Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m6A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the "reader" protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.

lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus.

The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism.

Somatostatin-secreting δ-cells have aroused great attention due to their powerful roles in coordination of islet insulin and glucagon secretion and maintenance of glucose homeostasis. δ-cells exhibit neuron-like morphology with projections which enable pan-islet somatostatin paracrine regulation despite their scarcity in the islets. The expression of a range of hormone and neurotransmitter receptors allows δ-cells to integrate paracrine, endocrine, neural and nutritional inputs, and provide rapid and precise feedback modulations on glucagon and insulin secretion from α- and β-cells, respectively. Interestingly, the paracrine tone of δ-cells can be effectively modified in response to factors released by neighboring cells in this interactive communication, such as insulin, urocortin 3 and γ-aminobutyric acid from β-cells, glucagon, glutamate and glucagon-like peptide-1 from α-cells. In the setting of diabetes, defects in δ-cell function lead to suboptimal insulin and glucagon outputs and lift the glycemic set-point. The interaction of δ-cells and non-δ-cells also becomes defective in diabetes, with reduces paracrine feedback to β-cells to exacerbate hyperglycemia or enhanced inhibition of α-cells, disabling counter-regulation, to cause hypoglycemia. Thus, it is possible to restore/optimize islet function in diabetes targeting somatostatin signaling, which could open novel avenues for the development of effective diabetic treatments.

δ-Cells: The Neighborhood Watch in the Islet Community

Neurological evidence suggests that beta-hydroxybutyrate (BHBA) has positive effects on the central nervous system. Previous studies have explored the molecular mechanisms by which BHBA affects different brain functions, but the effects of BHBA on epigenetic modifications remain elusive. Here, we showed that BHBA enhanced brain-derived neurotrophic factor (BDNF) expression by increasing H3K4me3 and decreasing H2AK119ub occupancy at the Bdnf promoters I, II, IV, and VI in hippocampal neurons. Moreover, BHBA treatment induced the upregulation of H3K4me3 and downregulation of H2AK119ub on the global level, both of which were dependent on the L-type calcium channel. Additionally, the BHBA-activated L-type calcium channel subsequently triggered the activation of Ca2+/CaMKII/CREB signaling, and promoted the binding of p-CREB and CBP to Bdnf promoters. These results indicate that BHBA regulates cellular signaling and multiple histone modifications to cooperatively modulate BDNF, suggesting a wide range of regulatory effects of BHBA in the central nervous system.

/pdf/beta-hydroxybutyrate-enhances-bdnf-expression-by-increasing-5bcqf79bf1.pdf

Beta-Hydroxybutyrate Enhances BDNF Expression by Increasing H3K4me3 and Decreasing H2AK119ub in Hippocampal Neurons.

Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the δ cell-specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.

/pdf/a-cullin-4b-ring-e3-ligase-complex-fine-tunes-pancreatic-d-59izh0t95k.pdf

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Introduction Computed tomography (CT)-guided liquid material (LM) and hook-wire (HW) are usually localized for pulmonary nodules (PNs) before video-assisted thoracic surgery (VATS) resection, but the relative advantages of these 2 techniques remain uncertain. Aim This meta-analysis was conceived to juxtapose the efficacy and safety of HW localization (HWL) and LM localization (LML), both guided by CT, for the preoperative localization of PNs. Material and methods The PubMed, Web of Science, and Wanfang databases were searched to identify relevant studies published as of March 2023, after which pooled analyses of study outcomes were conducted. Results A total of 7 studies were included in this meta-analysis from 142 relevant studies. These 7 studies included 551 patients (583 PNs) with CT-guided HWL and 551 patients (612 PNs) with LML. The successful localization rate was significantly higher in the LM group (LMG) than in the HW group (HWG) (p = 0.002). The LMG also exhibited significantly lower pooled total complication and lung haemorrhage rates than the HWG (p = 0.007 and 0.00001, respectively). Pooled localization duration, pneumothorax rates, and VATS procedure duration were comparable in both groups (p = 0.45, 0.15, and 0.74, respectively). Furthermore, the pooled postoperative hospital stay was significantly shorter in the LMG than in the HWG (p = 0.009). Significant heterogeneity was detected in the endpoints of localization duration and pneumothorax rate (I2 = 93% and 66%, respectively). Conclusions CT-guided LML is safer and more successful than HWL for patients with PNs before VATS resection.

/pdf/comparison-between-preoperative-hook-wire-and-liquid-leh2xouv.pdf

Comparison between preoperative hook-wire and liquid material localization for pulmonary nodules: a meta-analysis

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A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Comparison between preoperative hook-wire and liquid material localization for pulmonary nodules: a meta-analysis