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DMH-CBD, a cannabidiol analog with reduced cytotoxicity, inhibits TNF production by targeting NF-kB activity dependent on A(2A) receptor

Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB…

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Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a μM concentration range: CBD (IC50 = 15 μM) and DMH-CBD (IC50 = 38 μM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC50 = 58 μM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A2A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A2A receptor dependent-manner.

Keywords: Cannabidiol; DHM-Cannabidiol; Macrophages; NF-kB; TNF.

Source: https://pubmed.ncbi.nlm.nih.gov/30796934/?utm_source=no_user_agent&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1TQbL92JdzYTve0m3OsSoggMby2JyZDVBLRHiDMYZkT1hs6YNQ&fc=20200804223051&ff=20200816094834&v=2.11.5

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Good cbd carts in LA?

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Live in LA so have access to all the dispensaries. Looking for a good cart recommendation as it seems to be the only method that has an effect for me before bed. Currently using a brand called “cannabis by design” 18:1 ratio and like it but I feel like there are better brands out there?

Thanks!

Source: https://www.reddit.com/r/CBD/comments/l0velw/good_cbd_carts_in_la/

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There may still be hope for the ‘not perfect’ USDA final rule on hemp

United States Department of Agriculture’s finalized hemp regulations, which were published on January 15, evoked a variety of responses f…

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United States Department of Agriculture’s finalized hemp regulations, which were published on January 15, evoked a variety of responses from those invested in the industry. In a previous blog post, we covered some of the changes between the final rule and the interim final rule (IFR) that have industry leaders celebrating. However, the final rule might be more of a mixed bag overall.

Although it includes some provisions that are expected to benefit the hemp industry, there are others that may leave industry leaders disappointed, including the requirements for harvest samples to come from hemp flowers, for total tetrahydrocannabinol (THC) testing, and for testing to occur in labs certified by the Drug Enforcement Administration (DEA).

“It does not seem to be clear that it is a definite improvement over the interim final rule but that it is not perfect. It does not go as far as some of the key things we requested,” Jonathan Miller told Marijuana Moment. Miller is the general counsel for the U.S. Hemp Roundtable.

Industry stakeholders reportedly encouraged the United States Department of Agriculture (USDA) to allow pre-harvest samples to come from a greater part of the plant or the whole plant instead of just the flower. The USDA did not include this change in its final rule. Instead, it claims that the flower is the most appropriate place to sample because THC is concentrated there.

Under the final rule, pre-harvest samples must still come from the cannabis flower. However, this requirement has been modified slightly. When the final rule goes into effect on March 22, the samples can be taken from about five to eight inches from the main stem, terminal bud, or central cola of the flowering top of the plant.

Another request made by industry stakeholders was for hemp crops to be tested for delta-9 THC instead of total THC content. Delta-9 THC is the main psychoactive component in cannabis — the component that can make people feel high. Total THC includes the possible conversion of tetrahydrocannabinolic acid (THCA) into THC.

Some reportedly believe that the total THC better represents the sample’s potential to get someone high because it accounts for the cannabinoids that could be activated with heat when the product is consumed through vaping, smoking , or cooking. However, THCA is not psychoactive, and not all products that may be made from hemp would result in THCA being converted to delta-9 THC.

Unfortunately, the USDA maintained that hemp must be tested for total THC content, and that the THC concentration for a legal hemp crop must be below 0.3%.

Perhaps the biggest disappointment to industry stakeholders is that the USDA’s final rule did not change the requirement for hemp testing to occur only at labs certified by the DEA.

“Registration is necessary because laboratories could possibly handle cannabis that tests above 0.3% THC on a dry weight basis, which is, by definition, marijuana and a Schedule 1 controlled substance,” the final rule states.

However, there are not enough qualifying labs available to efficiently handle the number of hemp tests needed in this growing industry, a fact that was acknowledged in the final rule.

The final rule adds, “[S]ince the IFR was published, numerous laboratories have applied for registration and DEA is working diligently to process these requests.”

In the meantime, the USDA is delaying the enforcement of this rule. It was first delayed in 2020, and the final rule extended this delay until December 2022.

Although the USDA’s final rule did include some positive steps, it also lacked several important changes that industry stakeholders were hoping to see.

“USDA seems to have declined to act upon many of the comments submitted, particularly concerning sampling uncertainty, DEA labs and Total THC among others,” Herrick Fox reportedly told Hemp Industry Daily. Fox is the owner of Meristem Farms and a former USDA rulemaker.

“Many are justifiably disappointed by the DEA’s continued (and in some ways expanded) role in the agricultural hemp program,” said Shawn Hauser in a press release. Hauser is a partner and chair of the Hemp and Cannabinoids Department at Vincente Sederberg LLP.

The USDA released its final rule in the last week of the Trump administration, but some industry leaders remain hopeful that the situation regarding hemp regulations may change under the Biden administration.

“We anticipate, as is customary of new administrations, that this rule will be one of many that will be frozen on the first day of the Biden administration,” Larry Farnsworth, a spokesperson for the National Industrial Hemp Council, reportedly told Marijuana Moment.

“We look forward to working through these issues with the incoming Biden administration,” he added.

Sources

[1] https://www.marijuanamoment.net/usda-releases-final-rule-for-hemp-two-years-after-crop-was-federally-legalized/

[2] https://www.federalregister.gov/documents/2021/01/19/2021-00967/establishment-of-a-domestic-hemp-production-program

[3] https://cannabusiness.law/what-is-total-thc-and-does-it-matter/

[4] https://www.ams.usda.gov/rules-regulations/hemp

[5] https://hempindustrydaily.com/hemp-industry-advocates-dish-reactions-on-usda-final-hemp-rules/

[6] https://vicentesederberg.com/press/usda-announces-final-rule-regulating-the-production-of-hemp-in-the-u.s/

Source: https://www.nothingbuthemp.net/post/there-may-still-be-hope-for-the-not-perfect-usda-final-rule-on-hemp

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Alginate Affects Bioactivity of Chimeric Collagen-Binding LL37 Antimicrobial Peptides Adsorbed to Collagen-Alginate Wound Dressings

Chronic infected wounds cause more than 23,000 deaths annually. Antibiotics and antiseptics are conventionally used to treat infected wounds; however, they can be toxic to mammalian cells, and their use can contribute to antimicrobial resistance. Antimicrobial peptides (AMPs) have been utilized to address the limitations of antiseptics and antibiotics. In previous work, we modified the human AMP LL37 with collagen-binding domains from collagenase (cCBD) or fibronectin (fCBD) to facilitate…

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Chronic infected wounds cause more than 23,000 deaths annually. Antibiotics and antiseptics are conventionally used to treat infected wounds; however, they can be toxic to mammalian cells, and their use can contribute to antimicrobial resistance. Antimicrobial peptides (AMPs) have been utilized to address the limitations of antiseptics and antibiotics. In previous work, we modified the human AMP LL37 with collagen-binding domains from collagenase (cCBD) or fibronectin (fCBD) to facilitate peptide tethering and delivery from collagen-based wound dressings. We found that cCBD-LL37 and fCBD-LL37 were retained and active when bound to 100% collagen scaffolds. Collagen wound dressings are commonly made as composites with other materials, such as alginate. The goal of this study was to investigate how the presence of alginate affects the tethering, release, and antimicrobial activity of LL37 and CBD-LL37 peptides adsorbed to commercially available collagen-alginate wound dressings (FIBRACOL Plus-a 90% collagen and 10% alginate wound dressing). We found that over 85% of the LL37, cCBD-LL37, and fCBD-LL37 was retained on FIBRACOL Plus over a 14-day release study (90.3, 85.8, and 98.6%, respectively). Additionally, FIBRACOL Plus samples loaded with peptides were bactericidal toward Pseudomonas aeruginosa, even after 14 days in release buffer but demonstrated no antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis. The presence of alginate in solution induced conformational changes in the cCBD-LL37 and LL37 peptides, resulting in increased peptide helicity, and reduced antimicrobial activity against P. aeruginosa. Peptide-loaded FIBRACOL Plus scaffolds were not cytotoxic to human dermal fibroblasts. This study demonstrates that CBD-mediated LL37 tethering is a viable strategy to reduce LL37 toxicity, and how substrate composition plays a crucial role in modulating the antimicrobial activity of tethered AMPs.

Keywords: Pseudomonas aeruginosa; alginate; antimicrobial peptide; collagen scaffold; collagen-binding domain; peptide delivery.

Source: https://pubmed.ncbi.nlm.nih.gov/33463166/?utm_source=no_user_agent&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1zmroqAMnEquTZFTfdGx1V1gPEavo-Be3-FKTecJpOlB7LykCL&fc=20200804213506&ff=20210119175353&v=2.14.2

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