Search

Atopic dermatitis (AD) is a common allergic skin disease, and its pathogenesis involves genetic and environmental factors, as well as the immune response and skin barrier. PJ-001 is a small-molecule proteolysis-targeting chimera, which can degrade proteins related to the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. In the present study, 0.5% 2,4-dinitrofluorobenzene was used to induce a mouse model of AD. Following treatment with PJ-001, the number of scratches and the severity of skin damage in the AD mice were recorded. Pathological changes in skin lesions were observed with hematoxylin and eosin staining. The expression levels of JAK2/STAT3, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB), Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3) were detected using western blotting. Furthermore, reverse transcription-PCR was used to detect the mRNA expression levels of filaggrin (FLG) and keratin 17, and the change in interleukin-10 levels in the splenic tissue of the mice. Compared with in the control group, the model group exhibited severe skin lesions. Following treatment with PJ-001, the AD-like inflammation in mice decreased. The expression levels of LC3 II/LC3 I and Beclin 1 were significantly reduced (P<0.01), and the expression levels of JAK2, STAT3, TLR4 and NF-κB were significantly downregulated (P<0.001). Additionally, the mRNA expression levels of FLG were significantly upregulated (P<0.001). These results indicated that PJ-001 may alleviate the skin condition in a mouse model of AD. The underlying mechanism may involve inhibition of the JAK/STAT signaling pathway, thereby suppressing the release of inflammatory factors, reducing excessive autophagy at the site of skin lesions, and enhancing the skin barrier function. In conclusion, PJ-001 could be considered a potential therapeutic option for AD. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a clinically common and severe complication of ischemia-reperfusion (I/R), associated with high morbidity and mortality rates, and prolonged hospitalization. Rapamycin is a type of macrolide, primarily used for anti-rejection therapy following organ transplantation and the treatment of autoimmune diseases. Rapamycin has been identified to exert a protective effect against AKI induced by renal I/R as an autophagy inducer. However, whether rapamycin preconditioning may relieve AKI following cerebral I/R (CIR) remains to be fully elucidated. The purpose of the present study was to investigate the effects of CIR on the renal system of rats and the role of rapamycin in AKI following CIR. In the present study, a CIR model was established in Sprague-Dawley rats via a 90-min period of middle cerebral artery occlusion and 24 h reperfusion, and pretreatment with an intraperitoneal injection of rapamycin (dosage: 1 mg/kg; 0.5 h) prior to CIR. The levels of serum creatinine and blood urea nitrogen (BUN), and the expression of inflammation-, apoptosis- and autophagy-associated markers were subsequently measured. In addition to certain histopathological alterations to the kidney, it was identified that CIR significantly increased the levels of serum creatinine, BUN, tumor necrosis factor-α and interleukin-1β, and significantly induced apoptosis and autophagy. It was observed that rapamycin induced autophagy through the mammalian target of rapamycin complex 1/autophagy-related 13/unc-51 like autophagy activating kinase 1 signaling pathway, and that rapamycin pre-treatment significantly improved renal function and alleviated renal tissue inflammation and cell apoptosis in rats following CIR. In conclusion, the results suggested that rapamycin may alleviate AKI following CIR via the induction of autophagy. [ABSTRACT FROM AUTHOR]

The present study evaluated the retinoic acid (RA) enhancement of temozolomide (TMZ) effects on the human glioma cells U251 and explored its underlying molecular mechanism. The cell growth was detected using the MTT assay and the cell cycle was assessed by flow cytometry. Cell apoptosis was analyzed by Annexin V/propidium iodide staining, and the cell morphology was evaluated using transmission electron microscopy (TEM). Additionally, reverse transcription-PCR and western blot analysis were applied to detect the mRNA and protein levels. The RA treatment in combination with TMZ in the human U251 cells further inhibited cells growth, arresting cell cycle progression at the G0/G1 phase, and significantly induced apoptosis of U251 cells. After the RA+TMZ treatment of U251 cells, autophagy associated proteins Beclin 1 and LC3B were significantly increased, and the TEM analysis were consistent with autophagy protein levels. Moreover, Keap1/Nrf2/ARE expression was downregulated significantly, indicating the involvement in the mechanisms that RA treatment could enhance the TMZ effects on U251 cells. RA treatment in combination with TMZ may provide some experimental evidence for the possible effect of RA+TMZ against the growth and the proliferation of glioma cells. Therefore, the RA+TMZ administration may have potential utility for glioblastoma treatment. [ABSTRACT FROM AUTHOR]

The pathogenesis of acute lung injury (ALI) induced by lipopolysaccharide (LPS) involves excessive pulmonary inflammation and oxidative stress. In turn, autophagy is associated with inflammatory diseases and organ dysfunction, and studies have demonstrated that LPS treatment may trigger autophagy. Thus, excessive autophagy may stimulate the strong inflammatory response observed in the development of LPS-induced ALI. Saturated hydrogen saline may alleviate LPS-induced ALI by inhibiting autophagy, however its underlying mechanisms of action remain unknown. It has been suggested that saturated hydrogen saline may downregulate expression of nuclear factor (NF)-κB, leading to a decrease in Beclin-1 transcription and inhibition of autophagy. Inhibition of autophagy also occurs via the phosphorylation of Unc-51-like autophagy activating kinase 1 and autophagy-related protein-13 by mechanistic target of rapamycin, which in turn may be upregulated by saturated hydrogen saline. In addition, signaling pathways involving heme oxygenase-1 and p38 mitogen-activated protein kinase are associated with the alleviative effects of saturated hydrogen saline on LPS-induced autophagy. The present review focuses on potential molecular mechanisms regarding the effects of saturated hydrogen saline in the reduction of autophagy during LPS-induced ALI. [ABSTRACT FROM AUTHOR]

Hypoxia is widely accepted as a fundamental biological phenomenon, which is strongly associated with tissue damage and cell viability under stress conditions. Insulin-like growth factor-1 (IGF-1) is known to protect tissues from multiple types of damage, and protect cells from apoptosis. Hypoxia is a regulatory factor of the IGF system, however the role of the IGF-1 receptor (IGF-1R) in hypoxia-induced apoptosis remains unclear. The present study investigated the potential mechanisms associated with IGF-1R-associated apoptosis under hypoxic conditions. Mouse embryonic fibroblasts exhibiting disruption or overexpression of IGF-1R (R- cells and R+ cells) were used to examine the level of apoptosis, autophagy, and production of reactive oxygen species (ROS). The autophagy inhibitor 3-methyladenine was used to assess the effect of autophagy on ROS production and apoptosis under hypoxic conditions. A potential downstream signaling pathway involving phosphatidylinositol 3-kinase (PI3K)/threonine protein kinase B (Akt)/mammalian target of rapamycin (mTOR) was identified by western blot analysis. The results demonstrated that hypoxia induced apoptosis, increased ROS production, and promoted autophagy in a time-dependent manner relative to that observed under normoxia. R+ cells exhibited a lower percentage of apoptotic cells, lower ROS production, and higher levels of autophagy when compared to that of R- cells. In addition, inhibition of autophagy led to increased ROS production and a higher percentage of apoptotic cells in the two cell types. Furthermore, IGF-1R is related with PI3K/Akt/mTOR signaling pathway and enhanced autophagy-associated protein expression, which was verified following treatment with the PI3K inhibitor LY294002. These results indicated that IGF-1R may increase cell viability under hypoxic conditions by promoting autophagy and scavenging ROS production, which is closed with PI3K/Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]