Cannabicitran: Its unexpected racemic nature and potential origins.

Cannabicitran is a cannabinoid found in levels up to ~10% in commercial "purified" cannabidiol (CBD) extracts. The structure of this natural product was first reported more than 50 years ago. However, few studies have investigated cannabicitran or its origin despite the rapidly increasing interest in the use of cannabinoids for the treatment of a wide range of physiological conditions. Following on a recent detailed NMR and computational characterization of cannabicitran, our group initiated ECD and TDDFT studies aimed at unequivocally determining the absolute configuration of cannabicitran present in Cannabis sativa extracts. To our surprise, we discovered the natural product was racemic, raising questions around its presumed enzymatic origin. Herein, we report the isolation and absolute configuration of (-)-cannabicitran and (+)-cannabicitran. Several possible scenarios for production of the racemate in the plant and/or during extract processing are discussed.

Nephroprotective plant species used in traditional Mayan Medicine for renal-associated diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: The prevalence of kidney disease has increased rapidly in recent years and has emerged as one of the leading causes of mortality worldwide. Natural products have been suggested as valuable nephroprotective agents due to their multi-target and synergistic effects on modulating important proteins involved in kidney injury. There is a large number of plant species that have been used traditionally for kidney-related conditions in Mesoamerican medicine by different cultural groups that could provide a valuable source of nephroprotective therapeutic candidates and could lead to potential drug discovery. AIM OF REVIEW: This review aims to provide an overview of the currently known efficacy of plant species used traditionally in Mesoamerica by Mayan groups to treat kidney-related conditions and to analyze the phytochemical, pharmacological, molecular, toxicological, and clinical evidence to contribute to public health efforts and for directing future research. METHODS: Primary sources of plant use reports for traditional kidney-related disorders in Mesoamerica were searched systematically from library catalogs, theses, and scientific databases (PubMed, Google Scholar; and Science Direct), and were filtered according to usage frequency in Mayan groups and plant endemism. The database of traditional plants was further analyzed based on associations with published reports of the phytochemical, pharmacological, molecular, toxicological, and clinical evidence. RESULTS: The most reported kidney-related conditions used traditionally in Mayan medicine involve reducing renal damage (a cultural interpretation that considers an inflammatory or infectious condition), cleaning or purifying the blood and kidney, reducing kidney pain, and eliminating kidney stones. A total of 208 plants used for kidney-related problems by 10 Mayan groups were found, representing 143 native species, where only 42 have reported pharmacological activity against kidney damage, mainly approached by in vitro and in vivo models of chemical- or drug-induced nephrotoxicity, diabetes nephropathy, and renal injury produced by hypertension. Nephroprotective effects are mainly mediated by reducing oxidative stress, inflammatory response, fibrosis mechanisms, and apoptosis in the kidney. The most common nephroprotective compounds associated with traditional Mayan medicine were flavonoids, terpenoids, and phenolic acids. The most widely studied traditional plants in terms of pharmacological evidence, bioactive compounds, and mechanisms of action, are Annona muricata L., Carica papaya L., Ipomoea batatas (L.) Lam., Lantana camara L., Sechium edule (Jacq.) Sw., Tagetes erecta L., and Zea mays L. Most of the plant species with reported pharmacological activity against kidney damage were considered safe in toxicological studies. CONCLUSION: Available pharmacological reports suggest that several herbs used in traditional Mayan medicine for renal-associated diseases may have nephroprotective effects and consistent pharmacological evidence, nephroprotective compounds, and mechanisms of action in different models of kidney injury. However, more research is required to fully understand the potential of traditional Mayan medicine in drug discovery given the limited ethnobotanical studies and data available for most species with regards to identification on bioactive components, pharmacological mechanisms, and the scarce number of clinical studies.

Myrica cerifera, a Medicinal Plant of the Lumbee Tribe, has Antibacterial and Nematicidal Properties.

Currently threatening the world of medicine is a growing number of antibiotic-resistant diseases. More specifically, bacteria and nematodes have gained resistance to many of the world's leading antibiotics and nematicides, respectively, making infections more difficult to treat. Subsequently, these parasitic organisms are able to continue damaging crops and other living organisms like humans without strong interference. To help people and the environment, the development of new and novel antibiotics is vital. Previous research suggests that phytochemicals are a potential solution that will not only help inhibit bacterial growth but also reduce nematode survival. We hypothesized that Myrica cerifera, a plant often used by the Lumbee tribe to treat illness, possesses antibacterial and nematicidal properties. To answer our hypothesis, we began by collecting plant specimens to extract material for biological assays and to subsequently isolate and elucidate the structures of active components. The extract was evaluated for antibacterial properties with an agar diffusion assay and then nematicidal properties using Caenorhabditis elegans. M. cerifera extract was added onto an agar lawn at various doses, and the nematodes' lifespans were scored. The findings of this study show that extracts of this plant, more commonly referred to as 'wax myrtle', do significantly decrease the lifespan of C. elegans and increase the zone of inhibition for Staphylococcus epidermidis and Staphylococcus aureus. In addition, two compounds were isolated and characterized through chemical extraction, chromatographic separation, and spectroscopic analysis. These compounds could potentially be used to treat bacterial and nematode infections.

Suitability of Creeping Bentgrass and Bermudagrass Cultivars for Black Cutworms and Fall Armyworms (Lepidoptera: Noctuidae).

The black cutworm, Agrotis ipsilon Hufnagel, and fall armyworm, Spodoptera frugiperda Smith (Lepidoptera: Noctuidae), are common turfgrass pests of golf courses in the southeastern United States. Heat-tolerant bentgrass (Agrostis stolonifera L.) cultivars are expanding the range of bentgrass further south, but these cultivars have not been studied for their potential host plant resistance to black cutworm or fall armyworm. The goals of the study were to investigate feeding response of black cutworm and fall armyworm to these newer heat-tolerant creeping bentgrass cultivars, as well as commonly used cultivars of bermudagrass [Cynodon dactylon (Loppers.)]. Choice and no-choice feeding assays and fecundity tests were conducted in the laboratory and greenhouse to evaluate performance and preference of the two insects. When given a choice, neither black cutworm nor fall armyworm showed a preference for the majority of new cultivars tested. There were no differences in leaf area consumption or insect development for either pest in no-choice feeding assays. Black cutworm females preferred laying eggs in bentgrass compared with bermudagrass, but will oviposit onto bermudagrass, suggesting that both turf species are suitable hosts of this pest. The broad host ranges of generalist caterpillar pests of turfgrass hinder the application of host plant resistance in integrated pest management on golf courses.

Homodecoupled 1,1- and 1,n-ADEQUATE: Pivotal NMR Experiments for the Structure Revision of Cryptospirolepine.

Cryptospirolepine is the most structurally complex alkaloid discovered and characterized thus far from any Cryptolepis specie. Characterization of several degradants of the original, sealed NMR sample a decade after the initial report called the validity of the originally proposed structure in question. We now report the development of improved, homodecoupled variants of the 1,1- and 1,n-ADEQUATE (HD-ADEQUATE) NMR experiments; utilization of these techniques was critical to successfully resolving long-standing structural questions associated with crytospirolepine.

An experimental study of the use of hyperbaric oxygen to reduce the side effects of radiation treatment for malignant disease.

Hyperbaric oxygen (HBO) has been used for more than 20 years to assist wound healing in the treatment of the more severe complications associated with the side effects of therapeutic radiation treatment. A prospective study was performed in an irradiated rat model to determine whether HBO is effective in reducing the long-term side effects of therapeutic radiation treatment on normal tissue, when given 1 week after the completion of the radiation treatment. The experimental model was designed to simulate a fractionated course of therapeutic radiation that is commonly used in the treatment of cancer of the mandible. One week following completion of the radiotherapy, the animals underwent a 4-week course of HBO treatment, and two animals from each group were killed at 8-week intervals until the end of the experiment at 36 weeks. Histological sections of tissue clearly showed continued growth of teeth and maintenance of specialized tissues, such as salivary gland and bone, in the treated group compared to the non-treated group. This experimental model demonstrated that HBO is effective in reducing the long-term side effects of therapeutic radiation treatment in normal tissue, when given 1 week after the completion of the radiation treatment.

Bioactive constituents of Artemisia monosperma.

During a study on the chemistry and biological activity of Kuwaiti plants, new metabolites including 4,6-dihydroxy-3-[3'-methyl-2'-butenyl]-5-[4''-hydroxy-3''-methyl-2''-butenyl]-cinnamic acid (1), the 3R,8R stereoisomer of the C17 polyacetylene dehydrofalcarindiol (2) and a C10 polyacetylene glucoside (3) were characterised by spectroscopic means. Additionally, the previously characterised natural products 1,3R,8R-trihydroxydec-9-en-4,6-yne (4), spathulenol (5) and eriodyctiol-7-methyl ether (6) were also isolated. Compounds 2, 3, and 4 were evaluated for their ability to inhibit the enzyme 12-lipoxygenase and 3 and 4 showed moderate activity at 30 microg/ml. Compound 2 was evaluated against a panel of colorectal and breast cancer cell lines and IC50 values ranged from 5.8 to 37.6 microg/ml. Against a panel of fast-growing mycobacteria and a standard ATCC strain of Staphylococcus aureus, compound 6 exhibited minimum inhibitory concentrations in the range of 64-128 microg/ml.

Evaluation of a nonconventional insecticide and appropriate application timing for destruction of gypsy moth (Lepidoptera: Lymantriidae) egg masses.

Two field studies were conducted in 2001-2002 and 2003 to evaluate the effectiveness and appropriate application timing of Golden Pest Spray Oil (GPSO) for destruction of gypsy moth, Lymantria dispar (L.) (Lepidoptera: Lymantriidae), egg masses in Wisconsin. GPSO is a commercially available, registered pesticide that is predominantly comprised of a soybean-oil base (93%); its primary mode of action is by means of suffocation. Because gypsy moth spends the majority (>75%) of its life cycle in the egg stage (August-April), the potential utility of this product by arborists, city foresters, landscapers, and homeowners is high, especially because GPSO is a United States Environmental Protection Agency registered, nonconventional pesticide that is considered relatively nontoxic. When GPSO was applied at a 1:1 ratio with water, >96% control of gypsy moth egg masses was achieved, regardless of application timing (October, 3 d before egg hatch).

New constituents of Artemisia monosperma.

A new eudesmane sesquiterpene (1) and a C(10) diyne (2) were isolated from the aerial parts of Artemisia monosperma. The structures of these compounds were determined as rel-1beta,3alpha,6beta-trihydroxyeudesm-4-ene (1) and 1,3R,8R-trihydroxydec-9-en-4,6-yne (2) on the basis of spectral data interpretation. The absolute stereochemistry of 2 was determined using Mosher ester methodology in which the terminal primary hydroxyl group was first protected to simplify the stereochemical analysis.

A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma.

Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2-69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m(-2) i.v. day 1 and gemcitabine 1000 mg m(-2) i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20-46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life.

Achyrofuran, a new antihyperglycemic dibenzofuran from the South American medicinal plant Achyrocline satureioides.

A new prenylated dibenzofuran, achyrofuran (2), was isolated from an extract of Achyrocline satureioides by bioassay-guided fractionation using the db/db mouse model for type 2 diabetes. Compound 2significantly lowered blood glucose levels in this model when administered orally at 20 mg/kg q.d.

Detecting absolute human knee angle and angular velocity using accelerometers and rate gyroscopes.

Knee joint angle and angular velocity were calculated in real time during standing up and sitting down. Two small modules comprising rate gyroscopes and accelerometers were attached to the thigh and shank of two able-bodied volunteers and one T5 ASIA(A) paraplegic assisted by functional electrical stimulation (FES). The offset and drift of the rate gyroscopes was compensated for by auto-resetting and auto-nulling algorithms. The tilt of the limb segments was calculated by combining the signals of the accelerometer and the rate gyroscope. The joint angle was calculated as the difference in tilt of the segments. The modules were also tested on a two-dimensional model. The mean differences between the rate gyroscope-accelerometer system and the reference goniometer for the model, able-bodied and paraplegic standing trials were 2.1 degrees, 2.4 degrees and 2.3 degrees respectively for knee angle and 2.3 degrees s(-1), 5.0 degrees s(-1) and 11.8 degrees s(-1) respectively for knee velocity. The rate gyroscope-accelerometer system was more accurate than using the accelerometer as a tilt meter, possibly due to the greater bandwidth of the rate gyroscope-accelerometer system.

Inhibition of stimulated Jurkat cell adenosine 3',5'-cyclic monophosphate synthesis by the immunomodulatory compound HR325.

HR325 (2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'(trifluoromethyl)-phenyl]-propenamide) is an immunomodulatory compound through pyrimidine biosynthesis inhibition with antiproliferative properties which was derived from the isoxazol compound A77 1726 [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide]. During studies of the effects on early signal transduction events of this type of compound, it was found that HR325 dose-dependently inhibited adenosine 3',5'-cyclic monophosphate (cAMP) synthesis by Jurkat cells stimulated with prostaglandin E(2), (PGE(2)), cholera toxin (CTX), or forskolin (FKN). The potency of inhibition by HR325 of FKN-stimulated cells (IC(50) 30.4 microM) was approximately 3-fold higher than that of the other agonists (11.6 and 11.7 microM) and was independent of time of preincubation for both PGE(2) and FKN. Interestingly, A77 1726, an analogue of HR325, displayed a markedly different profile of stimulus-dependent potencies. The inhibition of cAMP synthesis by HR325 when stimulated by both PGE(2) and FKN was unaffected by glucose supplementation, in contrast to HR325-inhibited ATP levels, which were restored under such conditions. Further studies revealed that HR325 reduced intracellular ATP levels by uncoupling oxidative phosphorylation, albeit with a 1000-fold lower potency than the antihelmintic drug niclosamide. In addition, glucose supplementation experiments showed that, in contrast to HR325, the niclosamide-mediated reduction of ATP levels was wholly responsible for its inhibition of PGE(2)- and FKN-stimulated cAMP synthesis.

Prevention of birth defects: folic acid.

Neural tube defects (NTDs) comprise an important category contributing to infant mortality. While some NTDs may be due to identifiable inherited or specific environmental factors, most are multifactorial, with genetic and environmental factors contributing to their occurrence. Folic acid has been found to have a protective effect against the recurrence and occurrence of NTDs. In addition to natural dietary sources, in the United States, all enriched grain products now are fortified with folic acid. In addition, all women who could become pregnant are recommended to consume 0.4 mg of folic acid daily. Despite these measures, not all women of childbearing age have added sufficient folic acid to their diets or take a vitamin supplement. Challenges remain regarding educating women of childbearing age about the potential health benefits of adequate folic acid consumption.

Sensor systems for lower limb functional electrical stimulation (FES) control.

Two sensor systems comprising clusters of accelerometers, magnetic sensors, a rate gyroscope, and a strain gauge were designed. For one system, the clusters were located at the belt and AFO. In the other system, the clusters were located at the AFO and the thigh. The maximum cluster size was 14 cm(3) and 75 g. The clusters of each sensor system were interconnected by a single flexible wire bus, which minimized the effects of cabling. The sensors detected five phases of normal gait to a resolution of 40 ms in an able bodied test. Using a threshold method, the sensor system repeatedly predicted an incipient knee buckle in a paraplegic individual by a minimum of 30 ms. One system detected knee flexion angle analytically to an accuracy of 3.2 degrees during sit to stand trials. The second system determined knee and hip flexion angle to an accuracy of 3.8 degrees during sit to stand trials through neural networks. The signal processing of the acquired sensor signals in each system was performed on a MC68332 microcomputer in conjunction with the data sampling, and suggested the possibility for each sensor system to be used in real time control of FES.

Magnesium deficiency in patients with chronic pancreatitis identified by an intravenous loading test.

Magnesium deficiency is a common clinical condition that may exist despite a normal serum magnesium concentration. Patients with chronic pancreatitis could develop magnesium deficiency due to either malabsorption, diabetes mellitus, or chronic alcoholism. Since serum levels of magnesium are a poor indicator of magnesium deficiency, the retention of a low-dose intravenous magnesium load (0.1 mmol/kg body weight) was determined in 13 patients with chronic pancreatitis (10 due to alcoholism) and eight healthy controls. Percentage magnesium retention was greater in patients with chronic pancreatitis than controls (59.8+/-37.3% S.D. versus 22.0+/-38.2% S. D.: P=0.038), and 10 of 13 patients showed evidence of magnesium deficiency. Routine evaluation of magnesium status could allow appropriate supplementation and conceivably symptomatic improvement in patients with severe chronic pancreatitis.

Gait event detection for FES using accelerometers and supervised machine learning.

Rule based detectors were used with a single cluster of accelerometers attached to the shank for the real time detection of the main phases of normal gait during walking. The gait phase detectors were synthesized from two rule induction algorithms, Rough Sets (RS) and Adaptive Logic Networks (ALNs), and compared with to a previously reported stance/swing detector based on a hand crafted, rule based algorithm. Data was sampled at 100 Hz and the detection errors determined at each sample for 50 steps. For three able bodied subjects, the sample by sample accuracy of stance/swing detection ranged within 94-97%, 87-94%, and 87-95% for the RS, ALN, and the handcrafted methods, respectively. A heuristically formulated postdetector filter improved the RS and ALN detectors' accuracy to 98%. RS and ALN also detected five gait phases to an overall accuracy of 82-89% and 86-91%, respectively. The postdetector filter localized the errors to the phase transitions, but did not change the detection accuracy. The average duration of the error at each transition was 40 ms and 23 ms for RS and ALN, respectively. When implemented on a microcontroller, the RS-based detector executed ten times faster and required one tenth of the memory than the ALN-based detector.

Biosynthesis of 4'-O-methylpyridoxine (Ginkgotoxin) from primary precursors.

Cell suspension cultures of Ginkgo biloba and Albizia tanganyicensis were investigated for the presence of 4'-O-methylpyridoxine (ginkgotoxin, 2), the 4'-O-methyl derivative of vitamin B(6) (pyridoxine, 1). The cultures produced the toxin even in the absence of vitamin B(6) (a common additive to plant cell culture media). This indicates that the pyridoxine ring system of ginkgotoxin is synthesized de novo by the cultured cells. A feeding experiment with D-[U-(13)C(6)]glucose revealed that the mode of incorporation of label into the pyridoxine moiety of 2 matched that observed for 1 in Escherichia coli. Thus, the data obtained in this investigation provide independent proof supporting the current hypothesis on vitamin B(6) biosynthesis. The 4'-O-methyl group of ginkgotoxin (2) was labeled from L-[methyl-(13)C(1)]methionine. This indicates that ginkgotoxin is likely to be derived by 4'-O-methylation of pyridoxine (1). The G. biloba cell suspension culture may be a suitable system to get further insight into vitamin B(6) and/or ginkgotoxin biosynthesis.

Ranitidine bismuth citrate can help to overcome Helicobacter pylori resistance to clarithromycin in vivo.

BACKGROUND: Helicobacter pylori eradication usually fails when clarithromycin is used against resistant strains. OBJECTIVE: The objective of this study was to test whether the apparent synergy found in vitro between ranitidine bismuth citrate (RBC) and clarithromycin also exists in vivo against resistant strains. METHODS: H. pylori was cultured and clarithromycin susceptibility was determined before and after treatment, from duodenal ulcer patients receiving RBC and clarithromycin or omeprazole and clarithromycin for 2 weeks in a multicenter randomized clinical trial. RESULTS: The overall eradication rate was 88.7% in the RBC group (71 patients) and 52.7% in the omeprazole group (74 patients). The demographic characteristics of the two groups were not different. Clarithromycin-resistant strains were isolated in 22 cases (15.1%). A difference between the eradication rates of susceptible and resistant strains was found in the omeprazole group but not in the RBC group. After treatment, resistance to clarithromycin developed in three of the seven strains (42.3%) cultured from the patients of the RBC group, compared with 11 of the 26 strains (42%) of the omeprazole group. That is, clarithromycin-resistant strains were found in 6% and 27% in the RBC group and the omeprazole group, respectively, on considering the global results. CONCLUSION: A synergy between RBC and clarithromycin may exist in vivo and, while clarithromycin resistance is increasing, it is an argument for using RBC in triple therapies.