Protection of Intestinal Barrier in Uremic Mice by Electroacupuncture via Regulating the Cannabinoid 1 Receptor of the Intestinal Glial Cells

Intestinal barrier injuries are common in uremia, which aggravates uremia. The goal of this study is to learn moreabout how electroacupuncture regulates gastrointestinal function, as well as to identify the importance of microglia in electroacupuncture regulation and the cannabinoid receptor signaling pathway in controlling the activity of intestinal glial cells. The mice were arbitrarily assigned to four groups: control, CKD, electroacupuncture stimulation, or AM251 (CB1 receptor antagonist). The mice model of uremia was established by adenine gavage. Western blotting revealed the development of tight junction proteins ZO-1, cannabinoid 1 receptor, glial specific GFAP, occludin, S100 β, claudin-1, and JNK. GFAP and CB1R protein expression and co-localization of the intestinal glial cells were observed by double-labeled fluorescence. The expression of cannabinoid 1 receptor CB1R in the intestinal glial cells was increased after electroacupuncture. The expression of tight junction protein, GFAP, S100 β, and CB1R protein was up-regulated after electroacupuncture, and the dysfunction of the intestinal barrier in uremia was corrected. Nevertheless, AM251, a CB1R antagonist, reversed the effect of electroacupuncture. Electroacupuncture can protect the intestinal barrier through the intestinal glial cell CB1R, and the effect is achieved by inhibiting the JNK pathway.

Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis

The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.

Structural, QSAR, machine learning and molecular docking studies of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 receptor antagonists

We performed a structural study followed by a theoretical analysis of the chemical descriptors and the biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective Cannabinoid-1...

Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-κB signaling

Cannabinoid 1 receptor (CB1R) expression is upregulated in the liver with viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin-induced injury, would also be beneficial. We found that intrinsic CB1R in hepatocytes regulated liver inflammation-related gene transcription. We tested if nullification of hepatocyte-specific CB1R (hCNR1−/−) in mice protects against concanavalin A (Con A)-induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1−/− and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1−/− mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1−/− mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially cAMP-dependent cannabinoid signaling and membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.