Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid 2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders.

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Cannabis is a plant with high pharmacological and nutrition values, its potentialities and applications are not only circumscribed to cannabinoids biological activities, but also defined by noncannabinoid compounds. The combination of other cannabinoids together with noncannabinoid components could enhance the beneficial effects of THC and could reduce undesirable side effects.

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The dimeric nonprenylated acylphloroglucinol semimyrtucommulone (6) was obtained from the leaves of myrtle (Myrtus communis) as a 2:1 mixture of two rotamers. The known trimeric phloroglucinol myrtucommulone A (1) was also isolated and characterized spectroscopically as a silylated cyclized derivative (5). Myrtucommulone A showed significant antibacterial activity against multidrug-resistant (MDR) clinically relevant bacteria, while semimyrtucommulone was less active.

The lack of a safe and reliable alternative to hormone therapy (HT) for treating menopausal symptoms underscores the need for alternative therapies. OBJECTIVE: The purpose of this study was to assess the in vivo estrogenic effects of the botanical dietary supplements Trifolium pratense (red clover) and Humulus lupulus (hops), and two compounds obtained from H. lupulus, isoxanthohumol and 8-prenylnaringenin (8-PN) using the ovariectomized uterotrophic adult rat model. A H. lupulus extract and a 30% isoflavone extract of T. pratense were tested at three escalating doses as was one dose of isoxanthohumol for 21 days. 8-Prenylnaringenin, the major estrogen in H. lupulus, was also tested at three relevant escalating doses. In order to determine the in vivo metabolism of 8-PN, the major Phase I and Phase II metabolites were also identified. The primary outcome measure, uterus weight gain, indicated that H. lupulus and T. pratense did not have an estrogenic effect on the uterus, and none of the secondary outcome measures were positive. In contrast, there was a clear dose response when 8-PN was evaluated where the middle and high doses of 8-PN were active. 8-Prenylnaringenin in rat plasma, liver, and mammary gland was measured and the major Phase I and Phase II 8-PN metabolites were detected. Our findings suggest that while both the H. lupulus and T. pratense extracts do not have an effect on the rat uterus, 8-PN at equivalent doses to those previously used in humans did have an effect, and may therefore have a deleterious effect in women. IntroductionSymptoms associated with menopause such as insomnia, loss of libido, vaginal atrophy, depression, and hot flashes can greatly affect the quality of life for women. Many women have used hormone therapy (HT) to alleviate menopausal symptoms; however, with the publication The strobiles of Humulus lupulus L. (Cannabaceae) (hops) are primarily used to flavor beer, and have been studied since 1953 for a potential estrogenic mechanism of action [13][14][15]. In the past, the flavonoids 8-PN and 6-PN, and the chalcone, isoxanthohumol (IX), have been isolated and reported to be estrogenic in vitro and/or in vivo [16,17]. The most potent estrogen in H. lupulus is 8-PN, which is in actuality an artifact formed through isomerization of the precursor chalcone, desmethylxanthohumol [18,19]. 8-Prenylnaringenin has been shown in a variety of in vitro assays to be estrogenic in the nanomolar range [16,17,20,21]. It can also be formed from precursors such as IX, and xanthohumol (XH), through metabolism [22].In previous metabolic studies, it has been shown that human liver microsomes convert 8-PN to 12 metabolites [22]. Among them, are the most abundant monooxygenated metabolites (Figure 1). The estrogenicities of the 8-PN alcohols have been previously determined [23] and were found to be ∼10 fold less estrogenic than 8-PN. Phase II metabolites of 8-PN, including glucuronides and sulfate conjugates, have been identified in incubations with human Caco-2 cells and human hepatocytes [2...

Capsiate and its dihydroderivatives are the major capsaicinoids of sweet pepper. These new capsaicinoids do not activate the vanilloid receptor type 1 (VR1) but they share with capsaicin (CPS)some biological activities mediated in a VR1‐independent fashion. In this study we show that CPS and nordihydrocapsiate (CPT) inhibit early and late events in T cell activation, including CD69, CD25 and ICAM‐1 cell surface expression, progression to the S phase of the cell cycle and proliferation in response to TCR and CD28 co‐engagement. Moreover, both CPS and CPT inhibit NF‐κB activation in response to different agents including TNF‐α. CPS itself does not affect the DNA‐binding ability of NF‐κB but it prevents IκB kinase activation and IκBα degradation in a dose‐dependent manner, without inhibiting the activation of the mitogen‐activated protein kinases, p38, extracellular regulated kinase and c‐Jun N‐terminal protein kinase. Moreover, intraperitoneal pretreatment with CPT prevented mice from lethal septic shock induced by lipopolysaccharide. In a second model of inflammation CPT pretreatment greatly reduced the extensive damage in the glandular epithelium observed in the bowel of DSS‐treated mice. Taken together, these results suggest that CPT and related synthetic analogues target specific pathways involved in inflammation, and hold considerable potential for dietary health benefits as well as for pharmaceutical development.