Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) has become the leading cause of chronic liver disease, but there has been no approved pharmacotherapy to date.

Methods: We used a network analysis approach to delineate protein-protein interactions that contribute to the transition from steatosis to MASH, in order to identify and target this transition as a potential pharmacotherapeutic strategy. Acyl-CoA thioesterase 1 (ACOT1) was identified as a critical node in the protein-protein interaction (PPI) network of the transition from steatosis to MASH in patient samples.

Stereoisomers of cannabidiols and their pharmacological activities - A potentially novel direction for cannabinoids.

Cannabidiol (CBD), a bicyclic non-psychoactive cannabinoid biosynthesized by Cannabis spp. of plants, has attracted significant interest in the past decade due to its therapeutic properties. In 2018, the US FDA approved Epidiolex®, a CBD-based drug for the treatment of two rare epileptic seizure disorders.

A novel small molecule phagocytosis inhibitor, KB-208, ameliorates ITP in mouse models with similar efficacy as IVIG.

Background: The characteristic feature of immune cytopenias involves the process of extravascular phagocytosis, wherein macrophages in the spleen and/or liver engage in the destruction of blood cells that have been opsonized by auto- or alloantibodies. Therefore, new treatments that prevent phagocytosis will be advantageous, especially for short-term usage along with alternative options.

Study Design And Methods: KB-208, a small molecule drug, previously shown to be efficacious for the in vitro inhibition of phagocytosis was synthesized.

The State of Synthetic Cannabinoid Medications for the Treatment of Pain.

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects.

Murine model for chronic rhinosinusitis: an interventional study.

Background: Chronic rhinosinusitis (CRS) is a complex inflammatory disease of the sinonasal tract. To understand this disease entity and develop targeted treatments, a reproducible animal model is paramount.

Aims/objectives: To optimize a murine model of eosinophilic CRS by establishing benchmark histological markers and validate its fidelity in evaluating intranasal treatments.

Small Molecule Drugs That Inhibit Phagocytosis.

In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that a small molecule drug discovery-based approach to the treatment of immune cytopenias (ITP, AIHA, HTR, DHTR) is feasible. Those earlier studies showed that small molecules with anti-phagocytic groups, such as the pyrazole core, are good models for producing efficacious phagocytosis inhibitors with low toxicity.

Medical Cannabis Use and Inflammatory Cytokines and Chemokines Among Adult Chronic Pain Patients.

Utilizing cannabis as a therapeutic option for chronic pain (CP) has increased significantly. However, data regarding the potential immunomodulatory effects of cannabis in CP patients remain scarce. We aimed at exploring the relationship between cannabis use and inflammatory cytokines and chemokines among a cohort of CP patients.

Patient-reported outcomes in those consuming medical cannabis: a prospective longitudinal observational study in chronic pain patients.

Purpose: We investigated patients with chronic pain seeking medical cannabis. We assessed their demographics, patterns of cannabis use, and the long-term effectiveness of cannabis on their pain and functional domains.

Methods: This observational study enrolled patients between 8 September 2015 and 31 July 2018 from community-based cannabis clinics in Ontario, Canada.

Bioactive Chemical Composition of Cannabis Extracts and Cannabinoid Receptors.

Cannabis is widely used as a therapeutic drug, especially by patients suffering from psychiatric and neurodegenerative diseases. However, the complex interplay between phytocannabinoids and their targets in the human receptome remains largely a mystery, and there have been few investigations into the relationship between the chemical composition of medical cannabis and the corresponding biological activity. In this study, we investigated 59 cannabis samples used by patients for medical reasons.

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice.

Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro.

The Impact of Perioperative Cannabis Use: A Narrative Scoping Review.

As countries progressively embrace the legalization of both medicinal and recreational cannabis, there remains a significant knowledge gap when it comes to the perioperative uses of cannabis, as well as the management of cannabis users. This review summarizes the information available on the subject based on existing published studies. Articles outlining the physiological changes occurring in the human body during acute and chronic use of cannabis (outside the context of anesthesia) are also taken into consideration as understanding these changes allows a more calculated approach to better anticipate patients' needs in the perioperative setting.

Cannabis Use Disorder and Perioperative Outcomes in Major Elective Surgeries: A Retrospective Cohort Analysis.

Background: Although cannabis is known to have cardiovascular and psychoactive effects, the implications of its use before surgery are currently unknown. The objective of the present study was to determine whether patients with an active cannabis use disorder have an elevated risk of postoperative complications.

Methods: The authors conducted a retrospective population-based cohort study of patients undergoing elective surgery in the United States using the Nationwide Inpatient Sample from 2006 to 2015.

Extractions of Medical Cannabis Cultivars and the Role of Decarboxylation in Optimal Receptor Responses.

Phytocannabinoids, characteristic compounds produced by medical cannabis, interact with cannabinoid (CB) receptors (CB1 and CB2) as well as other receptor systems to exhibit their corresponding pharmacological effects. In their natural form, CBs such as Δ-tetrahydrocannabinolic acid and cannabidiolic acid are inactive at these receptors, while their decarboxylated forms (Δ-tetrahydrocannabinol and cannabidiol, respectively) are potent ligands at CB receptors. Thus, extraction and processing of medical cannabis for active constituents are important.

Chemical Profiling of Medical Cannabis Extracts.

Medical cannabis has been legally available for patients in a number of countries. Licensed producers produce a variety of cannabis strains with different concentrations of phytocannabinoids. Phytocannabinoids in medical cannabis are decarboxylated when subjected to heating for consumption by the patients or when extracted for preparing cannabis derivative products.

Drug Repurposing in the Development of Anticancer Agents.

Background: Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established.

Objective: This review provides an overview of anticancer drug development strategies which is one of the important areas of drug restructuring.

Surfactant protein D regulates caspase-8-mediated cascade of the intrinsic pathway of apoptosis while promoting bleb formation.

Surfactant-associated protein D (SP-D) is a soluble innate immune collectin present on many mucosal surfaces. We recently showed that SP-D suppresses the extrinsic pathway of apoptosis by downregulating caspase-8 activation. However, the effects of SP-D on the intrinsic pathway of apoptosis are not clearly understood.

(Hemp) Seeds, Δ-Tetrahydrocannabinol, and Potential Overdose.

(hemp) seeds are popular for their high nutrient content, and strict regulations are in place to limit the amount of potentially harmful phytocannabinoids, especially Δ-tetrahydrocannabinol (Δ-THC). In Canada, this limit is 10 μg of Δ-THC per gram of hemp seeds (10 ppm), and other jurisdictions in the world follow similar guidelines. We investigated three different brands of consumer-grade hemp seeds using four different procedures to extract phytocannabinoids, and quantified total Δ-THC and cannabidiol (CBD).

Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis.

Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD enzymes. Among the various heterocycles investigated, compound 23, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo.

A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents.

The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities.

A Conserved Residue, Tyrosine (Y) 84, in H5N1 Influenza A Virus NS1 Regulates IFN Signaling Responses to Enhance Viral Infection.

The non-structural protein, NS1, is a virulence factor encoded by influenza A viruses (IAVs). In this report, we provide evidence that the conserved residue, tyrosine (Y) 84, in a conserved putative SH2-binding domain in A/Duck/Hubei/2004/L-1 [H5N1] NS1 is critical for limiting an interferon (IFN) response to infection. A phenylalanine (F) substitution of this Y84 residue abolishes NS1-mediated downregulation of IFN-inducible STAT phosphorylation, and surface IFNAR1 expression.

Ultraviolet irradiation increases green fluorescence of dihydrorhodamine (DHR) 123: false-positive results for reactive oxygen species generation.

Dihydrorhodamine (DHR) 123 is a fluorophore commonly used for measuring reactive oxygen species (ROS), often after exposing cells to ultraviolet (UV) irradiation or oxidative burst inducers such as Phorbol 12-myristate 13-acetate (PMA). However, the negative effects of UV irradiation on oxidation of DHR123 itself to green fluorescence rhodamine (R) 123 under different experimental conditions (e.g.