Memory loss or dementia is a progressive disorder, and one of its common forms is Alzheimer's disease (AD), effecting mostly middle aged and older adults. In the present study, we developed Rivastigmine (RIV) nanoparticles using poly(lactic-co-glycolic acid) (RIV-loaded PLGA NPs) and polyvinyl alcohol (PVA). The prepared RIV-PLGA nanoparticles was evaluated for the management of Alzheimer's disease (AD). The nanoparticles were prepared by the slightly modified nano-precipitation technique. The developed formulations were evaluated for particle size, zeta potential (ZP), polydispersibility index (PDI) and surface morphology and drug content. The experimental result revealed that prepared RIV-loaded PLGA NPs (F1) was optimized having particle size (61.2 ± 4.6 nm), PDI (0.292), ZP (-11.2 ± 1.2). SEM study confirms the prepared nanoparticles depicted non-aggregated as well smooth surface particles without any fracture. This formulation (F1) was further assessed for in vivo studies on animal model. A pharmacological screening on an animal model of Alzheimer's disease revealed that RIV-loaded PLGA NPs formulations treat CNS disorders like Alzheimer's effectively. In addition to that, an in-vivo brain cholinesterase estimation study found that, animals treated with optimized formulation significantly (p < 0.01) reduced brain cholinesterase activity when compared to scopolamine-treated animals. According to the above results, it can be concluded that RIV-loaded PLGA NPs are ideal carriers for delivering the drug at a specific target site in the brain, thus may treat Alzheimer's disease efficiently and improve patient compliance.
Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.
Compared to the general population, patients with arthritis have a higher risk of fertility abnormalities, which have deleterious effects on both reproductive function and pregnancy outcomes, especially in patients wishing to conceive. These may be due to the disease itself or those of drug therapies. Despite the increasing use of rituximab in arthritis, limited data are available on its potential to induce aneuploidy in germ cells. Therefore, the aim of the current investigation was to determine if repeated treatment with rituximab affects the incidence of aneuploidy and redox imbalance in arthritic mouse sperm. Mice were treated with 250 mg/kg rituximab once weakly for 3 weeks, and then sperm were sampled 22 days after the last dose of rituximab. Fluorescence in situ hybridization assay with chromosome-specific DNA probes was used to evaluate the disomic/diploid sperm. Our results showed that rituximab had no aneuploidogenic effect on the meiotic stage of spermatogenesis. Conversely, arthritis induced a significantly high frequency of disomy, and treatment of arthritic mice with rituximab reduced the increased levels of disomic sperm. The occurrence of total diploidy was not significantly different in all groups. Reduced glutathione and8-hydroxydeoxyguanosine, markers of oxidative stress were significantly altered in arthritic animals, while rituximab treatment restored these changes. Additionally, arthritis severity was reduced after rituximab treatment. We conclude that rituximab may efficiently alleviate the arthritis-induced effects on male meiosis and avert the higher risk of abnormal reproductive outcomes. Therefore, treating arthritic patients with rituximab may efficiently inhibit the transmission of genetic anomalies induced by arthritis to future generations.
Arthritis, Rheumatoid , Semen , Humans , Male , Mice , Animals , Rituximab/pharmacology , Rituximab/therapeutic use , In Situ Hybridization, Fluorescence/methods , Mice, Inbred DBA , Spermatozoa , Aneuploidy , Arthritis, Rheumatoid/drug therapy
Fluoropyrimidine 5-fluorouracil (5-FU) is a DNA analogue broadly used in chemotherapy, though treatment-associated nephrotoxicity limits its widespread clinical use. Sinapic acid (SA) has potent antioxidant, anti-inflammatory, and anti-apoptotic effects, we investigated its protective effects against 5-FU-induced nephrotoxicity in a rat model. We designated four treatment groups each Group I (control) received five intraperitoneal saline injections (once daily) from days 17 to 21; Group II received five intraperitoneal injections of 5-FU (50 mg/kg/day) from days 17 to 21; Group III received an oral administration of SA (40 mg/kg) for 21 days and five intraperitoneal injections of 5-FU (50 mg/kg/day) from days 17 to 21; and Group IV received an oral administration of SA (40 mg/kg) for 21 days (n-six rats in each group). blood samples were collected on day 22 from each group. Animals were sacrificed and their kidneys removed, and instantly frozen. 5-FU caused oxidative stress, inflammation, and activation of the apoptotic pathway by upregulating Bax and Caspase-3 and downregulating Bcl-2. However, SA exposure reduced serum toxicity indicators, boosted antioxidant defences, and reduced kidney apoptosis, which was confirmed by histopathological analysis. Therefore, prophylactic administration of SA could inhibit 5-FU-induced renal injuries in rats via suppression of renal inflammation and oxidative stress, primarily through regulation of NF-κB and proinflammatory cytokines, inhibition of renal apoptosis, and restoration of tubular epithelial antioxidant activities and cytoprotective defences.
Purpose: The clinical study of fulminant hepatic failure is challenging due to its high mortality and relative rarity, necessitating reliance on pre-clinical models to gain insight into its pathophysiology and develop potential therapies. Methods and Results: In our study, the combination of the commonly used solvent dimethyl sulfoxide to the current-day model of lipopolysaccharide/d-galactosamine-caused fulminant hepatic failure was found to cause significantly greater hepatic damage, as indicated by alanine aminotransferase level. The effect was dose-dependent, with the maximum increase in alanine aminotransferase observed following 200 µl/kg dimethyl sulfoxide co-administration. Co-administration of 200 µl/kg dimethyl sulfoxide also remarkably increased histopathological changes induced by lipopolysaccharide/d-galactosamine. Importantly, alanine aminotransferase levels and survival rate in the 200 µl/kg dimethyl sulfoxide co-administration groups were both greater than those in the classical lipopolysaccharide/d-galactosamine model. We found that dimethyl sulfoxide co-administration aggravated lipopolysaccharide/d-galactosamine-caused liver damage by stimulating inflammatory signaling, as indicated by tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) levels. Further, nuclear factor kappa B (NF-kB) and transcription factor activator 1 (STAT1) were upregulated, as was neutrophil recruitment, indicated by myeloperoxidase activity. Hepatocyte apoptosis was also increased, and greater nitro-oxidative stress was noted, as determined based on nitric oxide, malondialdehyde, and glutathione levels. Conclusion: Co-treatment with low doses of dimethyl sulfoxide enhanced the lipopolysaccharide/d-galactosamine-caused hepatic failure in animals, with higher toxicity and greater survival rates. The current findings also highlight the potential danger of using dimethyl sulfoxide as a solvent in experiments involving the hepatic immune system, suggesting that the new lipopolysaccharide/d-galactosamine/dimethyl sulfoxide model described herein could be used for pharmacological screening with the goal to better understand hepatic failure and evaluate treatment approaches.
Recent research has shown that phytocomponents may be useful in the treatment of renal toxicity. This study was conducted to evaluate the renal disease hirsutidin in the paradigm of renal toxicity induced by cisplatin. Male Wistar rats were given cisplatin (3 mg/kg body weight/day, for 25 days, i.p.) to induce renal toxicity. Experimental rats were randomly allocated to four different groups: group I received saline, group II received cisplatin, group III received cisplatin + hirsutidin (10 mg/kg) and group IV (per se) received hirsutidin (10 m/kg) for 25 days. Various biochemical parameters were assessed, oxidative stress (superoxide dismutase (SOD), glutathione transferase (GSH), malonaldehyde (MDA) and catalase (CAT)), blood-chemistry parameters (blood urea nitrogen (BUN) and cholesterol), non-protein-nitrogenous components (uric acid, urea, and creatinine), and anti-inflammatory-tumor necrosis factor-α (TNF-α), interleukin-1ß(IL-1ß). IL-6 and nuclear factor-kB (NFκB) were evaluated and histopathology was conducted. Hirsutidin alleviated renal injury which was manifested by significantly diminished uric acid, urea, urine volume, creatinine, and BUN, compared to the cisplatin group. Hirsutidin restored the activities of several antioxidant enzyme parameters-MDA, CAT, GSH, and SOD. Additionally, there was a decline in the levels of inflammatory markers-TNF-α, IL-1ß, IL-6, and NFκB-compared to the cisplatin group. The current research study shows that hirsutidin may act as a therapeutic agent for the treatment of nephrotoxicity induced by cisplatin.
Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS.
Acetaminophen/toxicity , Liver/drug effects , Oligopeptides/therapeutic use , Proteasome Inhibitors/therapeutic use , Acetaminophen/administration & dosage , Acetaminophen/adverse effects , Animals , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/genetics , Gene Expression Regulation , Glutathione , Inflammation/drug therapy , Injections, Intraperitoneal , Liver/metabolism , Male , Mice , Nitric Oxide Synthase Type II/drug effects , Nitric Oxide Synthase Type II/genetics , Oligopeptides/administration & dosage , Oligopeptides/pharmacology , Oxidative Stress/drug effects , Proteasome Inhibitors/pharmacology , Reactive Oxygen Species
Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen-induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N-acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N-acetylcystiene in the treatment of acetaminophen toxicity.
Acetaminophen/toxicity , Acetylcarnitine/pharmacology , Chemical and Drug Induced Liver Injury/drug therapy , Liver/drug effects , Animals , Antioxidants , Chemical and Drug Induced Liver Injury/prevention & control , Male , Mice , Oxidative Stress , Protective Agents/pharmacology
