Evaluation of butyric acid as a potential supportive treatment in anterior uveitis

Background: The aim of the study was to evaluate the anti-inflammatory effect of topically administered aqueous sodium butyrate solution in an endotoxin-induced uveitis rat model and compare the results with corticosteroid treatment. Material and methods: Forty female Lewis rats were randomly divided into five groups. Uveitis was induced by a single lipopolysaccharide (LPS) injection into each footpad of each LPS+ rat. Group I (naive) received saline injected into the footpad of each rat at a dose of 0.1 mL/each footpad; Group II (LPS+) received saline solution topically. Group III (LPS+ Dex) — an aqueous dexamethasone sodium phosphate solution topically; Group IV (LPS+ But 0.5 mM) — 0.5 mM aqueous sodium butyrate solution topically, Group V (LPS+ But 1 mM) — 1.0 mM aqueous sodium butyrate solution topically. Clinical scoring of inflammation in rat eyes was evaluated before LPS injection and after 24 hours. The iris involvement, posterior synechiae presence, and insight into the eye fundus were clinicallyassessed. A histopathological examination was also performed. The rats were euthanatized 24 hours after LPS injection, and aqueous humor (AqH) was collected from the eyes by anterior chamber puncture. Levels of inflammatory cytokines and chemokines in the AqH were determined with commercially available Luminex assays. Results: Development of iris hyperemia associated with miosis and poor visibility of fundus details occurred 24 hours after LPS injection. Compared to the LPS+ group, the clinical scores were strongly suppressed in rats treated with Dexamethasone and moderately diminished in LPS+ But 0.5 mM. These clinical features were not observed in the controls (Group 1 — naive). Data from inflammatory cytokines evaluation indicates no significant differences between the LPS+ group (Group 2) and the LPS+ But groups (Groups 4 and 5). Histopathological examinations suggest that hyperemia, corneal stratification, and lesions were less common in the group of animals treated with BA in a lower concentration. Conclusion: Topical administration of sodium butyrate as a therapeutic agent might alleviate the severity of intraocular inflammation in eyes with uveitis. The effect of sodium butyrate was slight but clinically significant in 0.5 mM dose, so other doses of topically administered sodium butyrate should be considered and evaluated in further research

In Vivo Assessment of Parenteral Formulations of Oligo(3-Hydroxybutyric Acid) Conjugates with the Model Compound Ibuprofen

Polymer-drug conjugates have gained significant attention as pro-drugs releasing an active substance as a result of enzymatic hydrolysis in physiological environment. In this study, a conjugate of 3-hydroxybutyric acid oligomers with a carboxylic acid group-bearing model drug (ibuprofen) was evaluated in vivo as a potential pro-drug for parenteral administration. Two different formulations, an oily solution and an o/w emulsion were prepared and administered intramuscularly (IM) to rabbits in a dose corresponding to 40 mg of ibuprofen/kilogramme. The concentration of ibuprofen in blood plasma was analysed by HPLC, following solid–phase extraction and using indometacin as internal standard (detection limit, 0.05 μg/ml). No significant differences in the pharmacokinetic parameters (Cmax, Tmax, AUC) were observed between the two tested formulations of the 3-hydroxybutyric acid conjugate. In comparison to the non-conjugated drug in oily solution, the relative bioavailability of ibuprofen conjugates from oily solution, and o/w emulsion was reduced to 17% and 10%, respectively. The 3-hydroxybutyric acid formulations released the active substance over a significantly extended period of time with ibuprofen still being detectable 24 h post-injection, whereas the free compound was almost completely eliminated as early as 6 h after administration. The conjugates remained in a muscle tissue for a prolonged time and can hence be considered as sustained release systems for carboxylic acid derivatives

Idebenone and Resveratrol Extend Lifespan and Improve Motor Function of HtrA2 Knockout Mice

Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD

Molecular Biology of Osteosarcoma

Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond–Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future

Tryptophan Pathway Abnormalities in a Murine Model of Hereditary Glaucoma

BACKGROUND It has been shown that a possible pathogenetic mechanism of neurodegeneration in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. METHODS Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. RESULTS TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. CONCLUSIONS Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma