4-(4-Hydroxy-3-methoxyphenyl)-2-butanone modulates redox signal in gamma-irradiation-induced nephrotoxicity in rats

Cellular exposure to ionising radiation leads to oxidative stress events, which refer to elevated intracellular levels of reactive oxygen species (ROS). The elevated levels of ROS significantly contributed to γ-radiation (IR) induced cytotoxicity. In an attempt to minimise these cytotoxic effects, antioxidant compounds have been identified to counteract radiation- associated toxicities. We mainly aimed to study the protective effect of 4-(4-hydroxy-3-methoxyphenyl)-2-butanone (HMB) on IR-induced nephrotoxicity, whereas it was previously shown to have anti-inflammatory effects in different inflammation models. Animals were treated orally with HMB (25?mg/kg b.wt daily) then performed by whole-body gamma-irradiation of animals with 6?Gy; a single dose applied on the 15th day and animals were sacrificed at the end of the 23rd day. It was found that IR exposure significantly induced renal oxidative injury that accompanied by inflammatory disturbance. Also, NADPH oxidase and iNOS gene expressions were significantly up-regulated, while the mitochondrial enzymes (complex I &; II) were significantly down-regulated in IR exposed animals. Additionally, Western immunoblotting analysis of signalling growth factor protein; p38 MAPK was significantly overexpressed. Interestingly, HMB treatment showed statistically significant amelioration in parameters with an improved histological structure upon the IR-induced nephrotoxicity. It can be concluded that modulation of NADPH-oxidase, iNOS and mitochondrial enzymes by HMB might be responsible for the amendment of the antioxidant status and impairment of p38 MAPK signal, thus attenuate the nephrotoxicity induced post IR exposure.     

Gadopentatic acid affects in vitro proliferation and doxorubicin response in human breast adenocarcinoma cells

Contrasting agents (CAs) that are administered to patients during magnetic resonance imaging to facilitate tumor identification are generally considered harmless. However, gadolinium (Gd) based contrast agents can be retained in the body, inflicting specific cell line cytotoxicity. We investigate the effect of Gadopentatic acid (Gd-DTPA) on human breast adenocarcinoma MCF-7 cells. These cells exhibit a toggle switch response: exposure to 0.1 and 1 mM concentrations of Gd-DTPA enhances proliferation, which is hindered at a higher 10 mM concentration. Proliferation is enhanced when cells transition to 3D morphologies in post confluent conditions. The proliferation dependence on the concentration of CA is absent for Hs 578T and MDA-MB-231 triple negative cell lines. MCF-7 cells reveal a double toggle switch related to the expression of VEGF, which goes through high–low–high downregulation when cells are exposed to 0.1, 1, and 10 mM Gd-DTPA, respectively. Finally, doxorubicin drug response is assessed, which also reveals a double toggle switch behavior, where drug cytotoxicity exhibits a nonlinear dependence on the CA concentration. A toggle switch in cell characteristics that are exposed to 1 mM of Gd-DTPA amplifies the importance of this threshold, affecting several cell behaviors if surpassed. This work emphasizes the important effects that CAs can have on cells, specifically Gd-DTPA on MCF-7 cells, and the implications for cell growth and drug response during clinical and synthetic biology procedures.     

Pharmacokinetic evaluation of daclatasvir and ledipasvir in healthy volunteers using a validated highly sensitive spectrofluorimetric method

A simple, highly sensitive and selective spectrofluorimetric method has been developed and fully validated for the determination of daclatasvir (DAC) and ledipasvir (LED) in tablets and human plasma. The method is based on measurement of the native fluorescence in methanol at λ_em 384 nm after excitation at λ_ex 318 nm for DAC and in acetonitrile at λ_em 402 nm after excitation at λ_ex 340 nm for LED. The fluorescence intensity (FI) concentration plot was rectilinear over the ranges 1.2–12, 0.1–18 ng ml^?1 and 9–90, 1–100 ng ml^?1 with a good correlation of r = 0.9994 to r = 0.9997 in standard solution and human plasma for DAC and LED, respectively. The extraction of analytes from plasma was performed using methanol and acetonitrile as a precipitating agent with lower limit of quantification (LLOQ) of 0.1 and 1.0 ng ml^?1 for DAC and LED; respectively. The proposed method was validated according to the US Food and Drug Administration (FDA) guidelines and successfully applied for estimating the pharmacokinetic parameters of DAC and LED following oral administrations of their tablets.     

Serum circulating cell free DNA as potential diagnostic and prognostic biomarker in non small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) is leading cause of cancer related death and the survival rate for patients with NSCLC remain poor so early diagnosis of NSCLC represents the best opportunity for cure. Cell-free DNA (cf-DNA) is extracellular nucleic acids found in cell-free plasma/serum of humans, given the recent approval of a liquid biopsy in lung cancer, the use of circulating tumor DNA as a novel non-invasive diagnostic and prognostic biomarker is promising.ObjectivesStudying whether the concentrations of circulating Cell Free DNA in serum can be used as a diagnostic and prognostic biomarker for NSCLC patients.MethodThis study was carried out on 140 subjects included 60 patients with non small cell lung cancer,40 patients with Chronic Obstructive Pulmonary Disease (COPD) and 40 healthy controls. Quantitative analysis of serum circulating cf-DNA was done b y AlU-based quantitative real time PCR. Serum level of CEA was measured by ELISA.ResultsNSCLC patients demonstrated significantly higher values of each of ALU 215, ALU 247, and DNA integrity than both COPD patients and controls. On ROC curve analysis, the total accuracy of ALU 247, ALU 115, DNA integrity (92.1%, 83.6%, 56.4%) at cutoff points (325, 565 & 0.48) respectively. On combining both DNA integrity and CEA, improved sensitivity to 93.3% was noted. For NSCLC patients, ALU 115 & ALU 247 increased significantly with more advanced stage and highest level was noticed in metastatic patients. Regarding survival there was better overall survival among patients with low DNA integrity.ConclusionSerum cf-DNA concentrations and integrity index may be valuable tool in early diagnosis of NSCLC and prediction of prognosis of those patients.     

Ultrastructure of spermatogenesis and mature spermatozoa in the flatworm Prosthiostomum siphunculus (Polycladida,Cotylea)

This is the first study investigating spermatogenesis and spermatozoan ultrastructure in the polyclad flatworm Prosthiostomum siphunculus. The testes are numerous and scattered as follicles ventrally between the digestive ramifications. Each follicle contains the different stages of sperm differentiation. Spermatocytes and spermatids derive from a spermatogonium and the spermatids remain connected by intercellular bridges. Chromatoid bodies are present in the cytoplasm of spermatogonia up to spermatids. During early spermiogenesis, a differentiation zone appears in the distal part of spermatids. A ring of microtubules extends along the entire sperm shaft just beneath the cell membrane. An intercentriolar body is present and gives rise to two axonemes, each with a 9 + “1” micro‐tubular pattern. Development of the spermatid leads to cell elongation and formation of a filiform, mature spermatozoon with two free flagella and with cortical microtubules along the sperm shaft. The flagella exit the sperm shaft at different levels, a finding common for acotyleans, but so far unique for cotylean polyclads. The Golgi complex produces numerous electron‐dense bodies of two types and of different sizes. These bodies are located around a perinuclear row of mitochondria. The elongated nucleus extends almost along the entire sperm body. The nucleus is wide in the proximal part and becomes narrow going towards the distal end. Thread‐like chromatin mixed with electron‐dense intranuclear spindle‐shaped bodies are present throughout nucleus. The general sperm ultrastructure, the presence of intranuclear bodies and a second type of cytoplasmic electron‐dense bodies may provide characters useful for phylogenetic analysis.     

Bioerosion in the Miocene Reefs of the northwest Red Sea,Egypt

Macroborings provide detailed information on the bioerosion, accretion and palaeoenvironment of both modern and fossil reefs. Dolomitized reefal carbonates in the Um Mahara Formation exhibit an outstanding example of spatially distributed, well‐preserved bioerosion structures in tropical to subtropical syn‐rift Miocene reefs. Ten ichnospecies belonging to five ichnogenera are identified; three belonging to the bivalve‐boring ichnogenus Gastrochaenolites, three attributed to the sponge‐boring ichnogenus Entobia, and four ichnospecies assigned to three worm‐boring ichnogenera Trypanites, Maeandropolydora and Caulostrepsis. The distribution of the reported borings is strongly linked to the palaeo‐reef zones. Two distinctive ichnological boring assemblages are recognized. The Gastrochaenolites‐dominated assemblage reflects shallower‐marine conditions, under water depths of a few metres, mostly in back‐reef to patch‐reef zones of a back‐reef lagoon. The Entobia‐dominated assemblage signifies relatively deeper marine conditions, mostly in reef core of the fringing Miocene reefs. These ichnological assemblages are attributed herein to the Entobia sub‐ichnofacies of the Trypanites ichnofacies. This ichnofacies indicates boring in hard carbonate substrates (such as corals, rhodoliths, carbonate cements and hardgrounds) during periods of non‐sedimentation or reduced sediment input.