Receptor Protein Kinase Research Articles

Phoenix dactylifera (date palm; Arecaceae) putative lectin homologs: Genome-wide search, architecture analysis, and evolutionary relationship

The date palm, Phoenix dactylifera, is a vital crop in nations in the Middle East and North Africa. The date palm was thought to have outstanding traditional medicinal value because it was abundant in phytochemicals with diverse chemical structures. The date palm's ability to withstand harsh environments could be partly attributed to a class of proteins known as lectins, which are carbohydrate-binding proteins that can bind sugar moieties reversibly and without changing their chemical structures. After scanning the genome of P. dactylifera (GCF 009389715.1), this in silico study discovered 196 possible lectin homologs from 11 different families, some specific to plants. At the same time, others could also be found in other kingdoms of life. Their domain architectures and functional amino acid residues were investigated, and they yielded a 40% true-lectin with known conserved carbohydrate-binding residues. Further, their probable subcellular localization, physiochemical and phylogenetic analyses were also performed. Scanning all putative lectin homologs against the anticancer peptide (ACP) dataset found in the AntiCP2.0 webpage identified 26 genes with protein kinase receptors (Lec-KRs) belonging to 5 lectin families, which are reported to have at least one ACP motif. Our study offers the first account of Phoenix-lectins and their organization that can be used for further structural and functional analysis and investigating their potential as anticancer proteins.

Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function.

Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

RNA-Sequencing Characterization of lncRNA and mRNA Functions in Septic Pig Liver Injury.

We assessed differentially expressed (DE) mRNAs and lncRNAs in the liver of septic pigs to explore the key factors regulating lipopolysaccharide (LPS)-induced liver injury. We identified 543 DE lncRNAs and 3642 DE mRNAs responsive to LPS. Functional enrichment analysis revealed the DE mRNAs were involved in liver metabolism and other pathways related to inflammation and apoptosis. We also found significantly upregulated endoplasmic reticulum stress (ERS)-associated genes, including the receptor protein kinase receptor-like endoplasmic reticulum kinase (PERK), the eukaryotic translation initiation factor 2α (EIF2S1), the transcription factor C/EBP homologous protein (CHOP), and activating transcription factor 4 (ATF4). In addition, we predicted 247 differentially expressed target genes (DETG) of DE lncRNAs. The analysis of protein-protein interactions (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway detected key DETGs that are involved in metabolic pathways, such as N-Acetylgalactosaminyltransferase 2 (GALNT2), argininosuccinate synthetase 1 (ASS1), and fructose 1,6-bisphosphatase 1 (FBP1). LNC_003307 was the most abundant DE lncRNA in the pig liver, with a marked upregulation of >10-fold after LPS stimulation. We identified three transcripts for this gene using the rapid amplification of the cDNA ends (RACE) technique and obtained the shortest transcript sequence. This gene likely derives from the nicotinamide N-methyltransferase (NNMT) gene in pigs. According to the identified DETGs of LNC_003307, we hypothesize that this gene regulates inflammation and endoplasmic reticulum stress in LPS-induced liver damage in pigs. This study provides a transcriptomic reference for further understanding of the regulatory mechanisms underlying septic hepatic injury.

Protective Effects of Selenium Nanoparticles against Bisphenol A-Induced Toxicity in Porcine Intestinal Epithelial Cells.

Bisphenol A (BPA) is widely used to harden plastics and polycarbonates and causes serious toxic effects in multiple organs, including the intestines. Selenium, as an essential nutrient element for humans and animals, exhibits a predominant effect in various physiological processes. Selenium nanoparticles have attracted more and more attention due to their outstanding biological activity and biosafety. We prepared chitosan-coated selenium nanoparticles (SeNPs) and further compared the protective effects, and investigated the underlying mechanism of SeNPs and inorganic selenium (Na2SeO3) on BPA-induced toxicity in porcine intestinal epithelial cells (IPEC-J2). The particle size, zeta potential, and microstructure of SeNPs were detected by using a nano-selenium particle size meter and a transmission electron microscope. IPEC-J2 cells were exposed to BPA alone or simultaneously exposed to BPA and SeNPs or Na2SeO3. The CCK8 assay was performed to screen the optimal concentration of BPA exposure and the optimal concentration of SeNPs and Na2SeO3 treatment. The apoptosis rate was detected by flow cytometry. Real-time PCR and Western blot methods were used to analyze the mRNA and protein expression of factors related to tight junctions, apoptosis, inflammatory responses and endoplasmic reticulum stress. Increased death and morphological damage were observed after BPA exposure, and these increases were attenuated by SeNPs and Na2SeO3 treatment. BPA exposure disturbed the tight junction function involved with decreased expression of tight junction protein Zonula occludens 1 (ZO-1), occludin, and claudin-1 proteins. Proinflammatory response mediated by the transcription factor nuclear factor-k-gene binding (NF-κB), such as elevated levels of interleukin-1β(IL-1β), interleukin-6 (IL-6), interferon-γ (IFN-γ), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α) expression was induced at 6 and 24 h after BPA exposure. BPA exposure also disturbed the oxidant/antioxidant status and led to oxidative stress. IPEC-J2 cell apoptosis was induced by BPA exposure, as indicated by increased BCL-2-associated X protein (Bax), caspase 3, caspase 8, and caspase 9 expression and decreased B-cell lymphoma-2 (Bcl-2) and Bcl-xl expression. BPA exposure activated the endoplasmic reticulum stress (ERS) mediated by the receptor protein kinase receptor-like endoplasmic reticulum kinase (PERK), Inositol requiring enzyme 1 (IRE1α), and activating transcription factor 6 (ATF6). We found that treatment with SeNPs and Na2SeO3 can alleviate the intestinal damage caused by BPA. SeNPs were superior to Na2SeO3 and counteracted BPA-induced tight junction function injury, proinflammatory response, oxidative stress, apoptosis, and ERS stress. Our findings suggest that SeNPs protect intestinal epithelial cells from BPA-induced damage, partly through inhibiting ER stress activation and subsequently attenuating proinflammatory responses and oxidative stress and suppressing apoptosis, thus enhancing the intestinal epithelial barrier function. Our data indicate that selenium nanoparticles may represent an effective and reliable tool for preventing BPA toxicity in animals and humans.

Synthesis and Bioactivity Evaluation of Nepetaefolin F and Its Analogues.

Nepetaefolin F (5), an abietane diterpenoid, showed significant inhibitory activity against human cancer cells in vitro with an IC50 value of 6.3 μM. The syntheses of nepetaefolin F and its analogues are presented herein. The cytotoxicity against various cancer cell lines was evaluated; notably, the cyclopropanecarboxylate ester 42 displayed significant antitumor activity against MGC 803 cells with an IC50 value of 20.9 μM. Further studies revealed that 42 could upregulate the expression of p62, microtubule-associated protein 1 light-chain 3 β (LC3 B-I), cleaved caspase-3, and cleaved caspase-9 and downregulate the expression of Beclin-1 and LC3B-II. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 42 could modulate multiple signaling pathways, especially for peroxisome proliferator-activated receptor (PPAR) and AMP-activated protein kinase (AMPK), which are closely related to autophagy. These results suggested that compound 42 is a promising lead by inhibiting cell proliferation and autophagy, as inducing cell apoptosis in MGC 803 cells.

The receptor-like kinase EMS1 and BRI1 coordinately regulate stamen elongation via the transcription factors BES1/BZR1 in Arabidopsis

Plants possess a large family of receptor kinase proteins to mediate cell-to-cell and cell-to-environment communication, and these regulations are essential for plant growth and development as well as resistance to biotic or abiotic stresses. EMS1 is a receptor kinase which involved in tapetum cell fate determination during anther development, while brassinosteroid (BR) receptor, BRI1, controls most aspects of plant growth and development. Although EMS1 and BRI1 are known to regulate independent biological processes, they interact with identical components of the downstream signaling pathways. However, the biological processes other than the tapetum development controlled by the EMS1 signal are not clear. Here, we report that EMS1 signaling-related mutants exhibited an insufficient stamen elongation phenotype, similar to BR signaling mutants. Transgenic expression of BRI1 restored the short filament phenotype of ems1. Conversely, co-expression of EMS1 and TPD1 also restored the short filaments of BRI1 mutants, bri1. Genetic experiments confirmed that EMS1 and BRI1 regulate filament elongation through their downstream transcription factors BES1/BZR1. Molecular analysis suggested that the decrease in BR signaling output in filaments of the ems1 mutant caused deficient filament development. Moreover, in vitro and in vivo experiments proved BES1 interacts with filament-specific transcription factor MYB21. Together, we found that the two receptor-like kinases (RLKs) EMS1 and BRI1 are cooperatively involved in the regulation of filament elongation via the transcription factors BES1/BZR1. These results indicated that the biological processes regulated by EMS1 and BRI1 in plants are both independent and interactive, which provides us with insights into multidimensional molecular control of the RLK pathway.

RNA sequencing analysis of the longissimus dorsi to identify candidate genes underlying the intramuscular fat content in Anqing Six-end-white pigs.

Intramuscular fat (IMF) is a significant marker for pork quality. The Anqing Six-end-white pig has the characteristics of high meat quality and IMF content. Owing to the influence of European commercial pigs and a late start in resource conservation, the IMF content within local populations varies between individuals. This study analyzed the longissimus dorsi transcriptome of purebred Anqing Six-end-white pigs with varying IMF content to recognize differentially expressed genes. We identified 1528 differentially expressed genes between the pigs with high (H) and low (L) IMF content. Based on these data, 1775 Gene Ontology terms were significantly enriched, including lipid metabolism, modification and storage, and regulation of lipid biosynthesis. Pathway analysis revealed 79 significantly enriched pathways, including the Peroxisome proliferator-activated receptor and mitogen-activated protein kinase signaling pathways. Moreover, gene set enrichment analysis indicated that the L group had increased the expression of genes related to ribosome function. Additionally, the protein-protein interaction network analyses revealed that VEGFA, KDR, LEP, IRS1, IGF1R, FLT1 and FLT4 were promising candidate genes associated with the IMF content. Our study identified the candidate genes and pathways involved in IMF deposition and lipid metabolism and provides data for developing local pig germplasm resources.

The role of gut-dependent molecule trimethylamine N-oxide as a novel target for the treatment of chronic kidney disease.

Trimethylamine N-oxide (TMAO) is an intestinal uremic toxin molecule mainly excreted by the kidney. Therefore, the plasma TMAO concentration is significantly increased in chronic kidney disease (CKD) patients, and plasma TMAO can be cleared by dialysis. Furthermore, TMAO damage the kidney mainly through three mechanisms: oxidative stress, inflammation and endoplasmic reticulum stress. Clinical experiments have indicated that higher TMAO levels are strongly related to the elevated incidence and mortality of cardiovascular (CV) events in CKD patients. Moreover, experimental data have shown that high levels of TMAO directly aggravate atherosclerosis, thrombosis and enhance myocardial contractility, resulting in myocardial ischemia and stroke. Specially, there are currently four potential ways to reduce blood TMAO concentration or block the effect of TMAO, including reducing the intake of trimethylamine (TMA) precursors in the diet, regulating the intestinal flora to reduce TMA production, interrupting the role of flavin-dependent monooxygenase isoforms (FMOs) to reduce the generation of TMAO, and blocking the TMAO receptor protein kinase R-like endoplasmic reticulum kinase (PERK). We hope that more clinical studies and clinicians will focus on clinical treatment to reduce the concentration of TMAO and alleviate renal damage.

Inhibitory Effect of Styrylpyrone Extract of Phellinus linteus on Hepatic Steatosis in HepG2 Cells.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be approximately about 25.24% of the population worldwide. NAFLD is a complex syndrome and is characterized by a simple benign hepatocyte steatosis to more severe steatohepatitis in the liver pathology. Phellinus linteus (PL) is traditionally used as a hepatoprotective supplement. Styrylpyrone-enriched extract (SPEE) obtained from the PL mycelia has been shown to have potential inhibition effects on high-fat- and high-fructose-diet-induced NAFLD. In the continuous study, we aimed to explore the inhibitory effects of SPEE on free fatty acid mixture O/P [oleic acid (OA): palmitic acid (PA); 2:1, molar ratio]-induced lipid accumulation in HepG2 cells. Results showed that SPEE presented the highest free radical scavenging ability on DPPH and ABTS, and reducing power on ferric ions, better than that of partitions obtained from n-hexane, n-butanol and distilled water. In free-fatty-acid-induced lipid accumulation in HepG2 cells, SPEE showed an inhibition effect on O/P-induced lipid accumulation of 27% at a dosage of 500 μg/mL. As compared to the O/P induction group, the antioxidant activities of superoxide dismutase, glutathione peroxidase and catalase were enhanced by 73%, 67% and 35%, respectively, in the SPEE group. In addition, the inflammatory factors (TNF-α, IL-6 and IL-1β) were significantly down-regulated by the SPEE treatment. The expressions of anti-adipogenic genes involved in hepatic lipid metabolism of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were enhanced in the SPEE supplemented HepG2 cells. In the protein expression study, p-AMPK, SIRT1 and PGC1-α were significantly increased to 121, 72 and 62%, respectively, after the treatment of SPEE. Conclusively, the styrylpyrone-enriched extract SPEE can ameliorate lipid accumulation and decrease inflammation and oxidative stress through the activation of SIRT1/AMPK/PGC1-α pathways.

Comparative Transcriptome Analysis Reveals Potential Genes Conferring Resistance or Susceptibility to Bacterial Canker in Tomato

Bacterial canker of tomato is a systemic disease caused by Clavibacter michiganensis (Cm), which poses a grave threat to tomato production worldwide. Towards the identification of genes underlying resistance to Cm infection, the transcriptome of the resistant inbred backcross line IBL2353 carrying the Rcm2.0 locus derived from Solanum habrochaites LA407 and the susceptible Solanum lycopersicum line Ohio88119 was comparatively analyzed after Cm inoculation, and the analysis focused on the genes with different expression patterns between resistant and susceptible lines. Gene ontology (GO) analysis revealed that top terms of differentially expressed genes comprised ubiquitin protein ligases, transcription factors, and receptor kinases. Then we screened out some genes which are potentially associated with the defense response against Cm infection in IBL2353 including the wall-associated receptor kinase-like 20 (WAKL20), and virus-induced gene silencing showed it contributes resistance to Cm infection. In addition to Cm-induced genes related to resistance, the expression of eight homologs from six susceptibility (S) gene families was analyzed. These putative resistance and susceptibility genes are valuable resources for molecular resistance breeding and contribute to the development of new control methods in tomato.

Octopamine-MAPK-SKN-1 signaling suppresses mating-induced oxidative stress in Caenorhabditis elegans gonads to protect fertility

Sexual conflict over mating is costly to female physiology. Caenorhabditis elegans hermaphrodites generally produce self-progeny, but they can produce cross-progeny upon successfully mating with a male. We have uncovered that C.elegans hermaphrodites experience sexual conflict over mating, resulting in severe costs in terms of their fertility and longevity. We show that reactive oxygen species (ROS) accumulate on the apical surfaces of spermathecal bag cells after successful mating and induce cell damage, leading to ovulation defects and fertility suppression. To counteract these negative impacts, C.elegans hermaphrodites deploy the octopamine (OA) regulatory pathway to enhance glutathione (GSH) biosynthesis and protect spermathecae from mating-induced ROS. We show that the SER-3 receptor and mitogen-activated protein kinase (MAPK) KGB-1 cascade transduce the OA signal to transcription factor SKN-1/Nrf2 in the spermatheca to upregulate GSH biosynthesis.

Arabidopsis immune responses triggered by cellulose and mixed-linked glucan oligosaccharides require a group of Leucine-Rich Repeat-Malectin Receptor Kinases.

The plant immune system perceives a diversity of carbohydrate ligands from plant and microbial cell walls through the extracellular ectodomains (ECDs) of Pattern Recognition Receptors (PRRs), which activate Pattern-Triggered Immunity (PTI). Among these ligands are oligosaccharides derived from mixed-linked β-1,3/β-1,4-glucans (MLGs, e.g., β-1,4-D-(Glc)2 -β-1,3-D-Glc, MLG43) and cellulose (e.g., β-1,4-D-(Glc)3 , CEL3). The mechanisms of carbohydrates perception by plants are poorly characterised, except for fungal chitin oligosaccharides (e.g., β-1,4-D(GlcNAc)6 , CHI6) that involves several Receptor Kinase proteins (RK) with LysM-ECDs. Here, we describe the isolation and characterisation of Arabidopsis thaliana mutants impaired in glycan perception (igp) that are defective in PTI activation mediated by MLG43 and CEL3, but not by CHI6. igp1-igp4 are altered in three RKs [AT1G56145 (IGP1), AT1G56130 (IGP2/IGP3), and AT1G56140 (IGP4)] with Leucine-Rich-Repeat (LRR) and Malectin (MAL) domains in their ECDs. igp1 and igp2/3 harbour point mutations (E906K and G773E, respectively) in their kinase domains whereas igp4 is a T-DNA insertional, loss of function mutant. Notably, Isothermal Titration Calorimetry (ITC) assays with purified ECD-RKs of IGP1 and IGP3 showed that IGP1 binds with high-affinity CEL3 (Kd=1.19 ± 0.03 μM) and cellopentaose (Kd=1.40 ± 0.01 μM), but not MLG43, supporting its function as a plant PRR for cellulose oligosaccharides. Our data suggest that these LRR-MAL RKs are components of a novel recognition mechanism for both cellulose and MLG-derived oligosaccharides perception and downstream PTI activation in Arabidopsis.

Identification of AXL as a co-receptor for human parvovirus B19 infection of human erythroid progenitors.

Parvovirus B19 (B19V) infects human erythroid progenitor cells (EPCs) and causes several hematological disorders and fetal hydrops. Amino acid (aa) 5-68 of minor capsid protein VP1 (VP1u5-68aa) is the minimal receptor binding domain for B19V to enter EPCs. Here, we carried out a genome-wide CRISPR-Cas9 guide RNA screen and identified tyrosine protein kinase receptor UFO (AXL) as a proteinaceous receptor for B19V infection of EPCs. AXL gene silencing in ex vivo expanded EPCs remarkably decreased B19V internalization and replication. Additions of the recombinant AXL extracellular domain or a polyclonal antibody against it upon infection efficiently inhibited B19V infection of ex vivo expanded EPCs. Moreover, B19V VP1u interacted with the recombinant AXL extracellular domain in vitro at a relatively high affinity (KD=103 nM). Collectively, we provide evidence that AXL is a co-receptor for B19V infection of EPCs.

Research on PAR-1 in Cancer, Cardiovascular Disease and Nerve-related Diseases

PAR-1 (protein kinase receptor 1, also known as thrombin receptor) is a member of the G protein-coupled receptor family, and its main ligand is thrombin. PAR-1 is mainly expressed in platelets, endothelial cells, smooth muscle cells and some neural cells, involved in hemostasis and atherosclerosis formation. At present, a great deal of research has also confirmed that PAR-1 is involved in epithelial-to-mesenchymal transition and epithelial-to-endothelial transformation; PAR-1 can regulate the NF-κB pathway, stimulate the formation of tumor angiogenesis, and participate in the development of tumors through a variety of ways. At the same time, the blood state of tumor patients often presents a hypercoagulable state. As one of the thrombin receptors, PAR-1 may participate in the formation of hypercoagulable state in tumor patients. The review focuses on the expression and activation mechanism of PAR-1 and its physiological pathological process; And how to participate in the occurrence and development of tumors and the relationship with cardiovascular diseases. The aim is to point out that PAR-1 may be a potential target for tumor therapy and may be helpful to improve the hypercoagulable state and prolong the survival of patients with advanced cancer.

Exogenous Lipoxin A4 attenuates IL4-induced Mucin Expression in Human Airway Epithelial Cells.

Introduction: The proinflammatory cytokine interleukin-4 (IL-4) induces mucus hypersecretion by human airway epithelial cells and the MAP kinase signalling pathway may be important in terms of IL-4-induced MUC5AC gene expression. Lipoxin A4 (LXA4) is an arachidonic acid-derived mediator that promotes inflammation by binding to the anti-inflammatory receptors (ALXs) or the formyl-peptide receptor like-1 (FPRL1) protein expressed by airway epithelial cells. Here, we explore the effects of LXA4 on IL-4-induced mucin gene expression in, and secretion from, human airway epithelial cells. Methods: We co-treated cells with IL-4 (20 ng/mL) and LXA4 (1 nM) and measured the expression levels of mRNAs encoding MUC5AC and 5B via real-time polymerase chain reaction; protein expression levels were determined by Western blotting and immunocytofluorescence. The ability of IL-4 and LXA4 to suppress protein expression was determined by Western blotting. Results: IL-4 increased MUC5AC and 5B gene and protein expression. LXA4 suppressed IL-4-induced MUC5AC and 5B gene and protein expression by interacting with the IL4 receptor and mitogen-activated protein kinase (MAPK) pathway, including both phospho-p38 MAPK and phospho-extracellular signal-regulated kinase (phospho-ERK). IL-4 and LXA4 increased and decreased, respectively, the number of cells that stained with anti-MUC5AC and 5B antibodies. Conclusions: LXA4 may regulate mucus hypersecretion induced by IL4 in human airway epithelial cells.

Efficiency of Biobran/MGN-3, an Arabinoxylan Rice Bran, in Attenuating Diabetes-Induced Cognitive Impairment of the Hippocampus via Oxidative Stress and IR/Akt/NF-κB in Rats.

Type 2 diabetes mellitus (T2DM) is a common metabolic disease accompanied by cognitive impairment, hippocampal malfunctioning, and inflammation. Biobran/MGN-3, an arabinoxylan rice bran, has been shown to have an antidiabetic effect in streptozotocin-induced diabetic rats. The present study investigates Biobran's effect against diabetes-induced cognitive impairment and synaptotoxicity in the hippocampus via oxidative stress and the IR/A/NF-κB signaling pathway in rats. Diabetes was induced via i.p. injection of streptozotocin (STZ) (40 mg/kg BW); STZ-treated rats were then administered Biobran (100 mg/kg BW) for 4 wks. Biobran supplementation improved motor coordination and muscular strength, as assessed by Kondziella's inverted screen test. Biobran also improved concentration levels of glutathione (GSH), antioxidant enzymes, acetylcholine (ACh), dopamine, serotonin, insulin receptor (IR), and alpha serine-threonine protein kinase (Akt); it protected against elevated levels of glucose, total cholesterol, triglycerides, oxidative stress markers, TBARS, NO, AChE, and MAO; and it significantly decreased inflammatory cytokines levels of IL-1β, NF-κB, TNF-α, and amyloid β1-42. Moreover, Biobran ameliorated hippocampal histological alterations. Immunohistochemical observations showed that Biobran reduced overexpression of hippocampal synaptophysin and Ki67 relative to untreated diabetic rats. Biobran may ameliorate hippocampal alterations in diabetic rats via its antidiabetic, antiproliferative, anti-inflammatory, antiapoptotic, and antioxidant effects.

Differential expression analysis in epithelial ovarian cancer using functional genomics and integrated bioinformatics approaches

BackgroundEpithelial Ovarian Cancer (EOC) has remained the most frequent and leading cause of death among gynecologic malignancies, with a remarkably elevated and alarming global mortality rate and a poor prognosis. As a result of its asymptomatic characteristics in the early stages, the disease is typically diagnosed at advanced stages, with extensive dissemination. Therefore, it is of great importance to explore more reliable diagnostic and prognostic biomarkers. The present study intended to design an integrative bioinformatics approach to investigate robust differentially expressed genes (DEGs) associated with EOC progression as valuable diagnostic and prognostic biomarkers, providing inspiring insights into cancer mechanisms. Materials and methodsThree mRNA (GSE40595, GSE14407, and GSE18520) expression profiles related to EOC were retrieved from Gene Expression Omnibus (GEO) database. Significant DEGs were screened out following raw data quality assessment, preprocessing, and statistical computing. Gene ontology and pathway enrichment analyses were performed on candidate DEGs. Next, the interactions between genes were visualized by constructing their networks, and subsequently, a list of hub genes was extracted through the estimation of their connections, which were subjected to further evaluations for validation and survival analysis. ResultsWe identified 241 overlapping DEGs (20 up- and 221 down-regulated) between 3 mRNA datasets. After evaluating the protein-protein interactions, validation, and survival analysis, five hub genes including four up-regulated (AURKA, CD24, CDCA3, CENPF) and one down-regulated (PGR) were eventually selected as potential biomarkers of EOC. GO and Enriched pathways related to selected genes compromised cell growth, actin filament organization, enzyme inhibitor, peptidase regulator, and receptor protein kinase activities, glycosaminoglycan binding, glycine, serine, and threonine metabolism pathways, proteoglycans, and EGFR tyrosine kinase inhibitor resistance. ConclusionIn summary, these findings will shed further light on the molecular mechanisms underlying EOC. In addition, the candidate genes, related metabolites, and signaling pathways could serve as promising prognostic, diagnostic, or even potential drug targets.

Elucidating the Focal Immunomodulatory Clues Influencing Mesenchymal Stem Cells in the Milieu of Intervertebral Disc Degeneration.

The intervertebral discs (IVDs) are a relatively mobile joint that interconnects vertebrae of the spine. Intervertebral disc degeneration (IVDD) is one of the leading causes of low back pain, which is most often related to patient morbidity as well as high medical costs. Patients with chronic IVDD often need surgery that may sometimes lead to biomechanical complications as well as augmented degeneration of the adjacent segments. Moreover, treatment modalities like rigid intervertebral fusion, dynamic instrumentation, as well as other surgical interventions are still controversial. Mesenchymal stem cells (MSCs) have exhibited to have immunomodulatory functions and the ability to differentiate into cartilage, making these cells possibly an epitome for IVD regeneration. Transplanted MSCs were able to repair IVDD back to the normal disc milieu via the activation of the generation of extracellular matrix (ECM) proteins such as aggrecan, proteoglycans and collagen types I and II. IVD milieu clues like, periostin, cluster of differentiation, tumor necrosis factor alpha, interleukins, chemokines, transforming growth factor beta, reactive oxygen species, toll-like receptors, tyrosine protein kinase receptor and disialoganglioside, exosomes are capable of influencing the MSCs during treatment of IVDD. ECM microenvironment clues above have potentials as biomarkers as well as accurate molecular targets for therapeutic intervention in IVDD.

The Influence of Lifestyle and Treatment on Oxidative Stress and Inflammation in Diabetes

Diabetes is considered a new pandemic of the modern world, and the number of sufferers is steadily increasing. Sustained hyperglycemia promotes the production of free radicals and leads to persistent, low-grade inflammation. Oxidative stress causes mitochondrial destruction, which along with activation of the hexosamine pathway, nuclear factor-κB (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), c-jun NH2 terminal kinase/stress-activated protein kinase (JNK/SAPK) or toll-like receptors (TLRs), leads to pancreatic β-cell dysfunction. However, there is also the protective mechanism that counteracts oxidative stress and inflammation in diabetes, mitophagy, which is a mitochondrial autophagy. An important part of the strategy to control diabetes is to lead a healthy lifestyle based on, among other things, regular physical activity, giving up smoking, eating a balanced diet containing ingredients with antioxidant potential, including vegetables and fruits, and using hypoglycemic pharmacotherapy. Tobacco smoke is a recognized modifiable risk factor for many diseases including diabetes, and it has been shown that the risk of the disease increases in proportion to the intensity of smoking. Physical activity as another component of therapy can effectively reduce glucose fluctuations, and high intensity interval exercise appears to have the most beneficial effect. A proper diet not only increases cellular sensitivity to insulin, but is also able to reduce inflammation and oxidative stress. Pharmacotherapy for diabetes can also affect oxidative stress and inflammation. Some oral drugs, such as metformin, pioglitazone, vildagliptin, liraglutide, and exenatide, cause a reduction in markers of oxidative stress and/or inflammation, while the new drug Imeglimin reverses pancreatic β-cell dysfunction. In studies of sitagliptin, vildagliptin and exenatide, beneficial effects on oxidative stress and inflammation were achieved by, among other things, reducing glycemic excursions. For insulin therapy, no corresponding correlation was observed. Insulin did not reduce oxidative stress parameters. There was no correlation between glucose variability and oxidative stress in patients on insulin therapy. The data used in this study were obtained by searching PubMed online databases, taking into account recent studies.

Mechanisms Underlying Cognitive Impairment Induced by Prenatal Alcohol Exposure.

Alcohol is one of the most commonly used illicit substances among pregnant women. Clinical and experimental studies have revealed that prenatal alcohol exposure affects fetal brain development and ultimately results in the persistent impairment of the offspring's cognitive functions. Despite this, the rate of alcohol use among pregnant women has been progressively increasing. Various aspects of human and animal behavior, including learning and memory, are dependent on complex interactions between multiple mechanisms, such as receptor function, mitochondrial function, and protein kinase activation, which are especially vulnerable to alterations during the developmental period. Thus, the exploration of the mechanisms that are altered in response to prenatal alcohol exposure is necessary to develop an understanding of how homeostatic imbalance and various long-term neurobehavioral impairments manifest following alcohol abuse during pregnancy. There is evidence that prenatal alcohol exposure results in vast alterations in mechanisms such as long-term potentiation, mitochondrial function, and protein kinase activation in the brain of offspring. However, to the best of our knowledge, there are very few recent reviews that focus on the cognitive effects of prenatal alcohol exposure and the associated mechanisms. Therefore, in this review, we aim to provide a comprehensive summary of the recently reported alterations to various mechanisms following alcohol exposure during pregnancy, and to draw potential associations with behavioral changes in affected offspring.