Single-cell and transcriptomic analyses reveal the influence of diabetes on ovarian cancer.

BACKGROUND: There has been a significant surge in the global prevalence of diabetes mellitus (DM), which increases the susceptibility of individuals to ovarian cancer (OC). However, the relationship between DM and OC remains largely unexplored. The objective of this study is to provide preliminary insights into the shared molecular regulatory mechanisms and potential biomarkers between DM and OC. METHODS: Multiple datasets from the GEO database were utilized for bioinformatics analysis. Single cell datasets from the GEO database were analysed. Subsequently, immune cell infiltration analysis was performed on mRNA expression data. The intersection of these datasets yielded a set of common genes associated with both OC and DM. Using these overlapping genes and Cytoscape, a protein‒protein interaction (PPI) network was constructed, and 10 core targets were selected. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then conducted on these core targets. Additionally, advanced bioinformatics analyses were conducted to construct a TF-mRNA-miRNA coregulatory network based on identified core targets. Furthermore, immunohistochemistry staining (IHC) and real-time quantitative PCR (RT-qPCR) were employed for the validation of the expression and biological functions of core proteins, including HSPAA1, HSPA8, SOD1, and transcription factors SREBF2 and GTAT2, in ovarian tumors. RESULTS: The immune cell infiltration analysis based on mRNA expression data for both DM and OC, as well as analysis using single-cell datasets, reveals significant differences in mononuclear cell levels. By intersecting the single-cell datasets, a total of 119 targets related to mononuclear cells in both OC and DM were identified. PPI network analysis further identified 10 hub genesincludingHSP90AA1, HSPA8, SNRPD2, UBA52, SOD1, RPL13A, RPSA, ITGAM, PPP1CC, and PSMA5, as potential targets of OC and DM. Enrichment analysis indicated that these genes are primarily associated with neutrophil degranulation, GDP-dissociation inhibitor activity, and the IL-17 signaling pathway, suggesting their involvement in the regulation of the tumor microenvironment. Furthermore, the TF-gene and miRNA-gene regulatory networks were validated using NetworkAnalyst. The identified TFs included SREBF2, GATA2, and SRF, while the miRNAs included miR-320a, miR-378a-3p, and miR-26a-5p. Simultaneously, IHC and RT-qPCR reveal differential expression of core targets in ovarian tumors after the onset of diabetes. RT-qPCR further revealed that SREBF2 and GATA2 may influence the expression of core proteins, including HSP90AA1, HSPA8, and SOD1. CONCLUSION: This study revealed the shared gene interaction network between OC and DM and predicted the TFs and miRNAs associated with core genes in monocytes. Our research findings contribute to identifying potential biological mechanisms underlying the relationship between OC and DM.

A Novel Platinum Resistance-Related Immune Gene Signature for Overall Survival Prediction in Patients with Ovarian Cancer.

Ovarian cancer (OV) is a highly heterogeneous gynecological tumor that makes the prognostic prediction challenging. Resistance to platinum-based chemotherapy is associated with a poor prognosis in OV. There seems to be an overlap between molecular mechanisms responsible for platinum resistance and immunogenicity in OV. However, the predictive role of platinum resistance-related immune genes for OV prognosis needs to be further explored. In our study, the mRNA expression data of OV patients with corresponding clinical information were collected from The Cancer Genome Atlas (TCGA) cohort and International Cancer Genome Consortium (ICGC) cohort. A multigene signature was constructed for OV patients in the TCGA cohort using the least absolute shrinkage and selection operator (LASSO) Cox regression model according to the optimal value of λ and was validated in the ICGC cohort. Furthermore, we performed functional analysis to explore the immune status between low- and high-risk groups based on the median value of the risk score for the multigene signature. Our data showed that there were 41.1% of the platinum resistance-related genes which differentially expressed between immune score low- and high-OV patients in the TCGA cohort. Univariate Cox regression analysis identified 30 differentially expressed genes (DEGs) associated with overall survival (OS) (P < 0.05). 14 genes were identified to construct a novel platinum resistance-related immune model for classifying OV patients into the low- and high- risk groups. Patients in the low-risk group showed significantly higher OS than those in the high-risk group (P < 0.0001 in the both TCGA and ICGC cohort), which was associated with different immune status for the two risk groups. A novel platinum resistance-related immune model can be used for prognostic prediction in OV. Targeting tumor immunity may be a therapeutic alternative for OV with platinum resistance.

Bibliometric and visualized analysis of drug resistance in ovarian cancer from 2013 to 2022.

Objective: As one of the cancers that seriously threatens women's health, ovarian cancer has a high morbidity and mortality rate. Surgery and chemotherapy are the basic treatment strategies for ovarian cancer, and chemotherapy resistance is a significant factor in affecting the prognosis, survival cycle, and recurrence of ovarian cancer. This article aims to analyze articles about ovarian cancer and drug resistance via bibliometric software, offering new ideas and directions for researchers in this field. Methods: Both Citespace and Vosviewer are bibliometric software on the Java platform. Articles were collected on ovarian cancer and drug resistance in the Web of Science Core Collection database from 2013 to 2022. The countries, institutions, journals, authors, keywords, and references were analyzed, and the development status of this field was indicated from multiple perspectives. Results: Studies on ovarian cancer and drug resistance generally showed an increasing trend from 2013 to 2022. The People's Republic of China and Chinese institutions contributed more to this field. Gynecologic Oncology published the most articles, and the journal with the most citations was Cancer Research. Li Li was the author with the most publications, and Siegel RL was the author with the most citations. Through burst detection, it can be found that the research hotspots in this field mainly focused on the in-depth exploration of the drug resistance mechanism of ovarian cancer and the progress of PARP inhibitors and bevacizumab in the treatment of ovarian cancer. Conclusions: Many studies on the mechanism of drug resistance in ovarian cancer have been discovered; however, the deeper mechanism remains to be explored. Compared with traditional chemotherapy drugs, PARP inhibitors and bevacizumab have shown better efficacy, but PARP inhibitors have initially shown drug resistance. The future direction of this field should be to overcome the resistance of existing drugs and actively develop new ones.

Corrigendum: Bibliometric and visualized analysis of drug resistance in ovarian cancer from 2013 to 2022.

[This corrects the article DOI: 10.3389/fonc.2023.1173863.].

[Rehmanniae Radix and Rehmanniae Radix Praeparata improve diabetes induced by high-fat diet coupled with streptozotocin in mice through AMPK-mediated NF-κB/NLRP3 signaling pathway].

This study investigated the differential mechanisms of Rehmanniae Radix and Rehmanniae Radix Praeparata in improving diabetes in mice through AMPK-mediated NF-κB/NLRP3 signaling pathway. The diabetic mouse model was established with high-fat diet coupled with streptozotocin(STZ, intraperitoneal injection, 100 mg·kg~(-1), once a day for three consecutive days), after which the mice were randomly divided into model group, low-dose(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix groups, low-dose(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix Praeparata groups, catalpol group(250 mg·kg~(-1)), 5-hydroxymethylfurfural(5-HMF) group(250 mg·kg~(-1)), metformin group(250 mg·kg~(-1)), with the normal group also set. The organ indexes of heart,liver, spleen, lung, kidney and pancreas were calculated after four weeks of administration. The pathological changes and fibrosis of pancreas, kidney and liver in mice were observed by hematoxylin-eosin(HE) staining and Masson staining. Western blot was used to determine the expression levels of Toll-like receptor-4(TLR4), nuclear factor-κB(NF-κB), Nod-like receptor protein 3(NLRP3),interleukin-1ß(IL-1ß), adenosine monophosphate-activated protein kinase(AMPK), phosphorylated AMPK(p-AMPK) in the pancreas, kidney and liver of mice. Compared with the model group, the administration groups witnessed significant decrease in the liver,spleen, kidney, pancreas and fat indexes of diabetic mice, and there was no significant difference in heart and lung indexes. The pathological states and fibrosis of pancreatic, kidney and liver tissues were significantly improved after administration. Additionally, the expression levels of TLR4, NF-κB and NLRP3 in pancreas, kidney and liver of diabetic mice were significantly lowered. The expression levels of p-AMPK/AMPK were enhanced significantly in kidney and liver of mice in Rehmanniae Radix group while in pancreas, kidney and liver in Rehmanniae Radix Praeparata group. This suggests that Rehmanniae Radix and Rehmanniae Radix Praeparata differ in the mechanism of regulating energy metabolism of multiple organs and thereby exerting anti-inflammatory effects to alleviate symptoms of diabetic mice.

Metabolomics and Network Pharmacology-Based Investigation into the Mechanisms Underlying the Therapeutic Effect of a New Chinese Traditional Medicine (Cui Nai Ling) on Bromocriptine-Induced Hypogalactia.

As a traditional veterinary medicine to promote lactation, Cui Nai Ling (CNL) can not only increase milk supply and promote health but also improve the overall physiological function and immunity of the animals. In order to further improve CNL's effect on lactation, we have previously made a new CNL (NCNL) by adding Tetrapanacis Medulla and replacing Vaccariae Semen with fried Vaccariae Semen in CNL. We have demonstrated that the lactation-promoting effect of NCNL is better than that of CNL. However, the underlying mechanisms by which NCNL promotes lactation are unclear. In this study, we performed metabolomics, network pharmacology, and pharmacodynamic studies to explore the underlying mechanisms by which NCNL promotes lactation in rats with bromocriptine-induced hypogalactia. The results showed that NCNL significantly improved the loss of appetite in female adult rats and the weight loss of pups caused by the disorder of lactation. Biochemical analysis showed that NCNL could regulate the levels of PRL, T4, E2, Ca, UREA, GLU, ALT, AST, TCHO, and TG in serum. The pathological results showed that NCNL could promote lactation and increase the mammary gland index by improving breast acinar tissue morphology in rats with hypogalactia. Network pharmacology studies showed that NCNL promotes lactation through P13K-Akt, insulin resistance, and prolactin signaling pathways, among which the most frequently affected pathway was the P13K-Akt signaling pathway. Metabolomics studies showed that NCNL can significantly upregulate phenylalanine, tyrosine, and tryptophan biosynthesis and tyrosine metabolism pathways and downregulate cysteine and methionine metabolism pathways. NCNL can significantly increase the serum prolactin concentration, improve the glucose and lipid metabolism disorders, and regulate PI3K-Akt, insulin resistance, and prolactin pathways to affect the amino acids' metabolism in the mammary gland and ultimately exert its therapeutic effect on bromocriptine-induced postpartum hypogalactia. These findings revealed the effect and application value of NCNL on animals with postpartum hypogalactia.

Regulatory effects of the fruit extract of Lycium chinense and its active compound, betaine, on muscle differentiation and mitochondrial biogenesis in C2C12 cells.

Our study was conducted to investigate the effects of the fruits of Lycium chinense Mill. (Lycii Fructus, LF) and its bioactive compound, betaine, on muscle differentiation and mitochondrial biogenesis in C2C12 cells. LF extract and betaine was analyzed by high-performance liquid chromatography (HPLC). The expression of myosin heavy chain (MyHC) and peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), sirtuin-1(Sirt-1), nuclear respiratory factor-1 (NRF-1), transcription factor A, mitochondrial (TFAM) and the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), were determined in cellular or mitochondrial levels by quantitative polymerase chain reaction (qPCR) or Western blot, respectively. The glucose levels and total ATP contents were measured by the glucose consumption in a culture medium, cellular glucose uptake and ATP assays. LF extract at 4 mg/ml and betaine at 2 and 5 mM significantly increased the expression of MyHC in C2C12 myotubes, compared with non-treated cells. LF extract and betaine significantly increased the expression of PGC-1α, Sirt-1, NRF-1 and TFAM mRNA and protein in the myotubes, as well as phosphorylation of AMPK and ACC. Furthermore, LF extract and betaine significantly increased the mitochondrial protein contents, as the TFAM and NRF-1 expressions were increased. LF extract and betaine also significantly increased the glucose uptake and ATP contents in the myotubes. The LF extract contained 3.18% betaine was quantitated by HPLC. LF extract and betaine enhanced muscle differentiation and energy metabolism through the up-regulation of mitochondrial biogenesis-regulating factors, suggesting that LF extract and betaine can help to prevent the dysfunction of skeletal muscle.

Effects of Rhizome Extract of Dioscorea batatas and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes.

With the aging process, a loss of skeletal muscle mass and dysfunction related to metabolic syndrome is observed in older people. Yams are commonly use in functional foods and medications with various effects. The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and allantoin was analyzed by high performance liquid chromatography (HPLC). The expression of myosin heavy chain (MyHC) and mitochondrial biogenesis-regulating factors, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (Sirt-1), nuclear respiratory factor-1 (NRF-1) and transcription factor A, mitochondrial (TFAM), and the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were determined in C2C12 myotubes by reverse transcriptase (RT)-polymerase chain reaction (RT-PCR) or western blot. The glucose levels and total ATP contents were measured by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of PGC-1α, Sirt-1, NRF-1 and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased glucose uptake levels and ATP contents. Finally, HPLC analysis revealed that the yam water extract contained 1.53% of allantoin. Yam extract and allantoin stimulated myoblast differentiation into myotubes and increased energy production through the upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent skeletal muscle dysfunction through the stimulation of the energy metabolism.