Effect of saline irrigation and plant-based biostimulant application on fiber hemp (Cannabis sativa L.) growth and phytocannabinoid composition.

Phytocannabinoids represent the hallmark of the secondary metabolism of Cannabis sativa. The content of major phytocannabinoids is closely related to genetic variation as well as abiotic elicitors such as temperature, drought, and saline stress. The present study aims to evaluate hemp response to saline irrigation supplied as NaCl solutions with an electrical conductivity (EC) of 2.0, 4.0, and 6.0 dS m-1 (S1, S2, and S3, respectively) compared to a tap water control (S0). In addition, the potential beneficial effect of a plant-based biostimulant (a legume protein hydrolysate) in mitigating the detrimental effects of saline irrigation on crop growth and phytocannabinoid composition was investigated. Sodium chloride saline irrigation significantly reduced biomass production only with S2 and S3 treatments, in accordance with an induced nutrient imbalance, as evidenced by the mineral profile of leaves. Multivariate analysis revealed that the phytocannabinoid composition, both in inflorescences and leaves, was affected by the salinity level of the irrigation water. Interestingly, higher salinity levels (S2-S3) resulted in the predominance of cannabidiol (CBD), compared to lower salinity ones (S0-S1). Plant growth and nitrogen uptake were significantly increased by the biostimulant application, with significant mitigation of the detrimental effect of saline irrigations.

Glucose Uptake-Stimulating Metabolites from Aerial Parts of Centaurea sicula.

A comprehensive phytochemical investigation of aerial parts obtained from Centaurea sicula L. led to the isolation of 14 terpenoids (1-14) and nine polyphenols (15-23). The sesquiterpenoid group (1-11) included three structural families, namely, elemanolides (1-6), eudesmanolides (7 and 8), and germacranolides (9-11) with four unreported secondary metabolites (5-8), whose structure has been determined by extensive spectroscopic analysis, including 1D/2D NMR, HR-MS, and chemical conversion. Moreover, an unprecedented alkaloid, named siculamide (24), was structurally characterized, and a possible biogenetic origin was postulated. Inspired by the traditional use of the plant and in the frame of ongoing research on compounds with potential activity on metabolic syndrome, all the isolated compounds were evaluated for their stimulation of glucose uptake, disclosing remarkable activity for dihydrocnicin (10) and the lignan salicifoliol (15).

Pulicaria incisa (Lam.) DC. as a Potential Source of Antioxidant, Antibacterial, and Anti-Enzymatic Bioactive Molecules: Phytochemical Constituents, In Vitro and In Silico Pharmacological Analysis.

Plants with medicinal benefits are a crucial source of compounds for developing drugs. This study was designed to determine the chemical composition, antibacterial, antibiofilm, antioxidant, and anti-enzymatic activities of Pulicaria incisa (Lam.) DC. We also reported the molecular interaction between identified molecules and several receptors associated with antimicrobial and antibiofilm activities. A total of seventeen and thirteen compounds were identified in aqueous and methanolic extracts of P. incisa, respectively. The methanolic extract yielded a higher total content of polyphenols and flavonoids of about 84.80 ± 2.8 mg GAE/g and 28.30 ± 1.2 mg QE/g, respectively. Significant antibacterial activity was recorded for both extracts, with minimum inhibitory concentration (MIC) values ranging from 30 to 36 µg/mL, and the result was comparable to the reference antibiotic control. Antibiofilm assays revealed that both extracts were able to reduce the attachment of bacterial cells to 96-well plates, but the highest antibiofilm activity was recorded against Staphylococcus aureus. The methanolic extract also showed anti-enzymatic potency and high antioxidant activity, as demonstrated by all assays used, including DPPH, FRAP, and ABTS. These results were further validated by in silico approaches, particularly the molecular interaction of the identified compounds with the targeted receptors. These findings present P. incisa as a significant source of antibacterial, antibiofilm, antioxidant, and anti-enzymatic molecules.

Phytochemical Constituents and Biological Activity of Wild and Cultivated Rosmarinus officinalis Hydroalcoholic Extracts.

Rosmarinus officinalis L. is an aromatic evergreen plant from the Lamiaceae family. The purpose of this study was to compare the chemical profile and bioactivities of hydroalcoholic extracts derived from wild and cultivated R. officinalis. The chemical composition of the extracts was evaluated via LC-MS analysis, which revealed the presence of a wide range of phenolic compounds, including flavonoids, phenolic and terpenes. Both extracts showed a similar interesting antioxidant activity, probably related to their content of phenol and flavonoids. The analysis of anti-acetylcholinesterase (AChE), anti-butyrylcholinesterase (BChE), and anti-α-amylase activities showed analogous inhibition, except for AChE, in which the wild type was more active than the cultivated one. Finally, in vitro studies were performed using the J774A.1 murine macrophage cell line, to characterize the anti-inflammatory and the antioxidant effects of the extracts. As expected, pretreatment with the extracts significantly reduced the production proinflammatory cytokines and ROS through modulation of the nitric oxide pathway and the mitochondrial activity. Importantly, it is observed that the anti-inflammatory effect of the extracts was explicated through the inhibition of NF-kB and its downstream mediator COX-2. Collectively, these results demonstrated that these extracts could represent a starting point for developing novel therapeutic strategies for the treatment of inflammation-based diseases. Moreover, since no significant changes were observed in terms of composition and activity, both wild and cultivated R. officinalis extracts can be recommended for food and pharmaceutical purposes.

Ircinia ramosa Sponge Extract (iSP) Induces Apoptosis in Human Melanoma Cells and Inhibits Melanoma Cell Migration and Invasiveness.

Marine compounds represent a varied source of new drugs with potential anticancer effects. Among these, sponges, including those belonging to the Irciniidae family, have been demonstrated to exert cytotoxic effects on different human cancer cells. Here, we investigated, for the first time, the therapeutic effect of an extract (referred as iSP) from the sponge, Ircinia ramosa (Porifera, Dictyoceratida, and Irciniidae), on A375 human melanoma cells. We found that iSP impaired A375 melanoma cells proliferation, induced cell death through caspase-dependent apoptosis and arrested cells in the G1 phase of the cell cycle, as demonstrated via both flow cytometry and qPCR analysis. The proapoptotic effect of iSP is associated with increased ROS production and mitochondrial modulation, as observed by using DCF-DHA and mitochondrial probes. In addition, we performed wound healing, invasion and clonogenic assays and found that iSP was able to restrain A375 migration, invasion and clonogenicity. Importantly, we observed that an iSP treatment modulated the expression of the EMT-associated epithelial markers, E-CAD and N-CAD, unveiling the mechanism underlying the effect of iSP in modulating A375 migration and invasion. Collectively, this study provides the first evidence to support the role of Ircinia ramosa sponge extracts as a potential therapeutic resource for the treatment of human melanoma.

Cynaropicrin disrupts tubulin and c-Myc-related signaling and induces parthanatos-type cell death in multiple myeloma.

The majority of blood malignancies is incurable and has unforeseeable remitting-relapsing paths in response to different treatments. Cynaropicrin, a natural sesquiterpene lactone from the edible parts of the artichoke plant, has gained increased attention as a chemotherapeutic agent. In this study, we investigated the effects of cynaropicrin against multiple myeloma (MM) cells in vitro and assessed its in vivo effectiveness in a xenograft tumor zebrafish model. We showed that cynaropicrin exerted potent cytotoxicity against a panel of nine MM cell lines and two leukemia cell lines with AMO1 being the most sensitive cell line (IC50 = 1.8 ± 0.3 µM). Cynaropicrin (0.8, 1.9, 3.6 µM) dose-dependently reduced c-Myc expression and transcriptional activity in AMO1 cells that was associated with significant downregulation of STAT3, AKT, and ERK1/2. Cell cycle analysis showed that cynaropicrin treatment arrested AMO1 cells in the G2M phase along with an increase in the sub-G0G1 phase after 24 h. With prolonged treatment times, cells accumulated more in the sub-G0G1 phase, implying cell death. Using confocal microscopy, we revealed that cynaropicrin disrupted the microtubule network in U2OS cells stably expressing α-tubulin-GFP. Furthermore, we revealed that cynaropicrin promoted DNA damage in AMO1 cells leading to PAR polymer production by PARP1 hyperactivation, resulting in AIF translocation from the mitochondria to the nucleus and subsequently to a novel form of cell death, parthanatos. Finally, we demonstrated that cynaropicrin (5, 10 µM) significantly reduced tumor growth in a T-cell acute lymphoblastic leukemia (T-ALL) xenograft zebrafish model. Taken together, these results demonstrate that cynaropicrin causes potent inhibition of hematopoietic tumor cells in vitro and in vivo.

Chemical Identification of Secondary Metabolites from Rhizospheric Actinomycetes Using LC-MS Analysis: In Silico Antifungal Evaluation and Growth-Promoting Effects.

The rhizosphere is a rich source of actinomycetes which can produce several potential biologically active secondary metabolites. The principal goal for this research is to extract, purify, and characterize the bioactive secondary metabolites produced by three different strains of actinomycetes isolated from the rhizosphere of rosemary, black locust, and olive. The plant growth-promoting effect (PGPE) of the studied strains of actinomycetes on Ocimum basilicum L. (basil) and the disease-control effect on necrotic stem lesions of "black leg" caused by Fusarium tabacinum on basil were evaluated in silico. The cell-free culture filtrates from the studied actinomycetes isolates were evaluated in vitro for their antimicrobial activity against some common phytopathogens. The secondary metabolites obtained from the cell-free culture filtrates have been chemically characterized using high-resolution electrospray ionization of liquid-chromatography/mass-spectrometric detection (ESI-(HR)Orbitrap-MS). Results of the in silico trial showed that all studied isolates demonstrated PGPE on basil seedlings, improved some eco-physiological characteristics, and reduced the disease incidence of F. tabacinum. The extracted metabolites from the studied actinomycetes demonstrated antimicrobial activity in a Petri-plates assay. The chemical analysis revealed the presence of 20 different components. This research emphasizes how valuable the examined isolates are for producing bioactive compounds, indicating their putative antimicrobial activity and their potential employment as fungal biocontrol agents. In particular, the obtained results revealed the possibility of green synthesis of some important secondary metabolites, such as N-Acetyl-l-histidinol, Rhizocticin A, and Eponemycin, from actinomycetes. The bioactive metabolites may be successively used to develop novel bio-formulations for both crop protection and/or PGPE.

Evaluations of Andrographolide-Rich Fractions of Andrographis paniculata with Enhanced Potential Antioxidant, Anticancer, Antihypertensive, and Anti-Inflammatory Activities.

Andrographis paniculata is widely used as a traditional medicine in Asian countries. It has been classified as a safe and non-toxic medicine by traditional Chinese medicine. The investigation of the biological activities of A. paniculata is still focused on the crude extract and isolation of its main active compound, andrographolide, and its derivatives. However, the use of andrographolide alone has been shown to exacerbate unwanted effects. This highlights the importance of developing a fraction of A. paniculata with enhanced efficacy as an herbal-based medicine. In this study, the extraction and fractionation of A. paniculata, followed by quantitative analysis using high-performance liquid chromatography coupled with a DAD detector, were established to quantify the andrographolide and its derivative in each fraction. Biological activities, such as antioxidant, anticancer, antihypertensive, and anti-inflammatory activities, were evaluated to study their correlations with the quantification of active substances of A. paniculata extract and its fractions. The 50% methanolic fraction of A. paniculata exhibited the best cytotoxic activities against CACO-2 cells, as well as the best anti-inflammatory and antihypertensive activities compared to other extracts. The 50% methanolic fraction also displayed the highest quantification of its main active compound, andrographolide, and its derivatives, 14-deoxy-11,12-didehydroandrographolide, neoandrographolide, and andrograpanin, among others.

Chamomile essential oils exert anti-inflammatory effects involving human and murine macrophages: Evidence to support a therapeutic action.

ETHNOPHARMACOLOGICAL RELEVANCE: Chamomile (M. chamomilla L.) is an herbaceous plant from family Astereaceae, that has a long history of use in traditional medicine. It has been used as herbal remedies for thousands of years to treat several diseases, including infections, neuropsychiatric, respiratory, gastrointestinal, and liver disorders. Chronic inflammation is involved in the pathogenesis of most infectious and non-infectious diseases and macrophages are considered the major cellular players that drive disease initiation and maintenance. AIM OF THE STUDY: The aim of this study was to evaluate the variation in the chemical profile of the essential oil of M. chamomilla plants collected in three experimental field sites in the Molise region. Additionally, we evaluated the pharmacological mechanism behind the anti-inflammatory effect of M. chamomilla essential oils. MATERIAL AND METHODS: Three essential oils (called GC1, GC2 and GC3) were extracted from aerial parts of M. chamomilla by hydrodistillation and chemical composition was analyzed by gas chromatography-mass spectrometry (GC-MS). The essential oils were tested for their ability to modulate pro-inflammatory murine macrophages and human peripheral blood mononuclear cells (PBMCs) functions. RESULTS: The chemical analysis of the samples revealed the presence of a high content of the oxygenated sesquiterpenes that represented more than the half of the entire oils. GC1, GC2 and GC3 essential oils significantly attenuated LPS/IFN-γ-induced inflammation by reducing M1 polarization. In details, they showed significant anti-inflammatory property by inhibiting NO, TNF-α and IL-6 production. These effects were correlated to a suppression of LPS-mediated p65 activation, the critical transactivation subunit for NF-κB transcription factor. Oxidative stress may trigger macrophages activation and elicit strong immune responses. Our study demonstrated that GC1, GC2 and GC3 were highly effective at increasing GCL and HMOX-1 anti-oxidant enzymes expression leading to the rapid scavenging of ROS. The antioxidant activity of these oils was explained throughout the activation of NRF2 signaling pathway. Next, we demonstrated that essential oils were able to reduce CD4+ T cell activation which are also involved in inflammatory processes. CONCLUSIONS: Our data describe for the first time that chamomile essential oils exerted their anti-inflammatory and antioxidant activity by modulating macrophages and CD4+ T cells-mediate immune response.

Prasterone in the treatment of mild to moderate urge incontinence: an observational study.

OBJECTIVE: To assess the effects of prasterone compared with hyaluronic acid on symptoms of mild to moderate urinary urgency in women with genitourinary syndrome of menopause. METHODS: This is an observational prospective cohort study. A total of 58 postmenopausal women were enrolled (from December 2019 to May 2021). Overactive Bladder Screener questionnaire, Patient Global Impression of Improvement questionnaire, International Consultation on Incontinence Questionnaire-Short Form, and International Quality of Life questionnaire were used. RESULTS: Fifty-eight women, 29 (50%) and 29 (50%), were treated with prasterone and hyaluronic acid for 12 weeks, respectively. At the end of the study, 26 (89.7%) versus 3 (10.3%) women reported an improvement (Patient Global Impression of Improvement score ≤3) of the symptoms in the prasterone versus hyaluronic acid group. According to the International Consultation on Incontinence Questionnaire-Short Form, no statistically significant difference was recorded before treatment between the prasterone and hyaluronic acid groups (median, 12 [6-12] vs 11 [8-12]; P = 0.8). Conversely, a statistically significant difference was recorded after treatment between the two groups (median, 8 [5-11] vs 10 [8-11]; P = 0.03). According to the International Quality of Life, a statistically significantly lower median score was recorded in the prasterone compared with the hyaluronic acid group, before (73 [interquartile range {IQR}, 55-81] vs 89 [IQR, 67-94]; P < 0.01) and after (78 [IQR, 65-86] vs 87 [IQR, 72-99]; P = 0.04) treatment. CONCLUSIONS: The current observational study supports the hypothesis that prasterone might improve the severity of urinary urge incontinence in this set of women. However, these results need to be confirmed in further studies with a controlled design and a larger population.

Guaiane-rich phytochemical profile of Centaurea kotschyi subsp. persica (Boiss.) Wagenitz and identification of hypoglycaemic metabolites.

Phytochemical investigation of the aerial parts obtained from the Turkish plant Centaurea kotschyi subsp. persica led to the isolation of nine sesquiterpene lactones belonging to the guaiane class, including the undescribed kotschyols A and B, a monoterpene lactone (daphnauranin E), four known lignans (matairesinol, matairesinoside, arctiin and arctigenin) and an undescribed dihydrobenzofuran neolignan (4-O-glucosylcrataegifin A). The structures of these compounds were defined by spectroscopic analysis, including ECD and 1D/2D NMR, and chemical conversion. Spurred from the traditional use of C. kotschyi subsp. persica and previous reports on the activity of its extracts, the isolated compounds were evaluated for their hypoglycaemic activity disclosing the bioactive components.

Inhibitory effects of cynaropicrin on human melanoma progression by targeting MAPK, NF-κB, and Nrf-2 signaling pathways in vitro.

Malignant melanoma is the deadliest skin cancer, due to its propensity to metastasize. MAPKs and NF-κB pathways are constitutively activated in melanoma and promote cell proliferation, cell invasion, metastasis formation, and resistance to therapeutic regimens. Thus, they represent potential targets for melanoma prevention and treatment. Phytochemicals are gaining considerable attention for the management of melanoma because of their several cellular and molecular targets. A screening of a small library of sesquiterpenes lactones selected cynaropicrin, isolated from the aerial parts of Centaurea drabifolia subsp. detonsa, for its potential anticancer effect against melanoma cells. Treatment of human melanoma cells A375 with cynaropicrin resulted in inhibition of cell proliferation and induction of caspase-3-dependent apoptosis. Furthermore, cynaropicrin reduced several cellular malignant features such migration, invasion, and colonies formation through the inhibition of ERK1/2 and NF-κB activity. Cynaropicrin was able to reduce intracellular reactive oxygen species generation, which are involved in all the stages of carcinogenesis. Indeed, cynaropicrin increased the expression of several antioxidant genes, such as glutamate-cysteine ligase and heme oxygenase-1, by promoting the activation of the transcription factor Nrf-2. In conclusion, our results individuate cynaropicrin as a potential adjuvant chemotherapeutic agent for melanoma by targeting several protumorigenic signaling pathways.

Glycosylated Phenols and an Unprecedented Diacid from the Saudi Plant Cissus rotundifolia.

Bioassay-guided investigation of the Saudi medicinal and edible plant Cissus rotundifolia yielded seven metabolites, including the new sucrose diester cissuxinoside (1) and the unprecedented cissoic acid (2), belonging to unusual classes of secondary metabolites. Their chemical structures were elucidated through a combination of HR-MS and NMR data. The absolute configuration of cissoic acid was assigned by comparison of experimental and TDDFT-calculated electronic circular dichroism spectra. In addition, three rare C-glycosyl flavones (3-5) were fully characterized, and for 3 and 4 NMR data are reported here for the first time. This study identified 1-O-(4-coumaroyl)-ß-d-glucopyranose (7) as the main compound responsible for the glucose uptake stimulation effect exerted by the extract.

Effect of Immunomodulatory Supplements Based on Echinacea Angustifolia and Echinacea Purpurea on the Posttreatment Relapse Incidence of Genital Condylomatosis: A Prospective Randomized Study.

Introduction. HPV infection is a highly infectious disease; about 65% of partners of individuals with genital warts will develop genital condylomatosis. Only in 20-30% it regresses spontaneously and relapse rates range deeply (9-80%). Echinacea extracts possess antiviral and immunomodulator activities. The aim of this study was to evaluate the efficacy of the therapy, using a formulation based on HPVADL18® (on dry extracts of 200 mg Echinacea Purpurea (EP) roots plus E. Angustifolia (EA)), on the posttreatment relapse incidence of genital condylomatosis. Materials and Methods. It is a prospective single-arm study. Patients with a satisfactory and positive vulvoscopy, colposcopy, or peniscopy for genital condylomatosis were divided into two random groups and subjected to destructive therapy with Co2 Laser. Group A (N=64) immediately after the laser therapy started a 4-month treatment with oral HPVADL18®; Group B (N=61) did not undergo any additional therapy. Patients were subjected to a follow-up after 1, 6, and 12 months. Differences in relapse incidence between the two groups during follow-up controls were evaluated by χ2-test; the groups were stratified by age, gender, and condylomatosis extension degree. Results and Discussion. Gender, age, and condyloma lesions' extension degree showed no statistically significant differences between the two trial groups. The relapse incidence differs statistically between the two studied groups and progressively decreases during the 12 months after treatment in both groups. Statistically significant reduction of relapse rates has been shown in Group A in patients over 25 years old. This difference is significant for both men and women. The relapse incidence is superior in case of extended condylomatosis. Conclusions. In conclusion, the presence of a latent infection causes condylomatosis relapse; in order to reduce the relapse risk an induction of a protective immune response seems to be essential to allow rapid viral clearance from genital areas surrounding lesion and treatment zones. Echinacea promotes this process. EP and EA dry root extracts seem to be a valid adjuvant therapy in reducing relapse incidence of lesions in patients treated for genital condylomatosis.

Detailed Phytochemical Characterization of Bergamot Polyphenolic Fraction (BPF) by UPLC-DAD-MS and LC-NMR.

Bergamot ( Citrus bergamia) is cultivated in Southern Italy almost exclusively to produce the prized essential oil, a top note in several perfumes. The juice of bergamot, until recently poorly studied, is the object of a growing scientific interest due to its claimed activity to treat metabolic syndrome. The aim of this investigation was a detailed characterization of bergamot juice polyphenolic fraction (BPF) based on a UPLC-DAD-MS analysis complemented by preparative chromatographic separations, followed by NMR characterization of the isolated compounds. The combination of these techniques efficiently covered different classes of secondary metabolites, leading to the identification of 39 components, several of which had never been reported from bergamot. One of them, bergamjuicin (35), is a new flavanone glycoside, whose structure has been determined by MS and NMR techniques. The reported results could provide a guide for future routine analyses of BPF, a material of great nutraceutical and industrial interest.

Dual HIV-1 reverse transcriptase and integrase inhibitors from Limonium morisianum Arrigoni, an endemic species of Sardinia (Italy).

During our search for potential templates of HIV-1 reverse transcriptase (RT) and integrase (IN) dual inhibitors, the methanolic extract obtained from aerial parts of Limonium morisianum was investigated. Repeated bioassay-guided chromatographic purifications led to the isolation of the following secondary metabolites: myricetin, myricetin 3-O-rutinoside, myricetin-3-O-(6″-O-galloyl)-ß-d-galactopyranoside, (-)-epigallocatechin 3-O-gallate, tryptamine, ferulic and phloretic acids. The isolated compounds were tested on both HIV-1 RT-associated RNase H and IN activities. Interestingly, (-)-epigallocatechin-3-O-gallate and myricetin-3-O-(6″-O-galloyl)-ß-d-galactopyranoside potently inhibited both enzyme activities with IC50 values ranging from 0.21 to 10.9 µM. Differently, tryptamine and ferulic acid exhibited a significant inhibition only on the IN strand transfer reaction, showing a selectivity for this viral enzyme. Taken together these results strongly support the potential of this plant as a valuable anti HIV-1 drugs source worthy of further investigations.

Cardioprotective Effects of Nanoemulsions Loaded with Anti-Inflammatory Nutraceuticals against Doxorubicin-Induced Cardiotoxicity.

Doxorubicin is a highly active antineoplastic agent, but its clinical use is limited because of its cardiotoxicity. Although nutraceuticals endowed with anti-inflammatory properties exert cardioprotective activity, their bioavailability and stability are inconsistent. In an attempt to address this issue, we evaluated whether bioavailable nanoemulsions loaded with nutraceuticals (curcumin and fresh and dry tomato extracts rich in lycopene) protect cardiomyoblasts (H9C2 cells) from doxorubicin-induced toxicity. Nanoemulsions were produced with a high-pressure homogenizer. H9C2 cells were incubated with nanoemulsions loaded with different nutraceuticals alone or in combination with doxorubicin. Cell viability was evaluated with a modified MTT method. The levels of the lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-2-butanone (4-HNA), and of the cardiotoxic-related interleukins IL-6, IL-8, IL-1ß and IL-10, tumor necrosis factor-alpha (TNF-α), and nitric oxide were analyzed in cardiomyoblasts. The hydrodynamic size of nanoemulsions was around 100 nm. Cell viability enhancement was 35⁻40% higher in cardiomyoblasts treated with nanoemulsion + doxorubicin than in cardiomyoblasts treated with doxorubicin alone. Nanoemulsions also protected against oxidative stress as witnessed by a reduction of MDA and 4-HNA. Notably, nanoemulsions inhibited the release of IL-6, IL-8, IL-1ß, TNF-α and nitric oxide by around 35⁻40% and increased IL-10 production by 25⁻27% versus cells not treated with emulsions. Of the nutraceuticals evaluated, lycopene-rich nanoemulsions had the best cardioprotective profile. In conclusion, nanoemulsions loaded with the nutraceuticals described herein protect against cardiotoxicity, by reducing inflammation and lipid oxidative stress. These results set the stage for studies in preclinical models.

Iodine-mediated cyclization of cannabigerol (CBG) expands the cannabinoid biological and chemical space.

Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the chemical space of the cannabinoid chemotype, we have investigated an oxidative trigger based on the addition of iodine to the terminal isoprenyl double bond of cannabigerol (CBG, 1b), the decarboxylated and thermally stable version of CBGA (1a). Apart from the predictable product of an iodine-induced cascade cyclization (3), also a pair of unprecedented spiranes named spirocannabigerols (4a,b), derived from the formation of an edge-protonated cyclopropyl cation was also formed, along with a product (5) resulting from the incorporation, in a Friedel-Craft fashion, of the reaction solvent (toluene). Biological evaluation of these compounds on six thermo-transient receptor potential channels (TRPs) showed a remodeling of bioactivity compared to GBC, with emphasis on TRPA1 rather than TRPM8.

Successful management of a third-trimester pregnancy complicated by pheochromocytoma: case report.

Pheochromocytoma (PH) is a tumor that arises from chromaffin cells of the adrenal medulla. Though being this benign neoplasm very rare in pregnancies, lack of treatment nevertheless causes high mortality rates for both the mother and the fetus. Classic symptoms related to PH are hypertension, abdominal pain, diaphoresis, and headache; but it can be easily misdiagnosed as gestational hypertension or preeclampsia. Its appearance is sporadic, but there are some genetic disorders that favor its onset (e.g. MEN 2A and 2B). Individual management is needed, because no single protocol is suitable in such a complex and rare condition. In this paper we describe our experience in the clinical and surgical management of a young pregnant patient affected by PH, and in particular the specific and unique pharmacological treatment with doxazosin, the use of corticosteroids and a close monitoring of fetal well-being, which proved being an effective approach.