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Background: Bioactive lipids involved in the progression of various diseases. Nevertheless, there is still a lack of biomarkers and relative regulatory targets. The lipidomic analysis of the samples from platinum-resistant in gastric cancer patients is expected to help us further improve our understanding of it. Methods: We employed LC–MS based untargeted lipidomic analysis to search for potential candidate biomarkers for platinum resistance in GC patients. Partial least squares discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify differential lipids. The possible molecular mechanisms and targets were obtained by metabolite set enrichment analysis and potential gene network screened. Finally, verified them by immunohistochemical of a tissue microarray. Results: There were 71 differential lipid metabolites identified in GC samples between the chemotherapy-sensitivity group and the chemotherapy resistance group. According to Foldchange (FC) value, VIP value, P values (FC > 2, VIP > 1.5, p < 0.05), a total of 15 potential biomarkers were obtained, including MGDG(43:11)-H, Cer(d18:1/24:0) + HCOO, PI(18:0/18:1)-H, PE(16:1/18:1)-H, PE(36:2) + H, PE(34:2p)-H, Cer(d18:1 + hO/24:0) + HCOO, Cer(d18:1/23:0) + HCOO, PC(34:2e) + H, SM(d34:0) + H, LPC(18:2) + HCOO, PI(18:1/22:5)-H, PG(18:1/18:1)-H, Cer(d18:1/24:0) + H and PC(35:2) + H. Furthermore, we obtained five potential key targets (PLA2G4A, PLA2G3, DGKA, ACHE, and CHKA), and a metabolite-reaction-enzyme-gene interaction network was built to reveal the biological process of how they could disorder the endogenous lipid profile of platinum resistance in GC patients through the glycerophospholipid metabolism pathway. Finally, we further identified PLA2G4A and ACHE as core targets of the process by correlation analysis and tissue microarray immunohistochemical verification. Conclusion: PLA2G4A and ACHE regulated endogenous lipid profile in the platinum resistance in GC patients through the glycerophospholipid metabolism pathway. The screening of lipid biomarkers will facilitate earlier precision medicine interventions for chemotherapy-resistant gastric cancer. The development of therapies targeting PLA2G4A and ACHE could enhance platinum chemotherapy effectiveness. [ABSTRACT FROM AUTHOR]

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients. Chemical Compounds Studied in this Article: Rutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542). [ABSTRACT FROM AUTHOR]

Abstract Background Vasculogenic mimicry (VM) was increasingly recognized as a form of aggressive melanoma acquiring blood supply. Genistein had attracted much attention as a potential anticancer agent. Therefore, we examined the effect of Genistein on VM in human uveal melanoma cells. Methods VM structure was detected by periodic acid-Schiff (PAS) staining for uveal melanoma C918 cells cultured on the three-dimensional type I collagen gels after exposed to Genistein. We used reverse transcription polymerase chain reaction (RT-PCR) and Western Blot analysis to examine the effect of Genistein on vascular endothelial cadherin (VE-cadherin) mRNA and protein expression. The nude mice models of human uveal melanoma C918 cells were established to assess the number of VM using immunohistochemical and PAS double-staining. Results Genistein inhibited the survival of C918 cells in vitro. The ectopic model study showed that VM in tumor tissue sections were significantly reduced by Genistein in vivo. In vitro, the VM structure was found in control, 25 and 50 μM Genistein-treatment groups but not in 100 and 200 μM. RT-PCR and Western Blot showed that 100 and 200 μM concentration of Genistein could significantly decrease VE-cadherin mRNA and protein expression of C918 cells compared with control (P < 0.05). However, the 25 and 50 μM Genistein slightly decreased the VE-cadherin level in vitro (P > 0.05). Conclusion Genistein inhibits VM formation of uveal melanoma cells in vivo and in vitro. One possible underlying molecular mechanism by which Genistein could inhibit VM formation of uveal melanoma is related to down-regulation of VE-cadherin.

Aims. Epidemiological data on diabetic retinopathy (DR) in Chinese population is still rather scarce, and risk factors for diabetic retinopathy are inconsistent because of study designs, grading standards, and population samples. Materials and Methods. This hospital-based retrospective study included 1052 type 2 diabetes patients. Diabetic retinopathy was diagnosed by nonmydriatic fundus photography and/or fundus examination apparatus. Logistic regression analysis was performed to evaluate the risk of diabetic retinopathy. Results. A total of 352 (33.5% prevalence) subjects were diagnosed with diabetic retinopathy based on our population. The patients in the DR group not only had significantly higher hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), urinary microalbumin-creatinine ratio (ACR), and systolic blood pressure but also had higher follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG) levels compared to those in the non-DR group. Moreover, we confirmed that diabetes duration and HbA1c are strongly associated with DR risk. We also found that serum LH was an independent risk factor in male diabetic retinopathy patients (OR = 1.086 , 95% CI 1.024–1.152), and the levels of LH were significantly associated with diabetic retinopathy prevalence (P = 0.018). Conclusions. Our study strengthens the argument that diabetes duration and HbA1c are risk factors for patients with DR. Additionally; we firstly confirmed that serum LH was an independent risk factor in male diabetic retinopathy patients. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Type 2 diabetes mellitus is frequently accompanied by fatty liver disease. Lipid accumulation within the liver is considered as one of the risk factors for insulin resistance. Hepatocyte growth factor (HGF) is used to treat liver dysfunction; however, the effect and mechanism of HGF on hepatic lipid metabolism are still not fully understood. Materials and Methods: Male C57BL/6 mice were induced with a high‐fat diet for 12 weeks, followed by a 4‐week treatment of HGF or vehicle saline. The levels of fasting blood glucose, fasting insulin and homeostatic model assessment of insulin resistance were calculated for insulin sensitivity. Biochemical plasma parameters were also measured to assess the effect of HGF on lipid accumulation. Additionally, genes in the lipid metabolism pathway were evaluated in palmitic acid‐treated HepG2 cells and high‐fat diet mice. Results: HGF treatment significantly decreased the levels of fasting blood glucose, hepatic triglyceride and cholesterol contents. Additionally, HGF‐regulated expression levels of sterol regulatory element‐binding protein‐1c/fatty acid synthase, peroxidase proliferator‐activated receptor‐α, and upstream nuclear receptors, such as farnesoid X receptor and small heterodimer partner. Furthermore, c‐Met inhibitor could partially reverse the effects of HGF. Conclusions: HGF treatment can ameliorate hepatic insulin resistance and steatosis through regulation of lipid metabolism. These effects might occur through farnesoid X receptor–small heterodimer partner axis‐dependent transcriptional activity. HGF reduced the levels of fasting blood glucose, blood lipid level, and improved the HFD‐fed mice. HGF significantly regulated lipogenesis‐related genes SREBP‐1c/FAS as well as PPARα, and nuclear receptors such as FXR, SHP. HGF ameliorates hyperglycemia and by improving hepatic insulin resistance and steatosis in HFD‐fed C57BL/6 mice. [ABSTRACT FROM AUTHOR]

Jianpi Yangzheng Xiaozheng decoction (JPYZXZ) is an empirical traditional Chinese medicine formula that has been reported to significantly prolong the survival of patients with advanced gastric cancer (GC). However, its underlying mechanism have not been fully elucidated. The present work aims to explore the possible mechanism of JPYZXZ on regulating GC progression. We firstly confirmed the inhibitory effect of JPYZXZ in GC MKN74 cells and 615-strain mice, which was possibly mediated with IL-6/JAK2/STAT3 pathway dependent PD-L1 expression. Moreover, we showed that JPYZXZ diminished the expression levels of GC-derived exosomal PD-L1 in MFC murine cells and xenograft GC model, as well as stage IIA-IIIB GC patients. We further found that in different types of tumor-infiltrating immune cells, PD-L1 expression was most positively correlated with myeloid-derived suppressor cells (MDSCs) in GC in the TISIDB database. We isolated exosomes derived from supernatants of MFC cells and co-cultured with bone marrow cells derived from C57BL/6 mice, and further revealed that the expansion of MDSCs was mediated by GC-derived exosomal PD-L1. Meanwhile, our results indicated that JPYZXZ inhibited the delivery of exosomal PD-L1 from GC cells to bone marrow cells, thereby alleviating exosomal PD-L1-induced differentiation and expansion of MDSCs in the tumor microenvironment. This led to a decrease in the levels of several immunosuppressive factors, including iNOS, Arg-1, TGF-β, IL-10, and IL-6, in 615-strain mice. Moreover, clinical data also revealed a significant positive relationship between exosomal PD-L1 and polymorphonuclear MDSCs under the JPYZXZ treatment in stage IIA-IIIB GC patients. In conclusion, our study confirmed that exosomal PD-L1 could be a key factor in controlling MDSCs differentiation in GC. JPYZXZ alleviated GC progression via suppressing exosomal PD-L1 mediated expansion of MDSCs, thereby remodeling the immunosuppressive tumor microenvironment, which provided the experimental evidence for the clinical application of JPYZXZ in the treatment of GC via PD-L1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Liu, Chen, Zhang, Tao, Chen, Wang, Sun, Wu and Liu.)

Background: Traditional Chinese medicine (TCM) is increasingly extensively being applied as a complementary and alternative therapy for gastric cancer (GC); however, there is a lack of large-scale evidence-based deep learning for the guidance of its clinical prescription., Methods: The combinational search terms of "Gastric cancer and/or gastric malignancy" and "Traditional Chinese Medicine" were used to retrieve clinical study-based herbal prescriptions from public database over the past 3 decades [1990-2020]. Association rules mining (ARM) was used to analyze the prescription patterns of the herbs extracted from the eligible studies. Deep machine learning and computational prediction were conducted to explore candidate prescriptions with general applicability for GC. The action mechanism of the preferred prescription was investigated through network pharmacology, and further validated via in vivo and in vitro experiments., Results: A total of 194 clinical study-based herbal prescriptions with good efficacy for GC were collected. TCM with focus on invigorating the Spleen and tonifying the vital- Qi is a promising adjuvant therapy for GC. The preferred prescription is composed of Atractylodis Macrocephalae Rhizoma , Astragali Radix , Pinelliae Rhizoma , Citri Reticulatae Pericarpium, Herba Hedyotidis Diffusae , Crataegi Fructus , and so on. We screened 74 bioactive compounds and 2,128 predictive targets of the preferred prescription from public databases. Eventually, 135 GC-related genes were identified as the targets of the preferred prescription. The compound-target network revealed that the crucial substances in the preferred prescription are quercetin, kaempferol, baicalein, and nobiletin. Experimentally, the preferred prescription was validated to modulate GC cell survival and inhibit tumor progression mainly via the hTERT/MDM2-p53 signaling pathway in vivo and in vitro ., Conclusions: TCM aimed at invigorating the Spleen and tonifying the vital- Qi is a promising adjuvant therapy for GC, which offers a guidance for worldwide use of TCM in the treatment of GC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-6301). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: CCN3 plays important roles in growth, differentiation, angiogenesis and adhesion. Recently, the role of CCN3 in human carcinogenesis has become an area of great interest. However, little is known about the function of CCN3 in human cervical cancer., Objectives: The aim of this study was to investigate the expression profile of CCN3 in cervical cancer and to assess its clinical significance., Material and Methods: In this study, qRT-PCR, immunohistochemistry and Western blotting analysis were used in the detection of CCN3 mRNA and protein expression, both in cervical cancer and in corresponding normal tissue, respectively. The data was correlated with clinicopathological features. A survival analysis was performed to assess the prognostic significance., Results: CCN3 mRNA was overexpressed in cervical cancer tissue when compared with corresponding normal tissue, as was CCN3 protein. Upregulation of CCN3 was significantly associated with the stage of the disease (P = 0.017) and with lymph node involvement (P = 0.006). Using the Kaplan-Meier analysis, a comparison of survival curves of low vs. high expressers of CCN3 revealed a highly significant difference in human cervical cancer tissue (P = 0.021), which suggests that overexpression of CCN3 is associated with a poorer prognosis., Conclusions: The results of the current study suggest that CCN3 may play an important role in cervical carcinogenesis and therefore may have potential as a biomarker for prognosis and as a therapeutic target in cervical cancer.

MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention. However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In this study, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile, transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found that treatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellular mechanistic studies revealed that genistein down-regulated miR-27a expression, which was accompanied by significantly increased expression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an important role in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growth and migration, offering novel insights into the mechanisms of genistein therapeutic actions.