ABSTRACT
In recent years, mesenchymal stem cell (MSCs)-derived exosomes have attracted much attention in the field of tissue regeneration. Mesenchymal stem cell-derived exosomes are signaling molecules for communication among cells. They are characterized by natural targeting and low immunogenicity, and are mostly absorbed by cells through the paracrine pathway of mesenchymal stem cells. Moreover, they participate in the regulation and promotion of cell or tissue regeneration. As a scaffold material in regenerative medicine, hydrogel has good biocompatibility and degradability. Combining the two compounds can not only improve the retention time of exosomes at the lesion site, but also improve the dose of exosomes reaching the lesion site by in situ injection, and the therapeutic effect in the lesion area is significant and continuous. This paper summarizes the research results of the interaction of exocrine and hydrogel composite materials to promote tissue repair and regeneration, in order to facilitate research in the field of tissue regeneration in the future.
Subject(s)
Hydrogels/metabolism , Exosomes/metabolism , Wound Healing , Regenerative Medicine , Mesenchymal Stem Cells/metabolismABSTRACT
Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.
ABSTRACT
Objective@#To study the role of corticotropin-releasing hormone (CRH) system in locus ceruleus (LC) in irritable bowel syndrome (IBS) and to explore its molecular mechanism.@*Methods@#The IBS rat was established by maternal separation following with postnatal stress. The tissues sample of LC was obtained by micropunched nuclei. The expression of c-Fos, CRH and its receptors including corticotropin-releasing hormone receptor (CRHR) 1 and CRHR2 of rats’ LC tissues of control group and IBS group was detected by quantitative polymerase chain reaction(PCR). The expression of DNA methyltransferase (DNTM) 1, DNMT3a and DNMT3b at the mRNA level were also measured. In addition, the expression of histone methyltransferase ASH2-like protein (ASH2L) and SET and MYND domain containing 2 (SMYD2) was determined by Western blotting. T test was used for statistical analysis.@*Results@#The rectal pneumatic pressure of IBS group was lower than that of control group ((69.82±5.47) mmHg vs. (86.86±5.98) mmHg; 1 mmHg=0.133 kPa), however compared with that of control group, the expression of c-Fos at the mRNA level increased (2.11±0.44 vs.1.00±0.19), and the differences were statistically significant (t=6.215 and 2.321, P<0.01 and 0.05). In addition, compared with that of control group, the expression of CRH at the mRNA level increased (1.99±0.35 vs.1.00±0.13), and the difference was statistically significant (t= 2.797, P<0.05). Compared with that of control group, the expression of SMYD2 at the protein level up-regulated (1.04±0.21 vs. 0.61±0.12), and the difference was statistically significant (t=4.451, P<0.01). However, there were no statistically significant differences in the expression of CRHR-1, CRHR2, DNMT1, DNMT3a, DNMT3b at the mRNA level, and the expression of ASH2L between IBS group and control group (0.96±0.13 vs. 1.00±0.26, 1.35±0.63 vs. 1.00±0.43, 1.40±0.61 vs.1.00±0.19, 1.39±0.58 vs. 1.00±0.21, 1.45±0.71vs.1.00±0.39 and 0.80±0.19 vs. 1.05±0.26, respectively; all P>0.05).@*Conclusions@#Maternal separation combined with postnatal stress affect the transcription of Crh gene in LC and cause the activation of the stress regulation network CRH and norepinephrine system, resulting in the increase of the visceral sensitivity of rats. The abnormal transcription of Crh gene may be related with SMYD2-mediated histone H3K36 methylation, but not related with the modification of DNA methylation.
ABSTRACT
Objective:To study the role of corticotropin-releasing hormone (CRH) system in locus ceruleus (LC) in irritable bowel syndrome (IBS) and to explore its molecular mechanism.Methods:The IBS rat was established by maternal separation following with postnatal stress. The tissues sample of LC was obtained by micropunched nuclei. The expression of c- Fos, CRH and its receptors including corticotropin-releasing hormone receptor (CRHR) 1 and CRHR2 of rats’ LC tissues of control group and IBS group was detected by quantitative polymerase chain reaction(PCR). The expression of DNA methyltransferase ( DNTM) 1, DNMT3a and DNMT3b at the mRNA level were also measured. In addition, the expression of histone methyltransferase ASH2-like protein (ASH2L) and SET and MYND domain containing 2 (SMYD2) was determined by Western blotting. T test was used for statistical analysis. Results:The rectal pneumatic pressure of IBS group was lower than that of control group ((69.82±5.47) mmHg vs. (86.86±5.98) mmHg; 1 mmHg=0.133 kPa), however compared with that of control group, the expression of c- Fos at the mRNA level increased (2.11±0.44 vs.1.00±0.19), and the differences were statistically significant ( t=6.215 and 2.321, P<0.01 and 0.05). In addition, compared with that of control group, the expression of CRH at the mRNA level increased (1.99±0.35 vs.1.00±0.13), and the difference was statistically significant ( t= 2.797, P<0.05). Compared with that of control group, the expression of SMYD2 at the protein level up-regulated (1.04±0.21 vs. 0.61±0.12), and the difference was statistically significant ( t=4.451, P<0.01). However, there were no statistically significant differences in the expression of CRHR-1, CRHR2, DNMT1, DNMT3a, DNMT3b at the mRNA level, and the expression of ASH2L between IBS group and control group (0.96±0.13 vs. 1.00±0.26, 1.35±0.63 vs. 1.00±0.43, 1.40±0.61 vs.1.00±0.19, 1.39±0.58 vs. 1.00±0.21, 1.45±0.71vs.1.00±0.39 and 0.80±0.19 vs. 1.05±0.26, respectively; all P>0.05). Conclusions:Maternal separation combined with postnatal stress affect the transcription of Crh gene in LC and cause the activation of the stress regulation network CRH and norepinephrine system, resulting in the increase of the visceral sensitivity of rats. The abnormal transcription of Crh gene may be related with SMYD2-mediated histone H3K36 methylation, but not related with the modification of DNA methylation.