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The prior system was entirely paper-based. The web-based portal will shorten processing time and eliminate the need to fill out and mail paper documents. The new system, known as the Rhode Island Cannabis Licensing Portal see link below , lets existing card holders renew registrations, update personal information, and make necessary changes to their existing registration cards. New patients applying for a medical marijuana registration card will now apply through the Cannabis Licensing Portal as well. The portal may also be used by caregivers who have been selected by a card holding patient and approved by the Rhode Island Department of Business Regulation DBR to obtain their own marijuana registration card. RIDOH will stop mailing registration reminders and renewal forms in the coming months. It is very important that patients create an account in the portal to be sure they get important messages and updates from RIDOH, including renewal reminders 60 days before the expiration date. Other questions should be emailed to doh. RIDOH approves or denies new applications and renewals within 35 days of receiving applications and all required documents. This post was originally published on this site. Skip to content. Photo by Michael Fischer on Pexels.

Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts

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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Cannabidiol CBD is a non-intoxicating phytocannabinoid from cannabis sativa that has demonstrated anti-inflammatory effects in several inflammatory conditions including arthritis. However, CBD binds to several receptors and enzymes and, therefore, its mode of action remains elusive. These effects were pronounced under inflammatory conditions by activating transient receptor potential ankyrin TRPA1 , and by opening of the mitochondrial permeability transition pore. In addition, an inhibitor of the mitochondrial permeability transition pore, cyclosporin A, also blocked the effects of CBD on cell viability and IL-8 production. PoPo3 uptake was inhibited by the voltage-dependent anion-selective channel inhibitor DIDS and Decynium, an inhibitor for all organic cation transporter isoforms. Thus, CBD possesses anti-arthritic activity and might ameliorate arthritis via targeting synovial fibroblasts under inflammatory conditions. Cannabidiol CBD is a non-intoxicating cannabinoid found in cannabis sativa 1. In contrast to the psychoactive constituent tetrahydrocannabinol THC , CBD demonstrates no direct effect at cannabinoid receptors 1 and 2 CB 1 and CB 2 but modulates the effect of agonists suggesting an allosteric function 2. Despite its promiscuous pharmacology, CBD is well tolerated even when given in high concentrations 12 , Side effects of CBD in humans include diarrhea and fatigue and, more importantly, CBD interacts with other drugs since it is metabolized by CYP enzymes in the liver thereby inhibiting the degradation of other therapeutic compounds 14 , While the therapeutic benefits of CBD in childhood epilepsy are well documented, its effects on inflammation have only been investigated in animal models 13 , Studies in rodents with osteoarthritis or collagen-induced arthritis demonstrated anti-inflammatory and analgesic effects of CBD, but these studies did not identify the mechanism of action 17 , 18 , Here, we investigate the effect of CBD on intracellular calcium, cell viability, and cytokine production in rheumatoid arthritis synovial fibroblasts RASF. RASF are one major contributor of joint destruction in RA as they secrete pro-inflammatory cytokines and matrix degrading enzymes In fact, subsets of RASF selectively mediate joint destruction or the inflammatory response, emphasizing their important role in the pathogenesis of RA CBD also binds TRPA1 7 , 23 , and therefore we hypothesized that CBD has detrimental effects on cell viability, which might explain in part its mechanism of action at sites of inflammation. Therefore, we investigated the effect of fetal calf serum content with CBD on proliferation. DMSO vehicle control alone had a stimulatory effect on proliferation Fig. These findings underline the need for relatively high concentrations of CBD when used in in vivo settings Two-tailed t -test was used for comparisons in f. The error bars in c — f represent the standard error of mean sem. Under these conditions, intracellular calcium levels were significantly increased compared to untreated RASF Fig. PoPo3 uptake increases when membrane integrity is compromised during apoptosis or necrosis. RR, a general inhibitor for several TRP channels 26 , 27 , 28 , reduced intracellular calcium levels Fig. A increased PoPo3 uptake under basal conditions Fig. Mean intracellular calcium mobilization a , b , e , f , i , j , m , n , q , r , u , v and mean PoPo3 uptake c , d , g , h , k , l , o , p , s , t , w , x of RASF after CBD challenge and concomitant inhibition with the antagonists given in the figure. CBD stabilizes a closed conformation of VDAC, which excludes the exchange of metabolites from the cytosol into mitochondria, but enhances its calcium transport function 8 , Cationic and uncharged compounds are taken up by organic cation transporters OCT 39 , 40 and therefore we assessed the effects of Decynium D22 , an inhibitor of all OCT isoforms on intracellular calcium and the uptake of PoPo3. Mean intracellular calcium mobilization a , b , e , f , i , j , m , n and mean PoPo3 uptake c , d , g , h , k , l , o , p of RASF after CBD challenge and concomitant inhibition with the antagonists given in the figure. The error bars represent the standard error of mean. In this study, we demonstrated that CBD decreases cell viability, proliferation, and cytokine production but increases intracellular calcium and PoPo3 levels of RASF and all effects were enhanced by TNF pre-stimulation. We demonstrated that CBD reduces cell viability, but RealTime-Glo assays were conducted in serum-free medium without carrier protein. Consequently, for in vivo applications, CBD needs to be administered in high concentrations to elicit beneficial effects as shown in the treatment of Dravet syndrome Moreover, we found that CsA reversed the detrimental effects of CBD on cell viability, which confirms results from Olivas-Aguirre et al. This confirms own previous results demonstrating calcium mobilization in response to TRPA1 ligation In fact, in dorsal root ganglia neurons it has been shown that TRPA1 is located in lysosomes, where its activation fosters neurotransmitter release Although we do not provide direct evidence regarding the localization of TRPA1, the use of the cell-impermeable pan-TRP inhibitor RR 43 , which was only able to slightly attenuate the effects of CBD suggests an intracellular target protein. In line with this, the lipophilic antagonist A decreased calcium mobilization and PoPo3 uptake after CBD challenge. Moreover, we used Thapsigargin to deplete ER calcium stores and GPN to disrupt lysosomes and both compounds reduced the elevation of intracellular calcium after CBD exposure. This shows that ER calcium stores are involved and it has been shown that even if calcium originates from lysosomes, the signal is amplified by depletion of ER stores This is important, because although GPN has been reported to mobilize lysosomal calcium, a recent study claimed that GPN increases calcium through an ER-dependent mechanism CPZ is also an agonist at TRPA1 48 , and we did detect a small increase in basal intracellular calcium in response to this ligand alone. Besides binding to TRPs, it has been demonstrated that CBD ligates several proteins 11 , 49 with mitochondrial targets being the most prominent 8 , 9 , 10 , 25 , Although protective effects of CBD against mitochondrial toxins have been shown 10 , 50 , the majority of studies demonstrated that CBD induces cell death by disturbing calcium homeostasis 8 , 9 , This confirms our results, since CBD augmented calcium levels with a concomitant increase in cell death. Excess cytosolic calcium is taken up by mitochondria which are depolarized in this process If mitochondrial calcium levels exceed a certain threshold, mPTP is assembled leading to cell death In line with this, CsA reduced intracellular calcium, which is another indicator that mitochondria provide a significant contribution to the increase in calcium by CBD. Calcium is increased by mPTP formation as mitochondria are permeabilized releasing stored calcium into the cytosol Thus, inhibiting mPTP formation by CsA decreases calcium leakage from mitochondria and subsequent cell death. CGP blocks calcium transport from the mitochondrial matrix into the intermembrane space, thus increasing mitochondrial and reducing cytosolic calcium levels In the latter it can act as forward or reverse mode antagonist dependent on cell type, NCLX isoform, and concentration 55 , This might depend on the initial calcium signal generated by CBD, because DIDS can permeabilize the inner mitochondrial membrane depending on calcium concentration leading to formation of mPTP Besides calcium, PoPo3 uptake served as readout for changes in cell viability as it is supposed to enter cells with a compromised plasma membrane only. In addition, it has been demonstrated that the family of organic cation transporters OCT mediates the uptake of many charged but also electroneutral compounds into the cell Therefore, it is quite possible that PoPo3 is also taken up by OCT and indeed we show that decynium, which inhibits all OCT isoforms 39 strongly reduced PoPo3 uptake and it also blunted the increase of intracellular calcium, which might be due to the electrogenic properties of D22 D22 did not influence basal uptake of PoPo3, but reduced the CBD-induced uptake and this might be related to changes in intracellular calcium since the activity of OCT is regulated by calcium-dependent proteins CsA was able to rescue RASF from cell death and increased Il-6 and IL-8 production confirming that cell death is the influencing factor on cytokine production. Eventually, mitochondrial calcium overload occurs and mPTP is assembled leading to cell death. CBD has been used in animal model of RA, demonstrating anti-inflammatory and analgesic effects but the mechanism of action has not been identified 17 , CBD might decrease chronic inflammation since RA is characterized by a hypoxic environment in the joint with concomitant mitochondrial dysfunction In addition, CBD might also synergize with anti-rheumatic drugs like methotrexate or JAK inhibitors, since it has been reported in tumor cell lines that CBD works in synergy with e. In conclusion, CBD might be beneficial as an adjuvant treatment in rheumatoid arthritis that might support the action of currently used disease-modifying anti-rheumatic drugs. In total, 40 patients with long-standing RA fulfilling the American College of Rheumatology revised criteria for RA 24 were included in this study. The RA group comprised of 32 females and 8 males with a mean age of C-reactive protein was IN all, 11 out of 40 patients received glucocorticoids, 7 out of 40 methotrexate, 3 out of 40 biologicals, and 1 out of 40 a JAK inhibitor. All patients underwent elective knee joint replacement surgery, and they were informed about the purpose of the study and gave written consent. We confirm that all experiments were performed in accordance with relevant guidelines and regulations Table 1. Samples from RA synovial tissue were isolated and prepared as described previously 22 for details see also Supplementary methods. Cells were permeabilized with 0. Then, 0. The statistic tests used are given in the figure legends. When data are presented as box plots, the boxes represent the 25th to 75th percentiles, the lines within the boxes represent the median, and the lines outside the boxes represent the 10th and 90th percentiles. When data are presented as line plots, the line represents the mean. When data are presented as bar charts, the top of the bar represents the mean and error bars depict the standard error of the mean sem. ElSohly, M. Phytochemistry of Cannabis sativa L. Navarro, G. Sonego, A. Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARgamma receptors. Brain Behav. Miller, S. Delta9-tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Lin, X. Laun, A. Acta Pharmacol. Iannotti, F. Nonpsychotropic plant cannabinoids, cannabidivarin CBDV and cannabidiol CBD , activate and desensitize transient receptor potential vanilloid 1 TRPV1 channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem. Rimmerman, N. Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 VDAC1 by cannabidiol: a novel mechanism for cannabinoid-induced cell death. Cell Death Dis. Wu, H. Cannabidiol induced apoptosis in human monocytes through mitochondrial permeability transition pore-mediated ROS production. Free Radic. Ryan, D. De Gregorio, D. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain , — PubMed Google Scholar. Millar, S. A systematic review of cannabidiol dosing in clinical populations. Laux, L. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results. Epilepsy Res. Jiang, R. Identification of cytochrome P enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. Huestis, M. Cannabidiol adverse effects and toxicity. Burstein, S. Cannabidiol CBD and its analogs: a review of their effects on inflammation. Hammell, D. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Pain 20 , — Philpott, H. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Malfait, A. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. USA 97 , — Bustamante, M. Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res. Croft, A. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature , — Lowin, T. Selective killing of proinflammatory synovial fibroblasts via activation of transient receptor potential ankyrin TRPA1. De, P. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Elmes, M. Olivas-Aguirre, M. Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia. Caterina, M. A capsaicin-receptor homologue with a high threshold for noxious heat. Ambrus, L. Human podocytes express functional thermosensitive TRPV channels. Hamilton, N. Weller, K. Neuropeptides 45 , — Brenneman, D. Knockdown siRNA targeting the mitochondrial sodium-calcium exchanger-1 inhibits the protective effects of two cannabinoids against acute paclitaxel toxicity. Kim, J. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Ben-Hail, D. Acta , — Benitez-Rangel, E. Cell Death Discov. Shoshan-Barmatz, V. VDAC, a multi-functional mitochondrial protein as a pharmacological target. Mitochondrion 12 , 24—34 Papp, B. Demonstration of two forms of calcium pumps by thapsigargin inhibition and radioimmunoblotting in platelet membrane vesicles. Thastrup, O. The calcium mobilizing tumor promoting agent, thapsigargin elevates the platelet cytoplasmic free calcium concentration to a higher steady state level. A possible mechanism of action for the tumor promotion. Morgan, A. McGuinness, L. Neuropharmacology 52 , — Hayer-Zillgen, M. Inyushin, M. Papa, V. The effects of pH and temperature on the in vitro bindings of deltatetrahydrocannabinol and other cannabinoids to bovine serum albumin. CAS Google Scholar. Shang, S. Cell Biol. Buch, T. Functional expression of the transient receptor potential channel TRPA1, a sensor for toxic lung inhalants, in pulmonary epithelial cells. Kilpatrick, B. Cell Sci. Atakpa, P. Luo, H. Cannabidiol increases proliferation, migration, tubulogenesis, and integrity of human brain endothelial cells through TRPV2 activation. Nabissi, M. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34 , 48—57 Kistner, K. Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain. Ferro, R. GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene 37 , — Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection. Duchen, M. Mitochondria and calcium: from cell signalling to cell death. Giorgi, C. The machineries, regulation and cellular functions of mitochondrial calcium. Kinnally, K. Is mPTP the gatekeeper for necrosis, apoptosis, or both? Ruiz, A. Amran, M. Drug Rev. Santo-Domingo, J. Bernardes, C. Acta , 93— Stueber, T. Anesthesiology , — Schilling, W. Sodin-Semrl, S. Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. Fearon, U. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Fraguas-Sanchez, A. CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer. Laragione, T. The cation channel Trpv2 is a new suppressor of arthritis severity, joint damage, and synovial fibroblast invasion. Skonieczna, M. Cox, D. Sahoo, S. Transient receptor potential ankyrin1 channel is endogenously expressed in T cells and is involved in immune functions. Sandor, Z. Effects of cinnamaldehyde on smooth muscle preparations. Pharmacology , — Mayer, F. Liver Physiol. Maher, M. Activation of TRPA1 by farnesyl thiosalicylic acid. Engler, A. Expression of transient receptor potential vanilloid 1 TRPV1 in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Radulovic, M. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. Perez, M. Redox Biol. Download references. We thank Birgit Opgenoorth for excellent technical assistance. This work was supported by an unlimited grant of the Hiller Foundation. You can also search for this author in PubMed Google Scholar. Correspondence to Torsten Lowin. Reprints and permissions. Cannabidiol CBD : a killer for inflammatory rheumatoid arthritis synovial fibroblasts. Cell Death Dis 11 , Download citation. Received : 26 February Revised : 06 August Accepted : 06 August Published : 01 September Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Clinical and Translational Oncology Skip to main content Thank you for visiting nature. Download PDF. Subjects Immune cell death Rheumatoid arthritis. Abstract Cannabidiol CBD is a non-intoxicating phytocannabinoid from cannabis sativa that has demonstrated anti-inflammatory effects in several inflammatory conditions including arthritis. Differential inflammation-mediated function of prokineticin 2 in the synovial fibroblasts of patients with rheumatoid arthritis compared with osteoarthritis Article Open access 15 September Introduction Cannabidiol CBD is a non-intoxicating cannabinoid found in cannabis sativa 1. Full size image. Materials and methods Biochemicals Patients In total, 40 patients with long-standing RA fulfilling the American College of Rheumatology revised criteria for RA 24 were included in this study. Table 1 Biochemicals used in this study. Full size table. References ElSohly, M. Acknowledgements We thank Birgit Opgenoorth for excellent technical assistance. View author publications. Ethics declarations Conflict of interest The authors declare that they have no conflict of interest. Edited by H. Supplementary information. About this article. Cite this article Lowin, T. Copy to clipboard. This article is cited by A narrative review of the therapeutic and remedial prospects of cannabidiol with emphasis on neurological and neuropsychiatric disorders Oluwadara Pelumi Omotayo Yolandy Lemmer Shayne Mason Journal of Cannabis Research Association between cannabis use and physical activity in the United States based on legalization and health status Ray M. Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search.

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