Dystrophin Dp71 is expressed in all tissues, with the exception of skeletal muscle, and is the main Duchenne muscular dystrophy (DMD) gene product in brain. As full-length dystrophin does in skeletal muscle, Dp71 associates with dystroglycans, sarcoglycans, dystrobrevins, syntrophins, and accessory proteins to form the dystrophin-associated protein complex (DAPC) in non-muscle tissues. Although it has been nearly 20 years since the discovery of Dp71, its study has become relevant only recently due to its direct involvement with the two main DMD non-muscular phenotypes: cognitive impairment and abnormal retinal physiology. In this review, we describe the historical background of Dp71 and the experimental models developed for its study. Additionally, we present and discuss the experimental evidence supporting the participation of Dp71 in different cellular processes, including cell adhesion, water homeostasis, cell division, and nuclear architecture. The functional diversity of Dp71 is attributed to the formation of Dp71-containing DAPC in numerous cell types and different subcellular compartments, including in plasma membrane and nucleus, as well as to the capability of Dp71-containing DAPC to work as the scaffold for proper clustering and anchoring of structural and signaling proteins to the plasma membrane and of nuclear envelope proteins to the inner nuclear membrane.
Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the ␣ 1 2.1 subunit of Ca v 2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K v voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K v channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K v channels, reduced the frequency of restraint-and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K v channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K v channels. That both stress-and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.
Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K + -induced tonic, and Ca 2+ -induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca 2+ -induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC 50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.
Chia seeds (Salvia hispanica L.) are rich in omega fatty acids. Dyslipidemia and steatohepatitis are diseases that require effective treatments in obese and non‐obese patients. The aim was to evaluate the effect of chia intake on acute tyloxapol (TI)‐induced dyslipidemia, on acute carbon tetrachloride (TC)‐induced steatohepatitis, and on mixed damage (TC+TI) in non‐obese rats. Four experimental groups were fed for 4 weeks a diet with established rodent food (DE), and four groups were fed a diet with 15% added chia (DC). Plasma samples were analyzed for total cholesterol, triglycerides, glucose, biochemical liver damage markers, and tumor necrosis factor‐α (TNF‐α). Liver samples were used to quantify glycogen, catalase, lipid peroxidation, and TNF‐α. A histopathological analysis was performed. DC intake partially or totally prevented steatohepatitis, and reduced lipids in the dyslipidemic groups. The hypolipidemic and hepatoprotective effects of chia may be correlated to its high content of α‐linolenic acid (omega‐3) and phenolics. Practical applications Metabolic syndrome is associated with non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH), which are currently the most common causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. Dyslipidemia is a significant risk factor for NAFLD and NASH. Non‐obese patients may have NAFLD or NASH. Metabolic syndrome and dyslipidemia are more strongly associated with NAFLD in non‐obese than in obese patients. This is the first study evaluating the hypolipidemic and hepatoprotective effects of chia seed intake on acute dyslipidemia and/or steatohepatitis caused by the individual or combined administration of the inducers tyloxapol and carbon tetrachloride, respectively, in non‐obese rats. The pharmacological effects of dietary chia are correlated to its high content of omega‐3 and omega‐6 (1:1), protein, dietary fiber, and phenolics. The results suggest that inclusion of chia in diets of non‐obese patients with dyslipidemia and/or NAFLD/NASH may improve their health state and preventing cirrhosis or HCC.
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