Purpose: Eukaryotic initiation factor 2α (eIF2α) plays important roles in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in animal hypoxia-induced pulmonary hypertension models. However, the underlying mechanism remains unknown at large. Autophagy has been reported to play a key role in the vascular remodeling in pulmonary arterial hypertension (PAH). The purposes of this study are to determine the functions of eIF2α and autophagy in the vascular remodeling of the monocrotaline-induced PAH rats and to clarify the correlation between eIF2α and autophagy. Methods: We established a rat model of monocrotaline-induced PAH, and we established a cell model of platelet derived growth factor (PDGF)-induced PASMCs proliferation. The vascular morphology and the expression of eIF2α, LC3B, and p62 were assessed in the pulmonary arterial tissue of Sprague-Dawleyrats and PDGF-induced PASMCs. Results: Autophagy was significantly active in monocrotaline model group (MCT)-induced PAH rats, which obviously promotes vascular remodeling in MCT-induced PAH rats. Furthermore, the proliferation of PASMCs was induced by PDGF in vitro. The expression of LC3B, eIF2α was increased in the PDGF-induced PASMCs proliferation, and the expression of p62 was reduced in the PDGF-induced PASMCs proliferation. Moreover, eIF2α siRNA downregulated the expression of eIF2α and LC3B, and upregulated the expression of p62 in PDGF-induced PASMCs proliferation. eIF2α siRNA inhibited the PDGF-induced PASMCs proliferation. Finally, chloroquine can upregulate the protein expression of LC3B and p62, it also can inhibit proliferation in PDGF-induced PASMCs. Conclusion: Based on these observations, we conclude that eIF2α promotes the proliferation of PASMCs and vascular remodeling in monocrotaline-induced PAH rats through accelerating autophagy pathway. Keywords: eIF2α, autophagy, PASMCs, PAH, monocrotaline
The occurrence of depressive disorder has long been attributed to changes in monoamines, with the focus of drug treatment strategies being to change the effectiveness of monoamines. However, the success achieved by changing these processes is limited and further stimulates the exploration of alternative mechanisms and treatments. Fibroblast growth factor 2 (FGF-2), which occurs in a high-molecular weight (HMW) and low-molecular weight (LMW) form, is a potent developmental modulator and nervous system regulator that has been suggested to play an important role in various psychiatric disorders. In this study, we investigated the antidepressant effects of HMW and LMW FGF-2 on depression induced by chronic stress. Both peripheral LMW and HMW FGF-2 attenuated the depression-like behaviors in chronic unpredictable mild stress (CUMS) mice to a similar extent, as determined by the forced swimming, tail suspension, and sucrose preference tests. We then showed that CUMS-induced oxidative stresses in mice were inhibited by FGF-2 treatments both in central and peripheral. We also showed that both forms of FGF-2 increased the phosphorylation of ERK and AKT, increased Bcl-2 expression and inhibited caspase-3 activation in CUMS mice. Interestingly, HMW FGF-2 enhanced the activity of the brain-derived neurotrophic factor (BDNF) to a greater extent than did LMW FGF-2 in the hippocampus. Taken together, these results suggest that depressive symptoms can be relieved by administering different forms of FGF-2 peripherally in a CUMS-induced depression model through a similar antidepressant signaling pathway, therefore suggesting a potential clinical use for FGF-2 as a treatment for depression.
To explore the role of tumor necrosis factor-α (TNF-α) in immune response to urogenital chlamydial infection and urogenital pathology in mice.Fifteen female wild-type (WT) C57BL/6J mice and 15 TNF-α receptor knockout (TNF-αR KO) mice were inoculated intravaginally with 1×104 inclusion forming units (IFUs) of live C.muridarum. At 56 days after the first inoculation, 8 mice from each group were subjected to a second inoculation at the same dose. Vaginal swabs were taken every 3 or 4 days to detect the number of inclusion bodies of chlamydia. On day 80 after the first inoculation, the mice were euthanized and peritoneal macrophages were collected and the vaginal tract and spleen were dissected. The pathologies in the fallopian tube and the uterine horn were observed and the severity of inflammatory cell infiltration and lumen dilatation were semi-quantitatively scored. The levels of interleukin-6 (IL-6), IL-8, IL-1α, IL-1β and TNF-α in the supernatant of the peritoneal macrophage were detected. Spleen cell suspension was prepared, and after stimulation with chlamydia EB in vitro, the levels of the cytokines including IL-4, IL-5, IL-17 and interferon-γ (IFN-γ) were determined in the cells.The clearance rate of Chlamydia from the urogenital tract was similar between TNF-αR KO mice and WT mice regardless of the primary or second infection. The severity of inflammation in the fallopian tube and the uterine horn did not differ significantly between the two groups, but TNF-αR KO mice had significantly milder dilation of the fallopian tubes (P < 0.05). The peritoneal macrophages from TNF-αR KO mice produced a significantly higher level of TNF-α than those from WT mice (P < 0.05); the spleen cells from the two groups both produced high levels of IFN-γ, but IL-17 production by the spleen cells was significantly lower in TNF-αR KO mice than in WT mice (P < 0.05).TNF-α is not associated with protective immune response against C.muridarum infection, and can worsen the inflammatory damages of the urogenital tract caused by C.muridarum in mice.
Chlamydia psittaci is an important zoonotic factor associated with human and animal atypical pneumonia. Resisting host cell apoptosis is central to sustaining Chlamydia infection in vivo . Chlamydia can secrete inclusion membrane proteins (Incs) that play important roles in their development cycle and pathogenesis. CPSIT_0846 is an Inc protein in C. psittaci identified by our team in previous work. In the current study, we investigated the regulatory role of CPSIT_0846 in HeLa cell apoptosis, and explored potential mechanisms. The results showed that HeLa cells treated with CPSIT_0846 contained fewer apoptotic bodies and exhibited a lower apoptotic rate than untreated cells either with Hoechst 33258 fluorescence staining or flow cytometry with or without induction by staurosporine (STS). CPSIT_0846 could increase the phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) or stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) signaling pathways, and the Bcl-2 associated X protein (Bax)/B cell lymphoma 2 (Bcl-2) ratio, levels of cleaved caspase-3/9 and cleaved Poly-ADP-ribose polymerase (PARP) were significantly up-regulated following inhibition of ERK1/2 or SAPK/JNK pathways with U0126 or SP600125. After carbonyl cyanide 3-chlorophenylhydrazone (CCCP) treatment, the mitochondrial membrane potential (MMP) of cells was significantly decreased in control group, but stable in the CPSIT_0846 treated one, and less cytochrome c (Cyt.c) was released into the cytoplasm. Inhibition of the ERK1/2 or SAPK/JNK pathway significantly decreased the JC-1 red-green fluorescence signal, and promoted Cyt.c discharge into the cytoplasm in HeLa cells treated with CPSIT_0846. In conclusion, CPSIT_0846 can regulate mitochondrial pathway-mediated apoptosis in HeLa cells by activating the ERK/JNK signaling pathway.
The purpose of this study was to translate and evaluate the psychometric properties of the Chinese version of the Upper Limb Lymphedema Quality of Life Questionnaire (C-ULLQoL).Eighty-five participants completed the C-ULLQoL and the Functional Assessment of Cancer Therapy-Breast (C-FACT-B). The Cronbach's alpha (α) was used to determine the internal consistency, and intraclass correlation coefficients (ICCs) - to evaluate the test-retest reliability. The content validity index (CVI) was assessed by a group of experts. Construct validity was examined by performing factor analysis and criterion validity by observing the correlations between C-ULLQoL with C-FACT-B.Cronbach's α of the total scale was 0.930. ICC scores ranged from 0.874 to 0.938. The content validity of C-ULLQoL was acceptable. Two factors (65.488% of the variance) were extracted by exploratory factor analysis. A significant correlation was observed between C-ULLQoL and C-FACT-B (r = -0.611, p < 0.01).The C-ULLQoL is a reliable and valid questionnaire that can be used in clinic and scientific practice for evaluating health-related quality of life in Chinese patients with breast cancer-related lymphedema.IMPLICATIONS FOR REHABILITATIONAn effective and comprehensive scale to measure the health-related quality of life (HRQoL) is essential because breast cancer-related lymphedema (BCRL) leads to various complications for patients, caregivers, and society.The Chinese version of the Upper Limb Lymphedema Quality of Life Scale (C-ULLQoL) is a valid, reliable, and practical instrument to comprehensively assess HRQoL in Chinese patients with BCRL.The C-ULLQoL can be used in both clinical and research settings to evaluate HRQoL of BCRL patients in China.
Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM's effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM's protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What's more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP's positive effect on moderating spermatogenic disorder in T1DM mice's testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway's activation.
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