Specific interactions among biomolecules drive virtually all cellular functions and underlie phenotypic complexity and diversity. Biomolecules are not isolated particles, but are elements of integrated interaction networks, and play their roles through specific interactions. Simultaneous emergence or loss of multiple interacting partners is unlikely. If one of the interacting partners is lost, then what are the evolutionary consequences for the retained partner? Taking advantages of the availability of the large number of mammalian genome sequences and knowledge of phylogenetic relationships of the species, we examined the evolutionary fate of the motilin (MLN) hormone gene, after the pseudogenization of its specific receptor, MLN receptor (MLNR), on the rodent lineage. We speculate that the MLNR gene became a pseudogene before the divergence of the squirrel and other rodents about 75 mya. The evolutionary consequences for the MLN gene were diverse. While an intact open reading frame for the MLN gene, which appears functional, was preserved in the kangaroo rat, the MLN gene became inactivated independently on the lineages leading to the guinea pig and the common ancestor of the mouse and rat. Gain and loss of specific interactions among biomolecules through the birth and death of genes for biomolecules point to a general evolutionary dynamic: gene birth and death are widespread phenomena in genome evolution, at the genetic level; thus, once mutations arise, a stepwise process of elaboration and optimization ensues, which gradually integrates and orders mutations into a coherent pattern.
Jing He, David M Irwin, Rui Chen, and Ya-Ping Zhang
Hongjie Zhang, Jing Li, Xiangying Liang, Yun Luo, Ke Zen, and Chen-Yu Zhang
It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7–36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.
Hongjie Zhang, Jing Li, Xiangying Liang, Yun Luo, Ke Zen, and Chen-Yu Zhang
Bo Li, Yue Zhou, Jing Chen, Tingting Wang, Zhijuan Li, Yili Fu, Aixia Zhai, and Changlong Bi
Diabetic foot ulcer (DFU) is a chronic and non-healing complication of diabetes that leads to high hospital costs and, in extreme cases, to amputation. Recent studies have reported that long non-coding RNAs (lncRNAs) are linked to various diabetes-related symptoms. Thus, we aim to explore the role of lncRNA H19 in the wound healing process following DFU. Fibroblasts were isolated from the ulcer margin tissues of DFU patients, with the expression of lncRNA H19, connective tissue growth factor (CTGF) or serum response factor (SRF) altered by lentivirus infection. Next, rat models of DFU induced by high glucose and lipid diet were established, which was also infected with the corresponding lentivirus. The interaction among lncRNA H19, SRF and CTGF was determined. Afterward, cell proliferation and apoptosis, angiogenesis, ECM remodeling and wound healing in DFU tissues were evaluated to explore the effects of lncRNA H19/SRF/CTGF and MAPK signaling pathway on DFU. CTGF was poorly expressed in ulcer tissues from DFU rats and patients. CTGF overexpression was shown to activate the MAPK signaling pathway to promote cell proliferation, ECM remodeling, angiogenesis and wound healing while inhibiting cell apoptosis. lncRNA H19 was validated to elevate CTGF expression by recruiting SRF to the promoter region of CTGF, thus accelerating cell proliferation, ECM remodeling and wound healing while repressing cell apoptosis. Furthermore, MAPK signaling pathway activation is confirmed to be the underlying mechanism behind lncRNA H19/CTGF/SRF-induced results. Thus, lncRNA H19 accelerated wound healing in DFU through elevation of CTGF and activation of the MAPK signaling pathway.
Ting-Ting Zhou, Fei Ma, Xiao-Fan Shi, Xin Xu, Te Du, Xiao-Dan Guo, Gai-Hong Wang, Liang Yu, Vatcharin Rukachaisirikul, Li-Hong Hu, Jing Chen, and Xu Shen
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(1H)-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the Gαq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca2+)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.
Juan Liu, Xiaocen Kong, Long Wang, Hanmei Qi, Wenjuan Di, Xiao Zhang, Lin Wu, Xia Chen, Jing Yu, Juanmin Zha, Shan Lv, Aisen Zhang, Peng Cheng, Miao Hu, Yujie Li, Jianhua Bi, Yan Li, Fang Hu, Yi Zhong, Yong Xu, and Guoxian Ding
Brown adipose tissue (BAT) increases energy expenditure and is an attractive therapeutic target for obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), an amplifier of local glucocorticoid activity, has been shown to modulate white adipose tissue (WAT) metabolism and function. In this study, we investigated the roles of 11β-HSD1 in regulating BAT function. We observed a significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1, and Cox8b, in BVT.2733 (a selective inhibitor of 11β-HSD1)-treated and 11β-HSD1-deficient primary brown adipocytes of mice. By contrast, a remarkable decrease in BAT-specific gene expression was detected in brown adipocytes when 11β-HSD1 was overexpressed, which effect was reversed by BVT.2733 treatment. Consistent with the in vitro results, expression of a range of genes related to brown fat function in high-fat diet-fed mice treated with BVT.2733. Our results indicate that 11β-HSD1 acts as a vital regulator that controls the expression of genes related to brown fat function and as such may become a potential target in preventing obesity.