Eravacycline, an antibacterial drug, repurposed for pancreatic cancer therapy: insights from a molecular-based deep learning model.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a serious threat to health, with limited effective therapeutic options, especially due to advanced stage at diagnosis and its inherent resistance to chemotherapy, making it one of the leading causes of cancer-related deaths worldwide. The lack of clear treatment directions underscores the urgent need for innovative approaches to address and manage this deadly condition. In this research, we repurpose drugs with potential anti-cancer activity using machine learning (ML). METHODS: We tackle the problem by using a neural network trained on drug-target interaction information enriched with drug-drug interaction information, which has not been used for anti-cancer drug repurposing before. We focus on eravacycline, an antibacterial drug, which was selected and evaluated to assess its anti-cancer effects. RESULTS: Eravacycline significantly inhibited the proliferation and migration of BxPC-3 cells and induced apoptosis. CONCLUSION: Our study highlights the potential of drug repurposing for cancer treatment using ML. Eravacycline showed promising results in inhibiting cancer cell proliferation, migration and inducing apoptosis in PDAC. These findings demonstrate that our developed ML drug repurposing models can be applied to a wide range of new oncology therapeutics, to identify potential anti-cancer agents. This highlights the potential and presents a promising approach for identifying new therapeutic options.

Cannabinoids' Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases.

Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases. The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases. To our knowledge, few reviews are devoted to cannabinoids' impact on modulating central and peripheral immunity in neurodegenerative diseases. The objective of this review is to provide the best possible information about the cannabinoid receptors and immuno-modulation features, peripheral immune modulation by cannabinoids, cannabinoid-based therapies for the treatment of neurological disorders, and the future development prospects of making cannabinoids versatile tools in the pursuit of effective drugs.

An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release.

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects. Angiotensin II activates the angiotensin 1 receptor and regulates neuroinflammation and cognition. Angiotensin receptor 1 blockers (ARBs) were shown to be neuroprotective and prevent cognitive decline. The present study aimed to elucidate the combined role of CBD and ARBs in the modulation of lipopolysaccharide (LPS)-induced glial inflammation. While LPS significantly enhanced nitric oxide synthesis vs. the control, telmisartan and CBD, when administered alone, attenuated this effect by 60% and 36%, respectively. Exposure of LPS-stimulated cells to both compounds resulted in the 95% inhibition of glial nitric oxide release (additive effect). A synergistic inhibitory effect on nitric oxide release was observed when cells were co-treated with losartan (5 µM) and CBD (5 µM) (by 80%) compared to exposure to each compound alone (by 22% and 26%, respectively). Telmisartan and CBD given alone increased TNFα levels by 60% and 40%, respectively. CBD and telmisartan, when given together, attenuated the LPS-induced increase in TNFα levels without statistical significance. LPS-induced IL-17 release was attenuated by CBD with or without telmisartan (by 75%) or telmisartan alone (by 60%). LPS-induced Interferon-γ release was attenuated by 80% when telmisartan was administered in the absence or presence of CBD. Anti-inflammatory effects were recorded when CBD was combined with the known anti-inflammatory agent dimethyl fumarate (DMF)/monomethyl fumarate (MMF). A synergistic inhibitory effect of CBD and MMF on glial release of nitric oxide (by 77%) was observed compared to cells exposed to MMF (by 35%) or CBD (by 12%) alone. Overall, this study highlights the potential of new combinations of CBD (5 µM) with losartan (5 µM) or MMF (1 µM) to synergistically attenuate glial NO synthesis. Additive effects on NO production were observed when telmisartan (5 µM) and CBD (5 µM) were administered together to glial cells.

The Fundamental Role of Lipids in Polymeric Nanoparticles: Dermal Delivery and Anti-Inflammatory Activity of Cannabidiol.

This report presents a nanoparticulate platform for cannabidiol (CBD) for topical treatment of inflammatory conditions. We have previously shown that stabilizing lipids improve the encapsulation of CBD in ethyl cellulose nanoparticles. In this study, we examined CBD release, skin permeation, and the capability of lipid-stabilized nanoparticles (LSNs) to suppress the release of IL-6 and IL-8. The nanoparticles were stabilized with cetyl alcohol (CA), stearic acid (SA), lauric acid (LA), and an SA/LA eutectic combination (SALA). LSN size and concentration were measured and characterized by differential scanning calorimetry (DSC), in vitro release of loaded CBD, and skin permeability. IL-6 and IL-8 secretions from TNF-α-induced HaCaT cells were monitored following different LSN treatments. CBD released from the LSNs in dispersion at increasing concentrations of polysorbate 80 showed non-linear solubilization, which was explained by recurrent precipitation. A significant high release of CBD in a cell culture medium was shown from SALA-stabilized nanoparticles. Skin permeation was >30% lower from SA-stabilized nanoparticles compared to the other LSNs. Investigation of the CBD-loaded LSNs' effect on the release of IL-6 and IL-8 from TNF-α-induced HaCaT cells showed that nanoparticles stabilized with CA, LA, or SALA were similarly effective in suppressing cytokine release. The applicability of the CBD-loaded LSNs to treat topical inflammatory conditions has been supported by their dermal permeation and release inhibition of pro-inflammatory cytokines.

Cannabis as a Source of Approved Drugs: A New Look at an Old Problem.

Cannabis plants have been used in medicine since ancient times. They are well known for their anti-diabetic, anti-inflammatory, neuroprotective, anti-cancer, anti-oxidative, anti-microbial, anti-viral, and anti-fungal activities. A growing body of evidence indicates that targeting the endocannabinoid system and various other receptors with cannabinoid compounds holds great promise for addressing multiple medical conditions. There are two distinct avenues in the development of cannabinoid-based drugs. The first involves creating treatments directly based on the components of the cannabis plant. The second involves a singular molecule strategy, in which specific phytocannabinoids or newly discovered cannabinoids with therapeutic promise are pinpointed and synthesized for future pharmaceutical development and validation. Although the therapeutic potential of cannabis is enormous, few cannabis-related approved drugs exist, and this avenue warrants further investigation. With this in mind, we review here the medicinal properties of cannabis, its phytochemicals, approved drugs of natural and synthetic origin, pitfalls on the way to the widespread clinical use of cannabis, and additional applications of cannabis-related products.

Cannabidiol-Loaded Lipid-Stabilized Nanoparticles Alleviate Psoriasis Severity in Mice: A New Approach for Improved Topical Drug Delivery.

Cannabidiol (CBD) is a promising natural agent for treating psoriasis. CBD activity is attributed to inhibition of NF-kB, IL-1ß, IL-6, and IL-17A. The present study evaluated the anti-psoriatic effect of cannabidiol in lipid-stabilized nanoparticles (LSNs) using an imiquimod (IMQ)-induced psoriasis model in mice. CBD-loaded LSNs were stabilized with three types of lipids, Cetyl alcohol (CA), Lauric acid (LA), and stearic-lauric acids (SALA), and were examined in-vitro using rat skin and in-vivo using the IMQ-model. LSNs loaded with coumarin-6 showed a localized penetration depth of about 100 µm into rat skin. The LSNs were assessed by the IMQ model accompanied by visual (psoriasis area severity index; PASI), histological, and pro-psoriatic IL-17A evaluations. Groups treated with CBD-loaded LSNs were compared to groups treated with CBD-containing emulsion, unloaded LSNs, and clobetasol propionate, and to an untreated group. CBD-loaded LSNs significantly reduced PASI scoring compared to the CBD emulsion, the unloaded LSNs, and the untreated group (negative controls). In addition, SALA- and CA-containing nanoparticles significantly inhibited IL-17A release, showing a differential response: SALA > CA > LA. The data confirms the effectiveness of CBD in psoriasis therapy and underscores LSNs as a promising platform for delivering CBD to the skin.

Prodrug-Based Targeting Approach for Inflammatory Bowel Diseases Therapy: Mechanistic Study of Phospholipid-Linker-Cyclosporine PLA2-Mediated Activation.

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A2 (PLA2) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA2 in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA2. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA2.

Medicinal Properties of Anchusa strigosa and Its Active Compounds.

Anchusa strigosa is a widespread weed in Greece, Syria, Turkey, Lebanon, Israel, Jordan, and Iran. The purpose of this study was to identify the phytochemicals of Anchusa strigose and estimate the pro-wound healing (pro-WH) and antimicrobial activities of its active compounds. An identification of volatile compounds was performed by GC/MS analysis; HPLC, LC-ESI-MS, and MALDI-TOF-MS were also applied. Our results demonstrate that two specific combinations of compounds from A. strigosa extract significantly enhanced WH (p < 0.001). Several flavonoids of the plant extract, including quercetin 3-O-rutinoside, kaempferol, kaempferol 3-O-ß-rhamnopyranosyl(1→6)-ß-glucopyranoside, and kaempferol 3-O-α-rhamnopyranosyl(1→6)-ß-galactopyranoside, were effective against drug-resistant microorganisms. In addition, all the above-mentioned compounds had antibiofilm activity against Escherichia coli and Salmonella enteritidis.

Computational Simulations to Guide Enzyme-Mediated Prodrug Activation.

Prodrugs are designed to improve pharmaceutical/biopharmaceutical characteristics, pharmacokinetic/pharmacodynamic properties, site-specificity, and more. A crucial step in successful prodrug is its activation, which releases the active parent drug, exerting a therapeutic effect. Prodrug activation can be based on oxidation/reduction processes, or through enzyme-mediated hydrolysis, from oxidoreductases (i.e., Cytochrome P450) to hydrolytic enzymes (i.e., carboxylesterase). This study provides an overview of the novel in silico methods for the optimization of enzyme-mediated prodrug activation. Computational methods simulating enzyme-substrate binding can be simpler like molecular docking, or more complex, such as quantum mechanics (QM), molecular mechanics (MM), and free energy perturbation (FEP) methods such as molecular dynamics (MD). Examples for MD simulations used for elucidating the mechanism of prodrug (losartan, paclitaxel derivatives) metabolism via CYP450 enzyme are presented, as well as an MD simulation for optimizing linker length in phospholipid-based prodrugs. Molecular docking investigating quinazolinone prodrugs as substrates for alkaline phosphatase is also presented, as well as QM and MD simulations used for optimal fit of different prodrugs within the human carboxylesterase 1 catalytical site. Overall, high quality computational simulations may show good agreement with experimental results, and should be used early in the prodrug development process.

Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics.

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging.

Lipidic prodrug approach for improved oral drug delivery and therapy.

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.

Molecular Modeling-Guided Design of Phospholipid-Based Prodrugs.

The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood-brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation. The PL-prodrug design includes various structural modalities-different conjugation strategies and/or the use of linkers between the PL and the drug moiety, which considerably influence the prodrug characteristics and the consequent effects. In this article, we describe how molecular modeling can guide the structural design of PL-based prodrugs. Computational simulations can predict the extent of phospholipase A2 (PLA2)-mediated activation, and facilitate prodrug development. Several computational methods have been used to facilitate the design of the pro-drugs, which will be reviewed here, including molecular docking, the free energy perturbation method, molecular dynamics simulations, and free density functional theory. Altogether, the studies described in this article indicate that computational simulation-guided PL-based prodrug molecular design correlates well with the experimental results, allowing for more mechanistic and less empirical development. In the future, the use of molecular modeling techniques to predict the activity of PL-prodrugs should be used earlier in the development process.

Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease.

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA2, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA2 to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA2, and the optimal linker will enable maximal PLA2-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA2 transition state binding free energy of the prodrug molecule (∆∆Gtr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA2-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.

The role of pre-symbiotic auxin signaling in ectendomycorrhiza formation between the desert truffle Terfezia boudieri and Helianthemum sessiliflorum.

The ectendomycorrhizal fungus Terfezia boudieri is known to secrete auxin. While some of the effects of fungal auxin on the plant root system have been described, a comprehensive understanding is still lacking. A dual culture system to study pre mycorrhizal signal exchange revealed previously unrecognized root-fungus interaction mediated by the fungal auxin. The secreted fungal auxin induced negative taproot gravitropism, attenuated taproot growth rate, and inhibited initial host development. Auxin also induced expression of Arabidopsis carriers AUX1 and PIN1, both of which are involved in the gravitropic response. Exogenous application of auxin led to a root phenotype, which fully mimicked that induced by ectomycorrhizal fungi. Co-cultivation of Arabidopsis auxin receptor mutants tir1-1, tir1-1 afb2-3, tir1-1 afb1-3 afb2-3, and tir1-1 afb2-3 afb3-4 with Terfezia confirmed that auxin induces the observed root phenotype. The finding that auxin both induces taproot deviation from the gravity axis and coordinates growth rate is new. We propose a model in which the fungal auxin induces horizontal root development, as well as the coordination of growth rates between partners, along with the known auxin effect on lateral root induction that increases the availability of accessible sites for colonization at the soil plane of fungal spore abundance. Thus, the newly observed responses described here of the root to Terfezia contribute to a successful encounter between symbionts.

Effect of medicinal plants on wound healing.

In the United States alone, chronic wounds affect 6.5 million patients. It is expected that the number of chronic wounds will increase worldwide due to the increase in age-related conditions and pathologies such as diabetes, obesity, and cardiovascular diseases. An estimated excess of US$25 billion is spent annually on treatment of chronic wounds, and the burden is rapidly growing due to increasing healthcare costs, an aging population, and a sharp rise in the incidence of diabetes and obesity worldwide. While current therapeutic agents have generally inadequate efficacy and number of serious adverse effects, the medicinal plants have been used in medicine since ancient times and are well known for their abilities to promote wound healing and prevent infection without grave side effects. Thus, herbal therapy may be an alternative strategy for treatment of wounds. The purpose of this review is to provide the verified data on the medicinal plants of the world flora with wound healing activity including the biologically active substances belonging to these herbal preparations and describe in detail the various cellular and molecular mechanisms of their actions.

Modern prodrug design for targeted oral drug delivery.

The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

Guidelines and epilepsy practice: Antiseizure medication initiation following an unprovoked first seizure in adults.

OBJECTIVES: Adherence rate to evidence-based clinical practice guidelines is relatively low and the impact of guidelines on clinical practice in epilepsy is variable. The 2015 practice guideline on the management of an unprovoked first seizure in adults specifies clinical variables associated with increased risk of seizure recurrence and the impact of immediate antiseizure medication (ASM) treatment on seizure outcome. We aimed to evaluate the impact of the evidence-based guideline for the management of an unprovoked first seizure in adults on clinical practice in our adult neurology department. METHODS: We retrospectively reviewed the computerized database of 169 adult patients admitted to the adult neurology department at Shamir-Assaf Harofeh Medical Center following a first unprovoked seizure between October 2011 and October 2018. RESULTS: ASMs were initiated in 86% of patients with a first unprovoked seizure pre- and in all patients admitted post- guideline publication. Monotherapy and use of old generation ASMs were more common in both groups and a combination of old- and new generation ASMs - among the pre-guideline group. The pre-guideline decision to initiate ASM treatment was significantly influenced only by epileptiform discharges in the electroencephalogram (EEG). DISCUSSION: This is the first study to evaluate the impact of the 2015 practice guideline on the initiation of ASM treatment after a first unprovoked seizure in adults. Further studies are needed to assess the global contribution of the guideline to clinical practice and its impact on patient outcomes.

Selected cannabis cultivars modulate glial activation: in vitro and in vivo studies.

INTRODUCTION: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by neuroinflammation, demyelination and axonal loss. Cannabis, an immunomodulating agent, is known for its ability to treat MS effectively. However, due to variations in the profile of secondary metabolites, especially cannabinoids, among cannabis cultivars, the effectiveness of cannabis treatment can vary, with significant variability in the effects on different biological parameters. For screening available cultivars, cellular in vitro as well as pre-clinical in vivo assays, are required to evaluate the effectiveness of the wide range of chemical variability that exists in cannabis cultivars. This study evaluated comparatively three chemically diverse cannabis cultivars, CN2, CN4 and CN6, containing different ratios of phytocannabinoids, for their neuroinflammatory activity in MS model. MATERIALS AND METHODS: In vitro experiments were performed with lipopolysaccharide (LPS)-activated BV-2 microglia and primary glial cells to evaluate the effect of different cannabis cultivars on nitric oxide (NO) and inflammatory cytokines, as well as inducible nitric oxide synthase (iNOS) protein expression. An in vivo experiment using the experimental autoimmune encephalomyelitis (EAE) MS model was conducted using Myelin oligodendrocyte glycoprotein (MOG) as the activating peptide. The cannabis extracts of the cultivars CN2, CN4, CN6 or vehicle, were intraperitoneally injected with clinical scores given based on observed symptoms over the course of study. At the end of the experiment, the mice were sacrificed, and splenocyte cytokine secretion was measured using ELISA. Lumbar sections from the spinal cord of treated MS mice were evaluated for microglia, astrocytes and CD4+ cells. RESULTS: Extracts of the CN2 cultivar contained tetrahydrocannabinolic acid (THCA) and tetrahydrocannabinol (THC) without cannabidiol (CBD), and a number of monoterpenes. CN4 contained cannabidiolic acid (CBDA) and tetrahydrocannabidiolic acid (THCA), with significant amounts of THC: CBD in a 1:1 ratio, as well as sesquiterpenes and some monoterpenes; and CN6 contained primarily CBDA and THCA, as well as THC and CBD in a 2:1 ratio, with some sesquiterpenes and no monoterpenes. All extracts were not cytotoxic in glial cells up to 50 µg/ml. Dose dependent inhibition of LPS-induced BV2 as well as primary microglial NO secretion confirmed the anti-inflammatory and anti-oxidative activity of the three cannabis cultivars. CN2 but not CN4 reduced both astrocytosis and microglial activation in lumbar sections of EAE mice. In contrast, CN4 but not CN2 significantly decreased the secretion of TNFα and Interferon γ (IFNγ) in primary splenocytes extracted from EAE mice. CONCLUSIONS: While both cannabis cultivars, CN2 and CN4, significantly reduced the severity of the clinical signs throughout the course of the study, they modulated different inflammatory mediators and pathways, probably due to differences in their phytocannabinoid composition. This demonstrates the differential potential of cannabis cultivars differing in chemotype to regulate neuroinflammation and their potential to treat MS.

Root-secreted nucleosides: signaling chemoattractants of rhizosphere bacteria.

The rhizosphere is a complex ecosystem, consisting of a narrow soil zone influenced by plant roots and inhabited by soil-borne microorganisms. Plants actively shape the rhizosphere microbiome through root exudates. Some metabolites are signaling molecules specifically functioning as chemoattractants rather than nutrients. These elusive signaling molecules have been sought for several decades, and yet little progress has been made. Root-secreted nucleosides and deoxynucleosides were detected in exudates of various plants by targeted ultra-performance liquid chromatography-mass spectrometry/mass spectrometry. Rhizobacteria were isolated from the roots of Helianthemum sessiliflorum carrying the mycorrhizal desert truffle Terfezia boudieri. Chemotaxis was determined by a glass capillary assay or plate assays on semisolid agar and through a soil plate assay. Nucleosides were identified in root exudates of plants that inhabit diverse ecological niches. Nucleosides induced positive chemotaxis in plant beneficial bacteria Bacillus pumilus, Bacillus subtilis, Pseudomonas turukhanskensis spp., Serratia marcescens, and the pathogenic rhizobacterium Xanthomonas campestris and E coli. In a soil plate assay, nucleosides diffused to substantial distances and evoked chemotaxis under conditions as close as possible to natural environments. This study implies that root-secreted nucleosides are involved in the assembly of the rhizosphere bacterial community by inducing chemotaxis toward plant roots. In animals, nucleoside secretion known as "purinergic signaling" is involved in communication between cells, physiological processes, diseases, phagocytic cell migration, and bacterial activity. The coliform bacterium E. coli that inhabits the lower intestine of warm-blooded organisms also attracted to nucleosides, implying that nucleosides may serve as a common signal for bacterial species inhabiting distinct habitats. Taken together, all these may indicate that chemotaxis signaling by nucleosides is a conserved universal mechanism that encompasses living kingdoms and environments and should be given further attention in plant rhizosphere microbiome research.

Inhibition of cancer growth and induction of apoptosis by BGP-13 and BGP-15, new calcipotriene-derived vitamin D3 analogs, in-vitro and in-vivo studies.

One of the most innovative approaches to the treatment of cancer entails the use of 1α,25-dihydroxyvitamin D3 (calcitriol) analogs to inhibit cancer cell growth. We demonstrate here that BGP-13, a new calcipotriene-based 1α,25-dihydroxyvitamin D3 analog that we synthesized in our laboratory, inhibits the growth of prostate cancer (LNCaP), breast cancer (MCF-7), and colon cancer (HT-29) cell lines. Moreover, we also show that BGP-13 causes cells both to accumulate in G0-G1 and to activate caspase-3 and undergo apoptosis. In addition, we observed elevated vitamin D receptor (VDR) mRNA and protein levels in both LNCaP and MCF-7 cells following the exposure of the two cell lines to BGP-13. Importantly, we found that both the new analog BGP-13 and also BGP-15, another calcipotriene-based analog we synthesized previously and about which we published recently, inhibit the growth of HT-29 tumor xenografts in nude mice.