The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

BACKGROUND:Two platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control. METHODOLOGY/ PRINCIPLE FINDINGS:Here we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss. CONCLUSIONS/ SIGNIFICANCE:7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control

Ashfall Tephra in the Ogallala Group of the Great Plains: Characteristics and Significance

The Miocene Ogallala Group blankets the Great Plains east of the Rocky Mountains. This sheet of largely fluvial deposits, lying downwind of major silicic volcanic fields to the west, was ideally located to receive and preserve tephra from these fields. This investigation brings modern methods of tephrochronlogy to bear on the age and identity of Ogallala tephra. Results indicate that ~40 separate tephra layers, ranging in age from ~16.5–5.0 Ma, in the Ogallala. Most tephra came from Yellowstone hotspot sources. The relative frequency of hotspot tephra in the Ogallala matches that in more proximal regions to the west with peak intensities in the intervals ~16.5−15 Ma nd ~13.0−8.5 Ma. About 30 of the Ogallala tephra are correlated with tephra of known age the the Basin and Range to the west. Using the ages of correlative tephra to the west insight into the age of the Ogallala, the correlation of Ogallala tephra from region to region in the Great Plains, and sedimentation rates within the Ogallala. In the Ogallala sedimentation rates vary. The rates are lowest (3–9 m/Ma) in the Cap Rock Mbr. of the Ash Hollow Fm. along the Niobrara River and in undifferentiated Ogallala strata and in the undifferentiated Ogalala Gp. in NW Kansas. Rates of 40–80 m/Ma characterize the Valentine Fm. beneath the Cap Rock Mbr. Finally, one tephra, the 11.37 Ma Cougar Point Tuff XI, is recognized at 6 localies. This key horizon provides the first detailed structure contours within the Ogallala. These contours show a sharply increasing slope of the Ogallala west of 101° W that reflects the post–6 Ma tilt along the western edge of the Ogallala. East of 101º W the gradients mirror the gradients of the major rivers (1.3 to 1.6 m/km.). West of 101º W gradients increase and reach a maximun of 4.6 m/km at the crest of the Gangplank

Ashfall Tephra in the Ogallala Group of the Great Plains: Characteristics and Significance

The Miocene Ogallala Group blankets the Great Plains east of the Rocky Mountains. This sheet of largely fluvial deposits, lying downwind of major silicic volcanic fields to the west, was ideally located to receive and preserve tephra from these fields. This investigation brings modern methods of tephrochronlogy to bear on the age and identity of Ogallala tephra. Results indicate that ~40 separate tephra layers, ranging in age from ~16.5–5.0 Ma, in the Ogallala. Most tephra came from Yellowstone hotspot sources. The relative frequency of hotspot tephra in the Ogallala matches that in more proximal regions to the west with peak intensities in the intervals ~16.5−15 Ma nd ~13.0−8.5 Ma. About 30 of the Ogallala tephra are correlated with tephra of known age the the Basin and Range to the west. Using the ages of correlative tephra to the west insight into the age of the Ogallala, the correlation of Ogallala tephra from region to region in the Great Plains, and sedimentation rates within the Ogallala. In the Ogallala sedimentation rates vary. The rates are lowest (3–9 m/Ma) in the Cap Rock Mbr. of the Ash Hollow Fm. along the Niobrara River and in undifferentiated Ogallala strata and in the undifferentiated Ogalala Gp. in NW Kansas. Rates of 40–80 m/Ma characterize the Valentine Fm. beneath the Cap Rock Mbr. Finally, one tephra, the 11.37 Ma Cougar Point Tuff XI, is recognized at 6 localies. This key horizon provides the first detailed structure contours within the Ogallala. These contours show a sharply increasing slope of the Ogallala west of 101° W that reflects the post–6 Ma tilt along the western edge of the Ogallala. East of 101º W the gradients mirror the gradients of the major rivers (1.3 to 1.6 m/km.). West of 101º W gradients increase and reach a maximun of 4.6 m/km at the crest of the Gangplank

An Abeis procera-derived tetracyclic triterpene containing a steroid-like nucleus core and a lactone side chain attenuates in vitro survival of both Fasciola hepatica and Schistosoma mansoni

Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities. Therefore, the identification of new anthelmintics is necessary for the sustainable control of these NTDs in both animal and human populations. Here, continuing our work with phytochemicals, we isolated ten triterpenoids from the mature bark of Abies species and assessed their anthelmintic activities against F. hepatica and S. mansoni larval and adult lifecycle stages. Full 1H and 13C NMR-mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects. When compared to representative mammalian cell lines (MDBK and HepG2), the most potent triterpenoid (700015; anthelmintic EC50s range from 0.7 μM–15.6 μM) displayed anthelmintic selectivity (selectivity indices for F. hepatica: 13 for newly excysted juveniles, 46 for immature flukes, 2 for mature flukes; selectivity indices for S. mansoni: 14 for schistosomula, 9 for immature flukes, 4 for adult males and 3 for adult females) and induced severe disruption of surface membranes in both liver and blood flukes. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also severely inhibited by 700015. Together, our results describe the structural elucidation of a novel broad acting anthelmintic triterpenoid and support further investigations developing this compound into more potent analogues for the control of both fasciolosis and schistosomiasis. Keywords: Abies procera, Abies grandis, Triterpenoid, Anthelmintic drug discovery, Neglected tropical diseases, Fasciola hepatica, Schistosoma manson

Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition

INTRODUCTION: Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. METHODS: We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). RESULTS: We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. CONCLUSION: Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology

Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR)

Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer