Diagnostic Targets Research Articles

Identification of ZNF652 as a Diagnostic and Therapeutic Target in Osteoarthritis Using Machine Learning.

Osteoarthritis (OA) is the most common degenerative joint disease. However, its etiology remains largely unknown. Zinc Finger Protein 652 (ZNF652) is a transcription factor implicated in various biological processes. Nevertheless, its role in OA has not been elucidated. The search term "osteoarthritis" was utilized to procure transcriptome data relating to OA patients and healthy people from the Gene Expression Omnibus (GEO) database. Then a screening process was initiated to identify differentially expressed genes (DEGs). The DEGs were discerned using three distinct machine learning methods. The accuracy of these DEGs in diagnosing OA was evaluated using the Receiver Operating Characteristic (ROC) Curve. A competitive endogenous RNA (ceRNA) visualization network was established to delve into potential regulatory targets. The ZNF652 expression was confirmed in the cartilage of OA rats using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB) and analyzed using an independent t-test. ZNF652 was identified as a DEG and exhibited the highest diagnostic value for OA according to the ROC analysis. The GO and KEGG enrichment analyses suggest that ZNF652 plays a vital role in OA development through processes including nitric oxide anabolism, macrophage proliferation, immune response, and the PI3K/Akt and the MAPK signaling pathways. The increased expression of ZNF652 in OA was validated in qRT-PCR (1.193 ± 0.005 vs 1.000 ± 0.005, p < 0.001) and WB (0.981 ± 0.055 vs 0.856 ± 0.026, p = 0.012) analysis. ZNF652 was found to be related to OA pathogenesis and can potentially serve as a diagnostic and therapeutic target of OA. The underlying mechanism is that ZNF652 was related to nitric oxide anabolism, macrophage proliferation, various signaling pathways, and immune cells and their functions in OA. Nevertheless, the findings need to be confirmed in clinical trials and the molecular mechanism requires further study.

Label-free electrochemical assessment of human serum and cancer cells to determine the folate receptor cancer biomarker.

The folate receptor (FR) is a well-known biomarker that is overexpressed in many cancer cells, making it a valuable target for cancer diagnostics and therapeutic strategies. However, identifying cancer biomarkers remains a challenge due to factors such as lengthy procedures, high costs, and low sensitivity. This study presents the development of a novel, cost-effective biosensor designed for the detection of FR. To overcome the limitations of traditional immunological methods, which rely on antigen-antibody interactions, we utilized a charge-based affinity approach. Folic acid (FA) was conjugated with poly (diallyl dimethylammonium chloride) (PDDA) using an EDC-NHS linker on the surface of multi-walled carbon nanotubes. The biosensor enabled electrochemical detection of FR through differential pulse voltammetry (DPV), achieving an impressive detection limit of 1.6pg/mL and a dynamic range of 1-10,000ng/mL. Additionally, the biosensor exhibited excellent stability (30days), high selectivity, and repeatability (RSD=3.14%, n=5). This work presents a promising strategy for developing ligand-receptor-based biosensors. It paves the way for future applications in cancer diagnostics and biosystem interfaces, offering high performance and practical advantages.

A rare KLHDC4 variant Glu510Lys is associated with genetic susceptibility and promotes tumor metastasis in nasopharyngeal carcinoma.

Various genetic association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with nasopharyngeal carcinoma (NPC) risk. However, these studies have predominantly focused on common variants, leaving the contribution of rare variants to the "missing heritability" largely unexplored. Here, we integrate genotyping data from 3,925 NPC cases and 15,048 healthy controls to identify a rare SNP, rs141121474, resulting in a Glu510Lys mutation in KLHDC4 gene linked to increased NPC risk. Subsequent analyses reveal that KLHDC4 is highly expressed in NPC and correlates with poorer prognosis. Functional characterizations demonstrate that KLHDC4 acts as an oncogene in NPC cells, enhancing their migratory and metastatic capabilities, with these effects being further augmented by the Glu510Lys mutation. Mechanistically, the Glu510Lys mutant exhibits increased interaction with Vimentin compared to the wild-type KLHDC4 (KLHDC4-WT), leading to elevated Vimentin protein stability and modulation of the epithelial-mesenchymal transition process, thereby promoting tumor metastasis. Moreover, Vimentin knockdown significantly mitigates the oncogenic effects induced by overexpression of both KLHDC4-WT and the Glu510Lys variant. Collectively, our findings highlight the critical role of the rare KLHDC4 variant rs141121474 in NPC progression and propose its potential as a diagnostic and therapeutic target for NPC patients.

Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers.

Exosomal microRNAs (exomiRs) play a critical role in intercellular communication, especially in cancer, where they regulate key cellular processes like proliferation, angiogenesis, and metastasis, highlighting their significance as potential diagnostic and therapeutic targets. Here, we aimed to characterize the role of exomiRs, derived from seven cancer types (four cell lines and three tumors), in influencing the pre-metastatic niche (PMN). In each cancer type we extracted high confidence exomiRs (LogFC >= 2 in exosomes relative to control), their experimentally validated targets, and the enriched pathways among those targets. We then selected the top100 high-confidence targets based on their frequency of appearance in the enriched pathways. We observed significantly higher GC content in exomiRs relative to genomic background. Gene Ontology analysis revealed both general cancer processes, such as wound healing and epithelial cell proliferation, as well as cancer-specific processes, such as "angiogenesis" in the kidney and "ossification" in the lung. ExomiR targets were enriched for cancer-specific tumor suppressor genes and downregulated in PMN formed in lungs compared to normal. Motif analysis showed high inter-cancer similarity among motifs enriched in exomiRs. Our analysis recapitulated exomiRs associated with M2 macrophage differentiation and chemoresistance, such as miR-21 and miR-222-3p, regulating signaling pathways like PTEN/PI3/Akt, NF-kB, etc. Additionally, Cox regression analysis in TCGA indicated that exomiR targets are significantly associated with better overall survival of patients. Lastly, support vector machine model using exomiR targets gene expression classified responders and non-responders to therapy with an AUROC ranging from 0.72 to 0.96, higher than previously reported gene signatures.

Inhibition of USP22 by miR-200b-5p represses gastric cancer cell proliferation and migration by targeting the NF-κB signaling pathway.

Gastric cancer (GC) is an aggressive tumor type with an intricate pathogenesis and limited therapeutic options. Ubiquitin-specific protease 22 (USP22) is a protein implicated in cell proliferation, metastasis, and tumorigenesis. However, the regulatory mechanisms governing USP22 in GC are still not fully understood. In this study, we perform bioinformatics analysis to identify conserved miRNA recognition sites for miR-200b-5p within the 3'UTR of USP22. Validation via luciferase reporter assay confirms the transcriptional regulation of USP22 by miR-200b-5p. Overexpression of miR-200b-5p markedly inhibits the proliferation and migration of GC cells in vitro and suppresses tumor growth in vivo. Conversely, ectopic expression of USP22 reversed this effect by modulating the NF-κB signaling pathway. Additionally, qPCR analysis reveals an inverse correlation between the miR-200b-5p level and USP22 expression in GC. Collectively, our findings indicate that miR-200b-5p-mediated inhibition of USP22 attenuates cell proliferation by targeting the NF-κB signaling pathway in GC, suggesting that miR-200b-5p and USP22 could serve as potential diagnostic or therapeutic targets for gastric cancer and other related human diseases.

Enhancing Osteoblast Activity and Accelerating Fracture Healing via miR-656-3p Downregulation: A Novel Targeting Strategy Focused on BMP-2 Expression.

Delayed fracture healing (DFH), a common complication of post-fracture surgery, exhibits an incompletely understood pathogenesis. The present study endeavors to investigate the roles and underlying mechanisms of miR-656-3p and Bone Morphogenetic Protein-2 (BMP-2) in DFH. It was recruited 94 patients with normal fracture healing (NFH) and 88 patients with DFH of the femoral neck. Serum miR-656-3p and BMP-2 expressions were quantified using RT-qPCR and the diagnostic potential of them for DFH was evaluated using ROC analysis. Factors influencing fracture healing were identified through logistic regression analysis. Osteogenic differentiation of MC3T3-E1 cells was induced, followed by evaluations of cell proliferation, apoptosis, and differentiation capabilities utilizing CCK-8, flow cytometry, and mRNA expression analysis of osteogenic markers. The targeting relationship between miR-656-3p and BMP-2 was validated through luciferase reporter assays. The levels of miR-656-3p were significantly elevated in DFH patients compared to those with NFH, whereas BMP-2 levels exhibited a decrease, a negative correlation between their expression patterns. Logistic regression analysis revealed that miR-656-3p and BMP-2 serve as influential factors in fracture healing, with their combined assessment exhibiting enhanced predictive value for DFH. Downregulation of miR-656-3p promoted proliferation and differentiation of MC3T3-E1 cells while inhibiting apoptosis. BMP-2, identified as a target of miR-656-3p, negated the effects of miR-656-3p downregulation when BMP-2 expression was inhibited. miR-656-3p modulates osteoblast function by targeting BMP-2, offering novel therapeutic and diagnostic targets for the management of DFH.

Affinity Tag-Free Purification of SARS-CoV-2 N Protein and Its Crystal Structure in Complex with ssDNA.

The nucleocapsid (N) protein is one of the four structural proteins in SARS-CoV-2, playing key roles in viral assembly, immune evasion, and stability. One of its primary functions is to protect viral RNA by forming the nucleocapsid. However, the precise mechanisms by which the N protein interacts with viral RNA and assembles into a nucleocapsid remain unclear. Compared to other SARS-CoV-2 components, targeting the N protein has several advantages: it exhibits higher sequence conservation, lower mutation rates, and stronger immunogenicity, making it an attractive target for antiviral drug development and diagnostics. Therefore, a detailed understanding of the N protein's structure is essential for deciphering its role in viral assembly and developing effective therapeutics. In this study, we report the expression and purification of a soluble recombinant N protein, along with a 1.55 Å resolution crystal structure of its nucleic acid-binding domain (N-NTD) in complex with ssDNA. Our structure revealed new insights into the conformation and interaction of the flexible N-arm, which could aid in understanding nucleocapsid assembly. Additionally, we identified residues that are critical for ssDNA interaction.

Identification of the key targets for sepsis-associated acute kidney injury by RNA sequencing combined with bioinformatics methods

PurposeThis research probes into genes related to the risk of concurrent kidney injury in septic patients to provide reliable targets for early identification of sepsis-associated kidney injury and prognosis research.MethodsPeripheral blood samples were isolated from 10 healthy individuals and 22 septic patients for RNA sequencing and differential analyses. Meanwhile, the top 1000 kidney-associated genes were chosen from the GTEx website. Subsequently, DEGs in sepsis were intersected with kidney-specific genes, followed by GO and KEGG analyses on these intersection genes. The predictive ability of hub genes for prognosis was evaluated using survival analysis. A meta-analysis was carried out to determine the differential expression profiles of hub genes between the sepsis surviving and dead groups. ROC curves were plotted to screen hub genes and clarify their diagnostic value. Cell line localization of hub genes was further clarified through single-cell RNA sequencing.ResultsThere were 40 targets in the intersection between 1328 DEGs in sepsis and 1000 kidney-associated genes. These intersection genes were mainly engaged in functions and signaling pathways .Survival curves linked the higher levels of CD74 and IL32 to raised survival rates of patients, indicating positive correlations of CD74 and IL32 with patient prognosis. Meta-analysis revealed that CD74 and IL32 were highly expressed in the sepsis surviving group but poorly expressed in the sepsis dead group, showing statistically significant differences between these two groups. In the ROC analysis of hub genes, AUC values of CD74 (0.983) and IL32 (0.980) suggested their high diagnostic value. Lastly, CD74 was principally expressed in macrophages, while IL32 was mainly presented in T cells.ConclusionCD74 and IL32, as biomarkers for early diagnosis and prognostic evaluation of sepsis complicated with kidney injury, are highly expressed in macrophages and T cells, respectively, providing new diagnostic and prognostic targets for sepsis complicated with acute kidney injury.

Potential role of TWIST1 and its methylation in bladder urothelial carcinoma.

Bladder urothelial carcinoma (BLCA), like other cancers, is strongly associated with genetic and epigenetic changes. TWIST1 is an epithelial-mesenchymal transition (EMT) promoter that has been linked to the development of many malignancies. It is still unclear, however, what role TWIST1 plays in BLCA, and the relationship between TWIST1 transcript levels and its promoter methylation and immune infiltration has been reported even less. This study aimed to reveal the potential role of TWIST1 promoter methylation-related changes in BLCA. Transcriptional expression data of TWIST1 in BLCA were acquired from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and University of Alabama at Birmingham (UALCAN) databases. TWIST1 methylation levels and prognosis were sourced from Gene Expression Profiling Interactive Analysis 2 (GEPIA2), LinkedOmics, cBio Cancer Genomics Portal (c-BioPortal), MethSurv, and DNA Methylation Information Visualization Database (DNMIVD) databases. The methylation status of the BLCA-associated TWIST1 in preoperative and postoperative urinary exfoliated cells was subsequently analyzed using methylation-specific real-time fluorescence polymerase chain reaction, with validation of accuracy through pyrophosphate sequencing. Finally, from the Gene Set Cancer Analysis (GSCA) and Tumor-Immune System Interaction Database (TISIDB) databases, we obtained the association between TWIST1 transcript expression and DNA methylation and cancer immune infiltration and immunolabelling. Our study demonstrated that TWIST1 expression was down-regulated in BLCA, which was negatively correlated with DNA methylation. The association between TWIST1 promoter hypermethylation and the progression, staging, grading, and recurrence of BLCA is highly significant. Furthermore, we revealed that hypermethylation of both the preoperative and postoperative TWIST1 promoters is useful as a biomarker for monitoring BLCA recurrence, particularly when considering the methylation status of specific CpG sites. Additionally, we observed that TWIST1 expression, promoter methylation, and immune infiltration immunoreactive markers correlated significantly in BLCA. We propose that TWIST1 holds great promise as a diagnostic and therapeutic target for BLCA, with the potential to influence tumor progression and patient prognosis through the regulation of immune cell infiltration. We hope these findings contribute valuable insights to the field of BLCA research.

ADAR1 could be a potential diagnostic target for intrauterine infection patients

Intrauterine infection (IUI) is mainly an ascending infection in which vaginal and cervical pathogens ascend to the uterus and can affect the fetus. Until now, there is still no effective diagnostic biomarker for IUI, such as chorioamnionitis (CAM) and funisitis (FUN). Deoxyribonucleic acid (DNA)/Ribonucleic acid (RNA) editing molecules such as apolipoprotein-B mRNA-editing complex (APOBEC) 3 families and Adenosine deaminase family acting on RNA (ADAR)1 were examined in chorioamniotic membranes and umbilical cord of 83 patient samples. Furthermore, Ureaplasma parvum induced ADAR1 was investigated in human HTR-8/SVneo EVT cell line. ADAR1 had a significantly higher area under the curve (AUC) (0.721 and 0.745) than other APOBEC3s or cytokines in CAM and FUN patients. In vitro, ureaplasma parvum was demonstrated to activate ADAR1 (p = 0.025) and reduce RIG-I, IRF3, IFN-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:{\\upalpha\\:}$$\\end{document}, and IFN-β expression in EVT cell line (p = 0.005, p = 0.010, p < 0.001, and p = 0.018, respectively). High expression of ADAR1 was strongly associated with CAM and FUN patients (multivariate analyses; p = 0.035 and p = 0.002). ADAR1 could be a potential diagnostic target for IUI, such as CAM and FUN patients.

HMAGEA2 as a potential diagnostic and therapeutic target for melanoma progression and metastasis.

The incidence of melanoma, a highly aggressive skin cancer, continues to increase worldwide, particularly among populations with lighter skin tones. The diagnostic challenge of melanoma lies in the absence of a distinctive clinical presentation, as its characteristics vary based on anatomical location, growth type, and histopathology. The melanoma-associated antigen (MAGE) gene family is differentially expressed in various human cancers, including melanoma. In this study, we explored the association between human MAGEA2 (hMAGEA2) expression and melanoma. Using a human melanoma tissue array, we confirmed that hMAGEA2 expression was higher in melanoma and metastatic melanoma than in normal tissues. Additionally, we used SK-MEL-5 and SK-MEL-28 cell lines to investigate the cellular and molecular mechanisms underlying melanoma progression and invasiveness. In SK-MEL-5 and SK-MEL-28 cells, hMAGEA2 overexpression accelerated cell proliferation. Conversely, the knockdown of hMAEGA2 reduced cell proliferation, colony formation, and migration significantly and induced arrest at the G2/M phase of the cell cycle. With respect to the molecular mechanism, the knockdown of hMAGEA2 decreased the phosphorylation of Akt, JNK, and p38 MAPK. Additionally, hMAGEA2 knockdown reduced tumor formation significantly at the in vivo level. Collectively, the robust correlation between hMAGEA2 and melanoma metastasis supports the potential utility of hMAGEA2 as both a diagnostic marker and novel therapeutic target for patients with melanoma metastasis.

Identification of Key Genes and Drug Recommendations in Diffuse Large B-Cell Lymphoma Based on Analysis of Glutathione-Related Genes

Background: Various malignancies can be efficiently combated by focusing on glutathione. It is unclear how glutathione-related genes link to diffuse large B-cell lymphoma (DLBCL). Methods: Clinical information was gathered from DLBCL patients, and differences in glutathione-related differentially expressed genes (DEGs) between DLBCL and healthy groups were found. Enrichment analysis was run on the DEGs associated with glutathione. We discovered hub genes in glutathione, confirmed hub genes’ capacity for diagnosis and function prediction, and estimated drug sensitivity. Immune microenvironmental variations between healthy and DLBCL people were assessed, and hub genes for transcription factor (TF) targeting and miRNAs were found. Results: The glutathione-related DEGs were linked to biological processes such as response to oxidative stress and response to xenobiotic stimulus, according to enrichment analysis. Out of DEGs associated with glutathione, six hub genes were chosen. In the DLBCL population, there was a notable upregulation of the six hub genes. All the genes’ AUC values in the diagnostic ability category were more than 0.7, showing strong hub gene diagnostic capacity. The DLBCL population had a high level of T-cell infiltration, according to immune infiltration analysis techniques. Similar activities, such as the cell cycle G2/M phase transition and the negative control of organelle formation, are demonstrated by gene function prediction for hub. According to drug sensitivity prediction, there was a favorable link between KPNA2 with pracinostat, BRCA1 with B-7100, and LEE-011. The gene KPNA2 was shown to be concurrently targeted by many miRNAs and TFs, according to the miRNA-gene-TF interaction network. Conclusion: The relationship between DLBCL and glutathione-related genes was uncovered by our research, and six glutathione genes were linked to DLBCL. These genes might be used as diagnostic biomarkers or targets for treatment for DLBCL patients.

Endometrial extracellular vesicles regulate processes related to embryo development and implantation in human blastocysts.

What is the transcriptomic response of human blastocysts following internalization of extracellular vesicles (EVs) secreted by the human endometrium? EVs secreted by the maternal endometrium induce a transcriptomic response in human embryos that modulates molecular mechanisms related to embryo development and implantation. EVs mediate intercellular communication by transporting various molecules, and endometrial EVs have been postulated to be involved in the molecular regulation of embryo implantation. Our previous studies showed that endometrial EVs carry miRNAs and proteins associated with implantation events that can be taken up by human blastocysts; however, no studies have yet investigated the transcriptomic response of human embryos to this EV uptake, which is crucial to demonstrate the functional significance of this communication system. A prospective descriptive study was performed. Primary human endometrial epithelial cells (pHEECs), derived from endometrial biopsies collected from fertile oocyte donors (n = 20), were cultured in vitro to isolate secreted EVs. Following EV characterization, Day 5 human blastocysts (n = 24) were cultured in the presence or absence of the EVs for 24 h and evaluated by RNA-sequencing. EVs were isolated from the conditioned culture media using ultracentrifugation, and characterization was performed using western blot, nanoparticle tracking analysis, and transmission electron microscopy. Human blastocysts were devitrified, divided into two groups (n = 12/group), and cultured in vitro for 24 h with or without previously isolated EVs. RNA-sequencing analysis was performed, and DESeq2 was used to identify differentially expressed genes (DEGs) (FDR < 0.05). QIAGEN Ingenuity Pathway Analysis was used to perform the functional enrichment analysis and integration with our recently published data from the pHEECs' EV-miRNA cargo. Characterization confirmed the isolation of EVs from pHEECs' conditioned culture media. Among the DEGs in blastocysts co-cultured with EVs, we found 519 were significantly upregulated and 395 were significantly downregulated. These DEGs were significantly enriched in upregulated functions related to embryonic development, cellular invasion and migration, cell cycle, cellular organization and assembly, gene expression, and cell viability; and downregulated functions related to cell death and DNA fragmentation. Further, the intracellular signaling pathways regulated by the internalization of endometrial EVs were previously related to early embryo development and implantation potential, for their role in pluripotency, cellular homeostasis, early embryogenesis, and implantation-related processes. Finally, integrating data from miRNA cargo of EVs, we found that the miRNAs carried by endometrial EVs targeted nearly 80% of the DEGs in human blastocysts. This is an in vitro study in which conditions of endometrial cell culture could not mimic the intrauterine environment. This study provides novel insights into the functional relevance of EVs secreted by the human endometrium, and particularly the role of EV-miRNA regulation on global transcriptome behavior of human blastocysts during early embryogenesis and embryo implantation. It provides potential biomarkers that could become useful diagnostic targets for predicting implantation success. This study was supported by the Spanish Ministry of Education through FPU awarded to M.S.-B. (FPU18/03735), Generalitat Valenciana through VALi+d Programme awarded to M.C.C.-G. (ACIF/2019/139), and Instituto de Salud Carlos III and cofounded by the European Social Fund (ESF) "Investing in your future" through the Miguel Servet Program (CP20/00120 [H.F.]; CP19/00149 [I.C.]). The authors have no conflicts of interest to disclose. N/A.

Monkeypox virus A29L protein as the target for specific diagnosis and serological analysis

The unexpected monkeypox (Mpox) outbreak has been reported in many non-endemic countries and regions since May 2022. The mutant strains of Mpox virus (MPXV) were found with higher infectivity and greater capability for sustained human-to-human transmission, posing a significant public health threat. MPXV A29L, a protein homolog of vaccinia virus (VACV) A27L, plays an important role in viral attachment to host cell membranes. Therefore, MPXV A29L is considered the diagnostic target and the potential vaccine candidate for eliciting neutralizing antibodies and protective immune responses. In response to the escalating Mpox outbreak, three monoclonal antibodies (mAbs) (2-9B, 3-8G, and 2-5H) targeting the different domains of MPXV A29L have been developed in the study. Among them, 2-5H is highly specific for MPXV A29L without exhibiting cross-reactivity with VACV A27L. The antibody pairing composed of 2-5H and 3-8G has been developed as the lateral flow immunochromatographic assay for specific detection of MPXV A29L. However, these three mAbs were unable to inhibit A29L binding to heparin column or prevent MPXV infection in the neutralization test assays. The results of the serological assays using the truncated A29L fragments as the antigens showed that the Mpox patient sera contained significantly lower levels of antibodies targeting the N-terminal 1–34 residues of A29L, suggesting that the N-terminal portion of A29L is less immunogenic upon natural infection.Key points• MAbs 2-9B, 3-8G, and 2-5H neither interrupted A29L binding to heparin nor neutralized MPXV.• The LFIA composed of 3-8G and 2-5H can specifically distinguish MPXV A29L from VACV A27L.• Mpox patient sera contained lower levels of antibodies targeting the N-terminal portion of A29L.

Unraveling the impact of miRNAs on gouty arthritis: diagnostic significance and therapeutic opportunities.

Gouty arthritis is a prevalent inflammatory illness. Gout attacks begin when there is an imbalance in the body's uric acid metabolism, which leads to urate buildup and the development of the ailment. A family of conserved, short non-coding RNAs known as microRNAs (miRNAs) can regulate post-transcriptional protein synthesis by attaching to the 3' untranslated region (UTR) of messenger RNA (mRNA). An increasing amount of research is pointing to miRNAs as potential players in several inflammatory diseases, including gouty arthritis. miRNAs may influence the progression of the disease by regulating immune function and inflammatory responses. This review mainly focused on miRNAs and how they contribute to gouty arthritis. It also looked at how miRNAs could be used as diagnostic, prognostic, and potential therapeutic targets.

Identification of key genes and immune infiltration of diabetic peripheral neuropathy in mice and humans based on bioinformatics analysis.

Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes, while the underlying molecular mechanisms are still unclear. The aim of this study was to screen the key genes and the roles of immune infiltration in DPN using bioinformatics analysis. DPN mice datasets including GSE222778, GSE11343, GSE70852, GSE27382, and GSE34889 were retrieved from the GEO database. Data of human DPN were retrieved from the dbGaP. The differentially expressed genes (DEGs) were selected and further analyzed by using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and Gene Set Enrichment Analysis (GSEA) to find the shared key pathway. Protein-protein interaction networks were built in shared mouse and human DEGs. The hub genes were selected and verified in vitro using high- glucose-treated PC12 cells and Schwann cells. The single-sample GSEA (ssGSEA) algorithm was used to analyze the proportions of infiltrating immune cells in human DPN and the subsequent correlations with hub genes. A total of 323 mouse DEGs and 501 human DEGs were selected, and they were found significantly enriched in immune-related biological functions and pathways. A total of 13 DEGs were found shared in mice and human DPN datasets, and among them, there were 7 hub genes, namely, PLAUR, S100A8, IL7R, CXCL13, SRPX2, CD300LB, and CFI. The expression of Cfi, S100a8, Cxcl13, and Cd300lb was consistently confirmed in vitro. The scores of neutrophils and NK CD56bright cells varied most significantly by immune cell infiltration analysis (p < 0.01). Furthermore, the selected hub genes were found to be highly correlated with the immune infiltration. Our study indicated the importance of immune dysregulations in DPN and identified several hub genes through combined analysis in mice and human DPN samples, thus providing potential diagnostic and therapeutic targets in the future.

DKK3 as a diagnostic marker and potential therapeutic target for sarcopenia in chronic obstructive pulmonary disease

Sarcopenia, characterized by the progressive loss of muscle mass and function, significantly affects patients with chronic obstructive pulmonary disease (COPD) and worsens their morbidity and mortality. The pathogenesis of muscle atrophy in patients with COPD involves complex mechanisms, including protein imbalance and mitochondrial dysfunction, which have been identified in the muscle tissues of patients with COPD. DKK3 (Dickkopf-3) is a secreted glycoprotein involved in the process of myogenesis. However, the role of DKK3 in the regulation of muscle mass is largely unknown. This study investigated the role of DKK3 in COPD-related sarcopenia. DKK3 was found to be overexpressed in cigarette smoking-induced muscle atrophy and in patients with COPD. Importantly, plasma DKK3 levels in COPD patients with sarcopenia were significantly higher than those without sarcopenia, and plasma DKK3 levels could effectively predict sarcopenia in patients with COPD based on two independent cohorts. Mechanistically, DKK3 is secreted by skeletal muscle cells that acts in autocrine and paracrine manners and interacts with the cell surface-activated receptor cytoskeleton-associated protein 4 (CKAP4) to induce mitochondrial dysfunction and myotube atrophy. The inhibition of DKK3 by genetic ablation prevented cigarette smoking‐induced skeletal muscle dysfunction. These results suggest that DKK3 is a potential target for the diagnosis and treatment of sarcopenia in patients with COPD.

Personality and Psychoneuroimmunology: A Systems Biology Perspective.

Research in psychoneuroimmunology (PNI) underscores the intricate connections within the "whole mind-body system." Personality plays a pivotal role, with specific traits linked to stress influencing neural behavior and psychophysiological disorders. Gene expression networks associated with personality affect neuronal plasticity, epigenetic processes, and adaptive behaviors, highlighting the importance of systems biology mechanisms. Systemic inflammation correlates with key personality traits. Understanding the roles of inflammatory and oxidative biomarkers in personality traits and disorders can help identify diagnostic and therapeutic targets for various diseases. Neurobiological features contribute to our understanding of personality disorders and related conditions. Personality traits are linked to distributed neuroendocrine networks, particularly the hypothalamic-pituitary-adrenal (HPA) axis, rather than localized brain areas. Correlations have also been identified between personality traits and thyroid hormones. Disrupted hypothalamic-pituitary-thyroid (HPT) axis functions may be associated with disease severity, depression, and distress, highlighting the need for comprehensive endocrinological and psychopathological evaluations. The gut-brain axis influences personality traits, emotions, stress, and social behaviors. Altered gut microbiota is common in psychiatric conditions, suggesting potential treatments targeting the microbiota. Chronic stress impacts cognitive functions and correlates with personality and mental health, emphasizing the need for comprehensive, multi-dimensional patient profiles for effective prevention and therapy. A biopsychosocial model integrating personality traits will advance personalized and systems medicine.

Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impair muscle function, ultimately resulting in a loss of ambulation. A thorough analysis of molecular factors associated with the varying degrees of muscle impairment in FSHD is still lacking. This study investigates the molecular mechanisms and biomarkers in the biceps brachii of FSHD patients, classified according to the FSHD clinical score, the A-B-C-D classification scheme, and global proteomic variation. Our findings reveal distinct metabolic signatures and compensatory responses in patients. In severe cases, we observe pronounced metabolic dysfunction, marked by dysregulated glycolysis, activation of the reductive pentose phosphate pathway (PPP), a shift toward a reductive TCA cycle, suppression of oxidative phosphorylation, and an overproduction of antioxidants that is not matched by an increase in the redox cofactors needed for their function. This imbalance culminates in reductive stress, exacerbating muscle wasting and inflammation. In contrast, mild cases show metabolic adaptations that mitigate stress by activating polyols and the oxidative PPP, preserving partial energy flow through the oxidative TCA cycle, which supports mitochondrial function and energy balance. Furthermore, activation of the hexosamine biosynthetic pathway promotes autophagy, protecting muscle cells from apoptosis. In conclusion, our proteomic data indicate that specific metabolic alterations characterize both mild and severe FSHD patients. Molecules identified in mild cases may represent potential diagnostic and therapeutic targets for FSHD.

CircFOXP1: a potential diagnostic and therapeutic target in human diseases.

Circular RNA (circRNA) are a unique class of non-coding RNAs characterized by their covalently closed loop structures, which grant them properties such as stability and conservation. Among these, circFOXP1 has been implicated in various diseases, including cancers, respiratory, skeletal, and cardiovascular disorders. This review systematically examines circFOXP1's role in disease progression, highlighting its involvement in critical biological processes, including cell proliferation, invasion, apoptosis, and autophagy. Mechanistically, circFOXP1 functions through miRNA sponging, protein interactions, and modulation of key signaling pathways such as Wnt and PI3K/AKT. We discuss its potential as a diagnostic and therapeutic target. Our analysis also identifies key unresolved questions, such as the precise regulatory networks involving circFOXP1 and its translation potential, offering pathways for future research.