Knockdown of LRP5 Promotes Proliferation and Invasion of Tongue Squamous Cell Carcinoma through Compensatory Activation of Akt Signaling.

The role of LRP5, a critical receptor in the Wnt signaling pathway, remains unexplored in tongue squamous cell carcinoma (TSCC). This study investigates the impact of LRP5 knockdown on the biological behaviors of TSCC cell lines both in vitro and in vivo. Our findings indicate that LRP5 knockdown significantly enhances cell proliferation, migration, and invasion in CAL27 and SCC25 cell lines. RNA-seq analysis reveals compensatory activation of the Akt pathway, with 119 genes significantly upregulated post-LRP5 knockdown. Elevated MMP1 expression suggests its potential involvement in TSCC progression. Western blot analysis demonstrates increased Akt phosphorylation, upregulated proliferation-related PCNA, and downregulated apoptosis-related caspase-3 after LRP5 knockdown. Down-regulation of E-cadherin and ß-Catenin, proteins associated with cell adhesion and invasion, further elucidates the molecular mechanism underlying increased cell migration and invasion. Our study concludes that compensatory Akt pathway activation is essential for the LRP5 knockdown-induced migration and proliferation of CAL27 and SCC25 cells. These results highlight LRP5 as a potential therapeutic target for TSCC. Simultaneous inhibition of Wnt and Akt signaling emerges as a promising approach for TSCC treatment.

Automatic Identification of Pangolin Behavior Using Deep Learning Based on Temporal Relative Attention Mechanism.

With declining populations in the wild, captive rescue and breeding have become one of the most important ways to protect pangolins from extinction. At present, the success rate of artificial breeding is low, due to the insufficient understanding of the breeding behavior characteristics of pangolins. The automatic recognition method based on machine vision not only monitors for 24 h but also reduces the stress response of pangolins. This paper aimed to establish a temporal relation and attention mechanism network (Pangolin breeding attention and transfer network, PBATn) to monitor and recognize pangolin behaviors, including breeding and daily behavior. There were 11,476 videos including breeding behavior and daily behavior that were divided into training, validation, and test sets. For the training set and validation set, the PBATn network model had an accuracy of 98.95% and 96.11%, and a loss function value of 0.1531 and 0.1852. The model is suitable for a 2.40 m × 2.20 m (length × width) pangolin cage area, with a nest box measuring 40 cm × 30 cm × 30 cm (length × width × height) positioned either on the left or right side inside the cage. A spherical night-vision monitoring camera was installed on the cage wall at a height of 2.50 m above the ground. For the test set, the mean Average Precision (mAP), average accuracy, average recall, average specificity, and average F1 score were found to be higher than SlowFast, X3D, TANet, TSN, etc., with values of 97.50%, 99.17%, 97.55%, 99.53%, and 97.48%, respectively. The recognition accuracies of PBATn were 94.00% and 98.50% for the chasing and mounting breeding behaviors, respectively. The results showed that PBATn outperformed the baseline methods in all aspects. This study shows that the deep learning system can accurately observe pangolin breeding behavior and it will be useful for analyzing the behavior of these animals.

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms.

Background: CXC chemokine receptor 4 (CXCR4) is associated with the progression and metastasis of numerous malignant tumors. However, its relationship with Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3 (GEP-NENs G3) is unclear. The aim of this study was to characterize the expression of CXCR4 in GEP-NENS and to explore the clinical and prognostic value of CXCR4. Methods: This study retrospectively collected clinical and pathological data from patients with GEP-NENs who receiving surgery in Qilu Hospital of Shandong University from January 2013 to April 2021, and obtained the overall survival of the patients based on follow-up. Immunohistochemistry (IHC) was performed on pathological paraffin sections to observe CXCR4 staining. Groups were made according to pathological findings. Kaplan-Meier (K-M) curve was used to evaluate prognosis. SPSS 26.0 was used for statistical analysis. Results: 100 GEP-NENs G3 patients were enrolled in this study. There was a significant difference in primary sites (P=0.002), Ki-67 index (P<0.001), and Carcinoembryonic Antigen (CEA) elevation (P=0.008) between neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC). CXCR4 was highly expressed only in tumors, low or no expressed in adjacent tissues (P<0.001). The expression level of CXCR4 in NEC was significantly higher than that in NET G3 (P=0.038). The K-M curves showed that there was no significant difference in overall survival between patients with high CXCR4 expression and patients with low CXCR4 expression, either in GEP-NEN G3 or NEC (P=0.920, P=0.842. respectively). Conclusion: Differential expression of CXCR4 was found between tumor and adjacent tissues and between NET G3 and NEC. Our results demonstrated that CXCR4 can be served as a new IHC diagnostic indicator in the diagnosis and differential diagnosis of GEP-NENs G3. Further studies with multi-center, large sample size and longer follow-up are needed to confirm the correlation between CXCR4 expression level and prognosis.

Infantile hemangioma in a subadult Chinese pangolin: a case report.

BACKGROUND: Hemangiomas are a relatively common type of tumor in humans and animals. Various subtypes of hemangiomas have been described in the literature. The classification methods for hemangiomas differ between human and veterinary medicine, and the basis for tumor classification can be found in the literature. CASE PRESENTATION: This study describes a tumor in the subcutaneous tissue of the right dorsum of an artificially rescued juvenile Chinese pangolin. Computed tomography (CT) examination yielded the preliminary diagnosis of a vascular malformation, and surgery was performed to resect the tumor. Histopathological examination showed that the tumor mainly was consisted of adipose tissue, capillaries, and spindle cells in the fibrous stroma. Immunohistochemistry showed the positive expression of CD31, CD34, α-SMA, GLUT1 and WT-1 in the tumor tissue, and the tumor was eventually diagnosed as an infantile haemangioma. CONCLUSION: The final diagnosis of infantile hemangioma was depended on the histopathological immunohistochemical and CT examination of the neoplastic tissue. This is the first report of infantile hemangioma in a critically endangered species Chinese pangolin.

Traumatic inflammatory response: pathophysiological role and clinical value of cytokines.

Severe trauma is an intractable problem in healthcare. Patients have a widespread immune system response that is complex and vital to survival. Excessive inflammatory response is the main cause of poor prognosis and poor therapeutic effect of medications in trauma patients. Cytokines are signaling proteins that play critical roles in the body's response to injuries, which could amplify or suppress immune responses. Studies have demonstrated that cytokines are closely related to the severity of injuries and prognosis of trauma patients and help present cytokine-based diagnosis and treatment plans for trauma patients. In this review, we introduce the pathophysiological mechanisms of a traumatic inflammatory response and the role of cytokines in trauma patients. Furthermore, we discuss the potential of cytokine-based diagnosis and therapy for post-traumatic inflammatory response, although further clarification to elucidate the underlying mechanisms of cytokines following trauma is warranted.

Weak SARS-CoV-2-specific responses of TIGIT-expressing CD8 + T cells in people living with HIV after a third dose of a SARS-CoV-2 inactivated vaccine.

BACKGROUND: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), an inhibitory receptor expressed on T cells, plays a dysfunctional role in antiviral infection and antitumor activity. However, it is unknown whether TIGIT expression on T cells influences the immunological effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivated vaccines. METHODS: Forty-five people living with HIV (PLWH) on antiretroviral therapy (ART) for more than two years and 31 healthy controls (HCs), all received a third dose of a SARS-CoV-2 inactivated vaccine, were enrolled in this study. The amounts, activation, proportion of cell subsets, and magnitude of the SARS-CoV-2-specific immune response of TIGIT + CD4 + and TIGIT + CD8 + T cells were investigated before the third dose but 6 months after the second vaccine dose (0W), 4 weeks (4W) and 12 weeks (12W) after the third dose. RESULTS: Compared to that in HCs, the frequency of TIGIT + CD8 + T cells in the peripheral blood of PLWH increased at 12W after the third dose of the inactivated vaccine, and the immune activation of TIGIT + CD8 + T cells also increased. A decrease in the ratio of both T naïve (T N ) and central memory (T CM ) cells among TIGIT + CD8 + T cells and an increase in the ratio of the effector memory (T EM ) subpopulation were observed at 12W in PLWH. Interestingly, particularly at 12W, a higher proportion of TIGIT + CD8 + T cells expressing CD137 and CD69 simultaneously was observed in HCs than in PLWH based on the activation-induced marker assay. Compared with 0W, SARS-CoV-2-specific TIGIT + CD8 + T-cell responses in PLWH were not enhanced at 12W but were enhanced in HCs. Additionally, at all time points, the SARS-CoV-2-specific responses of TIGIT + CD8 + T cells in PLWH were significantly weaker than those of TIGIT - CD8 + T cells. However, in HCs, the difference in the SARS-CoV-2-specific responses induced between TIGIT + CD8 + T cells and TIGIT - CD8 + T cells was insignificant at 4W and 12W, except at 0W. CONCLUSIONS: TIGIT expression on CD8 + T cells may hinder the T-cell immune response to a booster dose of an inactivated SARS-CoV-2 vaccine, suggesting weakened resistance to SARS-CoV-2 infection, especially in PLWH. Furthermore, TIGIT may be used as a potential target to increase the production of SARS-CoV-2-specific CD8 + T cells, thereby enhancing the effectiveness of vaccination.

FABP4 in macrophages facilitates obesity-associated pancreatic cancer progression via the NLRP3/IL-1ß axis.

Obesity is an essential risk factor for pancreatic cancer (PC). Macrophage-induced inflammation plays a pivotal role in obesity-associated carcinogenesis and disease progression; however, the underlying molecular mechanisms remain unclear. In this study, we found that fatty acid-binding protein 4 (FABP4) overexpressed in serum of obese patients and was associated with poor overall survival. In vivo and in vitro experiments have revealed that FABP4 induces macrophage-related inflammation to promote cancer cell migration, invasion and metastasis under obese conditions. Mechanistically, FABP4 participates in transferring saturated fatty acid to induce macrophages pyroptosis in a caspase-1/GSDMD-dependent manner and mediates NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/IL-1ß axis in macrophages, which further regulates epithelial-mesenchymal transition signals to promote the migration, invasion, and metastasis of PC cells. Our results suggest that FABP4 in macrophages is a crucial regulator of the NLRP3/IL-1ß axis to promote the progression of PC under obese conditions, which could act as a promising molecular target for treating of PC patients with obesity.

RAD21 is the core subunit of the cohesin complex involved in directing genome organization.

BACKGROUND: The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation. RESULTS: We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes. CONCLUSIONS: Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.

The characteristics of serum lipid spectrum in PanNENs and its correlation with clinicopathological features and prognosis.

Background: The role of dyslipidemia in pancreatic neuroendocrine tumors (PanNENs) is unclear. The aim of this study is to analyze the characteristics of serum lipid spectrum in PanNENs, and the effect of the variation in lipid profile on the development of PanNENs clinicopathological features and prognosis. Methods: All PanNENs patients between November 2012 and September 2020 in the authors' research center were identified from patient medical records and databases. A total of 185 with PanNENs patients were ultimately included in this study, including 100 nonfunctional PanNENs and 85 insulinomas. Clinicopathologic features, serum lipid level and overall survival results were retrospectively analyzed using statistical methods. Results: In 185 PanNENs, 95 (51.4%) patients appear to have dyslipidemia. Patients with insulinoma had a lower proportion of abnormal HDL than those with nonfunctional PanNENs (10.6% vs 23%, P=0.026). The mean serum HDL levels of insulinomas were 0.131 mmol/L higher than the NF-PanNENs (1.306 ± 0.324 vs 1.175 ± 0.315, P=0.006). In multivariate logistic analysis, high levels of HDL are negatively correlated to tumor size (OR 0.233, 95% CI: 0.069-0.790, P=0.019), but HDL was not associated with pathological grade or metastasis. And a correlation has been found between hypercholesterolemia and the original location of the tumor (OR:0.224, 95%CI: 0.066-0.753, P =0.016). In addition, the outcome of the survival analysis revealed that dyslipidemia did not influence the prognosis of PanNENs patients (P>0.05). Conclusions: HDL was negatively correlated with the tumor size of PanNENs. The serum HDL level of insulinoma patients is higher than nonfunctional PanNENs.

Diagnostic role and prognostic value of tumor markers in high-grade gastro-enteropancreatic neuroendocrine neoplasms.

OBJECTIVES: High-grade gastro-enteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors of two different types: well differentiated neuroendocrine tumors grade 3 (NETs G3) and poorly differentiated neuroendocrine carcinomas (NECs). This study aimed to explore the value of eight common preoperative markers in differentiating NETs G3 from NECs and the prognosis prediction of high-grade GEP-NENs. METHODS: Seventy-two patients diagnosed with high-grade GEP-NENs who underwent surgery at our institution were recruited for this study. Demographic and clinicopathological characteristics, preoperative serum tumor markers, and survival data were collected and analyzed. Kaplan-Meier methods were used to analyze survival rates, and a Cox regression model was used to perform multivariate analyses. RESULTS: Serum carcinoembryonic antigen (CEA) was dramatically higher in NECs than in NETs G3 (P = 0.025). After follow-up, 57 of the 72 patients remained for survival analysis. Elevated serum carbohydrate antigen 19-9 (CA19-9), CEA, cancer antigen 125 and sialic acid (SA) levels indicated poorer survival of high-grade GEP-NEN patients. Only CA19-9 (HR: 6.901, 95% CI: 1.843 to 25.837, P = 0.004) was regarded as an independent risk factor for overall survival. Serum CA19-9 (HR: 4.689, 95% CI: 1.127 to 19.506, P = 0.034) was also regarded as an independent factor for overall survival in NECs. CONCLUSIONS: Serum CEA levels can be used to distinguish NETs G3 from NECs. Preoperative CA19-9, CEA, cancer antigen 125 and SA levels have predictive value in the prognosis of high-grade GEP-NENs. Preoperative CA19-9, neuron-specific enolase, and SA levels can predict the prognosis of NECs.

Porous composite hydrogels with improved MSC survival for robust epithelial sealing around implants and M2 macrophage polarization.

The application of mesenchymal stem cell (MSC)-based therapy is expected to make a significant contribution to the improvement of epithelial sealing around implants. However, there is currently no optimal MSC delivery biomaterial for clinical application in peri-implant epithelium (PIE) integration. In this study, we show that injectable photo-cross-linkable porous gelatin methacryloyl (GelMA)/silk fibroin glycidyl methacrylate (SilMA) hydrogels encapsulating gingival tissue-derived MSCs (GMSCs) are a simple and practical approach for re-epithelization applications. The hydrogels played a prominent role in supporting the proliferation, survival, and spread of GMSCs. Moreover, it was found that GMSCs-laden Porous GelMA/SilMA hydrogels could significantly upregulate the hemidesmosomes (HDs)-related genes and proteins expression and promote M2 polarization while inhibiting M1 polarization in vitro. Based on a rat model of early implant placement, application of the MSC-loaded hydrogels could enhance the protein expression of LAMA3 and BP180 (COL17A1) at the implant-PIE interface and reduce horseradish peroxidase (HRP) penetration between the implants and PIE. Noticeably, hydrogel-based MSC therapy contributed to augmenting M2 macrophage infiltration at two time points in the gingival connective tissue around implants. These findings demonstrated that GMSCs-laden Porous GelMA/SilMA hydrogels could facilitate epithelial sealing around implants and M2-polarized macrophages and may be a novel and facile therapeutic strategy for implant-PIE integration. STATEMENT OF SIGNIFICANCE: In the case of poor integration between the implant and gingival epithelium, peri-implantitis can develop, which is one of the main causes of implant failure. While stem cell therapy has tremendous potential for addressing this issue, poor cell survival and engraftment compromise the effectiveness of the therapy. Due to the excellent modifiable and tunable properties of gelatin and silk fibroin, injectable photo-cross-linkable porous hydrogels were developed using gelatin methacryloyl (GelMA) and silk fibroin glycidyl methacrylate (SilMA) as delivery vehicles for gingiva-derived MSCs (GMSCs). Porous GelMA/SilMA not only enhanced the proliferation and viability of GMSCs but also promoted their immunomodulatory capability for favorable epithelial sealing around implants. Overall, GMSCs-seeded porous hydrogels could be promising strategies for re-epithelization treatment.

Blood-based DNA methylation signatures in cancer: A systematic review.

DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and chromosome stability. Changes in DNA methylation patterns play important roles in carcinogenesis and primarily manifests as hypomethylation of the entire genome and the hypermethylation of individual loci. These changes may be reflected in blood-based DNA, which provides a non-invasive means for cancer monitoring. Previous blood-based DNA detection objects primarily included circulating tumor DNA/cell-free DNA (ctDNA/cfDNA), circulating tumor cells (CTCs) and exosomes. Researchers gradually found that methylation changes in peripheral blood mononuclear cells (PBMCs) also reflected the presence of tumors. Blood-based DNA methylation is widely used in early diagnosis, prognosis prediction, dynamic monitoring after treatment and other fields of clinical research on cancer. The reversible methylation of genes also makes them important therapeutic targets. The present paper summarizes the changes in DNA methylation in cancer based on existing research and focuses on the characteristics of the detection objects of blood-based DNA, including ctDNA/cfDNA, CTCs, exosomes and PBMCs, and their application in clinical research.

In-situ lignin sulfonation for enhancing enzymatic hydrolysis of poplar using mild organic solvent pretreatment.

Biomass pretreatment is an essential strategy to overcome biomass recalcitrance and promote lignocellulosic bioconversion. Here, a reusable organic solvent system (formic acid-methanesulfonic acid) was explored to pretreat poplar under a mild temperature (below 100 °C). The results showed that the co-solvent system could extract basically complete hemicelluloses and part of lignin with original cellulose retained in the pretreated substrates. Meanwhile, sulfonic acid groups were introduced into lignin structure remained in the substrates. The glucose conversion yield of the substrates with a higher concentration of sulfonic acid groups (13.2 mmol/kg) reached 45.9 % by reducing the hydrophobic interaction between lignin and cellulase, showing 89.3 % improvement compared with that of the substrates treated with single formic acid. This progressive study aimed to develop a new strategy to realize sulfonation and promote enzymatic hydrolysis of substrates by using mild organic solvent pretreatment.

Neoadjuvant therapy in pancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

Background and Objectives: Neoadjuvant therapy plays an increasingly important role in pancreatic neuroendocrine neoplasms (pNENs), but the systematic evaluation of its efficacy is still lacking. The purpose of this study is to explore the role of neoadjuvant therapy in pNENs. Methods: We systematically reviewed the literatures published online until October 1, 2021. Meta-analysis was conducted to generate proportion with 95% confidence intervals (95% CI) for tumor response, resection rate, R0 resection rate and survival time. Results: Nine studies with 468 patients were involved in the systematic review. None of these patients met complete response (CR). Furthermore, 43.6% (95% CI [18.1, 69.0]) patients were expected to achieve partial response (PR), 51.3% (95% CI [27.9, 78.3]) to stable disease (SD), and 4.3% (95% CI [0.7, 7.9]) to progressive disease (PD). The estimate resection rate and R0 resection rate after neoadjuvant therapy were 68.2% (95% CI [44.5, 91.9]) and 60.2% (95% CI [53.5, 66.9]), respectively. There was no significant difference in resection rate between different chemotherapy regimens (41.67% vs 33.93%, P=0.453), as well as R0 resection rate (62.50% vs 68.30%, P=0.605). In terms of objective response rate (ORR), there was no significant difference between CAPTEM and FAS (41.67% vs 33.93%, P=0.453), while PRRT showed a higher ORR compared with chemotherapy, although there was also no statistical difference (49.06% vs 36.96%, P=0.154). Conclusion: Neoadjuvant therapies could reduce the tumor size and stage of some borderline resectable or unresectable pNENs, and give some patients the chance of radical resection. However, according to the current data, the best treatment regimen for pNENs neoadjuvant therapy is still unknown.

Bilayer Designed Paper-Based Solar Evaporator for Efficient Seawater Desalination.

Solar desalination devices utilizing sustainable solar energy and the abundant resource of seawater has great potential as a response to global freshwater scarcity. Herein, a bilayered solar evaporator was designed and fabricated utilizing a facile paper sheet forming technology, which was composed of cellulose fibers decorated with Fe3O4 nanoparticles as the top absorbent layer and the original cellulose fibers as the bottom supporting substrate. The characterization of the cellulose fibers decorated with Fe3O4 nanoparticles revealed that the in situ formed Fe3O4 nanoparticles were successfully loaded on the fiber surface and presented a unique rough surface, endowing the absorber layer with highly efficient light absorption and photothermal conversion. Moreover, due to its superhydrophilic property, the cellulose fiber-based bottom substrate conferred ultra-speed water transport capability, which could enable an adequate water supply to combat the water loss caused by continuous evaporation on the top layer. With the advantages mentioned above, our designed bilayered paper-based evaporator achieved an evaporation rate ~1.22 kg m-2 h-1 within 10 min under 1 sun irradiation, which was much higher than that of original cellulose cardboard. Based on the simple and scalable manufacture process, the bilayered paper-based evaporator may have great potential as a highly efficient photothermal conversion material for real-world desalination applications.

COL17A1 facilitates tumor growth and predicts poor prognosis in pancreatic cancer.

OBJECTIVE: This study aimed to determine the role of COL17A1 in tumor progression and predict the prognosis of pancreatic cancer (PC). METHODS: RNA-seq data from The Cancer Genome Atlas and Genotype-Tissue Expression were analyzed using bioinformatics methods. "Limma" package was used to screen differentially expressed genes (DEGs). Prognostic-associated data were further analyzed using univariate Cox regression and verified using the GSE28375 and GSE62452 datasets. Protein-protein interaction (PPI) network analysis was integrated to screen for hub genes. In vitro quantitative real-time PCR (qPCR) and western blotting were used to detect gene expression. The functional attributes of PC cells were verified by wound healing assays, migration and invasion assays, Cell Counting Kit 8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EdU) assay. RESULTS: On analyzing PC data, 4637 DEGs were identified. Of these, 2399 genes were upregulated and 2238 were downregulated. Through PPI network analysis, we identified that COL17A1 expression was highly correlated with poor prognosis of patients with PC. Functional attribute assays in the in vitro study showed that COL17A1 knockdown inhibited PC cell proliferation, migration, and invasion. CONCLUSIONS: According to our results, COL17A1 promotes PC cell proliferation, migration, and invasion mediated by the epithelial-mesenchymal transition (EMT) pathway. Thus, COL17A1 could be used as a prognostic marker in PC.

FABP4 in obesity-associated carcinogenesis: Novel insights into mechanisms and therapeutic implications.

The increasing prevalence of obesity worldwide is associated with an increased risk of various diseases, including multiple metabolic diseases, cardiovascular diseases, and malignant tumors. Fatty acid binding proteins (FABPs) are members of the adipokine family of multifunctional proteins that are related to fatty acid metabolism and are divided into 12 types according to their tissue origin. FABP4 is mainly secreted by adipocytes and macrophages. Under obesity, the synthesis of FABP4 increases, and the FABP4 content is higher not only in tissues but also in the blood, which promotes the occurrence and development of various cancers. Here, we comprehensively investigated obesity epidemiology and the biological mechanisms associated with the functions of FABP4 that may explain this effect. In this review, we explore the molecular mechanisms by which FABP4 promotes carcinoma development and the interaction between fat and cancer cells in obese circumstances here. This review leads us to understand how FABP4 signaling is involved in obesity-associated tumors, which could increase the potential for advancing novel therapeutic strategies and molecular targets for the systematic treatment of malignant tumors.

mTOR is involved in LRP5-induced osteogenic differentiation of normal and aged periodontal ligament stem cells in vitro.

Periodontal ligament stem cells (PDLSCs) plays an important role in tissue engineering. As the age increased, the cell viability and osteogenic differentiation of PDLSCs all decreased. Low density lipoprotein receptor related protein 5 (LRP5) was found to promote bone marrow mesenchymal stem cells osteogenic differentiation. Therefore, our study explored the effect of LRP5 on normal and aged PDLSCs and relative mechanism. Here, we found that the expression of LRP5 in PDLSCs of 24 week-old mice was decreased compared with PDLSCs of 5 week-old mice (n = 5). . LRP5 overexpression in PDLSCs increased the intensity of alkaline phosphatase and alizarin red staining, accompanied with upregulated the levels of RUNX family transcription factor 2, collagen type I, and ß-Catenin. LRP5 knockdown displayed the opposite results in PDLSCs in vitro. LRP5 overexpression in aged PDLSCs restored part ability of osteogenic differentiation. Meantime, LRP5 increased the protein expression of phosphorylation of mammalian target of rapamycin (p-mTOR) in normal and aged PDLSCs. Immunofluorescence showed that LRP5 increased the accumulation of p-mTOR nucleus. The effect of LRP5 in promoting osteogenic differentiation of PDLSCs can be antagonized by mTOR inhibitor rapamycin. These findings suggest that LRP5 positively regulate osteogenic differentiation of normal and aged PDLSCs and may be a potential target for enlarging the application of PDLSCs in tissue regeneration.

ANGPTL4 regulates the osteogenic differentiation of periodontal ligament stem cells.

The molecular mechanism of mechanical force regulating the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) has not been clearly elucidated. In this study, two mRNA-seqs, GSE106887 and GSE109167, which contained several samples of PDLSCs under mechanical force, were downloaded from Gene Expression Omnibus. Differential expression analysis was firstly taken between GSE106887 and GSE109167, then the common 84 up-regulated genes and 26 down-regulated genes were selected. Function enrichment analysis was used to identify the key genes and pathways in PDLSCs subjected to the tension and compression force. PDLSCs were isolated from human periodontal ligament tissues. The effects of ANGPTL4 knockdown with shRNA on the osteogenic differentiation of PDLSCs were studied in vitro. Then, the orthodontic tooth movement (OTM) rat model was used to study the expression of HIF-1α and ANGPTL4 in alveolar bone remodeling in vivo. ANGPTL4 and the HIF-1 pathway were identified in PDLSCs subjected to the tension and compression force. alizarin red staining, alcian blue staining, and oil red O staining verified that PDLSCs had the ability of osteogenic, chondrogenic, and adipogenic differentiation, respectively. Verification experiment revealed that the expression of ANGPTL4 in PDLSCs significantly increased when cultured under osteogenic medium in vitro. While ANGPTL4 was knocked down by shRNA, the levels of ALPL, RUNX2, and OCN decreased significantly, as well as the protein levels of COL1A1, ALPL, RUNX2, and OCN. During the OTM, the expression of HIF-1α and ANGPTL4 in periodontal ligament cells increased on the tension and compression sides. We concluded the positive relationship between ANGPTL4 and osteogenic differentiation of PDLSCs.