positive effect of GPR81-mediated effects of lactate on intestinal stem cells may have clinical importance for the use of probiotics in preventing gut injury during radiation and chemotherapy.