Evidence for human-caused founder effect in populations of Solanum jamesii found at archaeological sites: I. Breeding experiments and the geography of sexual reproduction.

PREMISE: Plant domestication can be detected when transport, use, and manipulation of propagules impact reproductive functionality, especially in species with self-incompatible breeding systems. METHODS: Evidence for human-caused founder effect in the Four Corners potato (Solanum jamesii Torr.) was examined by conducting 526 controlled matings between archaeological and non-archaeological populations from field-collected tubers grown in a greenhouse. Specimens from 24 major herbaria and collection records from >160 populations were examined to determine which produced fruits. RESULTS: Archaeological populations did not produce any fruits when self-crossed or outcrossed between individuals from the same source. A weak ability to self- or outcross within populations was observed in non-archaeological populations. Outcrossing between archaeological and non-archaeological populations, however, produced fully formed, seed-containing fruits, especially with a non-archaeological pollen source. Fruit formation was observed in 51 of 162 occurrences, with minimal evidence of constraint by monsoonal drought, lack of pollinators, or spatial separation of suitable partners. Some archaeological populations (especially those along ancient trade routes) had records of fruit production (Chaco Canyon), while others (those in northern Arizona, western Colorado, and southern Utah) did not. CONCLUSIONS: The present study suggests that archaeological populations could have different origins at different times-some descending directly from large gene pools to the south and others derived from gardens already established around occupations. The latter experienced a chain of founder events, which presumably would further reduce genetic diversity and mating capability. Consequently, some archaeological populations lack the genetic ability to sexually reproduce, likely as the result of human-caused founder effect.

Biologically-Based Complementary and Alternative Medicine (CAM) Use in Cancer Patients: The Good, the Bad, the Misunderstood.

As complementary and alternative medicine (CAM) becomes more popular, it is being used in cancer patients to aid in recovery or to treat symptoms associated with the current chemotherapy. Numerous papers exist that discuss patients using CAM with cancer chemotherapy and their outcomes-both positive and negative. However, in the case of the negative outcomes, the reason for the dangers or interactions with drugs are not made clear. Indeed, many chemotherapy regimens are rendered less effective by the well-meaning but uninformed patient or their family members and friends. Similarly, reports of positive outcomes with CAM and chemotherapy provide a strong basis for further research, but do not identify specific mechanisms of action. These small clinical studies and in vitro studies identify a necessary area for further research and provide a much needed, although often rejected, alternative look at whole treatment plans. Careful review of the available information and evaluation of the nature of the CAM effects are necessary to combat the misunderstanding and sometimes unwarranted claims over CAM use. This mini review will explore some of the commonly used CAM agents and their mechanisms of interactions with other treatments. Suggestions as to which agents can be safe and when to use them will be an integral part of this review.

The Synthesis of a New Class of Highly Fluorescent Chromones via an Inverse-Demand Hetero-Diels-Alder Reaction.

A new class of fluorophores has been developed utilizing an inverse-demand hetero-Diels-Alder reaction with silyl enol ethers and substituted 3-formylchromones. These compounds yield blue to green fluorescence with quantum yields up to 73%. They also exhibit good potential for use as fluorescent probes in biological systems, as they are cell membrane permeable with low cytotoxicity.

Efficacy of the saponin component of Impatiens capensis Meerb.in preventing urushiol-induced contact dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Many different tribes of American Indians used jewelweed, Impatiens capensis Meerb, as a plant mash to reduce development of poison ivy dermatitis. Saponins are a natural soapy constituent found within plants. A 2012 study suggested that saponins may be present in jewelweed which could be responsible for its efficacy in preventing rash development following contact with Toxicodendron radicans (L.) Kuntze (poison ivy). This study validated this hypothesis and demonstrated additional biological activity of the jewelweed saponin containing extract. MATERIALS AND METHODS: Fresh I. capensis leaves were extracted with methanol and further partitioned between ethyl acetate and water, with a final separation between water and n-butanol, to obtain a saponin containing extract. The presence of saponins in the extract was demonstrated by the observation of foaming and using a vanillin colorimetric assay for total saponins. Efficacy of the saponin containing extracts in rash reduction was tested by brushing poison ivy (PI) onto the forearms of volunteers (N=23) in six locations and treating these PI exposed areas with distilled water (control), saponin containing extracts, fresh plant mashes, and soaps made with and without plant extracts. Saponin containing extracts were further tested for biological activity against both gram negative and gram positive bacteria and against cancer cell lines A-375, HT-29, and MCF-7. Additionally, because saponins have been shown to have a stimulatory effect in cardiac muscle 2 µl saponin extract was applied superficially to black worms, Lumbriculus variegatus (N=5). RESULTS, AND CONCLUSIONS: Both saponin containing extracts and all soaps tested were effective in reducing poison ivy dermatitis; thus, saponin content correlates with PI rash prevention. No apparent antibiosis was observed against any bacteria tested; however, dose response cytotoxicity was documented against MCF-7 breast cancer cells and cytostatic activity was seen against the HT-29 colon cancer cell lines. Lumbriculus variegatus exhibited a 138% increase in heart rate over baseline rate five minutes post treatment implying a possible positive chronotropic effect.

A comprehensive ligand based mapping of the σ2 receptor binding pocket.

The sigma (σ) receptor system consists of at least two major receptor subtypes: σ1 and σ2. Several potential therapeutic applications would benefit from structural knowledge of the σ2 receptor but gaining this knowledge has been hampered by the difficulties associated with its isolation and, thus, characterization. Here, a ligand based approach has been adopted using the program PHASE® and a group of 41 potent and structurally diverse σ2 ligands to develop several pharmacophore models for different families of σ2 ligands. These pharmacophores were analyzed to identify the different binding modes to the receptor and were combined together to construct a comprehensive pharmacophore that was used to develop a structural model for the σ2 binding pocket. A total of six binding modes were identified and could be classified as neutral or charged modes. The results presented here also indicate the significance of hydrophobic interactions to σ2 binding and the requirement of hydrogen bonding interactions to increase the affinity for this receptor subtype. This work adds breadth to our knowledge of this receptor's binding site, and should contribute significantly to the development of novel selective σ2 ligands.

The effectiveness of jewelweed, Impatiens capensis, the related cultivar I. balsamina and the component, lawsone in preventing post poison ivy exposure contact dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Impatiens capensis (jewelweed) is native to the Eastern and Midwestern US and Canada. Many Native American tribes used I. capensis and its close relatives to treat/prevent rash from plant sources particularly Toxicodendron radicans and Urtica dioica. I. balsamina (garden balsam) a native of China was used by the indigenous people of Asia for similar purposes. AIM OF STUDY: This study aims to validate ethnopharmacological use of jewelweed in poison ivy (PI) dermatitis prevention and to refute scientific papers denying this efficacy. Additionally, the content of lawsone, the purported effective agent in jewelweed preparations, was measured to see if its concentration correlated with jewelweed preparation efficacy. MATERIAL AND METHODS: Poison ivy was brushed onto forearms of volunteers in 6 locations and exposed areas were treated with jewelweed extracts, fresh plant mashes, soaps made of plant extracts, water and Dawn® dish soap. Rash development was scored on a scale of 0-14. RESULTS: Jewelweed mash was effective in reducing poison ivy dermatitis, supporting ethnobotanical use. However, jewelweed extracts were not effective; and soaps made of these extracts were effective but no more so than jewelweed-free soaps. Lawsone content varied with harvest season and did not appear to affect rash development. CONCLUSION: Jewelweed is an efficacious plant for preventing development of dermatitis following poison ivy contact, but soap is more effective. Lawsone content does not correlate with PI rash prevention. Perhaps saponins, the soapy component of jewelweed are the effective agents.

Computational strategies for the development of novel small molecule rheumatoid arthritis therapies.

Rheumatoid arthritis is a chronic autoimmune disorder that causes joint disfigurement and destruction leading to reduced quality of life. Effective drug therapies include the Disease Modifying Anti-Rheumatic Drugs which can help impede the progression of the disease but are not always effective. It is, therefore important to identify novel and effective therapies to combat this debilitating disorder. Several bioinformatics tools and computational approaches can be utilized to identify novel and effective therapies for rheumatoid arthritis and these are presented here.

1-Methylnicotinamide stimulates cell growth and inhibits hemoglobin synthesis in differentiating murine erythroleukemia cells.

Exposure of murine erythroleukemia cells (MELCs) to nicotinamide (NA) or its synthetic analog N'-methylnicotinamide (N'-MN) reduces cell growth and induces terminal differentiation, marked by increased heme and globin accumulation. On the contrary, 1-methylnicotinamide (1-MN), the primary metabolite of excess NA, was found to stimulate cell growth and reduce spontaneous differentiation of cultured MELCs. Log phase MELCs exhibited up to 50% higher cell density above untreated cells when cultured for up to 96 h with 2.5 mM 1-MN. When combined with NA or several chemically-unrelated inducers of hemoglobin synthesis in cultured MELCs, 1-MN reduced the globin mRNA levels and heme accumulation by 40-80%. 1-MN was able to inhibit heme production if present during only the first 24-48 h after NA exposure. Pre-treatment with 1-MN could not confer resistance of cells to effects of NA, suggesting the inhibition is reversible. Commitment to differentiate in semisolid medium by the most potent inducer, 5mM N'-MN, was inhibited up to 95% by 2.5mM concentrations of 1-MN. It appears that 1-MN has opposing effects on growth and induction of differentiation than those seen in MELC cultures exposed to NA or N'-MN.

The hallucinogen derived from Salvia divinorum, salvinorin A, has kappa-opioid agonist discriminative stimulus effects in rats.

Data from clinical and preclinical studies converge implicating the plant-derived hallucinogen salvinorin A as an important pharmacologic tool; this psychoactive compound may expand scientific understandings on mammalian kappa-opioid receptor systems. Human salvinorin A effects, consistent with kappa-opioid receptor agonism, include antinociception, sedation, dysphoria and distorted perceptions. The experiments reported here measured salvinorin A (1-3mg/kg, i.p.) discriminative stimulus properties in male Sprague-Dawley rats conditioned to recognize the discriminative stimulus cue generated by the well characterized kappa-opioid agonist U-69593 (0.56 mg/kg, i.p.). At three distinct active doses, salvinorin A fully substituted for U-69593 without altering response rates. The lever choice pattern in U-69593 trained animals reverted to vehicle lever responding when a kappa selective antagonist compound, nor-BNI (4.5 nM, i.c.v.) was administered 1h prior to salvinorin A, yet nor-BNI alone failed to impact the rate or pattern of subject responses. These findings confirm and extend results published after similar drug discrimination tests were performed in rhesus monkeys. The discussion section of this article highlights public concern over salvinorin A misuse and emphasizes several potential pharmacotherapeutic applications for salvinorin A or analogue compounds.

Effects of extracts of lupine seed on blood glucose levels in glucose resistant mice: antihyperglycemic effects of Lupinus albus (white lupine, Egypt) and Lupinus caudatus (tailcup lupine, Mesa Verde National Park).

Lupine is a medicinal food plant with potential value in the management of diabetes. In white mice, extracts of seeds of the white lupine [Lupinus albus (L. termis L.)] were associated with increased tolerance to an oral glucose bolus. Antihyperglycemic activity was present in extracts of the whole seed but not extracts of the seed coat, and was not detected when glucose was administered intraperitoneally rather than orally. However, in contrast to results seen with the prescription drug, acarbose, lupine extract did not appear to increase the bulk or carbohydrate content of the feces. Antihyperglycemic activity was also seen in extracts of the tailcup lupine (L. caudatus) found in the Four Corners Region of the United States.

Bromophenol blue staining of tumors in a rat glioma model.

OBJECTIVE: For patients with gliomas, decreasing the tumor burden with macroscopic surgical resection may affect quality of life, time to tumor progression, and survival. Injection of bromophenol blue (BPB) may enhance intraoperative visualization of an infiltrating tumor and its margins and improve the extent of resection. In this study, we investigated the uptake of BPB in experimental rat brain tumors. METHODS: We first conducted a toxicity study with bolus intravenous injections of 5, 60, and 360 mg/kg doses of BPB in nontumor-bearing Fischer 344 rats. No adverse effects were observed in any of the animals during the 60 day observation period. We then injected 9L tumor cells intracerebrally into Fischer 344 rats and approximately 2 weeks later, administered a bolus intravenous injection of 5 to 360 mg/kg BPB. Fifteen minutes after BPB injection, we sacrificed the animals and removed their brains. In a subsequent study, we injected 180 mg/kg BPB and sacrificed animals at several time points to monitor tumor staining over time. RESULTS: The stain was clearly visible and localized to the tumor for all BPB concentrations 60 mg/kg or greater, and in an additional experiment, we found that tumor staining persisted for at least 8 hours after BPB injection. CONCLUSION: We conclude that BPB helped visualize experimental tumors at time points from a few minutes to several hours after injection. Because BPB also proved to be nontoxic to the animals at effective concentrations, we believe the compound may be potentially useful in helping neurosurgeons visualize brain tumors in humans.

MCF-7 breast cancer cell line grown in agarose culture for study of COX-2 inhibitors in three-dimensional growth system.

Herein we report a method for studying slow acting pharmaceutical COX-2 inhibitors in the MCF-7 breast cancer cell line where cells are grown in a three-dimensional format within an agarose matrix. The cancer cells are suspended in agarose and plated in a cell culture dish, where they will form small multicellular 'tumors' in the agarose. The time frame for conducting experiments is up to 2.5 weeks, and gives ample time for COX-2 inhibitors to induce cell death. Etodolac was used for these experiments, and was found to induce cell death in a time dependent manner over a 2.5-week period. This is in contrast to the cell line grown in monolayer and treated with the same concentrations of etodolac. This method is appropriate for determining mechanisms of cell death caused by COX-2 inhibition.

In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol.

The abuse potential of tramadol was investigated using both in vivo microdialysis measures of dopamine (DA) release within the nucleus accumbens (NAc) shell and the conditioned place preference (CPP) paradigm in rats. Tramadol (75 mg/kg, i.p.) induced a statistically significant increase (starting 80 min posttreatment) in DA release within the NAc shell, which was maintained for at least 120 min posttreatment. Tramadol (18.75, 37.5, and 75 mg/kg i.p.) produced a statistically significant CPP, with the effects of the two highest doses comparable to those induced by morphine (5 mg/kg, s.c.). The release of DA within the NAc shell may be responsible for the rewarding properties of tramadol and, together with the CPP results, provide evidence that tramadol may possess greater abuse potential than originally believed.