Effects of Tamiflu and Adamine on histology and ultrastructure of the liver of albino mice

Background Tamiflu (Oseltamivir) and Adamine (Amantadine HCl) are antiviral drugs which are used for prevention and treatment for influenza. The present study was carried out to evaluate the effect of Tamiflu and Adamine on the liver of adult male albino mice from the histological and ultrastructural points of views. Results Histological examination of liver sections treated with Tamiflu and Adamine included enlargement and congestion of central and hepatic veins in addition to erosion of their endothelial lining cells, cytoplasmic vacuolation of hepatocytes, pyknosis of their nuclei, and dilatation of hepatic sinusoid. The electron microscopic investigation illustrated mitochondrial swelling, fragmented rough endoplasmic reticulum, cytoplasmic vacuolation, the nuclei with irregular envelope and condensed heterochromatin, dilated microvilli in sinusoid, in addition to active Kupffer cells have many lysosomes and filopodia in its membrane. Conclusion The study suggested that both drugs induced histopathological and ultrastructural alterations in hepatic tissue. In conclusion, Tamiflu and Adamine have pathological effects on liver of albino mice (Mus musculus).

Cytoplasmic vacuolation with endoplasmic reticulum stress directs sorafenib induced non-apoptotic cell death in hepatic stellate cells

The activated hepatic stellate cells (HSCs) are the major cells that secrete the ECM proteins and drive the pathogenesis of fibrosis in chronic liver disease. Targeting of HSCs by modulating their activation and proliferation has emerged as a promising approach in the development of anti-fibrotic therapy. Sorafenib, a multi-kinase inhibitor has shown anti-fibrotic properties by inhibiting the survival and proliferation of HSCs. In present study we investigated sorafenib induced cytoplasmic vacuolation mediated decreased cell viability of HSCs in dose and time dependent manner. In this circumstance, sorafenib induces ROS and ER stress in HSCs without involvement of autophagic signals. The protein synthesis inhibitor cycloheximide treatment significantly decreased the sorafenib-induced cytoplasmic vacuolation with increasing cell viability. Antioxidant human serum albumin influences the viability of HSCs by reducing sorafenib induced vacuolation and cell death. However, neither caspase inhibitor Z-VAD-FMK nor autophagy inhibitor chloroquine could rescue the HSCs from sorafenib-induced cytoplasmic vacuolation and cell death. Using TEM and ER organelle tracker, we conclude that the cytoplasmic vacuoles are due to ER dilation. Sorafenib treatment induces calreticulin and GPR78, and activates IRE1α-XBP1s axis of UPR pathway, which eventually trigger the non-apoptotic cell death in HSCs. This study provides a notable mechanistic insight into the ER stress directed non-apoptotic cell death with future directions for the development of efficient anti-fibrotic therapeutic strategies.

Cannabinoid Combination Induces Cytoplasmic Vacuolation in MCF-7 Breast Cancer Cells

This study evaluated the synergistic anti-cancer potential of cannabinoid combinations across the MDA-MB-231 and MCF-7 human breast cancer cell lines. Cannabinoids were combined and their synergistic interactions were evaluated using median effect analysis. The most promising cannabinoid combination (C6) consisted of tetrahydrocannabinol, cannabigerol (CBG), cannabinol (CBN), and cannabidiol (CBD), and displayed favorable dose reduction indices and limited cytotoxicity against the non-cancerous breast cell line, MCF-10A. C6 exerted its effects in the MCF-7 cell line by inducing cell cycle arrest in the G2 phase, followed by the induction of apoptosis. Morphological observations indicated the induction of cytoplasmic vacuolation, with further investigation suggesting that the vacuole membrane was derived from the endoplasmic reticulum. In addition, lipid accumulation, increased lysosome size, and significant increases in the endoplasmic reticulum chaperone protein glucose-regulated protein 78 (GRP78) expression were also observed. The selectivity and ability of cannabinoids to halt cancer cell proliferation via pathways resembling apoptosis, autophagy, and paraptosis shows promise for cannabinoid use in standardized breast cancer treatment.

Cytoplasmic Vacuolation and Tapetal Changes Induced by a Novel Analgesic Agent in Beagle Dogs

Drug-induced unique cytoplasmic vacuolation was found in the subchronic oral toxicity study of 4-dimethylamino-1-{3-(1-methyl-1H-imidazole-2-yl)propanoyl}piperidine (DMIP), a potential therapeutic agent for neuropathic pain, in beagle dogs. In the first study, DMIP was administered at a dose of 250, 500, or 1,000 mg/kg/day once daily for 14 days. Discoloration of tapetum lucidum accompanied by tapetal swelling was observed at ≥250 mg/kg/day. The tapetal swelling was correlated to the light microscopic observation of cytoplasmic vacuolation in tapetal cells, and similar vacuolation was observed in several other tissues, including the coronary artery and aortal arch, in a dose-dependent manner. Immunohistochemistry for lysosomal-associated membrane protein 2 indicated that the vacuoles were enlarged lysosomes. However, the nature of these vacuoles was different from that of phospholipidosis because no lamellar bodies were observed. In the second study, DMIP was administered at a dose of 10, 50, or 250 mg/kg/day once daily for 14 days followed by a 14-day recovery period. Tapetal changes and systemic vacuolation were not observed at ≤50 mg/kg/day, and vacuolation observed at 250 mg/kg/day was reversible. A few reports have described the enlargement of lysosomes not attributable to phospholipid accumulation. Our findings provide further information about the toxicological implications of drug-induced lysosomal swelling.

Toxicity assessment of agrochemical Almix in Heteropneustes fossilis through histopathological alterations

The present study was designed to assess the adverse effects of the agrochemical Almix on comparative basis in gill, liver and kidney of Heteropneustes fossilis through histological and ultrastructural observations under field (8 g/acre) and laboratory (66.67 mg/L) conditions. Exposure duration of both experiments was 30 days. Gill showed atrophy in secondary lamellae, hypertrophied gill epithelium, damage in chloride and pillar cells, and detachment of chloride cells from gill epithelium under laboratory condition, but hypertrophy in gill epithelium and fusion in secondary lamellae were seen under field condition. In gill, scanning electron microscopy (SEM) showed fragmentation in microridges, hyper-secretion of mucus and loss of normal array in microridges, while transmission electron microscopy (TEM) displayed dilated mitochondria and rough endoplasmic reticulum (RER), abnormal sized vacuolation in chloride cells under laboratory condition. In liver, hypertrophied and pyknotic nuclei, disarrangement of hepatic cords, and cytoplasmic vacuolation were prominent under laboratory study but in field condition the liver showed little alterations. TEM study showed severe degeneration in RER and mitochondria and cytoplasmic vacuolation under laboratory condition but dilated mitochondria were prominent in field observation. Kidney showed severe nephropathic effects including degenerative changes in proximal and distal convolute tubule, damage in glomerulus under light microscopy, while deformity in nucleus, fragmentation in RER, severe vacuolation and necrosis in kidney were prominent under TEM study. The results clearly demonstrated that responses were more prominent in laboratory than field study. Thus the responses displayed by different tissues of concerned fish species exposed to Almix could be considered as indications of herbicide toxicity in aquatic ecosystem.