Bladder-colon chronic cross-sensitization involves neuro-glial pathways in male mice

BACKGROUND Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity.Since pelvic organs share common sensory pathways,it is likely that those syndromes involve a cross-sensitization of the bladder and the colon.The precise pathophysiology remains poorly understood.AIM To develop a model of chronic bladder-colon cross-sensitization and to investigate the mechanisms involved.METHODS Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia.Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions.Myeloperoxidase,used as a marker of colorectal inflammation,was measured in the colon,and colorectal permeability was measured using chambers.c-Fos protein expression,used as a marker of neuronal activation,was assessed in the spinal cord(L6-S1 level)using immunohistochemistry.Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord.The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot.RESULTS Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline(P<0.0001).This effect started 1 h post-injection and lasted up to 7 d postinjection.No increased permeability or inflammation was shown in the bladder or colon 7 d postinjection.Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord(P<0.0001).In green fluorescent protein on the fractalkine receptor-positive mice,intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord(P<0.0001).NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection(P=0.007 and 0.023 respectively).Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline,a microglia inhibitor,by intracerebroventricular injection of CP-99994 dihydrochloride,a NK1 antagonist,and by intracerebroventricular injection of SB203580,a MAPK-p38 inhibitor.CONCLUSION We describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice.Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension,mediated by neuroglial interactions,MAPK-p38 phosphorylation and the NK1 receptor.

The role of lipid metabolism in osteoporosis:Clinical implication and cellular mechanism

In recent years,researchers have become focused on the relationship between lipids and bone metabolism balance.Moreover,many diseases related to lipid metabolism dis-orders,such as nonalcoholic fatty liver disease,atherosclerosis,obesity,and menopause,are associated with osteoporotic phenotypes.It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass.Furthermore,similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models.Abnormal lipid metabolism(such as increased oxidized lipids and elevated plasma cholesterol)affects bone microenvironment ho-meostasis via cross-organ communication,promoting differentiation of mesenchymal stem cells to adipocytes,and inhibiting commitment towards osteoblasts.Moreover,disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cyto-kines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts.Conclusively,this review addresses the possible link be-tween lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism bal-ance.We also summarize the possible approaches and prospects of intervening lipid meta-bolismforosteoporosistreatment.

Commentary:Indirect action pattern:A remote and cross-organ pharmacological mechanism for drug innovation

The development of molecular medicine has greatly promoted the research and development (R&D) of innovative drugs. However,drug design and development for those novel targets remains a big challenge with low success rates and high attrition of drug candidates1. The current methodology of new drug R&D is deeply influenced by the idea of allopathic medicine, which directly inhibits biological targets.