Silver nanoparticles (AgNPs) containing consumer products have been proliferating in the market due to its unique antimicrobial property, however, lack of in-depth knowledge about their potential ...effect on human health in a longer run is of great concern. Therefore, we investigated dose-dependent in vivo effect of AgNPs using Drosophila as a model system. Drosophila, a genetically tractable organism with distinct developmental stages, short life cycle and significant homology with human serves as an ideal organism to study nanomaterial-mediated toxicity. Our studies suggest that ingestion of AgNPs in Drosophila during adult stage for short and long duration significantly affects egg laying capability along with impaired growth of ovary. Additionally, dietary intake of AgNPs from larval stage has more deleterious effects that result in reduced survival, longevity, ovary size and egg laying capability at a further lower dosage. Interestingly, the trans-generational effect of AgNPs was also observed without feeding progeny with AgNPs, thereby suggesting its impact from previous generation. Our results strongly imply that higher doses of AgNPs and its administration early during development is detrimental to the reproductive health and survival of Drosophila that follows in generations to come without feeding them to AgNPs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fractal and dendrimer growth patterns of polypyrrole were obtained during electrochemical polymerization of pyrrole in systems (A) pyrrole−sodium dodecyl sulfate (NaDS)−water and (B) ...pyrrole−NaDS−cetyl trimethyl ammonium bromide (CTAB)−water. Different morphological transitions including compact → flower-like and fractal → dendrimer → fractal were observed depending on experimental conditions. Growth kinetics during electropolymerization of pyrrole was studied. Growth rate was found to be higher in system A than in B. Effect of NaDS, pyrrole, and field intensity on morphology and weight of polymer aggregates was also studied in both the systems. Different empirical equations were obeyed under different conditions. Electropolymerized aggregates were characterized by transmission electron microscopy (TEM), powder X-ray diffraction (XRD), electrical conductivity measurement, and reflectance spectroscopy. TEM studies revealed that the particle size decreased to ∼140−200 nm in the presence of CTAB. The decrease in particle size on addition of CTAB was also observed in XRD studies. Reflectance spectra of the polymer aggregates support the large π-conjugation in the dendrimer. During electropolymerization, oscillations in potential were monitored as a function of time. Results indicated that growth pattern and electric potential oscillations were interrelated. In the case of fractal growth, the amplitude of chaotic oscillation was higher than the amplitude of oscillation during the growth of dendrimer. Growth morphologies and electric potential oscillations have been explained on the basis of modified Diaz’s mechanism.
Among several nanoparticles, silver nanoparticles (AgNPs) are extensively used in a wide variety of consumer products due to its unique antimicrobial property. However, dosage effect of AgNPs on ...behavior and metabolic activity in an in vivo condition is not well studied. Therefore, to elucidate the impact of AgNPs on behavior and metabolism, systematic and detailed dosages study of AgNPs was performed by rearing Drosophila melanogaster on food without and with AgNPs. We found that dietary intake of AgNPs at early larval stage leads to behavioral abnormalities such as poor crawling and climbing ability of larvae and adults respectively. Interestingly, intake of higher dosage of AgNPs at larval stage significantly altered metabolic activity that includes lipid, carbohydrate and protein levels in adult flies. Further, detailed analysis revealed that AgNPs causes remarkable reduction in the number of lipid droplets (LDs) which are lipid storage organelles in Drosophila. We also observed an increased production of reactive oxygen species (ROS) in AgNPs ingested larval tissues. These results strongly imply that higher dosage of AgNPs ingestion from early larval stage of Drosophila is inimical and thereby draws concern towards the usage of AgNPs in consumer goods.
With the extensive usage of gold nanoparticles (AuNPs) in various industrial sectors and biomedical applications, evaluation of their possible effects on human health becomes imperative. Therefore, ...the present study was aimed toward assessing the dose-dependent impact of AuNPs ingestion on metabolic homeostasis using Drosophila melanogaster as a model system. We found that larval ingestion of higher dose of AuNPs significantly reduced body weight. Further analysis of the crucial energy reservoir showed selective alteration in carbohydrate levels without any change in the lipid and protein levels. Transcriptional downregulation of glycogen synthase further supported impaired glycogen metabolism in flies supplemented with higher dose of AuNPs. Additionally, ingestion of higher dose of AuNPs in larvae results in significantly increased levels of reactive oxygen species (ROS) in the peripheral tissues, suggestive of stress condition. Our findings clearly imply that supplementing higher doses of AuNPs at an early developmental stage can potentially cause weight loss, impair glycogen metabolism, and elevate ROS production. Therefore, determination of a biologically effective dose is critical for the safety of mankind and vulnerable populations at the workplace.
Cell growth and proliferation are two diverse processes yet always linked. Akt1, a serine/threonine kinase, is a multi-functional protein implicated in regulation of cell growth, survival and ...proliferation. Though it has a role in G1/S progression, the manner by which Akt1 controls cell cycle and blends cell growth with proliferation is not well explored. In this study, we characterize the Akt1 interactome as the cell cycle progresses from G0 to G1/S and G2 phase. For this, Akt1-overexpressing HEK293 cells were subjected to AP-MS. To distinguish between individual cell cycle stages, cells were cultured in the light, medium and heavy labelled SILAC media. We obtained 213 interacting partners of Akt1 from these studies. GO classification revealed that a significant number of proteins fall into functional classes related to cell growth or cell cycle processes. Of these, 32 proteins showed varying association with Akt1 in different cell cycle stages. Further analyses uncovered a subset of proteins showing counteracting effects so as to tune stage-specific progression through the cycle. Thus, our study provides some novel perspectives on Akt1-mediated regulation of the cell cycle and offers the framework for a detailed resolution of the downstream cellular mechanisms that are mediated by this kinase.
Huntington's disease (HD) is a devastating neurodegenerative disorder with no disease-modifying treatments available. The disease is caused by expansion of a CAG trinucleotide repeat and manifests ...with progressive motor abnormalities, psychiatric symptoms, and cognitive decline. Expression of an expanded polyglutamine repeat within the Huntingtin (Htt) protein impacts numerous cellular processes, including protein folding and clearance. A hallmark of the disease is the progressive formation of inclusions that represent the culmination of a complex aggregation process. Methylene blue (MB), has been shown to modulate aggregation of amyloidogenic disease proteins. We investigated whether MB could impact mutant Htt-mediated aggregation and neurotoxicity. MB inhibited recombinant protein aggregation in vitro, even when added to preformed oligomers and fibrils. MB also decreased oligomer number and size and decreased accumulation of insoluble mutant Htt in cells. In functional assays, MB increased survival of primary cortical neurons transduced with mutant Htt, reduced neurodegeneration and aggregation in a Drosophila melanogaster model of HD, and reduced disease phenotypes in R6/2 HD modeled mice. Furthermore, MB treatment also promoted an increase in levels of BDNF RNA and protein in vivo. Thus, MB, which is well tolerated and used in humans, has therapeutic potential for HD.
Huntington's disease (HD) is a progressive, dominantly inherited neurological disorder caused by an abnormal expansion of polyglutamine (polyQ) repeat within the Huntingtin (Htt) protein with no ...disease modifying treatments. In a Drosophila model of HD, expression of mutant Huntingtin (Htt) protein with expanded polyQ leads to formation of inclusion bodies (IBs), increase in cellular toxicity, progression of motor disabilities and reduced viability. Multiple cellular events such as oxidative stress, mitochondrial dysfunction, inflammation and transcriptional dysregulation are reported to contribute to pathology, however, till date there are no disease-modifying treatments with least side effects. Therefore, we investigated effect of the phytochemical curcumin on HD pathogenesis. Curcumin, a phytochemical and commonly used ingredient in Asian food has a wide spectrum of anti-oxidant, anti-inflammatory and anti-fibrilogenic properties. In this study, we provide evidence that curcumin significantly ameliorates disease symptoms in a Drosophila model of HD by suppressing cell death and can be a key to halting the progression of Huntington's disease with least side effects.
It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC.
The study population included 508 patients with ...561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed.
At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio HR = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β = 10 BED10, HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively).
In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.
Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment ...of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.
Huntington's disease (HD) is an inherited, progressively debilitating disorder marked by prominent degeneration in striatal and cortical brain regions. HD is caused by (CAG)n repeat expansion in ...huntingtin (HTT) gene that translates into a mutant form of the ubiquitously present Huntingtin (HTT) protein. Extensive metabolic dysfunction coexisting with overt neuropathies has been evidenced in clinical and experimental settings of HD. Body weight loss despite normal to high caloric intake remains a critical determinant of the disease progression and a challenge for therapeutic interventions. In the present study, we intended to monitor the cellular and molecular perturbations in Drosophila, caused by pan-neuronal expression of mHTT (mutant Huntingtin) protein. We found aberrant transcription profile of key lipolytic and lipogenic genes in whole-body of the fly with disease progression. Interestingly, fatbody undergoes extensive alteration of vital cellular processes and eventually surrenders to increased apoptotic cell death in terminal stage of the disease. Extensive mitochondrial dysfunction from early disease stage along with calcium derangement at terminal stage were observed in fatbody, which contribute to its deteriorating integrity. All the mechanisms were monitored progressively, at different disease stages, and many alterations were documented in the early stage itself. Our study hence provides insight into the mechanisms through which neuronal expression of mHTT might be inflicting the profound systemic effects, specifically on lipid metabolism, and may open new therapeutic avenues for alleviation of the multidimensional disease.
•Transcriptional dysregulation of brummer and lipin is evidenced in HD condition.•Fatbody undergoes apoptosis with disease progression.•Reduced mitochondrial membrane potential in fatbody contributes to its apoptosis.•Calcium derangement is evident at terminal stage in fatbody of HD flies.
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