Comparative effects of trichothecene mycotoxins on bovine platelet function: Acetyl T-2 toxin,a more potent inhibitor than T-2 toxin

The effects of the trichothecene mycotoxins (acetyl T-2 toxin, T-2 toxin, HT-2 toxin, palmityl T-2 toxin, diacetoxyscirpenol (DAS), deoxynivalenol (DON), and T-2 tetraol) on bovine platelet function were examined in homologous plasma stimulated with platelet activating factor (PAF). The mycotoxins inhibited platelet function with the following order of potency: acetyl T-2 toxin > palmityl T-2 toxin = DAS > HT-2 toxin = T-2 toxin. While T-2 tetraol was completely ineffective as an inhibitor, DON exhibited minimal inhibitory activity at concentrations above 10×10^?4M. The stability of the platelet aggregates formed was significantly reduced in all mycotoxin treated platelets compared to that of the untreated PAF controls. It is suggested that the increased sensitivity of PAF stimulated bovine platelets to the more lipophilic mycotoxins may be related to their more efficient partitioning into the platelet membrane compared to the more hydrophilic compounds.     

An extensive review on antifungal approaches in the treatment of mucormycosis

During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B ( 1 ) and isavuconazole ( 2 ) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole ( 3 ) and deferasirox ( 4 ) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 ( 5 ) and APX001A ( 6 ), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.     

Monoclonal antibodies to rabbit liver cytochrome P-448

Cytochrome P-448 (mol wt 55,000 Daltons) from rabbit liver was purified to a specific content of 16.6 nmol/mg. Mice were immunised with this preparation, their spleens removed and dissociated lymphocytes hybridised with myeloma cells. Four monoclonal antibodies against cytochrome P-448 were raised and partially characterised. All four antibodies interacted with cytochrome P-448 in intact microsomal fractions and selectively immunoadsorbed cytochrome P-448 from solubilised microsomal preparations. One of the antibodies inhibited benzo[a] pyrene hydroxylase activity in a reconstituted system, one had no effect on activity and two increased activity. The possible applications of such antibodies are discussed.     

Saikosaponin-d,a novel SERCA inhibitor,induces autophagic cell death in apoptosis-defective cells

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase pump, leading to autophagy induction through the activation of the Ca²⁺/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.     

Invasive Phragmites australis management outcomes and native plant recovery are context dependent

The outcomes of invasive plant removal efforts are influenced by management decisions, but are also contingent on the uncontrolled spatial and temporal context of management areas. Phragmites australis is an aggressive invader that is intensively managed in wetlands across North America. Treatment options have been understudied, and the ecological contingencies of management outcomes are poorly understood. We implemented a 5‐year, multi‐site experiment to evaluate six Phragmites management treatments that varied timing (summer or fall) and types of herbicide (glyphosate or imazapyr) along with mowing, plus a nonherbicide solarization treatment. We evaluated treatments for their influence on Phragmites and native plant cover and Phragmites inflorescence production. We assessed plant community trajectories and outcomes in the context of environmental factors. The summer mow, fall glyphosate spray treatment resulted in low Phragmites cover, high inflorescence reduction, and provided the best conditions for native plant recruitment. However, returning plant communities did not resemble reference sites, which were dominated by ecologically important perennial graminoids. Native plant recovery following initial Phragmites treatments was likely limited by the dense litter that resulted from mowing. After 5 years, Phragmites mortality and native plant recovery were highly variable across sites as driven by hydrology. Plots with higher soil moisture had greater reduction in Phragmites cover and more robust recruitment of natives compared with low moisture plots. This moisture effect may limit management options in semiarid regions vulnerable to water scarcity. We demonstrate the importance of replicating invasive species management experiments across sites so the contingencies of successes and failures can be better understood.     

Isolation of 11 polymorphic tri- and tetranucleotide microsatellite loci in a North American sedge (Carex scoparia: Cyperaceae) and cross-species amplification in three additional Carex species

We report on the isolation and evaluation of 11 microsatellites from a widespread eastern North American wetland sedge, Carex scoparia. Loci exhibit 3-9 alleles over five populations and significant F(IS) (0.204-0.717) in most populations. All primers cross-amplify in at least two other species, and 10 cross-amplify in the more distantly related C. stipata. These markers will be used to examine population genetics and patterns of chromosomal diversification in this ecologically important sedge species and its relatives.     

Life on the edge: reproductive mode and rate of invasive <Emphasis Type="Italic">Phragmites australis</Emphasis> patch expansion

The dynamics of plant invasions from initial colonization through patch expansion are driven in part by mode of reproduction, i.e., sexual (seed) and asexual (clonal fragments and expansion) means. Expansion of existing patches—both rate and mode of spread into a matrix of varying conditions—is important for predicting potential invader impacts. In this study, we used fine-scale genetic assessments and remote sensing to describe both the rate and mode of expansion for 20 Phragmites australis patches in flooded and unflooded wetland units on the Great Salt Lake, UT. We found that the majority of Phragmites patch expansion occurred via clonal spread but we also documented instances of (potentially episodic) seedling recruitment. The mode of patch expansion, inferred from patch edge genet richness, was unrelated to flooding in the wetland unit in the preceding growing season. The rate of Phragmites patch expansion varied from 0.09 to 0.35 year^?1 and was unrelated to the mode of spread. In six patches monitored across two years, monoclonal patches stayed monoclonal, whereas patches with higher genet richness had a marked increase in diversity in the second year. The findings of the present study suggest how this partially clonal species can exploit the benefits of both sexual (i.e., genetic recombination, widespread dispersal, colonization of new areas) and asexual reproduction (i.e., stability of established clones suited to local environmental conditions) to become one of the most successful wetland plant invaders. To control this species, both forms of reproduction need to be fully addressed through targeted management actions.     

3, 3′-diindolylmethane Enhances the Effectiveness of Herceptin against HER-2/Neu-Expressing Breast Cancer Cells

Herceptin failure is a major clinical problem in breast cancer. A subset of breast cancer patients with high HER-2/neu levels eventually experience metastatic disease progression when treated with Herceptin as a single agent. Mechanistic details of development of this aggressive disease are not clear. Therefore, there is a dire need to better understand the mechanisms by which drug resistance develops and to design new combined treatments that benefit patients with aggressive breast cancer and have minimal toxicity. We hypothesized that 3, 3′-diindolylmethane (DIM), a non-toxic agent can be combined with Herceptin to treat breast cancers with high levels of HER-2/neu. Here, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER-2/neu-expressing) and MDA-MB-468 (HER-2/neu negative) breast cancer cells. We found that DIM could enhance the effectiveness of Herceptin by significantly reducing cell viability, which was associated with apoptosis-induction and significant inhibition of colony formation, compared with single agent treatment. These results were consistent with the down-regulation of Akt and NF-kB p65. Mechanistic investigations revealed a significant upregulation of miR-200 and reduction of FoxM1 expression in DIM and Herceptin-treated breast cancer cells. We, therefore, transfected cells with pre-miR-200 or silenced FoxM1 in these cells for understanding the molecular mechanism involved. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients with breast cancer, particularly for the patients whose tumors express high levels of HER-2/neu.