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Diabetes is a group of metabolic disorders that is characterized by hyperglycemia which increases the risks of cardiovascular, microvascular, and macrovascular complications. Innovative therapeutic trials regarding diabetes control and management are continually being undertaken. The present review was aimed to explore the potential effects and mechanisms that lead to the pathogenesis of type 2 diabetes mellitus (T2DM) and its relation with asprosin. Asprosin is a newly discovered hormone that is encoded by protein fibrillin 1 (FBN1 gene), secreted by white adipose during fasting conditions at 5-10 nM levels, which acts on the liver through cell membrane receptors and activates the G protein cAMP- PKA pathway. Asprosin secretion is increased during fasting as the compensatory mechanism in hypoglycemia. Asprosin concentration is higher in patients with T2DM and impaired glucose regulation compared to healthy subjects. Genetic deficiency of asprosin may cause problems of poor appetite and extreme leanness in humans. Attenuating asprosin activity or depleting asprosin may serve as a novel therapeutic innovation for the treatment of T2DM and obesity. Hence, asprosin may serve as a beacon for the target of a future therapy in diabetes management.
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Shikonin, a naphthoquinone compound isolated from Lithospermum erythrorhizon Siebold & Zucc.(Pinyin: zPiny), has been reported to exert protective roles against psoriasis. However, the molecular mechanism remains largely unknown. The current study aimed to explore the mechanism of Shikonin in keratinocyte differentiation and apoptosis. It was found that overexpression of Jagged-1, Notch-1, Hes-5, but not Hes-1, on psoriatic lesions is involved in the pathogenesis of psoriasis. In vitro, the application of exogenous recombinant human Jagged-1 (rh-Jag1, ligand of Notch-1) promotes proliferation and suppresses apoptosis of keratinocytes from psoriasis, which could be blocked by DAPT (γ-secretase inhibitor). Additionally, in recombinant human Epidermal Growth Factor (rh-EGF)-stimulated HaCaT cells (to mimic hyperproliferation condition of psoriasis), Shikonin was effective on anti-proliferation and pro-apoptosis of keratinocytes with down-regulation of Jagged-1, Notch-1, Hes-5, Bcl-2, and up-regulation of caspase-9, inhibitor of caspase-activated deoxyribonucleases (ICAD). Taken together, we propose that Jagged1/Notch1/Hes5 signaling involved in the pathogenesis of psoriasis could be suppressed by Shikonin.
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Neuropathic pain (NP) after spinal cord injury (SCI) leads to compromised physical and cognitive functions in a majority of patients. Aberrant miRNA expression plays vital roles in the pathogenesis of SCI. This study aims to investigate the effect of miR-331-3p in rats following SCI. Microarray assay was performed in SCI- and sham-operated rats to evaluate the expression of miR-331-3p. Assigned SCI rats were treated with miR-331-3p agomiR alone or miR-331-3p agomiR plus RAP1A-expressing lentivirus or control agomiR. Rat locomotor performance was evaluated by BBB locomotor rating scale. Neuronal tissue damage and apoptosis were detected by histological analyses and Western blot. Inflammation in spinal cord was determined by detection of the expression of inflammatory genes with qRT-PCR, and ELISA. Downstream expression of RAP1A was measured by Western blot. The results showed that SCI induced the downregulation of miR-331-3p in the spinal cord of SCI rats. Overexpression of miR-331-3p improved the locomotor performance, reduced tissue damage, neuronal apoptosis and inflammation in rat SCI model. Rap1a (Ras-related protein Rap-1A) was predicted as a downstream target for miR-331-3p, and upregulation of RAP1A impaired the beneficial effect of miR-331-3p post- SCI, which was shown as worse locomotor activity, more severe tissue damage, as well as promoting apoptosis and inflammation in SCI rats. Furthermore, miR-331-3p reduced the activation of RAP1A downstream genes via inhibiting RAP1A expression. These findings indicate a protective role of miR- 331-3p in the development of SCI via the modulation of RAP1A, and may help to develop novel therapy against SCI-induced complications.
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Notch signaling plays a critical role in the development and function of macrophages. The aim of the present study was to investigate the relationship between Notch signaling pathway and macrophage apoptosis after LPS stimulation. In RAW 264.7 cells, the mRNA expression of Jagged1, Hes1, Hes 5 and GM-CSF, and protein expression of NICD1 and GM-CSF were increased after LPS stimulation. Inhibition of Notch signaling by γ-secretase inhibitor DAPT and the suppression of Notch1 expression using siRNA both significantly prevented LPS induced activation of JNK and NF-kB, and simultaneously the expression of GM-CSF was also down regulated significantly. JNK inhibitor SP600125 was used to block the phosphorylation of JNK signaling, Western blot results showed that the activation of NF-kB was blocked and expression of GM-CSF was down-regulated. Finally, flow cytometry analyses showed that the Notch signaling was involved in the regulation of macrophage apoptosis after LPS stimulation. Our study showed that the Notch signaling pathway was activated and involved in the regulation of macrophage apoptosis after LPS stimulation through JNK/ NF-kB signaling regulated GM-CSF expression.
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Dysregulation of lncRNA cancer susceptibility candidate 2 (CASC2) is involved in the pathogenesis of multiple malignancies. However, the underlying mechanisms by which lncRNA CASC2 regulates the proliferation of hemangiomas (HAs) remain undocumented. Herein, the expression levels of lncRNA CASC2 and VEGF in proliferating or involuting phase HAs were assessed by qRT-PCR analysis, and the effects of lncRNA CASC2 on HAs cell growth were evaluated by MTT, colony formation assays and Western blot analysis. lncRNA CASC2 specific binding with miR-18a-5p was confirmed by luciferase report assay. Consequently, we found that the expression of lncRNA CASC2 was reduced in proliferating phase HAs as compared with the involuting phase HAs or normal tissues, and possessed a negative correlation with VEGF expression in proliferating phase HAs. Restored expression of lncRNA CASC2 repressed cell viability and colony formation and downregulated VEGF expression, while silencing lncRNA CASC2 showed the opposite effects. Moreover, lncRNA CASC2 was confirmed to bind with miR-18a-5p, which could reverse lncRNA CASC2-induced anti-proliferative effects by targeting FBXL3 in HAs cells. Altogether, our findings demonstrated that lncRNA CASC2 suppressed the growth of HAs cells by regulating miR-18a-5p/FBXL3 axis.
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Klotho is a putative aging suppressor gene that is primarily expressed in renal tubular epithelial cells. Its expression has been reported to protect against fibrosis in human chronic kidney disease. However, the roles of klotho in epithelial-mesenchymal transition (EMT) and renal fibrosis are yet to be elucidated. The present study aimed to investigate the putative roles of klotho in angiotensin (Ang) II-induced damage of renal tubular epithelial cells. NRK-52E rat cells were treated with various combinations of Ang II, the Ang-converting enzyme inhibitor fosinopril (Fos) and the Ang II receptor antagonist valsartan (Val). The levels of transforming growth factor (TGF)-β1, soluble klotho, α-smooth muscle actin (α-SMA) and E-cadherin in NRK-52E culture supernatants were measured using enzyme-linked immunosorbent assays. Furthermore, the mRNA and protein expression of TGF-β1, klotho, α-SMA and E-cadherin was detected using semiquantitative reverse transcription-polymerase chain reaction, immunocytochemistry and Western blot analysis. The results demonstrated that Ang II inhibited the expression of klotho and E-cadherin, while it upregulated the expression of TGF-β1 and α-SMA, in NRK52E cells. Fos and/or Val were revealed to enhance klotho and E-cadherin expression, and suppress the expression of TGF-β1 and α-SMA, compared with the Ang II-only group. Furthermore, a positive linear correlation was detected between the expression of klotho and E-cadherin, while negative linear correlations with klotho expression were detected for TGF-β1 and α-SMA expression. In conclusion, the expression of klotho was demonstrated to be enhanced following treatment with Fos and Val in Ang II-treated NRK-52E cells. The present results indicate that klotho may be involved in the inhibition of Ang II-induced EMT in renal tubular epithelial cells. Therefore, klotho may serve as a protective factor in renal tubulointerstitial fibrosis and aid the treatment of chronic kidney disease (CKD) patients using precision therapy.
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Baicalin has been used in China to treat inflammation-related diseases, such as inflammation-induced acute kidney injury (AKI). However, the specific mechanism of baicalin remains unclear. To observe the protective effects of baicalin on lipopolysaccharide (LPS)-induced inflammatory injury of renal tubular epithelial cells (HK-2 cells) and to explore its protective mechanism. LPS (1 mg/L) was used to induce an HK-2 cell inflammatory injury model in vitro. The cells were divided into seven groups: the normal control group, LPS-induced group, LPS plus 5 μmol/L baicalin treatment group, LPS plus 15 μmol/L baicalin treatment group, LPS plus 25 μmol/L baicalin treatment group, LPS plus 50 μmol/L baicalin treatment group, and LPS plus 75 μmol/L baicalin treatment group. 3-(4,5-dimethyl-2-thiazolyl)-2,5- diphenyl-2-H-tetrazolium bromide (MTT) assay was employed for detecting the relative survival rate of HK-2 cells. Enzyme-linked immunosorbent assay was used for detecting the levels of inflammatory factors, including interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α). Moreover, the expression of inducible nitric oxide synthase (iNOS); cyclooxygenase-2 (COX-2); nuclear factor kB65 (NF-κB65); phosphorylated NF-κB inhibitory protein-α (p-IκB-α); NF-κB inhibitory protein (IκB); human thioredoxin interacting protein (TXNIP); and human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) were determined by Western blot analysis. The expression levels of NLRP3 and TXNIP mRNA and miR-223-3p were determined by RT-PCR. Results found that the relative survival rate of HK-2 cells treated with different baicalin concentrations was significantly increased (P<0.05) and the levels of the inflammatory factors IL-6, IL-1β, and TNF-α were significantly decreased (P<0.05) compared with those of the LPS-induced group. The expression levels of the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2 and the genes expressions of TXNIP and NLRP3 were significantly decreased in the cells (P<0.05), while the expression level of miR-223- 3p was significantly increased (P<0.05). These changes were induced in a dose-dependent manner. The results suggest that baicalin significantly inhibited the expression of inflammation-related proteins and alleviated LPS-induced inflammatory injury in HK-2 cells. The mechanism may be associated with the inhibition of activation of the TXNIP/NLRP3 inflammatory pathway, which might be mediated by increased expression of miR-223-3p. Thus, NLRP3 is a regulatory target of miR-223-3p.
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Expression of microRNA(miR)-142-3p has been implicated to be associated with several cancers, whereas its function in bladder cancer (BC) remains unknown. The present study aimed to explore the correlation between the expression of miR-142-3p and the proliferation, migration and invasion of bladder cancer cells by activating Rac1. qRT-PCR was used to measure the expression of miR-142- 3p in bladder cancer tissues and cell lines. RNA transfection was used to silence and accelerate the expression of miR-142-3p in bladder cancer cells. CCK-8 and trans-well assays were used to detect the proliferation, migration and invasion of cells before and after RNA transfection. The direct interaction between Rac1 and miR-142-3p was demonstrated by a dual luciferase reporter assay. qRT-PCR and Western blot assays were used to detect the expression changes in Rac1 before and after transfection. The results showed that miR-142-3p in bladder cancer tissues was significantly lower than that in adjacent tissues and lower than that in HT1376 and T-24 cells but higher than that in T5637 and BIU- 87 cells. Additionally, upregulating miR-142-3p expression not only inhibits the proliferation of SV-HUC-1 and BIU-87 cells but also inhibits migration and invasion, and downregulating miR-142-3p expression showed the opposite results. The expression of Rac1 was promoted after stimulating miR- 142-3p expression, but was inhibited after silencing miR-142-3p expression. In conclusion, miR-142-3p affects the proliferation, migration and invasion of bladder cancer cells by regulating Rac1.
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Endometriosis is a gynecological health problem for women of reproductive stage. Kallikrein 4 is a proliferative factor and has important roles in cancer development and progression. To explore the role of Kallikrein 4 in endometriosis, we detected the expression of Kallikrein 4 in ectopic and normal control endometriosis tissues. Moreover, the underlying influence of Kallikrein 4 on migration and invasion of endometrial stromal cells was investigated. Furthermore, the correlations between this gene and E-cadherin and N-cadherin were also evaluated. The results demonstrated that the expression level of Kallikrein 4 in endometrial tissues was significantly increased compared to normal endometrial tissues, and over-expression of Kallikrein 4 up-regulated expression of N-cadherin but down-regulated E-cadherin in endometrial stromal cells. The ability of migration and invasion of endometrial stromal cells in vitro was increased by up-regulating Kallikrein 4 expression, suggesting that Kallikrein 4 might be involved in the development of ovarian endometriosis.
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MicroRNAs (miRNAs) have been demonstrated to have promoting or inhibiting effects on the tumorigenesis of multiple cancers, including ovarian cancer (OC), by regulating its downstream target genes. In the presented experiment, our aim was to explore the role of miR-543 in OC cell proliferation and invasion. Results of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot revealed that miR-543 have lower expression levels, while Twist homolog 1 (TWIST1) was expressed with higher levels in OC tissues and cells. Furthermore, the effects of abnormal miR-543 expression in OC cell proliferation and invasion were detected by CCK-8 and Transwell assay. According to luciferase reporter assay results, TWIST1 was identified as a downstream target of miR-543 in OC, and a negative correlation was observed between TWIST1 and miR-543 expression by Spearman's correlation analysis in OC tissues. In addition, TWIST1 may reverse the miR-543 suppression effect on OC cell proliferation and invasion. To sum up, miR-543 may promote OC cell proliferation and invasion by targeting TWIST1.
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During the menopause women may experience increased oxidative stress and decreased antioxidant capacity and, together with the decline of neurosteroids, this represents a risk factor for Alzheimer's disease. The aim of the present study was to test a functional food (FPP-ORI, Osato Research Institute, Gifu, Japan) on redox and mitochondrial efficiency in post-menopausal women. The study population consisting of 69 untreated post-menopausal women were given supplements as follows: Group A was given a multivitamin (MV) 1c 2 times a day, and group B was given FPP 4.5 g 2 times a day. Group C consisted of 23 fertile premenopausal women as the control group. The tests carried out on entry, and at 3 and 6 months were erythrocyte redox parameters, plasma oxidated proteins, brain-derived neurotrophic factor (BDNF) and peripheral blood mononuclear cell (PBMC) mitochondria cytochrome c oxidase Vmax activity. Menopausal women showed an increased malondialdehyde (MDA) (p<0.05 vs control) which was normalized by both treatments (p<0.05), but MV failed to do so in the BMI ≥26 subgroup (p<0.05). All other redox enzymes and BDNF were significantly lower in menopausal women and they responded only to FPP (p<0.05). Carbonyl protein level was higher in "BMI ≥ 26" subgroup (p<0.05) and reduced only by FPP (p<0.05). The PBMC cyclooxygenase to citrate synthase activity was reduced (<40%) in the menopausal group (p<0.01) and only FPP caused a significant restoration (p<0.05). Although preliminary, these data confirm the redox and mitochondrial dysfunction occurring in post-menopause and responsive to FPP but very poorly to high dosage antioxidants. This may lead to potential preventive opportunities in menopause-associated neurodegenerative disease.
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The aim of this study was to evaluate calvarial grafts when used as bone substitute for maxillary vertical augmentation prior to dental implantology. Bone specimens were harvested from patients at T0 (time of bone harvesting), 4 months (T1), 6 months (T2) and 15 years (T3) after grafting procedure. Morphostructural analysis and immunohistochemical analyses of boneseialoprotein-2 (BSP2), Collagen I, Vascular endothelial growth factor (VEGF), ERK ½ and nitride oxide (iNOS) inflammatory protein, expression were carried out. Outcomes from T0 specimens were compared to T1, T2 and T3 samples. In immunohistochemical analysis T1 and T2 samples showed the presence of important remodeling phenomena, with areas of bone resorption and apposition, together with new blood vessel formations. The T3 sample showed morphological features very close to native bone, as shown by the disappearance of welding lines. However, small polygonal cells resembling osteoblasts were close to Havers channels. Immunohistochemical analyses showed a drastic decrease of Collagen expression, at T1 and T2, stabilized at T3, in parallel to BSP2 expression increase, which was, however, considerably reduced at T3. Moreover VEGF angiogenic factor was increased at T2, in respect to T0, T1 and T3 which are quite similar. The highest level of Erk1/2 is evidenced in the T2 sample, basal levels of iNOS, related to inflammatory events is highlighted in T0 and T3, in respect to T1. Thus, autologous calavarial bone grafts seem to be suitable as biomaterial for bone regeneration procedures of the jaws. Moreover, the used protocol could be useful for studying bone substitutes in oral surgery and implantology.
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