Melatonin Promotes Antler Growth by Accelerating MT1-Mediated Mesenchymal Cell Differentiation and Inhibiting VEGF-Induced Degeneration of Chondrocytes

The sika deer is one type of seasonal breeding animal, and the growth of its antler is affected by light signals. Melatonin (MLT) is a neuroendocrine hormone synthesized by the pineal gland and plays an important role in controlling the circadian rhythm. Although the MLT/MT1 (melatonin 1A receptor) signal has been identified during antler development, its physiological function remains almost unknown. The role of MLT on antler growth in vivo and in vitro is discussed in this paper. In vivo, MLT implantation was found to significantly increase the weight of antlers. The relative growth rate of antlers showed a remarkable increased trend as well. In vitro, the experiment showed MLT accelerated antler mesenchymal cell differentiation. Further, results revealed that MLT regulated the expression of Collage type II (Col2a) through the MT1 binding mediated transcription of Yes-associated protein 1 (YAP1) in antler mesenchymal cells. In addition, treatment with vascular endothelial growth factor (VEGF) promoted chondrocytes degeneration by downregulating the expression of Col2a and Sox9 (SRY-Box Transcription Factor 9). MLT effectively inhibited VEGF-induced degeneration of antler chondrocytes by inhibiting the Signal transducers and activators of transcription 5/Interleukin-6 (STAT5/IL-6) pathway and activating the AKT/CREB (Cyclin AMP response-element binding protein) pathway dependent on Sox9 expression. Together, our results indicate that MLT plays a vital role in the development of antler cartilage.

Effects of dihydropyridine receptor signal on sarcoplasmic reticulum Ca2+ leakage after muscle contractions in rats

The purpose of this study is to investigate the mechanism underlying sarcoplasmic reticulum (SR) Ca2+ leakage at recovery phase after in vivo contractions. Rat gastrocnemius muscles were electrically stimulated in vivo, and then mechanically skinned fibers were prepared from the muscles excised 30 min after repeated high-intensity contractions. SR Ca2+ leakage was increased in the skinned fibers from stimulated muscles. Thereafter, SR Ca2+ leakage in skinned fibers was measured (1) under a continuously depolarized condition and (2) in the presence of nifedipine in the sealed transverse tubular system. In either of the two conditions, SR Ca2+ leakage in the rested fibers reached a level similar to that in the stimulated fibers. Furthermore, 1 mM tetracaine (Tet) treatment, but not 3 mM Mg2+ (3 Mg) treatment, lessened SR Ca2+ leakage in stimulated fibers. Depolarization-induced force in skinned fibers was more greatly decreased by Tet treatment than by 3 Mg treatment (92% reduction in Tet versus 31% reduction in 3 Mg), whereas caffeine-induced force in skinned fibers was similarly decreased by either treatment (73% reduction in Tet versus 75% reduction in 3 Mg). This difference indicates that Tet exerts a greater inhibitory effect on the dihydropyridine receptor (DHPR) signal to ryanodine receptor (RYR) than 3 Mg, although their inhibitory effects on RYR are almost similar. These results suggest that the increased Ca2+ leakage after muscle contractions is mainly caused by the orthograde signal of DHPRs to RYRs.

Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice

Melatonin has been indicated to ameliorate tau hyperphosphorylation in the pathogenesis of tau diseases, but the role of melatonin-receptor signal transduction has not been clearly discovered. In this study, we found intensive tau hyperphosphorylation in melatonin receptor knockout mice. Bielschowsky silver staining showed ghostlike neurofibrillary tangles in melatonin receptor-2 knockout (MT2KO) as well as melatonin receptors-1 and -2 knockout (DKO) mice, and an argyrophilic substance was deposited in melatonin receptor-1 knockout (MT1KO) mice. Furthermore, we found significantly decreased activity of protein phosphatase 2A (PP2A) by Western blot and enzyme-linked immunosorbent assay (ELISA), which was partly due to the overexpression of protein phosphatase methylesterase-1 (PME-1), but not glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5) or protein kinase B (Akt). Finally, we observed a significant increase in cyclic adenosine monophosphate (cAMP) and a decrease in miR-125b-5p levels in MT1KO, MT2KO and DKO mice. Using a luciferase reporter assay, we discovered that miR-125b-5p largely decreased the expression of firefly luciferase by interfering with the 3′UTR of PME-1. Furthermore, miR-125b-5p mimics significantly decreased the expression of PME-1, while miR-125b-5p inhibitor induced tau hyperphosphorylation. These results show that melatonin-receptor signal transduction plays an important role in tau hyperphosphorylation and tangle formation.

Prognostic Signature based on Transcriptome Characteristics of the C-C Motif Chemokine Receptor Genes in Hepatocellular Carcinoma and Validation

Object: This investigation aimed to assess the clinical significance of C-C motif chemokine receptor (CCR) genes in HCC and construct the prognostic signature based on transcriptome characteristics of the CCRs. Methods: Clinical significance of CCRs were evaluated in TCGA database and GSE14520 dataset, and prognostic CCRs (CCR1,5,7) were screened out for validation and further analysis. The relationships between CCR1,5,7 and prognosis were then evaluated in the Guangxi cohort. Based on the expression levels of CCR1,5,7 and clinicopathological characteristics, the nomograms and prognostic signatures were respectively constructed in GSE14520 dataset and Guangxi cohort. Results: CCR1,5,7 were associated with overall survival of the HCC patients in GSE14520 database, TCGA database or Guangxi cohort. In the prognostic signature, the accuracy of prognosis risk assessment based on CCR1,5,7 expression was satisfactory. The nomogram constructed in terms of the expression levels of CCR1,5,7 and clinicopathological characteristics provided a convenient tool for clinician to assess the prognostic risk of each patient. GSEA results suggested that CCRs were mainly related to B cell receptor signal pathway, chemokine signaling pathway, T cell receptor signal pathway, etc. In addition, we also found that CCR1,5,7 were significantly positively correlated with the degree of immune infiltration of B cells, T cells, and macrophagesConclusion: CCR1,5,7 might serve as prognostic biomarkers in HCC; CCR1,5,7 might regulate the progression of HCC by impacting immune cells infiltration.

Vecabrutinib inhibits B-cell receptor signal transduction in chronic lymphocytic leukemia cell types with wild-type or mutant Bruton’s tyrosine kinase

Not available.

Immune classifier-based signatures provide good prognostic stratification and predict the clinical benefits of immune-based therapies for hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is an aggressive cancer with a high rate of death globally. The use of bioinformatics may help to identify immune cell-related genes both as targets for potential immunotherapies and for their value associated with predicting therapy responses. Methods In this study, mRNA expression profiles of HCC samples from The Cancer Genome Atlas (TCGA) database were subjected to gene enrichment, cell type abundance, immune cell infiltration, and pathway enrichment analyses to determine immune cell gene features, cell type abundance, and functional annotation characteristics. We also evaluated their prognostic values using Cox regression and Kaplan–Meier analyses and assessed potential responses to chemotherapy. Four subgroups (Groups 1–4) were identified. Group 4 was associated with advanced clinical characteristics, high immune cell enrichment scores, and the poorest outcomes. Results Differentially expressed genes (DEGs) in the HCC samples were enriched in the following pathways: antigen binding, cell surface receptor signal transduction of the immune response, and cell surface activated receptor signal transduction of the immune response. Highly expressed genes in Group 4 were enriched in elements of the WNT signalling pathway. We identified five immune-related genes (SEMA3A, TNFRSF11B, GUCA2A, SAA1, and CALCR) that were significantly related to HCC prognosis. A prognostic model based on these five genes exhibited good predictive value, with 1-year and 5-year area under the curve (AUC) values of > 0.66. Group 4 was also potentially more sensitive to EHT 1864, FH535, and lapatinib chemotherapies than the other groups. Conclusions We identified and validated four HCC subgroups based on immune system-related genes and identified five genes that may be used for an immune-based prognostic model for HCC treatment.

An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

The multifaceted nature of the renin-angiotensin system (RAS) makes it versatile due to its involvement in pathogenesis of the cardiovascular disease. Angiotensin II (Ang II), a multifaceted member of RAS family is known to have various potential effects. The knowledge of this peptide has immensely ameliorated after meticulous research for decades. Several studies have evidenced angiotensin I receptor (AT1 R) to mediate the majority Ang II-regulated functions in the system. Functional crosstalk between AT1 R mediated signal transduction cascades and other signaling pathways has been recognized. The review will provide an up-to-date information and recent discoveries involved in Ang II receptor signal transduction and their functional significance in the cardiovascular system for potential translation in therapeutics. Moreover, the review also focuses on the role of stem cell-based therapies in the cardiovascular system.

Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.