Seagrasses benefit from mild anthropogenic nutrient additions

Seagrasses are declining globally, in large part due to increased anthropogenic coastal nutrient loads that enhance smothering by macroalgae, attenuate light, and are toxic when in excessive concentrations of inorganic nitrogen and phosphorus. However, as sanitation is improved many seagrass meadows have been observed to recover, with a few studies suggesting that they may even benefit from mild anthropogenic nutrient additions. Monitoring seagrass demography and health has faced difficulties in establishing the adequate variables and metrics. Such uncertainty in the methods has caused uncertainty of the significance of results presented and compromised extrapolations to other seasons, areas, or species. One solution has come from within the plant self-thinning theories. During the 1980s, an interspecific boundary line (IBL) was determined as the upper limit of the combination of plant density and above-ground biomass for any stand on Earth, setting their maximum possible efficiency in space occupation. Recently, two meta-analyses to determine specific IBLs for algae and for seagrasses have been performed. The recently updated seagrass dataset comprises 5,052 observations from 78 studies on 18 species. These IBLs opened new perspectives for monitoring: the observed distance of a stand to the respective IBL (i.e., each stand's relative efficiency of space occupation) was demonstrated to be a valuable indicator of a population's health. Thus, this metric can be used to determine the impact of nutrients and pollutants on algae and seagrass populations. Furthermore, because the IBLs are common to all species, they may be used to compare all species from any location worldwide. This novel approach showed that Halodule wrightii, Halodule beaudettei, Halophila baillonii, Zostera marina, and Zostera noltei meadows benefit from anthropogenic additions of nitrogen and phosphorus, as long as these additions are moderate. In fact, the healthier Z. noltei meadows in Portugal (and among the healthiest meadows worldwide) were the ones exposed to effluents from wastewater treatment plants (WWTP) and a food factory. We conclude that those effluents are providing water with enough quality and that their optimal management should coordinate the technological solutions of the WWTP with the natural potential of seagrass meadows as water purifiers and biomass producers.info:eu-repo/semantics/publishedVersio

BASHY Dyes Are Highly Efficient Lipid Droplet-Targeting Photosensitizers that Induce Ferroptosis through Lipid Peroxidation

Ferroptosis is an iron-dependent lipid-peroxidation-driven mechanism of cell death and a promising therapeutic target to eradicate cancer cells. In this study, we discovered that boronic acid-derived salicylidenehydrazone (BASHY) dyes are highly efficient singlet-oxygen photosensitizers (PSs; Φ up to 0.8) that induce ferroptosis triggered by photodynamic therapy. The best-performing BASHY dye displayed a high phototoxicity against the human glioblastoma multiform U87 cell line, with an IC value in the low nanomolar range (4.40 nM) and a remarkable phototoxicity index (PI > 22,700). Importantly, BASHY dyes were shown to accumulate in lipid droplets (LDs) and this intracellular partition was found to be essential for the enhanced phototoxicity and the induction of ferroptosis through lipid peroxidation. The safety and phototoxicity of this platform were validated using an in vivo zebrafish model (Danio rerio

Facilitation of Male Sexual Behavior in Syrian Hamsters by the Combined Action of Dihydrotestosterone and Testosterone

Testosterone (T) controls male Syrian hamster sexual behavior, however, neither of T's primary metabolites, dihydrotestosterone (DHT) and estradiol (E(2)), even in highly supraphysiological doses, fully restores sexual behavior in castrated hamsters. DHT and T apparently interact with androgen receptors differentially to control male sexual behavior (MSB), but whether these two hormones act synergistically or antagonistically to control MSB has received scant experimental attention and is addressed in the present study.Sexually experienced male Syrian hamsters were gonadectomized and monitored 5 weeks later to confirm elimination of the ejaculatory reflex (week 0), at which time they received subcutaneous DHT-filled or empty capsules that remained in situ for the duration of the experiment. Daily injections of a physiological dose of 25 µg T or vehicle commenced two weeks after capsule implantation. MSB was tested 2, 4 and 5 weeks after T treatment began. DHT capsules were no more effective than control treatment for long-term restoration of ejaculation. Combined DHT + T treatment, however, restored the ejaculatory reflex more effectively than T alone, as evidenced by more rapid recovery of ejaculatory behavior, shorter ejaculation latencies, and a greater number of ejaculations in 30 minute tests.DHT and T administered together restored sexual behavior to pre-castration levels more rapidly than did T alone, whereas DHT and vehicle were largely ineffective. The additive actions of DHT and T on MSB are discussed in relation to different effects of these androgens on androgen receptors in the male hamster brain mating circuit

Potent Cardioprotective Effect of the 4-Anilinoquinazoline Derivative PD153035: Involvement of Mitochondrial KATP Channel Activation

Background: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function. Methodology/Principal Findings: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation. Conclusions/Significance: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation

Inhibition of radiation induced migration of human head and neck squamous cell carcinoma cells by blocking of EGF receptor pathways

<p>Abstract</p> <p>Background</p> <p>Recently it has been shown that radiation induces migration of glioma cells and facilitates a further spread of tumor cells locally and systemically. The aim of this study was to evaluate whether radiotherapy induces migration in head and neck squamous cell carcinoma (HNSCC). A further aim was to investigate the effects of blocking the epidermal growth factor receptor (EGFR) and its downstream pathways (Raf/MEK/ERK, PI3K/Akt) on tumor cell migration in vitro.</p> <p>Methods</p> <p>Migration of tumor cells was assessed via a wound healing assay and proliferation by a MTT colorimeritric assay using 3 HNSCC cell lines (BHY, CAL-27, HN). The cells were treated with increasing doses of irradiation (2 Gy, 5 Gy, 8 Gy) in the presence or absence of EGF, EGFR-antagonist (AG1478) or inhibitors of the downstream pathways PI3K (LY294002), mTOR (rapamycin) and MEK1 (PD98059). Biochemical activation of EGFR and the downstream markers Akt and ERK were examined by Western blot analysis.</p> <p>Results</p> <p>In absence of stimulation or inhibition, increasing doses of irradiation induced a dose-dependent enhancement of migrating cells (p < 0.05 for the 3 HNSCC cell lines) and a decrease of cell proliferation (p < 0.05 for the 3 HNSCC cell lines). The inhibition of EGFR or the downstream pathways reduced cell migration significantly (almost all p < 0.05 for the 3 HNSCC cell lines). Stimulation of HNSCC cells with EGF caused a significant increase in migration (p < 0.05 for the 3 HNSCC cell lines). After irradiation alone a pronounced activation of EGFR was observed by Western blot analysis.</p> <p>Conclusion</p> <p>Our results demonstrate that the EGFR is involved in radiation induced migration of HNSCC cells. Therefore EGFR or the downstream pathways might be a target for the treatment of HNSCC to improve the efficacy of radiotherapy.</p

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis

BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses of albumin (1 g/kg body weight every 2 weeks), and high doses (1.5 g/kg every week), on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs. the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg at day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6 (IL6). Long-term high-dose albumin but not low-dose albumin was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (IL6, GCSF, IL1RN, and VEGF) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (pilot-PRECIOSA study and INFECIR-2 study) we found that albumin treatment reduces systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov no: NCT00968695 and NCT03451292

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Introduction: Overexpression of the receptor tyrosine kinase HER2 has been reported in around 25% of human breast cancers, usually indicating a poor prognosis. As a result, HER2 has become a popular target for therapy. However, despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments. It is therefore important to understand the underlying mechanism of resistance and to develop more effective therapeutic interventions for breast cancer. Methods: The sensitivity of a panel of seven breast cancer cell lines to treatment with various types HER-family inhibitors alone, or in combination with a selection of other tyrosine kinase inhibitors (TKIs) or chemotherapeutic agents was determined using the Sulforhodamine B colorimetric assay. Receptor expression, cell-cycle distribution, cell signalling and cell migration were determined using flow cytometry, Western blot and Incucyte Zoom Live-Cell Analysis System respectively. Results: Overall, breast cancer cells were more sensitive to treatment with the irreversible pan-HER family inhibitors, particularly afatinib and neratinib, than treatment with the first-generation reversible inhibitors. Of three HER-2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors (IC50s as low as 3 nM), while MDA-MB-453 was relatively resistant (lowest IC50 = 0.11 μM). When the HER-family inhibitors were combined with other agents such as NVP-AEW541 (an IGF-1R inhibitor), dasatinib (a Src inhibitor) or crizotinib (a c-Met/ALK inhibitor), such combination produced synergistic effects in some of the cell lines examined. Interestingly, co-targeting of Src and HER-family members in MDA-MB-453 cells led to synergistic growth inhibition, suggesting the importance of Src in mediating resistance to HER2-targeting agents. Finally, treatment with the irreversible HER family blockers and dasatinib were also most effective at inhibiting the migration of breast cancer cells. Conclusion: We concluded that the irreversible inhibitors of HER-family members are generally more effective at inhibiting growth, downstream signalling and migration compared with reversible inhibitors, and that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation