RESUMO

BACKGROUND: Ischemia-reperfusion (IR) injury is one of the leading causes of early graft dysfunction in liver transplantation. Techniques such as ischemic preconditioning protect the graft through the activation of the hypoxia-inducible factors (HIF), which are downregulated by the EGLN family of prolyl-4-hydroxylases, a potential biological target for the development of strategies based on pharmacological preconditioning. For that reason, this study aims to evaluate the effect of the EGLN inhibitor sodium (S)-2-hydroxyglutarate [(S)-2HG] on liver IR injury in Wistar rats. METHODS: Twenty-eight female Wistar rats were divided into the following groups: sham (SH, n = 7), non-toxicity (HGTox, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days), IR (n = 7, total liver ischemia: 20 minutes, reperfusion: 60 minutes), and (S)-2HG+IR (HGIR, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days, total liver ischemia as the IR group). Serum ALT, AST, LDH, ALP, glucose, and total bilirubin were assessed. The concentrations of IL-1ß, IL-6, TNF, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured in liver tissue, as well as the expression of Hmox1, Vegfa, and Pdk1, determined by RT-qPCR. Sections of liver tissue were evaluated histologically, assessing the severity of necrosis, sinusoidal congestion, and cytoplasmatic vacuolization. RESULTS: The administration of (S)-2HG did not cause any alteration in the assessed biochemical markers compared to SH. Preconditioning with (S)-2HG significantly ameliorated IR injury in the HGIR group, decreasing the serum activities of ALT, AST, and LDH, and the tissue concentrations of IL-1ß and IL-6 compared to the IR group. IR injury decreased serum glucose compared to SH. There were no differences in the other biomarkers assessed. The treatment with (S)-2HG tended to decrease the severity of hepatocyte necrosis and sinusoidal congestion compared to the IR group. The administration of (S)-2HG did not affect the expression of Hmox1 but decreased the expression of both Vegfa and Pdk1 compared to the SH group, suggesting that the HIF-1 pathway is not involved in its mechanism of hepatoprotection. In conclusion, (S)-2HG showed a hepatoprotective effect, decreasing the levels of liver injury and inflammation biomarkers, without evidence of the involvement of the HIF-1 pathway. No hepatotoxic effect was observed at the tested dose.

RESUMO

Natural products are an important source of bioactive molecules. However, the development of biological applications based on these compounds is hindered by intrinsic problems in their solubility, volatility, degradation, and bioavailability. Nanocarriers as drug administration systems promise to overcome these limitations by providing controlled and directed delivery. This review aims to present 1) the most frequently used nanocarriers as natural product administration systems, based on the progress of controlled and directed release, and 2) the challenges associated with the use of nanocarriers as therapeutic agents.

Assuntos

Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/administração & dosagem , Animais , Produtos Biológicos/química , Humanos , Nanomedicina/métodos

RESUMO

The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX → π*C═O interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX → π*C═O interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-C═O interactions are through the nO → π*C═O electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.

RESUMO

BACKGROUND: Ischemia-reperfusion (IR) injury is the main cause of delayed graft function in solid organ transplantation. Hypoxia-inducible factors (HIFs) control the expression of genes related to preconditioning against IR injury. During normoxia, HIF-α subunits are marked for degradation by the egg-laying defective nine homolog (EGLN) family of prolyl-4-hydroxylases. The inhibition of EGLN stabilizes HIFs and protects against IR injury. The aim of this study was to determine whether the EGLN inhibitors sodium (S)-2-hydroxyglutarate [(S)-2HG] and succinic acid (SA) have a nephroprotective effect against renal IR injury in Wistar rats. METHODS: (S)-2HG was synthesized in a 22.96% yield from commercially available L-glutamic acid in a two-step methodology (diazotization/alkaline hydrolysis), and its structure was confirmed by nuclear magnetic resonance and polarimetry. SA was acquired commercially. (S)-2HG and SA were independently evaluated in male and female Wistar rats respectively after renal IR injury. Rats were divided into the following groups: sham (SH), nontoxicity [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg], IR, and compound+IR [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg]; independent SH and IR groups were used for each assessed compound. Markers of kidney injury (BUN, creatinine, glucose, and uric acid) and liver function (ALT, AST, ALP, LDH, serum proteins, and albumin), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), oxidative stress biomarkers (malondialdehyde and superoxide dismutase), and histological parameters (tubular necrosis, acidophilic casts, and vascular congestion) were assessed. Tissue HIF-1α was measured by ELISA and Western blot, and the expression of Hmox1 was assessed by RT-qPCR. RESULTS: (S)-2HG had a dose-dependent nephroprotective effect, as evidenced by a significant reduction in the changes in the BUN, creatinine, ALP, AST, and LDH levels compared with the IR group. Tissue HIF-1α was only increased in the IR group compared to SH; however, (S)-2HG caused a significant increase in the expression of Hmox1, suggesting an early accumulation of HIF-1α in the (S)-2HG-treated groups. There were no significant effects on the other biomarkers. SA did not show a nephroprotective effect; the only changes were a decrease in creatinine level at 12.5 mg/kg and increased IR injury at 50 mg/kg. There were no effects on the other biochemical, proinflammatory, or oxidative stress biomarkers. CONCLUSION: None of the compounds were hepatotoxic at the tested doses. (S)-2HG showed a dose-dependent nephroprotective effect at the evaluated doses, which involved an increase in the expression of Hmox1, suggesting stabilization of HIF-1α. SA did not show a nephroprotective effect but tended to increase IR injury when given at high doses.