Graphical Abstract Highlights d Exogenous insulin/IGF signal promotes heterogeneity in early mesoderm differentiation d Endogenous IGF induced during mesoderm differentiation suppresses cardiomyocyte fate d Inhibition of IGF pathway by LY294002 leads to effective cardiomyocyte differentiation d LY294002 inhibits the CK2 pathway to promote cardiomyocyte cell fate SUMMARYDuring embryogenesis, various cell types emerge simultaneously from their common progenitors under the influence of intrinsic signals. Human embryonic stem cells can differentiate to diverse cell types of three embryonic lineages, making them an excellent system for understanding the regulatory mechanism that maintains the balance of different cell types in embryogenesis. In this report, we demonstrate that insulin-like growth factor (IGF) proteins are endogenously expressed during differentiation, and their temporal expression contributes to the cell fate diversity in mesoderm differentiation. Small molecule LY294002 inhibits the IGF pathway to promote cardiomyocyte differentiation while suppressing epicardial and noncardiac cell fates. LY294002induced cardiomyocytes demonstrate characteristic cardiomyocyte features and provide insights into the molecular mechanisms underlying cardiac differentiation. We further show that LY294002 induces cardiomyocytes through CK2 pathway inhibition. This study elucidates the crucial roles of endogenous IGF in mesoderm differentiation and shows that the inhibition of the IGF pathway is an effective approach for generating cardiomyocytes.
Ca(2+) plays a key role in intracellular signaling and controls various cellular processes such as proliferation, differentiation, cell growth, death, and apoptosis. Aberrant changes in intracellular Ca(2+) levels can promote undesired cell proliferation and migration and are therefore associated with certain tumor types. Many research groups have suggested a potential role for voltage-gated Ca(2+) channels in the regulation of tumor growth and progression, particularly T-type channels due to their unique biophysical properties. T-type channels are expressed in normal tissues throughout the body and in different types of tumors such as breast carcinoma, retinoblastoma, neuroblastoma, and glioma. It has been demonstrated that increased functional expression of the α1 subunit of T-type channels plays a role in the abnormal proliferation of glioblastoma cells. As such, siRNA-mediated knockdown of the expression of the α1 subunit of T-type channels decreases the proliferation of these cells. Moreover, pharmacological blockade of T-type channels significantly decreases tumor growth. In this review, we focus on the use of T-type channel blockers for the potential treatment of cancers, particularly highly proliferative tumors such as glioblastoma. We conclude that T-type channel blockers such as endostatin can serve as a potential therapeutic tool for tumors whose proliferation depends on increased T-type channel expression.
Background Cholecystokinin (CCK) is implicated in the regulation of nociceptive sensitivity of primary afferent neurons. Nevertheless, the underlying cellular and molecular mechanisms remain unknown. Methods Using patch clamp recording, western blot analysis, immunofluorescent labelling, enzyme-linked immunosorbent assays, adenovirus-mediated shRNA knockdown and animal behaviour tests, we studied the effects of CCK-8 on the sensory neuronal excitability and peripheral pain sensitivity mediated by A-type K + channels. Results CCK-8 reversibly and concentration-dependently decreased A-type K + channel ( I A ) in small-sized dorsal root ganglion (DRG) neurons through the activation of CCK type B receptor (CCK-BR), while the sustained delayed rectifier K + current was unaffected. The intracellular subunit of CCK-BR coimmunoprecipitated with Gα o . Blocking G-protein signaling with pertussis toxin or by the intracellular application of anti-G β antibody reversed the inhibitory effects of CCK-8. Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its common downstream target Akts abolished the CCK-BR-mediated I A response. CCK-8 application significantly activated JNK mitogen-activated protein kinase. Antagonism of either JNK or c-Src prevented the CCK-BR-mediated I A decrease, whereas c-Src inhibition attenuated the CCK-8-induced p -JNK activation. Application of CCK-8 enhanced the action potential firing rate of DRG neurons and elicited mechanical and thermal pain hypersensitivity in mice. These effects were mediated by CCK-BR and were occluded by I A blockade. Conclusion Our findings indicate that CCK-8 attenuated I A through CCK-BR that is coupled to the G βγ -dependent PI3K and c-Src-mediated JNK pathways, thereby enhancing the sensory neuronal excitability in DRG neurons and peripheral pain sensitivity in mice.
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