Incretins Beyond the Pancreas: Exploring the Impact of GIP and GLP-1/2 on Bone Remodeling.

Incretin hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 and 2 (GLP-1, 2), belong to the group of gastrointestinal hormones. Their actions occur through interaction with GIP and GLP-1/2 receptors, which are present in various target tissues. Apart from their well-established roles in pancreatic function and insulin regulation, incretins elicit significant effects that extend beyond the pancreas. Specifically, these hormones stimulate osteoblast differentiation and inhibit osteoclast activity, thereby promoting bone anabolism. Moreover, they play a pivotal role in bone mineralization and overall bone quality and function, making them potentially therapeutic for managing bone health. Thus, this review provides a summary of the crucial involvement of incretins in bone metabolism, influencing both bone formation and resorption processes. While existing evidence is persuasive, further studies are necessary for a comprehensive understanding of the therapeutic potential of incretins in modifying bone health.

The effect of hearing impairment and social participation on depressive symptoms in older adults: a cross-lagged analysis.

Objective: This study aimed to investigate the relationship between hearing impairment, depressive symptoms, and social participation in older adults. Methods: The study used data from the China Health and Retirement Longitudinal Study (CHARLS) in 2013 and 2018, which included 3,980 samples. The analysis was conducted using cross-lagged structural equation modeling with SPSS 23.0 and Mplus 7.4. Results: The findings show that from 2013 to 2018, older people had significantly more hearing impairment and depressive symptoms and significantly less social participation. Hearing impairment was a significant negative predictor of social participation, and older adults with hearing impairment were less likely to participate in social activities. In addition, there may be a bidirectional relationship between hearing impairment and depressive symptoms, with both being positive predictors of each other. Finally, the study found that social participation played an important mediating role in the relationship between hearing impairment and depressive symptoms. Conclusion: The study's findings highlight the complex interplay between hearing impairment, social participation, and depressive symptoms in older adults. Therefore, it is important to intervene promptly when hearing impairment is detected in the elderly; pay attention to patient guidance and comfort for the elderly with hearing impairment, give them positive psychological support, encourage them to get out of the house and participate in more social activities to avoid depressive symptoms. The study's results may inform the development of targeted interventions to address the mental health needs of older adults with hearing impairment.

N6-methyladenosine methyltransferase WTAP-stabilized FOXD2-AS1 promotes the osteosarcoma progression through m6A/FOXM1 axis.

Long noncoding RNAs (lncRNAs) play critical roles in tumor progression regulation, including osteosarcoma. Evidence indicates that N6-methyladenosine (m6A) modification modulates mRNA stability to regulate osteosarcoma tumorigenesis. Here, present research aims to detect the roles of m6A-modified lncRNA FOXD2-AS1 in the osteosarcoma pathophysiological process. Clinical data unveiled that osteosarcoma patients with higher FOXD2-AS1 expression had a poorer overall survival rate compared to those with lower FOXD2-AS1 expression. Functional research illuminated that FOXD2-AS1 accelerated the migration, proliferation and tumor growth in vitro and in vivo. Mechanistically, a remarkable m6A-modified site was found on the 3'-UTR of FOXD2-AS1, and m6A methyltransferase WTAP (Wilms' tumor 1 associated protein) promoted the methylation modification, thus enhancing the stability of FOXD2-AS1 transcripts. Furthermore, FOXD2-AS1 interacted with downstream target FOXM1 mRNA through m6A sites, forming a FOXD2-AS1/m6A/FOXM1 complex to heighten FOXM1 mRNA stability. In conclusion, these findings propose a novel regulatory mechanism in which m6A-modified FOXD2-AS1 accelerates the osteosarcoma progression through m6A manner, which may provide new concepts for osteosarcoma tumorigenesis.

Identification of Abnormal Spindle Microtubule Assembly as a Promising Therapeutic Target for Osteosarcoma.

OBJECTIVE: To demonstrate the expression of abnormal spindle microtubule assembly (ASPM) in clinical osteosarcoma tissue specimens collected in our hospital, and to explore the function of ASPM in osteosarcoma in vitro and in vivo. METHODS: Tissue specimens from 82 cases of osteosarcoma were collected and analyzed by immunohistochemistry assay. We also investigated the relationship between ASPM expression and clinicopathological characteristics in the patients. We transfected shASPM plasmid and the empty control plasmid, respectively, and then used quantitative polymerase chain reaction and western blot analysis to detect ASPM expression. Cell colony assay and MTT were used to observe the proliferation ability. In vivo study was undertaken to explore the ASPM function further. RESULTS: In this study, ASPM showed high expression in osteosarcoma tissue samples compared with non-tumor normal tissues. ASPM was positively correlated with clinical pathological characteristics, including tumor size (P = 0.024) and clinical stage (P = 0.045). Our results further showed that ASPM depletion dramatically inhibited the proliferation of osteosarcoma cells (with fewer cells in the sh-RNA-ASPM group compared with the control group(P < 0.05, respectively), and the in vivo assays further confirmed that ASPM ablation markedly blocked tumor growth compared with control (P < 0.05). CONCLUSION: Our data provides strong evidence that the high expression of ASPM in osteosarcoma promotes proliferation in vitro and in vivo, indicating its potential role as an osteosarcoma therapeutic target.

Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells.

This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.

Liraglutide suppresses the metastasis of PANC-1 co-cultured with pancreatic stellate cells through modulating intracellular calcium content.

In this study, we aim to explore the anti-tumor effect of liraglutide (Lira), an anti-diabetic medicine, on pancreatic cancer cell PANC-1 co-cultured with or without pancreatic stellate cells (PSCs). The chemical count kit-8 and Annexin V-FITC apoptosis detection were conducted to investigate the effect of Lira on cell viability and proliferation of PANC-1 with or without PSCs co-culture. Then, the wound healing and transwell experiments were performed to explore the influence of Lira on PANC-1 cells' migration and invasion capabilities. To identify the potential action mechanism of Lira on PANC-1, the expression of E-cadherin and N-cadherin and the intracellular calcium content in PANC-1, after Lira administration, were detected. The results indicated that Lira in 100 and 1,000 nmol/L, effectively decreased the cell viability and dose-dependently promoted cell apoptosis of PANC-1 co-cultured with or without PSCs. Lira significantly reduced the migration and invasion of PANC-1 and also reduced the inducing effect of PSCs to PANC-1. Lira effectively induced the expression of E-cadherin and suppressed the expression of N-cadherin with a dose-dependent manner. Otherwise, Lira significantly reduced the abnormal high content of calcium in PANC-1 and also weakened the elevation of calcium in PANC-1 induced by cell-cell interaction. The current study firstly indicated that Lira suppressed the cell proliferation, migration and invasion of PANC-1 with or without PSCs co-culture. This effect was partially due to the calcium modulation of Lira and its influence on Ca2+-binding proteins, such as E-cadherin and N-cadherin.

The CTIP-mediated repair of TNF-α-induced DNA double-strand break was impaired by miR-130b in cervical cancer cell.

Chemotherapeutic drugs that induce DNA damage have the potential to kill cancer cells, but DNA repair protects cells from damage-induced cell death. Thus, eliminating DNA repair is a potential approach to overcome cell drug resistance. In this study, we observed that the gene expression of C-terminal binding protein interacting protein (CTIP) was promoted by TNF-α stimulation and prevented TNF-α-induced double-strand breaks (DSBs) in the genomes of cervical cancer cells. The putative miR-130b targeted site within 3' untranslated region (UTR) of CTIP mRNA was identified through in silico analysis and confirmed based on experimental data. By targeting the CTIP gene, miR-130b caused the accumulation of DSBs and accelerated cell apoptosis in combination with poly ADP ribose polymerase (PARP) inhibitors. Additionally, overexpression of the CTIP gene elevated cancer cell viability by promoting proliferation while miR-130b antagonized CTIP-stimulated cell reproduction. Consequently, miR-130b destruction of DNA repair should be employed as a strategy to treat cervical cancer. SIGNIFICANCE OF THE STUDY: Cervical cancer threatens the health of women all over the world. In this study, we observed that miR-130b was able to cause the accumulation of DNA double-strand breaks through suppressing the gene expression of C-terminal binding protein interacting protein and to accelerate cell apoptosis by preventing DNA damage repairs in cervical cancer cells. As far as we know, the impact of miR-130b on the DNA double-strand break repair and on the cell apoptosis induced by the destruction of DNA repair in cervical cancer cells was firstly documented. It is reasonable to believe that miR-130b destruction of DNA repair may be employed as a strategy to treat cervical cancer in the future.

HIF-1α induced long noncoding RNA FOXD2-AS1 promotes the osteosarcoma through repressing p21.

Emerging literature indicates the essential roles of long noncoding RNA (lncRNA) in the osteosarcoma (OS). However, the regulatory function and mechanism of FOXD2-AS1 in the OS is still elusive. In present research, the level of FOXD2-AS1 was significantly up-regulated in the OS tissue and cell lines compared to corresponding controls. The aberrant high-expression of FOXD2-AS1 indicated the poor clinical prognosis of OS patients. Transcription factor HIF-1α could bind with the promoter region of FOXD2-AS1 to activate the transcription in OS cells. Functionally, the knockdown of FOXD2-AS1 could repress the malignant biological properties of OS cells in vitro and vivo, including proliferation, invasion, apoptosis and tumor growth. Mechanistically, FOXD2-AS1 inhibited the expression of p21 via interacting with EZH2 to silence p21 gene expression. Overall, we conclude that FOXD2-AS1, induced by transcription factor HIF-1α, acts as an oncogene in the OS tumorigenesis and FOXD2-AS1 interacts with EZH2 to silence p21 protein. This finding could provide a novel insight and potential therapeutic target for the OS.

APLNR promotes the progression of osteosarcoma by stimulating cell proliferation and invasion.

Osteosarcoma is the most common type of bone malignancies with a poor prognosis. In recent years, targeted therapy has shown great potential in the treatment of osteosarcoma, and more effective therapeutic targets for this disease need to be developed. APLNR is a seven transmembrane G-protein-coupled receptor expressed widely in multiple tissues. As has been reported, APLNR is involved in various physiological and pathological processes. Although APLNR plays a role in the development and progression of multiple tumors, the potential role of APLNR in osteosarcoma, a highly malignant tumor, remains unclear. Here, we reported that APLNR expression was correlated positively with clinical features including tumor size and stage of osteosarcoma. We found that APLNR knockdown inhibited the proliferation and invasion of osteosarcoma cells in vitro. In addition, APLNR could promote the progression and metastasis of osteosarcoma in mice. Collectively, this study showed the potential link between APLNR and osteosarcoma and suggested APLNR as a novel therapeutic target for osteosarcoma.

GLP-1 analog liraglutide enhances proinsulin processing in pancreatic ß-cells via a PKA-dependent pathway.

Hyperproinsulinemia has gained increasing attention in the development of type 2 diabetes. Clinical studies have demonstrated that glucagon-like peptide-1 (GLP-1)-based therapies significantly decrease plasma proinsulin/insulin ratio in patients with type 2 diabetes. However, the underlying mechanism remains unclear. Prohormone convertase (PC)-1/3 and PC2 are primarily responsible for processing proinsulin to insulin in pancreatic ß-cells. We have recently reported that Pax6 mutation down-regulated PC1/3 and PC2 expression, resulting in defective proinsulin processing in Pax6 heterozygous mutant (Pax6(m/+)) mice. In this study, we investigated whether and how liraglutide, a novel GLP-1 analog, modulated proinsulin processing. Our results showed that liraglutide significantly up-regulated PC1/3 expression and decreased the proinsulin to insulin ratio in both Pax6(m/+) and db/db diabetic mice. In the cultured mouse pancreatic ß-cell line, Min6, liraglutide stimulated PC1/3 and PC2 expression and lowered the proinsulin to insulin ratio in a dose- and time-dependent manner. Moreover, the beneficial effects of liraglutide on PC1/3 and PC2 expression and proinsulin processing were dependent on the GLP-1 receptor-mediated cAMP/protein kinase A signaling pathway. The same mechanism was recapitulated in isolated mouse islets. In conclusion, liraglutide enhanced PC1/3- and PC2-dependent proinsulin processing in pancreatic ß-cells through the activation of the GLP-1 receptor/cAMP/protein kinase A signaling pathway. Our study provides a new mechanism for improvement of pancreatic ß-cell function by the GLP-1-based therapy.

Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner.

Glucagon-like peptide-1 (GLP-1) promotes pancreatic ß-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.