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Mukesh Khanna Tops Google Trending Chart After Shaktimaan's Revival Announcement

Mukesh Khanna will be reprising the role of Indian superhero Shaktimaan in the upcoming show




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Delaware Division of the Arts presents “Between Light & Shadow” by Hannah Whiddon – Opens August 4

Drawing inspiration from the beauty inherent in everyday life and the human form, Whiddon’s paintings transcend specific places and times, evoking feelings and memories rather than representing them. Her pieces celebrate human sensuality, employing compelling subjects, a vibrant palette, and bold, painterly textures.




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Delaware Farmers Encouraged To Participate In Environmental Deeds Questionnaire

Along with the Delaware Nutrient Management Program’s annual report mailing, Delaware farmers are being encouraged to complete an additional 16-question implementation questionnaire. The questionnaire aims to measure nutrient applications and environmental deeds, allowing Delaware to recognize farmers for their stewardship efforts in 2020.




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DPH Reports Zero Cases of High Blood Lead Levels in Children Consuming Recalled Cinnamon Applesauce Pouches

The Food and Drug Administration (FDA) has received reports from multiple states that suggest children may have higher blood lead levels (BLLs) after consuming recalled cinnamon-containing applesauce products. The Delaware Division of Public Health (DPH) has received no reports of children with high BLLs in response to the recall of cinnamon-containing applesauce products. Signs and […]



  • Delaware Health and Social Services
  • Division of Public Health

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DPH Reports High Levels of Lead in Certain Cinnamon Products

The Food and Drug Administration (FDA) has identified high lead levels in several ground cinnamon products. Several stores, including Dollar Tree, Save A Lot and Family Dollar, sold cinnamon products that contain lead levels that could be potentially harmful to consumers, particularly children. Signs and symptoms may include headaches, nausea, vomiting, diarrhea, changes in activity […]




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John Brennan named Deputy Warden of Baylor Women’s Correctional Institution 

New Castle, DE – The Delaware Department of Correction announced today that John Brennan, Security Superintendent of James T. Vaughn Correctional Center (JTVCC), has been promoted to Deputy Warden of Baylor Women’s Correctional Institution (BWCI), effective February 27.  Brennan fills the vacancy created when then-BWCI Deputy Warden Kimberly Hughey was promoted to BWCI Warden in December 2022. “Deputy Warden Brennan is a […]



  • Department of Correction

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Safe Harbor for Financial Institutions Serving Legal Cannabis Businesses

As Delaware readies for the upcoming launch of the state’s legal adult-use cannabis industry, state lawmakers approved legislation, proposed by State Treasurer Colleen Davis, providing protections for banks and other financial institutions that serve licensed marijuana businesses. Although marijuana remains illegal at the federal level, Delaware has joined many other states in legalizing it for […]



  • Office of the State Treasurer
  • State Treasurer Colleen C. Davis
  • Cannabis
  • Marijuana
  • Office of the Delaware State Treasurer
  • Safe Banking
  • State treasurer Colleen Davis

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Decomposed Body Of Kannada Director Guruprasad Found At Bengaluru Flat

Noted Kannada actor and director Guruprasad was found dead in his Bengaluru apartment today, the police said.




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Suspended Teacher Jailed For Sexually Harassing Students In Chennai School

A suspended teacher from the PSBB (Padma Seshadri Bala Bhavan) School in Chennai has been sentenced to two years of rigorous imprisonment for sexually harassing female students.






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UK firm targets booming medicinal cannabis market

Eco Equity is one of only a few Europe-based investors in medicinal cannabis from Africa and the Caribbean, an area in which the UK is missing an opportunity, according to CEO Jon-Paul Doran.




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Earthshot youth leader Lesedi Monnanyane on fighting pollution and water scarcity




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The Pinnacle of Faith




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Italy's 'cannabis light' trade may go up in smoke with law change

Italy's flourishing "cannabis light" industry is at risk, with Prime Minister Giorgia Meloni pushes a bill through parliament to deflower a crop that is legal across much of Europe. Her conservative coalition wants to ban the sale of hemp flower products, but those in the trade say it's economic suicide. - REUTERS




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Madonna part ways with Akeem Morris over silly reason

Madonna's close friend reveals she dated Tupac Shakur but never publicised about himPop singer, Madonna silently steps into her single era again, as she reportedly parted ways with her boyfriend, Akeem Morris.A close source revealed that the duo separated in the month of October and their bond had...




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L44429-IND: Climate Adaptation in Vennar Sub Basin in Cauvery Delta (CAVSCD) Project[Infrastructure Improvement and Reconstruction Works on Pandavaiyar river from 109.270 Km to 148.020 Km Package No CAVSCD/TN/ PDR]




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Geoscientists are using telecom 'dark fibres' to map Earth’s innards

The networks of fibre optic cables that criss-cross the planet could be used to better understand what’s happening inside it




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When did humans leave the trees for the savannah – or did they at all?

Ancient humans are said to have evolved to leave the trees, where our primate ancestors lived, in favour of open grassy savannahs – but we may have this idea wrong




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Cannabis and Pain Management

Family physicians are fielding questions about cannabis --particularly for the use of cannabis for treatment of pain. Like about every substance ingested to treat medical conditions, cannabis has risks and benefits. But regarding evidence-based practice and practice-based recommendations for patients about cannabis use, the cart is in front of the horse. Cannabis use is still illegal at a federal level and a Schedule 1 drug, but most states have challenged federal law by decriminalizing or legalizing cannabis for a variety of uses. Research is difficult due to this federal status as a Schedule 1 drug since federal funding is not readily available to support research. As a result, physicians have little to no guidance about the clinical usefulness of the product. This article explores what we know and what we are learning about cannabis, and the authors provide clinical guidance for patient care based on this evidence.




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Longitudinal validation of King's Sarcoidosis Questionnaire in a prospective cohort with mild sarcoidosis

Background

Quality of life is impaired in patients with sarcoidosis. The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health-related quality of life in patients with sarcoidosis, comprising subdomains of General Health Status (GHS), Lung, Medication, Skin and Eyes. The aim of this study was to enhance the validation of the KSQ, incorporating longitudinal validation and known-groups validity in a cohort with mild sarcoidosis.

Methods

The KSQ was linguistically validated according to guidelines. Patients with sarcoidosis completed KSQ and other questionnaires at baseline, after 2 weeks and at 12 months. Forced vital capacity (FVC) was measured. Concurrent validity, reliability and responsiveness were assessed.

Results

In patients (n=150), the KSQ had moderate to strong correlations with the Short Form-12 (Mental Component Summary), the King's Brief Interstitial Lung Disease questionnaire and the Fatigue Assessment Scale (r=0.30–0.70) and weak correlations with the Short Form-12 (Physical Component Summary) and FVC (r=0.01–0.29). The KSQ GHS and Lung domains were able to discriminate between groups of patients stratified according to fatigue, treatment and FVC. The KSQ had high internal consistency (Cronbach's α=0.73–0.90) and repeatability (interclass correlation coefficients 0.72–0.81). Correlations to comparable questionnaires at baseline were moderate or strong for the GHS, Lung and GHS–Lung subdomains and weak or moderate for FVC. The KSQ was responsive to changes over time.

Conclusion

This study strengthened the validation of the KSQ by introducing known-groups validity and assessments of responsiveness over 12 months in patients with mild sarcoidosis.




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Proteomic Analysis of Signaling Pathways Modulated by Fatty Acid Binding Protein 5 (FABP5) in Macrophages [Special Section: Cannabinoid Signaling in Human Health and Disease]

Although acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages toward an anti-inflammatory phenotype, yet signaling pathways regulated by macrophage-FABP5 have not been systematically profiled. We leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow-derived macrophages (BMDMs). Stable isotope labeling by amino acids-based analysis of M1 and M2 polarized wild-type and FABP5 knockout BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Toll-like receptor 2 (TLR2) emerged as a novel target of FABP5 and pharmacological FABP5 inhibition blunted TLR2-mediated activation of downstream pathways, ascribing a novel role for FABP5 in TLR2 signaling. This study represents a comprehensive characterization of the impact of FABP5 deletion on the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered pathways implicated in inflammatory responses, macrophage function, and TLR2 signaling. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling.

SIGNIFICANCE STATEMENT

This research offers a comprehensive analysis of fatty acid binding protein 5 (FABP5) in macrophages during inflammatory response. The authors employed quantitative proteomic and phosphoproteomic approaches to investigate this utilizing bone marrow-derived macrophages that were M1 and M2 polarized using lipopolysaccharide with interferon and interleukin-4, respectively. This revealed multiple pathways related to inflammation that were differentially regulated due to the absence of FABP5. These findings underscore the potential therapeutic significance of macrophage-FABP5 as a candidate for addressing inflammatory-related diseases.




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Regulation of Cannabinoid and Opioid Receptor Levels by Endogenous and Pharmacological Chaperones [Special Section: Cannabinoid Signaling in Human Health and Disease]

Cannabinoid and opioid receptor activities can be modulated by a variety of post-translational mechanisms including the formation of interacting complexes. This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB1 receptor (CB1R), opioid receptor (DOR), and CB1R-DOR interacting complexes. Focusing on endogenous protein chaperones, namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared with other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB1R, DOR, and CB1R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long-term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones. Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord. Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB1R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking.

SIGNIFICANCE STATEMENT

This study highlights a role for chaperones (endogenous and small membrane-permeable molecules) in modulating levels of cannabinoid CB1 receptor, delta opioid receptor, and their interacting complexes. These chaperones could be developed as therapeutics for pathologies involving these receptors.




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Evaluating the Abuse Potential of Lenabasum, a Selective Cannabinoid Receptor 2 Agonist [Special Section: Cannabinoid Signaling in Human Health and Disease]

Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings.

SIGNIFICANCE STATEMENT

This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.




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Chronic Administration of Cannabinoid Agonists ACEA, AM1241, and CP55,940 Induce Sex-Specific Differences in Tolerance and Sex Hormone Changes in a Chemotherapy-Induced Peripheral Neuropathy [Special Section: Cannabinoid Signaling in Human Health and Dise

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB1)-selective, cannabinoid receptor type 2 (CB2)-selective, and CB1/CB2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

SIGNIFICANCE STATEMENT

CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.




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Cannabinoid 2 Receptor Activation Protects against Diabetic Cardiomyopathy through Inhibition of AGE/RAGE-Induced Oxidative Stress, Fibrosis, and Inflammasome Activation [Special Section: Cannabinoid Signaling in Human Health and Disease]

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)–receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2–related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms.

SIGNIFICANCE STATEMENT

BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2β and TGF-β/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy.




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KLS-13019, a Novel Structural Analogue of Cannabidiol and GPR55 Receptor Antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy in Rats [Special Section: Cannabinoid Signaling in Human Health and Disease]

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

SIGNIFICANCE STATEMENT

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. The GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal-dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need.




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The Minor Phytocannabinoid Delta-8-Tetrahydrocannabinol Attenuates Collagen-Induced Arthritic Inflammation and Pain-Depressed Behaviors [Special Section: Cannabinoid Signaling in Human Health and Disease]

Patients with arthritis report using cannabis for pain management, and the major cannabinoid delta-9-tetrahydrocannabinol (9-THC) has anti-inflammatory properties, yet the effects of minor cannabinoids on arthritis are largely unknown. The goal of the present study was to determine the antiarthritic potential of the minor cannabinoid delta-8-tetrahydrocannabinol (8-THC) using the collagen-induced arthritis (CIA) mouse model. Adult male DBA/1J mice were immunized and boosted 21 days later with an emulsion of collagen and complete Freund’s adjuvant. Beginning on the day of the booster, mice were administered twice-daily injections of 8-THC (3 or 30 mg/kg), the steroid dexamethasone (2 mg/kg), or vehicle for two weeks. Dorsal-ventral paw thickness and qualitative measures of arthritis were recorded daily, and latency to fall from an inverted grid was measured on alternating days, to determine arthritis severity and functional impairment. On the final day of testing, spontaneous wire-climbing behavior and temperature preference in a thermal gradient ring were measured to assess CIA-depressed behavior. The 8-THC treatment (30 mg/kg) reduced paw swelling and qualitative signs of arthritis. 8-THC also blocked CIA-depressed climbing and CIA-induced preference for a heated floor without producing locomotor effects but did not affect latency to fall from a wire grid. In alignment with the morphologic and behavioral assessments in vivo, histology revealed that 8-THC reduced synovial inflammation, proteoglycan loss and cartilage and bone erosion in the foot joints in a dose-dependent manner. Together, these findings suggest that 8-THC not only blocked morphologic changes but also prevented functional loss caused by collagen-induced arthritis.

SIGNIFICANCE STATEMENT

Despite increasing use of cannabis products, the potential effects of minor cannabinoids are largely unknown. Here, the minor cannabinoid delta-8-tetrahydrocannabinol blocked the development of experimentally induced arthritis by preventing both pathophysiological as well as functional effects of the disease model. These data support the development of novel cannabinoid treatments for inflammatory arthritis.




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Select Minor Cannabinoids from Cannabis sativa Are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain [Special Section: Cannabinoid Signaling in Human Health and Disease]

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), 8-tetrahydrocannabinol (8-THC), and 9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose 8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose 8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential.

SIGNIFICANCE STATEMENT

Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study, we evaluated five minor cannabinoids (CBN, CBDV, CBG, THCV, and 8-THC) for their cannabimimetic and analgesic effects in mice. We found that four of the five minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.




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The Potential of Cannabichromene (CBC) as a Therapeutic Agent [Special Section: Cannabinoid Signaling in Human Health and Disease-Minireview]

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

SIGNIFICANCE STATEMENT

Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on 9-tetrahydrocannabinol and cannabidiol. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.




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The Intoxication Equivalency of 11-Hydroxy-{Delta}9-Tetrahydrocannabinol Relative to {Delta}9-Tetrahydrocannabinol [Special Section: Cannabinoid Signaling in Human Health and Disease]

9-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-9-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [Cmax, time to Cmax (Tmax), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a Tmax at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage Cmax was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower Cmax for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies.

SIGNIFICANCE STATEMENT

This study establishes that the primary metabolite of THC, 11-OH-THC, displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future in vivo cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.




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Sex Differences in the Neural and Behavioral Effects of Acute High-Dose Edible Cannabis Consumption in Rats [Special Section: Cannabinoid Signaling in Human Health and Disease]

The consumption of 9-tetrahydrocannabinol (THC)- or cannabis-containing edibles has increased in recent years; however, the behavioral and neural circuit effects of such consumption remain unknown, especially in the context of ingestion of higher doses resulting in cannabis intoxication. We examined the neural and behavioral effects of acute high-dose edible cannabis consumption (AHDECC). Sprague-Dawley rats (six males, seven females) were implanted with electrodes in the prefrontal cortex (PFC), dorsal hippocampus (dHipp), cingulate cortex (Cg), and nucleus accumbens (NAc). Rats were provided access to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg) for 10 minutes, during which they voluntarily consumed all of the provided Nutella and THC mixture. Cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24 hours after exposure. In another cohort (16 males, 15 females), we examined the effects of AHDECC on learning and prepulse inhibition and serum and brain THC and 11-hydroxy-THC concentrations. AHDECC resulted in higher brain and serum THC and 11-hydroxy-THC levels in female rats over 24 hours. AHDECC also produced: 1) Cg, dHipp, and NAc gamma power suppression, with the suppression being greater in female rats, in a time-dependent manner; 2) hypolocomotion, hypothermia, and antinociception in a time-dependent manner; and 3) learning and prepulse inhibition impairments. Additionally, most neural activity and behavior changes appear 2 hours after ingestion, suggesting that interventions around this time might be effective in reversing/reducing the effects of AHDECC.

SIGNIFICANCE STATEMENT

The effects of high-dose edible cannabis on behavior and neural circuitry are poorly understood. We found that the effects of acute high-dose edible cannabis consumption (AHDECC), which include decreased gamma power, hypothermia, hypolocomotion, analgesia, and learning and information processing impairments, are time and sex dependent. Moreover, these effects begin 2 hours after AHDECC and last for at least 24 hours, suggesting that treatments should target this time window in order to be effective.:




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{Delta}9-Tetrahydrocannabinol Alleviates Hyperalgesia in a Humanized Mouse Model of Sickle Cell Disease [Special Section: Cannabinoid Signaling in Human Health and Disease]

People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affects their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of 9-tetrahydrocannabinol (THC), cannabis’ intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1–3 mg/kg–1, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in human sickle hemoglobin (HbSS) but not human normal hemoglobin A (HbAA) mice. In the tail-flick assay, THC (1 and 3 mg/kg–1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg/kg–1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-hour novel object recognition). Subchronic THC treatment (1 and 3 mg/kg–1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents.

SIGNIFICANCE STATEMENT

The study explores 9-tetrahydrocannabinol (THC)’s efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.




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Analgesic Properties of Next-Generation Modulators of Endocannabinoid Signaling: Leveraging Modern Tools for the Development of Novel Therapeutics [Special Section: Cannabinoid Signaling in Human Health and Disease-Minireview]

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRABeCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

SIGNIFICANCE STATEMENT

Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, nonintoxicating mechanisms of action.




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The National Center for Complementary and Integrative Health: Priorities for Cannabis and Cannabinoid Research [Special Section: Cannabinoid Signaling in Human Health and Disease-Commentary]

The National Center for Complementary and Integrative Health (NCCIH), which is part of the US National Institutes of Health (NIH), has a broad interest in studying the biologic activities of natural products, especially those for which compelling evidence from preclinical research suggests biologic activities that may be beneficial to health or have a potential role in disease treatment, as well as products used extensively by the American public. As of 2023, use of cannabis for medical purposes is legal in 38 states and Washington, D.C. Such use continues to climb generally without sufficient knowledge regarding risks and benefits. In keeping with NCCIH’s natural product research priorities and recognizing this gap in knowledge, NCCIH formally launched a research program in 2019 to expand research on the possible benefits for pain management of certain substances found in cannabis: minor cannabinoids and terpenes. This Viewpoint provides additional details and the rationale for this research priority at NCCIH. In addition, NCCIH’s efforts and initiatives to facilitate and coordinate an NIH research agenda focused on cannabis and cannabinoid research are described.

SIGNIFICANCE STATEMENT

Use of cannabis for purported medical purposes continues to increase despite insufficient knowledge regarding risks and benefits. Research is needed to help health professionals and patients make knowledgeable decisions about using cannabis and cannabinoids for medical purposes. The National Center for Complementary and Integrative Health, along with other NIH Institutes, Centers, and Offices, is expanding study on the safety, efficacy, and harms of cannabis—a complex mixture of phytochemicals that needs to be studied alone and in combination.




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Cannabis and Cannabinoid Signaling: Research Gaps and Opportunities [Special Section: Cannabinoid Signaling in Human Health and Disease-Commentary]

Cannabis and its products have been used for centuries for both medicinal and recreational purposes. The recent widespread legalization of cannabis has vastly expanded its use in the United States across all demographics except for adolescents. Meanwhile, decades of research have advanced our knowledge of cannabis pharmacology and particularly of the endocannabinoid system with which the components of cannabis interact. This research has revealed multiple targets and approaches for manipulating the system for therapeutic use and to ameliorate cannabis toxicity or cannabis use disorder. Research has also led to new questions that underscore the potential risks of its widespread use, particularly the enduring consequences of exposure during critical windows of brain development or for consumption of large daily doses of cannabis with high content 9-tetrahydrocannabinol. This article highlights current neuroscience research on cannabis that has shed light on therapeutic opportunities and potential adverse consequences of misuse and points to gaps in knowledge that can guide future research.

SIGNIFICANCE STATEMENT

Cannabis use has escalated with its increased availability. Here, the authors highlight the challenges of cannabis research and the gaps in our knowledge of cannabis pharmacology and of the endocannabinoid system that it targets. Future research that addresses these gaps is needed so that the endocannabinoid system can be leveraged for safe and effective use.




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Special Section on Cannabinoid Signaling in Human Health and Disease--Editorial [Special Section on Cannabinoid Signaling in Human Health and Disease-Editorial]




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Minor Cannabinoids as an Emerging Frontier for Pain Relief [Viewpoint]




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Cross-Sectional Study of Cesarean Delivery and Safety Culture by Family Medicine Presence [Annals Journal Club]




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Joanna Cherry says SNP rules won't stop Flynn 'double-jobbing'

Former MP Joanna Cherry has said that the SNP rules which prevented her from standing for a seat at Holyrood would not block Stephen Flynn from doing the same.  





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Ed Miliband stopped in tracks by Susanna Reid over £300 energy bill promise



Secretary of State was questioned on Good Morning Britain over the pledge - with host asking 'how much will it have gone up by then?'





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Multiband Antenna Simulation and Wireless KPI Extraction



In this upcoming webinar, explore how to leverage the state-of-the-art high-frequency simulation capabilities of Ansys HFSS to innovate and develop advanced multiband antenna systems.

Overview

This webinar will explore how to leverage the state-of-the-art high-frequency simulation capabilities of Ansys HFSS to innovate and develop advanced multiband antenna systems. Attendees will learn how to optimize antenna performance and analyze installed performance within wireless networks. The session will also demonstrate how this approach enables users to extract valuable wireless and network KPIs, providing a comprehensive toolset for enhancing antenna design, optimizing multiband communication, and improving overall network performance. Join us to discover how Ansys HFSS can transform wireless system design and network efficiency approach.

What Attendees will Learn

  • How to design interleaved multiband antenna systems using the latest capabilities in HFSS
  • How to extract Network Key Performance Indicators
  • How to run and extract RF Channels for the dynamic environment

Who Should Attend

This webinar is valuable to anyone involved in antenna, R&D, product design, and wireless networks.

Register now for this free webinar!




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'AGT': Daredevil Annaliese Nock Terrifies Judges With Wheel of Death Stunt

'AGT' returned on Tuesday with live shows from Universal Studios Hollywood.

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‘We’ve lost the ability to safeguard children on social media’, says mother of murdered teen Brianna Ghey

Brianna Ghey's mother, Esther Ghey, is now campaigning to raise awareness about the dangers of social media and the "toxic" online world which her daughter came to inhabit. She wants tighter regulation on internet access and more parental controls.




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‘Fashion shows have a purpose,’ says British Vogue editor Chioma Nnadi

The huge four-storey walls of the Lightroom in London are showing ‘Vogue: Inventing the Runway'.




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Mukesh Khanna returns as ‘Shaktimaan’, shares teaser of beloved hero’s reprisal

The show originally aired on Doordarshan in 1997, became one of India’s most beloved superhero shows, running for over 450 episodes




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Influenceur en cryptomonnaie enlevé dans le Vieux-Montréal: le corps décomposé de Kevin Mirshahi retrouvé

Le corps ligoté en état de décomposition retrouvé le 30 octobre dans l’un des parcs les plus achalandés de Montréal est celui de Kevin Mirshahi.




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We Need to Ensure Legal Cannabis Is Safe

Today’s cannabis plant is highly cultivated and incredibly potent. Treating it like a commodity, and not a testable, regulated medicine, is hurting people