Cannabidiol-Treated Ovariectomized Mice Show Improved Glucose, Energy, and Bone Metabolism With a Bloom in Lactobacillus (original) (raw)
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Cannabidiol Decreases Intestinal Inflammation in the Ovariectomized Murine Model of Postmenopause
Biomedicines
Cannabidiol (CBD) (25 mg/kg peroral) treatment was shown to improve metabolic outcomes in ovariectomized (OVX) mice deficient in 17β-estradiol (E2). Herein, CBD effects on intestinal and hepatic bile acids (BAs) and inflammation were investigated. Following RNA sequencing of colon tissues from vehicle (VEH)- or CBD-treated sham surgery (SS) or OVX mice (n = 4 per group), differentially expressed genes (DEGs) were sorted in ShinyGO. Inflammatory response and bile secretion pathways were further analyzed. Colon content and hepatic BAs were quantified by LC-MS (n = 8–10 samples/group). Gut organoids were treated with CBD (100, 250, 500 µM) with or without TNFα and lipopolysaccharide (LPS) followed by mRNA extraction and qPCR to assess CBD-induced changes to inflammatory markers. The expression of 78 out of 114 inflammatory response pathway genes were reduced in CBD-treated OVX mice relative to vehicle (VEH)-treated OVX mice. In contrast, 63 of 111 inflammatory response pathway genes we...
The Role of Endocannabinoid System in Menopause and Its Related-Diseases
2021
Menopause is a crucial event in women’s health, characterized by the cessation of ovarian function. The estrogens deficiency exposes women to several diseases, including obesity, osteoporosis, cardiovascular diseases and cancer. Menopause-related diseases deeply impact on women’s quality of life and represent a serious public and economic health burden. The Endocannabinoid System (ECS) includes Cannabinoid Type 1 (CB1) and Cannabinoid Type 2 (CB2) receptors, endocannabinoids and all the enzymes involved in their biosynthesis and degradation. It plays a significant role in energy balance, bone metabolism, muscular contractility, vascular tone and cancer progression. CB1 activation is responsible for increasing food intake and body weight, stimulating osteoclast activity, inhibiting oxidative stress and preventing cancer progression. Conversely, the stimulation of CB2 induces a reduction in food intake and in body weight, inhibits osteoclast activity, prevents vascular risk and reduce...
Effectof Cannabinoid Receptors 1 Modulation on Osteoporosis in a Rat Model of Differentages
2017
Osteoporosis is a worldwide health problem with a high prevalence and is a skeletal disorder characterized by bone mass reduction, increased bone fracture risk and potential bone architecture alterations (1). The incidence of osteoporosis is increasing owing to increasing elderly population. Glucocorticoids are widely used for chronic treatment of a variety of diseases as bronchial asthma, collagen and skin diseases. Because of improvements in the outcome of these diseases, the long-term side ef fects of glucocorticoids, including osteoporosis which is the most common form of secondary osteoporosis, have become an important problem (1, 2). Activation of monomeric glucocorticoid receptor signaling participates in excessive bone remodeling, it impairs osteoblast survival and dif ferentiation (1-4), inhibit the production of bone matrix components, increase osteoblastic and osteocytic apoptosis, enhanced secretion of the osteoclast-promoting factor receptor activator of nuclear factor ...
eLife
The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as osteogenic growth peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse models and cells, and in human osteoblasts. We show that the OGP effects on osteoblast proliferation, osteoclastogenesis, and macrophage inflammation in vitro, as well as rescue of ovariectomy-induced bone loss and prevention of ear edema in vivo are all abrogated by genetic or pharmacological ablation of CB2. We also demonstrate that OGP binds at CB2 and may act as both an agonist and positive allosteric modulator in the presence of other lipophilic agonists. In premenopausal women, OGP circulating levels significantly decline with age. In adult mice, exogenous administration of OGP completely prevented age-related bone loss. Our findings suggest th...
Biomedical Reports, 2015
The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression. In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB). HOB cells were cultured in phenol red-free osteoblast growth medium (37˚C, 5% CO 2). In their 5th passage, HOB were exposed to different concentrations of i) 17-β-estradiol (1, 10 and 100 nM); ii) a specific CB-2 agonist (R,S)-AM1241 (1 and 7.5 µM); and iii) a specific CB-2 antagonist/inverse agonist AM630 (10 µM) and to selected combinations of the substances. After 24 and 48 h of incubation, HOB proliferation activity was measured using a WST-8 assay. Alkaline phosphatase activity was also evaluated using spectrophotometry. Concomitant exposure of HOB to 17-β-estradiol (10 nM) and to specific CB-2 antagonist/inverse agonist (10 µM) showed similar HOB proliferation activity to HOB incubated with 17-β-estradiol only at a 100 nM concentration. By contrast, concomitant incubation of HOB with 17-β-estradiol (10 nM) and specific CB-2 agonist (7.5 µM) resulted in decreased HOB proliferation activity as compared to HOB incubated with 17-β-estradiol only (10 nM). Similar findings were observed after 24 and 48 h of incubation. In all the experiments, HOB successfully passed the alkaline phosphatase differentiation test. In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB. Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.
Diabetes care, 2016
Cannabidiol (CBD) and Δ(9)-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and...
Bone, 2009
Age-related osteoporosis is characterized by reduced bone formation and accumulation of fat in the bone marrow compartment. Here, we report that the type 1 cannabinoid receptor (CB1) regulates this process. Mice with CB1 deficiency (CB1 À/À ) had increased peak bone mass due to reduced bone resorption, but developed age-related osteoporosis with reduced bone formation and accumulation of adipocytes in the bone marrow space. Marrow stromal cells from CB1 À/À mice had an enhanced capacity for adipocyte differentiation, a reduced capacity for osteoblast differentiation, and increased expression of phosphorylated CREB (pCREB) and PPARg. Pharmacological blockade of CB1 receptors stimulated adipocyte differentiation, inhibited osteoblast differentiation, and increased cAMP and pCREB in osteoblast and adipocyte precursors. The CB1 receptor is therefore unique in that it regulates peak bone mass through an effect on osteoclast activity, but protects against age-related bone loss by regulating adipocyte and osteoblast differentiation of bone marrow stromal cells.
Failure of cannabinoid compounds to stimulate estrogen receptors
Biochemical Pharmacology, 1997
, the primary active compound in Cannabis sativa (marihuana), and other cannabinoid receptor agonists exert potent effects on luteinizing hormone and prolactin release in animal models and humans. Compounds possessing the tricyclic cannabinoid structure, including A9-THC and cannabidiol, have been reported to interact with rodent uterine estrogen receptors in ligand binding assays. The present study tested the hypothesis that cannabinoid compounds produce a direct activation of estrogen receptors. We investigated whether cannabinoid compounds exhibit estrogen-induced mitogenesis in MCF-7 breast cancer cells. Under conditions in which 10 pM estradiol promoted MCF-7 cell proliferation, no response was observed with biologically relevant concentrations (~10 FM) of A9-THC or its tricyclic analog desacetyllevonantradol. No response was observed with cannabidiol, a bicyclic cannabinoid compound that exhibits no cannabimimetic behavioral effects but has been reported to bind to the estrogen receptor in vitro. A9-THC also failed to antagonize the response to estradiol under conditions in which the antiestrogen LY156758 (keoxifene; raloxifene) was effective. The phytoestrogen formononetin behaved as an estrogen at high concentrations, and this response was antagonized by LY156758. W e a so 1 investigated the ability of cannabinoid compounds to stimulate transcription of an EREtkCAT reporter gene transiently transfected into MCF-7 cells. Neither A9-THC, desacetyllevonantradol, nor cannabidiol stimulated transcriptional activity. We conclude that psychoactive or inactive compounds of the cannabinoid structural class fail to behave as agonists in appropriate assays of estrogen receptor responses in vitro. Copyright 0 1996 Elsevier Science Inc., BIOCHEM PHARMACOL 53;1:35-41, 1997. KEY WORDS. breast cancer cells; cannabinoid analgesics; cannabinoid receptors; environmental estrogens; gene regulatory response elements; phytoestrogens; steroid hormone receptors; tetrahydrocannabinols A9-THC,Q the primary active compound in Cannabis sativa (marihuana), and other cannabinoid receptor agonists exert potent effects on luteinizing hormone and prolactin release in animal models and humans. The abundant literature on this subject has been reviewed recently [l-3]. It is currently recognized that the majority of the actions of cannabimimetic compounds on reproductive physiology may be the result of interactions of these drugs with CB, cannabinoid receptors present on neurons in the brain that ultimately control pituitary hormone release. Of interest, CB, cannabinoid receptor mRNA has also been found in the testes, ovaries, and uterus [4][5][6]. recently [7-91. To summarize, CB, cannabinoid receptors are G-protein-coupled receptors that utilize Gi and G, in signal transduction pathways that inhibit adenylate cyclase and Ca" currents, and stimulate K' currents. A'-THC exhibits nanomolar affinity for the CB, receptor, and elicits cannabimimetic behavioral responses in rodents, such as analgesia, hypothermia, catalepsy, and hypoactivity in an open field test. However, CBD, also a member of the cannabinoid structural class of compounds isolated from C. sativa, interacts with the CB, receptor with >lOO-fold lower potency than A9-THC, and fails to elicit cannabimimetic behavioral responses in rodents. A synthetic cannabinoid agonist, DALN, binds to the CB, receptor with a lo-fold greater affinity than does A9-THC, and exhibits similarly increased potency in the behavioral tests in uivo. The interaction of cannabinoid compounds with estrogen receptors has been studied with conflicting results. Rawitch and colleagues [lo], performing heterologous competition assays for [3H]estradiol binding to rat uterine estrogen receptors in cytosol, found that 5 to 50 FM A9-THC or 11 -OH-A9-THC could displace specific binding with a ceiling of about 22%. In that same study, the [3H]estradiol-re-
Peripheral cannabinoid receptor, CB2, regulates bone mass
Proceedings of the National Academy of Sciences, 2006
The endogenous cannabinoids bind to and activate two G proteincoupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2 ؊/؊ phenotype is also characterized by