L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

A theoretical study on activation of transcription factor modulated by intracellular Ca2+ oscillations.

This work presents both deterministic and stochastic models of genetic expression modulated by intracellular calcium (Ca2+) oscillations, based on macroscopic differential equations and chemical Langevin equations, respectively. In deterministic case, the oscillations of intracellular Ca2+ decrease the effective Ca2+ threshold for the activation of transcriptional activator (TF-A). The average activation of TF-A increases with the increase of the average amplitude of intracellular Ca2+ oscillations, but decreases with the increase of the period of intracellular Ca2+ oscillations, which are qualitatively consistent with the experimental results on the gene expression in lymphocytes. In stochastic case, it is found that a large internal fluctuation of the biochemical reaction can enhance gene expression efficiency specifically at a low level of external stimulations or at a small rate of TF-A dimer phosphorylation activated by Ca2+, which reduces the threshold of the average intracellular Ca2+ concentration for gene expression.

A mesoscopic stochastic mechanism of cytosolic calcium oscillations.

Based on a model of intracellular calcium (Ca(2+)) oscillation with self-modulation of inositol 1,4,5-trisphosphate signal, the mesoscopic stochastic differential equations for the intracellular Ca(2+) oscillations are theoretically derived by using the chemical Langevin equation method. The effects of the finite biochemical reaction molecule number on both simple and complex cytosolic Ca(2+) oscillations are numerically studied. In the case of simple intracellular Ca(2+) oscillation, it is found that, with the increase of molecule number, the coherence resonance or autonomous resonance phenomena can occur for some external stimulation parameter values. In the cases of complex cytosolic Ca(2+) oscillations, each extremum of concentration of cytosolic Ca(2+) oscillations corresponds to a peak in the histogram of Ca(2+) concentration, and the most probability appeared during the bursting plateau level for bursting, but at the largest minimum of Ca(2+) concentration for chaos. For quasi-periodicity, however, there are only two peaks in the histogram of Ca(2+) concentration, and the most probability is located at low concentration state.