Folate-Equipped Cationic Liposomes Deliver Anti-MDR1-siRNA to the Tumor and Increase the Efficiency of Chemotherapy

In this study, we examined the in vivo toxicity of the liposomes F consisting of 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride, lipid-helper 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and folate lipoconjugate (O-{2-[rac-2,3-di(tetradecyloxy)prop-1-yloxycarbonyl]aminoethyl}-O’-[2-(pteroyl-L-glutam-5-yl)aminoethyl]octadecaethyleneglycol) and investigated the antitumor effect of combined antitumor therapy consisting of MDR1-targeted siMDR/F complexes and conventional polychemotherapy using tumor xenograft initiated in immunodeficient mice. Detailed analysis of acute and chronic toxicity of this liposomal formulation in healthy C57BL/6J mice demonstrated that formulation F and parent formulation L (without folate lipoconjugate) have no acute and chronic toxicity in mice. The study of the biodistribution of siMDR/F lipoplexes in SCID mice with xenograft tumors formed by tumor cells differing in the expression level of folate receptors showed that the accumulation in various types of tumors strongly depends on the abandons of folate receptors in tumor cells and effective accumulation occurs only in tumors formed by cells with the highest FR levels. Investigating the effects of combined therapy including anti-MDR1 siRNA/F complexes and polychemotherapy on a multidrug-resistant KB-8-5 tumor xenograft in SCID mice demonstrated that siMDR/F increases the efficiency of polychemotherapy: the treatment leads to pronounced inhibition of tumor growth, reduced necrosis and inflammation, and stimulates apoptosis in KB-8-5 tumor tissue. At the same time, it does not induce liver toxicity in tumor-bearing mice. These data confirm that folate-containing liposome F mediated the extremely efficient delivery of siRNA in FR-expressing tumors in vivo and ensured the safety and effectiveness of its action.

Acute and Chronic Toxicity of Prothioconazole and its Metabolite Prothioconazole-Desthio To Daphnia Magna

Prothioconazole (PTC) is a broad-spectrum triazole fungicide. Current research has mainly focused on its efficacy and residues, with few studies on its toxicological effects. This study assessed the effects of PTC, and its metabolite prothioconazole-desthio (PTCd), on the inhibition of activity, growth, and reproduction of Daphnia magna using acute and chronic toxicity tests. Additionally, the dose-response relationship was established to determine sensitive biological indicators. The acute toxicity test shows that the 48 h EC50 of PTC and PTCd to D. magna were 2.82 and 5.19 mg/L, respectively. The chronic toxicity of PTC and PTCd to D. magna were 0.00860 and 0.132 mg/L, respectively, with the parent compound being 15.3 times more toxic than its metabolite. The acute to chronic toxicity ratio (ACR) was calculated using chronic toxicity data, with ACR values of 227 and 27.5 for PTC and PTCd, respectively. These results indicate that both PTC and PTCd affect the growth and reproduction of D. magna, and the toxicity of the parent compound is greater than that of its metabolite. In conclusion, the metabolites of this pesticide have sufficient toxicity to harm D. magna at relevant environmental concentrations, and their environmental risk should not be neglected.

Acute and Chronic Toxicity Studies of Ethanol Leaf Extract of Merremia Tridentata (Linn) Hallier F.

The acute and chronic toxicity evaluation of Ethanol leaf extract of Merremia tridentata (Linn) Halier F. (MTELE) was carried out on albino wistar rats. Phytochemical screening and acute toxicity profile of the extract were determined using standard methods. The animals were assigned into groups and administered varying doses of MTELE (100, 200, 400 mg/kg body weight and 0.2 ml of distilled water) for a period of hundred days (fourteen weeks). The body weight, relative organ weight, haematology, serum biochemical indices and histopathological studies of the liver, kidney, spleen, heart, and lungs were appropriately carried out to determine propensity of possible toxicity. Phytochemical screening revealed the presence of alkaloids, tannins, cardiac glycosides, saponins, steroids, triterpenes, flavonoids while anthraquinone and cyanogenic glycosides were absent. The median lethal dose LD50 was estimated as 2200 mg/kg body weight. There was significant (p<0.05) reduction in the percentage change in body weight of rats administered 200 and 400 mg/kg/day dose of the extract for 100days when compared to the control group. Moreover, there was a significant (p<0.05) reduction in the relative weight of the spleen of rats and significant (p<0.05) increase in the relative weight of the liver, kidney, heart and lungs of rats administered 400 mg/kg/day dose. All serum biochemical parameters studied showed significant (p<0.05) increase in group administered 400 mg/kg body weight dose while alkaline phosphatase, aspartate amino transferase, creatine kinase, lactate dehydrogesase and potassium ion showed significant increase (p<0.05) in the group administered 200 mg/kg/day. There is no significant change in hematological parameters like RBC, hemoglobin, hematocrit, platelets, monocytes, basophils, MCV, MCH, MCHC, in the extract treated animals except the lymphocyte that showed a significant (p<0.05) reduction only in the group treated with 400 mg/kg body weight dose. Administration of MTELE at 200 mg/kg body weight did not occasioned any histo-architectural change in the liver and spleen but caused varying degree of remarkable histological derangement in the other tissues. Furthermore, there were remarkable pathologies in the liver, kidney, spleen, heart and lungs ranging from vascular congestion, haemorrhage, fibrosis, to renal and myocardial damage in the group treated with 400 mg/kg/day dose for hundred days. However, 100 mg/kg body weight dose showed no significant difference (p>0.05) in all the parameters evaluated indicating safety at this dosage. Ethanol leaf extract of Merremia tridentata (Linn) Halier F. (MTELE) may not be safe at chronic administration even at dosage as low as 200 mg/kg body weight. The plant should be cautiously employed to avoid unwarranted complication on long term administration.

Comparison of Joint Effect of Acute and Chronic Toxicity for Combined Assessment of Heavy Metals on Photobacterium sp.NAA-MIE

Predicting the crucial effect of single metal pollutants against the aquatic ecosystem has been highly debatable for decades. However, dealing with complex metal mixtures management in toxicological studies creates a challenge, as heavy metals may evoke greater toxicity on interactions with other constituents rather than individually low acting concentrations. Moreover, the toxicity mechanisms are different between short term and long term exposure of the metal toxicant. In this study, acute and chronic toxicity based on luminescence inhibition assay using newly isolated Photobacterium sp.NAA-MIE as the indicator are presented. Photobacterium sp.NAA-MIE was exposed to the mixture at a predetermined ratio of 1:1. TU (Toxicity Unit) and MTI (Mixture Toxic Index) approach presented the mixture toxicity of Hg2+ + Ag+, Hg2+ + Cu2+, Ag+ + Cu2+, Hg2+ + Ag+ + Cu2+, and Cd2+ + Cu2+ showed antagonistic effect over acute and chronic test. Binary mixture of Cu2+ + Zn2+ was observed to show additive effect at acute test and antagonistic effect at chronic test while mixture of Ni2+ + Zn2+ showing antagonistic effect during acute test and synergistic effect during chronic test. Thus, the strain is suitable and their use as bioassay to predict the risk assessment of heavy metal under acute toxicity without abandoning the advantage of chronic toxicity extrapolation.