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Peperomin E is a natural secolignan existing distributed in the plants of the genus Peperomia. Previous investigations demonstrated that peperomin E showed potential antitumor activity in some cancer lines, but it is unclear whether peperomin E has an effect on prostate cancer cell lines. The aim of the present study is to investigate its effects on proliferation inhibition, apoptosis-inducing and cell-cycle arrest activity using a prostate cancer PC-3 cell line. The proliferation inhibition was evaluated by MTT assay, apoptosis was detected by Annexin V/propidium iodide (PI) staining and Hoechst 33258 staining, cell cycle distributions were measured by flow cytometry, and western blot analysis was used to determine specific cellular apoptotic protein expressions of Bcl-2, Bax, caspase-3 and cleaved-caspase-3. According to the results of this study, peperomin E exhibited significant anti-proliferation activity on PC-3 cell lines in vitro in a dose-dependent manner. Peperomin E treatments lead to marked morphological changes. Apoptotic cell count and cell-cycle distribution at G2/M phase significantly increased with increasing concentrations of peperomin E. The down-regulated expression level of Bcl-2 and up-regulated expression level of Bax and cleaved-caspase-3 compared with the controls were also observed after peperomin E treatment. These data suggest that peperomin E exhibited proliferation inhabitation, apoptosis-inducing and cell-cycle arrest activity on PC-3 cell lines. The anti-proliferation effect of peperomin E on PC-3 cells should result partly from its cell-cycle arrest and apoptosis-inducing activity, whereas the increasing of the Bax/Bcl-2 ratio and activation of caspases-3 play an important role in the development of apoptosis. [ABSTRACT FROM AUTHOR]

Adult mammalian cardiomyocytes (CMs) lose their proliferative potential due to cell-cycle withdrawal and polyploidization and fail to mount a proliferative response to regenerate new CMs after cardiac injury. The decline in the proliferative potential of mammalian CMs occurs in the neonatal period when the endocrine system undergoes drastic changes for adaptation to extra-uterine life. There is an increase in circulating glucocorticoid (GC) levels shortly after birth in mammals, and thus, we sought to determine the roles and mechanisms of GCs in regulating CM proliferation. Here, we showed that GCs suppressed CM proliferation in vitro and in vivo , decreased the total number of CMs, and increased the cross-sectional area of CMs. However, the glucocorticoid receptor antagonist had no effect on CM proliferation. Agonists of adenylate cyclase and protein kinase A (PKA) inhibited CM proliferation, while PKA antagonists or knockdown of PKA alleviated the inhibitory effect of GCs on CM proliferation. GCs and the activation of the cyclic adenosine monophosphate (cAMP)/PKA signaling pathway facilitated yes-associated protein (YAP) phosphorylation in mouse CMs and promoted YAP protein translocation from the nucleus to the cytoplasm. Meanwhile, blocking the cAMP/PKA signaling pathway partially blocked the effect of GCs on YAP protein phosphorylation and YAP protein translocation. Thus, our findings suggest that GCs suppress mouse CM proliferation in vitro and in vivo , through a mechanism that involves targeting the cAMP-PKA-YAP signaling pathway. •GCs inhibited neonatal mouse CM proliferation in vivo and in vitro. •cAMP/PKA pathway is involved in the regulation of GCs on neonatal mouse CM proliferative potential. •GCs promoted YAP phosphorylation by activating the cAMP-PKA pathway. •GCs regulated neonatal mouse CM proliferative potential through cAMP-PKA-YAP pathway partially. [ABSTRACT FROM AUTHOR]

Abstract: We recently described that carbon monoxide (CO) participated in the regulation of rhythmic respiration in medullary slices. The present study was undertaken to further assess whether the large-conductance calcium-activated potassium channels (BKCa channels) are involved in the CO-mediated central regulation of respiratory rhythm in medullary slices. The rhythmic discharge of hypoglossal rootlets of medullary slices of neonatal rats was recorded. We observed that blocking BKCa channels could partially abolish the effects of CO on the rhythmic bursts of hypoglossal rootlets. With whole-cell patch-clamp recording technique, we further observed that CO could reversibly augment potassium current density of the neurons in the rostral ventrolateral medulla. The CO-induced increase in potassium current was entirely blocked by the pretreatment of slices with BKCa channels blocker; whereas blockade of CO generation with zinc protoporphyrin-IX produced an opposite response. Altogether, these data indicate that BKCa channels of the neurons in neonatal rostral ventrolateral medulla could be activated by CO and involved in CO-mediated central regulation of respiratory rhythm in medullary slices. [Copyright &y& Elsevier]

Hydrogen sulfide (H 2 S) has been identified as a novel gasotransmitter and a substantial antioxidant that can activate various cellular targets to regulate physiological and pathological processes in mammals. However, under physiological conditions, it remains unclear whether it is involved in regulating cardiomyocyte (CM) proliferation during postnatal development in mice. This study mainly aimed to evaluate the role of H 2 S in postnatal CM proliferation and its regulating molecular mechanisms. We found that sodium hydrosulfide (NaHS, the most widely used H 2 S donor, 50-200 μM) increased neonatal mouse primary CM proliferation in a dose-dependent manner in vitro. Consistently, exogenous administration of H 2 S also promoted CM proliferation and increased the total number of CMs at postnatal 7 and 14 days in vivo. Moreover, we observed that the protein expression of SIRT1 was significantly upregulated after NaHS treatment. Inhibition of SIRT1 with EX-527 or si-SIRT1 decreased CM proliferation, while enhancement of the activation of SIRT1 with SRT1720 promoted CM proliferation. Meanwhile, pharmacological and genetic blocking of SIRT1 repressed the effect of NaHS on CM proliferation. Taken together, these results reveal that H 2 S plays a promotional role in proliferation of CMs in vivo and in vitro and SIRT1 is required for H 2 S-mediated CM proliferation, which indicates that H 2 S may be a potential modulator for heart development in postnatal time window.

Background: Celastrol, an important extract of Tripterygium wilfordii , shows strong antitumor activity in a variety of tumors including nasopharyngeal carcinoma (NPC). However, little is known about its targets in NPC. We aimed to screen the key gene targets of Celastrol in the treatment of NPC by means of in silico analyses (including network pharmacology and molecular docking) and experimental evaluations. Methods: The main target genes of Celastrol and the genes related to NPC were obtained by retrieving the relevant biological databases, and the common targets were screened. Protein-protein interaction analysis was used to screen the hub genes. Then, a "compound-target-disease" network model was created and molecular docking was used to predict the binding of Celastrol to the candidate hub proteins. Afterward, the expression changes of the candidate genes under the administration of Celastrol were verified in vitro and in vivo . Results: Sixty genes common to Celastrol and NPC were screened out, which may be related to numerous biological processes such as cell proliferation, apoptosis, and tube development, and enriched in various pathways such as PI3K- Akt, EGFR tyrosine kinase inhibitor resistance, and Apoptosis. The tight binding ability of the candidate hub proteins (TNF, VEGFA, and IL6) to Celastrol was predicted by molecular docking [Docking energy: TNF, -6.08; VEGFA,-6.76; IL6,-6.91(kcal/mol)]. In vitro experiments showed that the expression of TNF and VEGFA decreased while the expression of IL6 increased in NPC cells (CNE2 and HONE1) treated with Celastrol. In vivo experiments suggested that Celastrol significantly reduced the weight and volume of the transplanted tumors in tumor-bearing mice in vivo . The expression of TNF, VEGFA, and IL6 in the transplanted tumor cells could be regulated by using Celastrol, and the expression trends were consistent with the in vitro model. Conclusion: Several gene targets have been filtered out as the core targets of Celastrol in the treatment of NPC, which might be involved in a variety of signaling pathways. Hence, Celastrol may exert its anti-NPC activity through multiple targets and multiple pathways, which will provide new clues for further research. Future experiments are warranted to validate the findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ling, Huang, Sun, Guo, Chang, Pan and Zhuo.)