Phosphatidylethanolamine (18:2e/18:2) may inhibit adipose tissue wasting in patients with cancer cachexia by increasing lysophosphatidic acid receptor 6.

BACKGROUND: Cancer associated cachexia is characterized by the significant loss of adipose tissue, leading to devastating weight loss and muscle wasting in the majority of cancer patients. The effects and underlying mechanisms of degradation metabolites on adipocytes in cachectic patients remain poorly understood. To address this knowledge gap, we conducted a comprehensive study combining lipidomic analysis of subcutaneous and visceral adipose tissue with transcriptomics data from the database to investigate the mechanisms of lipid regulation in adipocytes. METHODS: We collected subcutaneous and visceral adipose tissue samples from cachectic and noncachectic cancer patients. Lipidomic analysis was performed to identify differentially expressed lipids in both types of adipose tissue. Additionally, transcriptomics data from the GEO database were analyzed to explore gene expression patterns in adipocytes. Bioinformatics analysis was employed to determine the enrichment of differentially expressed genes in specific pathways. Furthermore, molecular docking studies were conducted to predict potential protein targets of specific lipids, with a focus on the PI3K-Akt signaling pathway. Western blot analysis was used to validate protein levels of the identified target gene, lysophosphatidic acid receptor 6 (LPAR6), in subcutaneous and visceral adipose tissue from cachectic and noncachectic patients. RESULTS: Significant lipid differences in subcutaneous and visceral adipose tissue between cachectic and noncachectic patients were identified by multivariate statistical analysis. Cachectic patients exhibited elevated Ceramides levels and reduced CerG2GNAc1 levels (P < 0.05). A total of 10 shared lipids correlated with weight loss and IL-6 levels, enriched in Sphingolipid metabolism, GPI-anchor biosynthesis, and Glyceropholipid metabolism pathways. LPAR6 expression was significantly elevated in both adipose tissues of cachectic patients (P < 0.05). Molecular docking analysis indicated strong binding of Phosphatidylethanolamine (PE) (18:2e/18:2) to LPAR6. CONCLUSIONS: Our findings suggest that specific lipids, including PE(18:2e/18:2), may mitigate adipose tissue wasting in cachexia by modulating the expression of LPAR6 through the PI3K-Akt signaling pathway. The identification of these potential targets and mechanisms provides a foundation for future investigations and therapeutic strategies to combat cachexia. By understanding the underlying lipid regulation in adipocytes, we aim to develop targeted interventions to ameliorate the devastating impact of cachexia on patient outcomes and quality of life. Nevertheless, further studies and validation are warranted to fully elucidate the intricate mechanisms involved and translate these findings into effective clinical interventions.

Elevated 18F-FDG uptake in subcutaneous adipose tissue correlates negatively with nutritional status and prognostic survival in cachexia patients with gastric cancer.

BACKGROUND: Browning of white adipose tissue is a crucial factor contributing to adipose loss in cachexia patients, detectable via 18F-Fluorodeoxyglucose (18F-FDG) uptake. The present study elucidates the clinical relevance of 18F-FDG uptake in the subcutaneous adipose tissue of gastric cancer patients, specifically focusing on adipose browning and its implications on patient clinical parameters and prognosis. METHODS: This investigation encompassed 770 gastric cancer patients, with PET-CT imaging and clinical data meticulously combined. The 18F-FDG uptake in subcutaneous adipose tissue at the third lumbar layer was quantified, and its correlation with clinical parameters, particularly those related to nutritional status and fat metabolism, was examined. Kaplan-Meier curves were subsequently employed to probe the relationship between 18F-FDG uptake and overall survival. RESULTS: Of the 770 gastric cancer patients, 252 exhibited cancer-associated cachexia, while 518 did not. Cachectic patients demonstrated elevated 18F-FDG uptake in subcutaneous adipose tissue relative to non-cachectic patients (P < 0.001). Increased 18F-FDG uptake was also correlated with reduced plasma concentrations of albumin, prealbumin, hemoglobin, platelets, cholesterol, apolipoprotein A, low-density lipoprotein, and elevated IL-6 concentrations (all P < 0.05). A significant inverse correlation was observed between 18F-FDG uptake and BMI, albumin, low-density lipoprotein, cholesterol, and apolipoprotein A (all P < 0.05). Patients with higher 18F-FDG uptake exhibited diminished overall survival rates compared to those with lower 18F-FDG uptake (P = 0.0065). Furthermore, 18F-FDG uptake in subcutaneous adipose tissue was an independent prognostic indicator in gastric cancer patients (P = 0.028). CONCLUSIONS: Browning of subcutaneous adipose tissue was markedly elevated in cachectic gastric cancer patients compared to non-cachectic counterparts. Increased 18F-FDG uptake in subcutaneous adipose tissue in cachectic gastric cancer patients was inversely correlated with nutritional status and survival prognosis.

Tumor-derived semaphorin 3D promoting cancer cachexia via regulating hypothalamic pro-opiomelanocortin neurons.

Cachexia is very common in cancer patients and predicts a poor prognosis; however, the molecular basis for progress in these individuals remains unclear, especially the effect of tumors on the hypothalamus energy regulation center. To investigate the regulatory pathway of tumors associated with hypothalamic pro-opiomelanocortin (POMC) neurons known as appetite-inhibiting neurons, we conducted observations both on patients and mice models. Results showed that the highly expressed exocrine semaphorin 3D (SEMA3D) both in cachexia patients and mice was positively related to the expression of POMC and its proteolytic peptide. Compared with the control group, mice inoculated with the SEMA3D-knockout C26 cell line decreased the activity of POMC neurons resulting in a 1.3-fold increase in food intake, a 22.2% increase in body weight, and reduced skeletal muscle and fat catabolism. The effect of SEMA3D on cachexia progression can be partially alleviated by knocking-down POMC expression in the brain. In terms of mechanism, SEMA3D enhances the activity of POMC neurons by activating the expression of NRP2 (membrane receptor) and PlxnD1 (intracellular receptor). Our research revealed the overexpression of SEMA3D in tumors works as an activator of POMC neurons, which may play a vital role in suppressing appetite and promoting catabolic metabolism.

Abdominal fat and muscle distributions in different stages of colorectal cancer.

BACKGROUND: The purpose of this study is to explore the difference of abdominal fat and muscle composition, especially subcutaneous and visceral adipose tissue, in different stages of colorectal cancer (CRC). MATERIALS AND METHODS: Patients were divided into 4 groups: healthy controls (patients without colorectal polyp), polyp group (patients with colorectal polyp), cancer group (CRC patients without cachexia), and cachexia group (CRC patients with cachexia). Skeletal muscle (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and intermuscular adipose tissue (IMAT) were assessed at the third lumbar level on computed tomography images obtained within 30 days before colonoscopy or surgery. One-way ANOVA and linear regression were used to analyze the difference of abdominal fat and muscle composition in different stages of CRC. RESULTS: A total of 1513 patients were divided into healthy controls, polyp group, cancer group, and cachexia group, respectively. In the development of CRC from normal mucosa to polyp and cancer, the VAT area of the polyp group was significantly higher than that of the healthy controls both in male (156.32 ± 69.71 cm2 vs. 141.97 ± 79.40 cm2, P = 0.014) and female patients (108.69 ± 53.95 cm2 vs. 96.28 ± 46.70 cm2, P = 0.044). However, no significant differences were observed of SAT area between polyp group and healthy controls in both sexes. SAT area decreased significantly in the male cancer group compared with the polyp group (111.16 ± 46.98 cm2 vs. 126.40 ± 43.52 cm2, P = 0.001), while no such change was observed in female patients. When compared with healthy controls, the SM, IMAT, SAT, and VAT areas of cachexia group was significantly decreased by 9.25 cm2 (95% CI: 5.39-13.11 cm2, P < 0.001), 1.93 cm2 (95% CI: 0.54-3.32 cm2, P = 0.001), 28.84 cm2 (95% CI: 17.84-39.83 cm2, P < 0.001), and 31.31 cm2 (95% CI: 18.12-44.51 cm2, P < 0.001) after adjusting for age and gender. CONCLUSION: Abdominal fat and muscle composition, especially SAT and VAT, was differently distributed in different stages of CRC. It is necessary to pay attention to the different roles of subcutaneous and visceral adipose tissue in the development of CRC.

Analysis of different adipose depot gene expression in cachectic patients with gastric cancer.

PURPOSE: This study aimed to identify the differentially expressed genes (DEGs) that contributed to the different amount of fat loss between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) among cachectic patients. METHODS: RNA sequencing was performed and bioinformatic tools were utilized to analyze the biological functions and construct regulation networks of DEGs. We presumed that iroquois homeobox 1 (IRX1) to be a hub gene and analyzed its clinical significance. Mouse model of cancer cachexia was established and differences between SAT and VAT were compared. The function of IRX1 on lipid metabolism was clarified by Oil Red O staining, qRT-PCR, and Western blotting in adipocytes. RESULTS: A total of 455 DEGs were screened between SAT and VAT in cachectic patients. Several hub genes were selected and IRX1 was presumed to contribute to the pathological difference between SAT and VAT in cancer cachexia. Patients with higher expression of IRX1 in SAT than VAT revealed significantly higher weight loss, IL-6 and TNF-α, as well as lower BMI, SAT, and VAT area. IRX1 expression in SAT was negatively correlated with SAT area. In cachectic mice, the expression of IRX1 in SAT was significantly higher than that in VAT. The inhibition effect on adipogenesis exerted by IRX1 was also proved in vitro. CONCLUSION: These data supported that DEGs contribute to the different degrees of fat loss among adipose depots in cachectic patients. IRX1 in SAT promoted fat loss by inhibiting adipocyte differentiation and adipogenesis.

Identification of an Immune-Related LncRNA Signature in Gastric Cancer to Predict Survival and Response to Immune Checkpoint Inhibitors.

Immune microenvironment in gastric cancer is closely associated with patient's prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of immune responses. In this study, we aimed to construct a prognostic model based on immune-related lncRNAs (IRLs) to predict the overall survival and response to immune checkpoint inhibitors (ICIs) of gastric cancer (GC) patients. The IRL signature was constructed through a bioinformatics method, and its predictive capability was validated. A stratification analysis indicates that the IRL signature can distinguish different risk patients. A nomogram based on the IRL and other clinical variables efficiently predicted the overall survival of GC patients. The landscape of tumor microenvironment and mutation status partially explain this signature's predictive capability. We found the level of cancer-associated fibroblasts, endothelial cells, M2 macrophages, and stroma cells was high in the high-risk group, while the number of CD8+ T cells and T follicular helper cells was high in the low-risk group. Immunophenoscore (IPS) is validated for ICI response, and the IRL signature low-risk group received higher IPS, representing a more immunogenic phenotype that was more inclined to respond to ICIs. In addition, we found RNF144A-AS1 was highly expressed in GC patients and promoted the proliferation, migration, and invasive capacity of GC cells. We concluded that the IRL signature represents a novel useful model for evaluating GC survival outcomes and could be implemented to optimize the selection of patients to receive ICI treatment.

miR-410-3P inhibits adipocyte differentiation by targeting IRS-1 in cancer-associated cachexia patients.

BACKGROUNDS: Cancer-associated cachexia (CAC) is a metabolic syndrome characterized by progressive depletion of adipose and muscle tissue that cannot be corrected by conventional nutritional therapy. Adipose tissue, an important form of energy storage, exhibits marked loss in the early stages of CAC, which affects quality of life and efficacy of chemotherapy. MicroRNAs (miRNAs) are a class of noncoding RNAs that widely exist in all kinds of eukaryotic cells and play regulatory roles in various biological processes. However, the role of miRNAs in adipose metabolism in CAC has rarely been reported. This study attempted to identify important miRNAs in adipose metabolism in CAC and explore their mechanism to identify a new predictive marker or therapeutic target for CAC-related adipose tissue loss (CAL). METHODS: In this study, miRNA sequencing was firstly used to identify differentially expressed miRNAs related to CAL and the reliability of the conclusions was verified in large population samples. Furthermore, functional experiments were performed by up and down regulating miR-410-3p in adipocytes. The binding of miR-410-3p to Insulin Receptor Substrate 1 (IRS-1) was verified by Luciferase reporter assay and functional experiments of IRS-1 were performed in adipocytes. Finally, the expression of miR-410-3p in serum exosomes was detected. RESULTS: miR-410-3p was selected as differentially expressed miRNA through screening and validation. Adipogenesis was suppressed in miR-410-3p upregulation experiment and increased in downregulation experiment. Luciferase reporter assay showed that miR-410-3p binds to 3' non-coding region of IRS-1 and represses its expression and ultimately inhibits adipogenesis. miR-410-3p was highly expressed in serum exosomes of CAC patients, which was consistent with results in adipose tissue. CONCLUSIONS: The expression of miR-410-3p was higher in subcutaneous adipose tissues and serum exosomes of CAC patients, which significantly inhibits adipogenesis and lipid accumulation. The study shows that miR-410-3p could downregulate IRS-1 and downstream adipose differentiation factors including C/EBP-a and PPAR-γ by targeting 3' noncoding region.

Novel noncoding RNA CircPTK2 regulates lipolysis and adipogenesis in cachexia.

OBJECTIVE: Cancer-associated cachexia is a devastating pathological disorder characterized by skeletal muscle wasting and fat storage depletion. Circular RNA, a newly discovered class of noncoding RNAs with important roles in regulating lipid metabolism, has not been fully understood in the pathology of cachexia. We aimed to identify circular RNAs that are upregulated in adipose tissues from cachectic patients and explore their function and mechanism in lipid metabolism. METHODS: Whole transcriptome RNA sequencing was used to screen for differentially expressed circRNAs. Quantitative reverse transcription PCR was applied to detect the expression level of circPTK2 in adipose tissues. The diagnostic value of circPTK2 was evaluated in adipose tissues from patients with and without cachexia. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circPTK2 on lipolysis and adipogenesis. Mechanistically, luciferase reporter assay, RNA immunoprecipitation, and fluorescent in situ hybridization were performed to confirm the interaction between circPTK2 and miR-182-5p in adipocytes. RESULTS: We detected 66 differentially expressed circular RNA candidates and proved that circPTK2 was upregulated in adipose tissues from cachectic patients. Then we identified that circPTK2 was closely related to the pathological process of cachexia and could be used as a diagnostic marker. Mechanistically, circPTK2 bound competitively to miR-182-5p and abrogated the suppression on its target gene JAZF1, which finally led to promotion of lipolysis and inhibition of adipogenesis. In vivo experiments demonstrated that overexpression of circPTK2 inhibited adipogenesis and enhanced lipolysis. CONCLUSIONS: Our findings reveal the novel role of circPTK2 in promoting lipolysis and reducing adipogenesis via a ceRNA mechanism and provide a potential diagnostic biomarker and therapeutic target for cancer-associated cachexia.

Development and Validation of a Novel Prognostic Model for Acute Myeloid Leukemia Based on Immune-Related Genes.

The prognosis of acute myeloid leukemia (AML) is closely related to immune response changes. Further exploration of the pathobiology of AML focusing on immune-related genes would contribute to the development of more advanced evaluation and treatment strategies. In this study, we established a novel immune-17 signature based on transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found that immune biology processes and transcriptional dysregulations are critical factors in the development of AML through enrichment analyses. We also formulated a prognostic model to predict the overall survival of AML patients by using LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Furthermore, we incorporated the immune-17 signature to improve the prognostic accuracy of the ELN2017 risk stratification system. We concluded that the immune-17 signature represents a novel useful model for evaluating AML survival outcomes and may be implemented to optimize treatment selection in the next future.

Prognostic role of cyclin D2/D3 in multiple human malignant neoplasms: A systematic review and meta-analysis.

Cyclin D2/D3 (CCND2/3) are core components of the machinery that drives cell cycle progression and therefore, are associated with tumorigenesis. Currently, there are contradictory evidences on the function of CCND2/3 in tumorigenesis. Thus, we conducted a comprehensive meta-analysis to derive a precise predictive value of CCND2/3 in various tumors. We searched PubMed, EMBASE, Web of Science for eligible studies up to October 8, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated using Forest plot analysis to demonstrate their associations. A total of 14 studies were ultimately included in this meta-analysis. Our results indicated CCND2/3 played an oncogenic role in all of the cancer patients (CCND2: pooled HR = 2.21, 95% CI: 1.67-2.93; CCND3: pooled HR = 2.29, 95% CI: 1.05-5.03). In tumor subgroup, CCND2 was associated with shorter OS in patients with gastric cancer (HR = 2.20, 95% CI: 1.66-2.92), whereas it might be a tumor suppressor in NSCLC (HR = 0.28, 95% CI: 0.12-0.64). In addition, CCND3 was correlated to reduced OS in breast cancer patients (HR = 1.64, 95% CI: 1.07-2.52) and shorter DFS/PFS/RFS in bladder cancer patients (HR = 4.60, 95% CI: 1.89-12.57). Taken together, CCND2/3 could be the promising biomarkers for predicting the prognosis of patients with malignant neoplasms.

Alteration of Sciatic Nerve Histology and Electrical Function After Compression and After Neurolysis in a Diabetic Rat Model.

BACKGROUND: Diabetic rats are more sensitive to nerve entrapment. This study was conducted to evaluate nerve function and histological changes in diabetic rats after nerve compression and subsequent decompression. METHODS: A total of 35 Wistar rats were included. The experimental group was divided into diabetic sciatic nerve compression group (DSNC, n = 5) and diabetic sciatic nerve decompression group (DSND, n = 20). The DSNC model was created by wrapping a silicone tube circumferentially around the nerve for 4 weeks, and then the DSND group accepted nerve decompression and was followed up to 12 weeks. The DSND group was equally divided into DSND 3 weeks (DSND3), 6 weeks (DSND6), 9 weeks (DSND9), and 12 weeks (DSND12) groups. Five rats were taken as normoglycemic control group (CR, n = 5), and another 5 rats as diabetic control group (DM, n = 5). The mechanical hyperalgesia of rats was detected by Semmes-Weinstein nylon monofilaments (SWMs) and by motor nerve conduction velocity (MNCV). These 2 physiological indicators and histology of sciatic nerves were compared among different groups. RESULTS: The SWM measurements improved toward normal values after decompression. The SWM value was significantly lower (more normal) in the DSNC groups than in the DSND group (P < 0.05). The MNCV was 53.7 ± 0.8 m/s in the CR group, whereas it was 28.4 ± 1.0 m/s in the DSNC group (P < 0.001). Six weeks after decompression, the MNCV was significantly faster than that in the DSNC group (P < 0.001). Histological examination demonstrated chronic nerve compression, which responded toward normal after decompression, but with degree of myelination never recovering to normal. CONCLUSIONS: Chronic compression of the diabetic sciatic nerve has measureable negative effects on sciatic nerve motor nerve function, associated with a decline of touch/pressure threshold and degeneration of myelin sheath and axon. Nerve decompression surgery can reverse these effects and partially restore nerve function.

Chronic Nerve Compression Accelerates the Progression of Diabetic Peripheral Neuropathy in a Rat Model: A Study of Gene Expression Profiling.

OBJECTIVE: This article investigates the role of chronic nerve compression in the progression of diabetic peripheral neuropathy (DPN) by gene expression profiling. METHODS: Chronic nerve compression was created in streptozotocin (STZ)-induced diabetic rats by wrapping a silicone tube around the sciatic nerve (SCN). Neurological deficits were evaluated using pain threshold test, motor nerve conduction velocity (MNCV), and histopathologic examination. Differentially expressed genes (DGEs) and metabolic processes associated with chronic nerve compression were analyzed. RESULTS: Significant changes in withdrawal threshold and MNCV were observed in diabetic rats 6 weeks after diabetes induction, and in DPN rats 4 weeks after diabetes induction. Histopathologic examination of the SCN in DPN rats presented typical changes of myelin degeneration in DPN. Function analyses of DEGs demonstrated that biological processes related to inflammatory response, extracellular matrix component, and synaptic transmission were upregulated after diabetes induction, and chronic nerve compression further enhanced those changes. While processes related to lipid and glucose metabolism, response to insulin, and apoptosis regulation were inhibited after diabetes induction, chronic nerve compression further enhanced these inhibitions. CONCLUSION: Our study suggests that additional silicone tube wrapping on the SCN of rat with diabetes closely mimics the course and pathologic findings of human DPN. Further studies are needed to verify the effectiveness of this rat model of DPN and elucidate the roles of the individual genes in the progression of DPN.

Synthesis and protective effects of novel salidroside analogues on glucose and serum depletion induced apoptosis in PC12 cells.

Salidroside is a natural product isolated from Rhodiola rosea L. which possesses a wide range of biological activities, especially neuroprotective effects in the treatment of ischemic stroke. In an attempt to improve its neuroprotective effects, a series of novel salidroside analogues were synthesized and their neuroprotective activities were evaluated against the glucose and serum depletion-induced cell death in differentiated PC12 cells. Most target compounds displayed protective effects on the cell viability, especially for compound 6, which had a great potency superior to salidroside. MTT assay and Hoechst 33342 staining collectively showed that pretreatment with 6 attenuated cell viability loss and reduced apoptotic death in cultured PC12 cells with glucose and serum depletion. And its neuroprotective effects might be associated with the increase of the apoptosis-related protein Bcl-2/Bax expression ratio, and also with the inhibition of caspase-3 activation. Therefore, our new findings may provide potentially important information for further development of salidroside analogues and lay the basis for further studies on the cerebral ischemic stroke and neurodegenerative diseases for human clinical treatment.