The harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergetics.

Clomipramine, a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder, has been linked to a few cases of acute hepatotoxicity. It is also recognized as a compound that hinders the functioning of mitochondria. Hence, the effects of clomipramine on mitochondria should endanger processes that are somewhat connected to energy metabolism in the liver. For this reason, the primary aim of this study was to examine how the effects of clomipramine on mitochondrial functions manifest in the intact liver. For this purpose, we used the isolated perfused rat liver, but also isolated hepatocytes and isolated mitochondria as experimental systems. According to the findings, clomipramine harmed metabolic processes and the cellular structure of the liver, especially the membrane structure. The considerable decrease in oxygen consumption in perfused livers strongly suggested that the mechanism of clomipramine toxicity involves the disruption of mitochondrial functions. Coherently, it could be observed that clomipramine inhibited both gluconeogenesis and ureagenesis, two processes that rely on ATP production within the mitochondria. Half-maximal inhibitory concentrations for gluconeogenesis and ureagenesis ranged from 36.87 µM to 59.64 µM. The levels of ATP as well as the ATP/ADP and ATP/AMP ratios were reduced, but distinctly, between the livers of fasted and fed rats. The results obtained from experiments conducted on isolated hepatocytes and isolated mitochondria unambiguously confirmed previous propositions about the effects of clomipramine on mitochondrial functions. These findings revealed at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the FoF1-ATP synthase complex, and inhibition of mitochondrial electron flow. The elevation in activity of cytosolic and mitochondrial enzymes detected in the effluent perfusate from perfused livers, coupled with the increase in aminotransferase release and trypan blue uptake observed in isolated hepatocytes, provided further evidence of the hepatotoxicity of clomipramine. It can be concluded that impaired mitochondrial bioenergetics and cellular damage are important factors underlying the hepatotoxicity of clomipramine and that taking excessive amounts of clomipramine can lead to several risks including decreased ATP production, severe hypoglycemia, and potentially fatal outcomes.

Density Gradients, Cellular Structure and Thermal Conductivity of High-Density Polyethylene Foams by Different Amounts of Chemical Blowing Agent.

LDPE (low-density polyethylene) foams were prepared using the improved compression moulding technique (ICM) with relative densities ranging from 0.3 to 0.7 and with different levels of chemical blowing agents (from 1% to 20%). The density gradients, cellular structure and thermal conductivity of the foams were characterized. The density and amount of CBA used were found to have a significant effect on the cellular structure both at the mesoscale (density gradients) and at the microscale (different cell sizes and cell densities). In addition, the thermal conductivity of the samples is very sensitive to the local structure where the heat flux is located. The technique used to measure this property, the Transient Plane Source method (TPS), makes it possible to detect the presence of density gradients. A simple method for determining these gradients based on thermal conductivity data was developed.

Load Distribution on PET-G 3D Prints of Honeycomb Cellular Structures under Compression Load.

Energy resulting from an impact is manifested through unwanted damage to objects or persons. New materials made of cellular structures have enhanced energy absorption (EA) capabilities. The hexagonal honeycomb is widely known for its space-filling capacity, structural stability, and high EA potential. Additive manufacturing (AM) technologies have been effectively useful in a vast range of applications. The evolution of these technologies has been studied continuously, with a focus on improving the mechanical and structural characteristics of three-dimensional (3D)-printed models to create complex quality parts that satisfy design and mechanical requirements. In this study, 3D honeycomb structures of novel material polyethylene terephthalate glycol (PET-G) were fabricated by the fused deposition modeling (FDM) method with different infill density values (30%, 70%, and 100%) and printing orientations (edge, flat, and upright). The effectiveness for EA of the design and the effect of the process parameters of infill density and layer printing orientation were investigated by performing in-plane compression tests, and the set of parameters that produced superior results for better EA was determined by analyzing the area under the curve and the welding between the filament layers in the printed object via FDM. The results showed that the printing parameters implemented in this study considerably affected the mechanical properties of the 3D-printed PET-G honeycomb structure. The structure with the upright printing direction and 100% infill density exhibited an extension to delamination and fragmentation, thus, a desirable performance with a long plateau region in the load-displacement curve and major absorption of energy.

Enhanced cytotoxicity of imidacloprid by biotransformation in isolated hepatocytes and perfused rat liver.

Imidacloprid (IMD) is a neonicotinoid insecticide widely used in crops, pets, and on farm animals for pest control, which can cause hepatotoxicity in animals and humans. In a previous study using isolated rat liver mitochondria, we observed that IMD inhibited the activity of FoF1-ATP synthase. The aim of this study was to evaluate the effects of IMD on rat isolated hepatocytes and perfused rat liver, besides the influence of its biotransformation on the toxicological potential. For the latter goal, rats were pretreated with dexamethasone or phenobarbital, two classical cytochrome P-450 stimulators, before hepatocytes isolation or liver perfusion. IMD (150 and 200 µM) reduced state 3 mitochondrial respiration in digitonin-permeabilized cells that were energized with glutamate plus malate but did not dissipate the mitochondrial membrane potential. In intact (non-permeabilized) hepatocytes, the intracellular ATP concentration and cell viability were reduced when high IMD concentrations were used (1.5-3.0 mM), and only in cells isolated from dexamethasone-pretreated rats, revealing that IMD biotransformation increases its toxicity and that IMD itself affects isolated mitochondria or mitochondria in permeabilized hepatocytes in concentrations that do not affect mitochondrial function in intact hepatocytes. Coherently, in the prefused liver, IMD (150 and 250 µM) inhibited gluconeogenesis from alanine, but without affecting oxygen consumption and urea production, indicating that such effect was not of mitochondrial origin. The gluconeogenesis inhibition was incomplete and occurred only when the rats were pretreated with phenobarbital, signs that IMD biotransformation was involved in the observed effect. Our findings reveal that changes in hepatic energy metabolism may be acutely implicated in the hepatotoxicity of IMD only when animals and humans are exposed to high levels of this compound, and that IMD metabolites seem to be the main cause for its toxicity.

Effects of copper and lead exposure on the ecophysiology of the brown seaweed Sargassum cymosum.

The effects of the heavy metals copper (Cu) and lead (Pb) on Sargassum cymosum were evaluated by determining uptake capacity, growth rates, photosynthetic efficiency, contents of photosynthetic pigments and phenolic compounds, 2,2-diphenyl-1-picrylhydrazyl radical-scavenging capacity, and morphological and cellular changes. S. cymosum was cultivated with Cu and Pb separately and combined at concentrations of 10, 25, and 50 µM for 7 days in laboratory-controlled conditions. Seaweeds under Cu treatment showed the highest biosorption capacity, and growth rates were significantly reduced compared to the control. The photosynthesis/irradiance curves showed alterations in kinetic patterns in the metal-treated samples. Specifically, Cu treatment alone inhibited electron transport rate (ETR) response, while Pb alone induced it. However, samples treated with both Cu and Pb (Cu + Pb) showed inhibition in ETR. The total amount of pigments increased relative to control. Light microscopy showed an increase in phenolic compounds, with physodes migrating towards cortical cells. Scanning electronic microscopy revealed alterations in the typical rough surface of thallus, when compared with control, especially for Pb treatments. Based on these results, it could be concluded that Cu and Pb are stress factors for S. cymosum, promoting alterations in seaweed metabolism and stimulating protective mechanisms against oxidative stress. However, the high bioaccumulation capacity of both heavy metals indicates a possible application for S. cymosum as a biosorbent agent for contaminated wastewater when metals are in low concentrations.