Diagnostic Targets Research Articles

Partial deletion of the Akap1 gene promotes abnormalities in gut barrier function, gut microbiota composition and cardiac function during cardiovascular aging in mice

Abstract Background Cardiovascular aging is characterized by mitochondrial dysfunction, changes in intestinal permeability and microbiota composition. Mitochondria-targeted A-kinase anchoring proteins (mitoAKAPs) are a group of structurally diverse proteins binding the regulatory subunits of protein kinase A (PKA), and targeting PKA at discrete intracellular locations. We analyzed the effects of global partial genetic deletion of Akap1 on intestinal barrier permeability, microbiota composition, inflammation, and cardiac function during aging in mice. Purpose The proposal of this study was to determine the role of mitoAKAPs in the gut-heart axis during cardiovascular aging. Methods Young (4-6-month) and old (18-24-month) genetically modified Akap1+/+ and Akap1+/− mice of either sex underwent evaluation of cardiac function by transthoracic echocardiography. To evaluate gut barrier integrity, we analyzed expression levels of intestinal junction proteins occludin (Ocln), zonulin (Tjp1) in colonic samples and FITC-dextran permeability in vivo, circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha), Lipopolysaccharide (LPS), Interleukin-1 (IL-1) and Interleukin-10 (IL-10). Fecal microbial composition was evaluated by Illumina Mi-Seq, Gut microbiota differences based on 16S rDNA sequencing at genus and species taxonomic levels were identified using linear discriminant analysis (LDA) combined with effect size (LEfSe) algorithm. Finally, faecal microbiota transplantation (FMT) was performed for five weeks to test whether modification of gut microbiota composition can affect cardiac function. Results A reduction in % left ventricular shortening (FS%) was observed in young and old Akap1+/- mice compared to Akap1+/+ mice. This finding was associated to increased intestinal permeability, as indicated by reduced mRNA levels of Ocln and Tjp1, increased LPS traslocation across intestinal epitelium into blood in 24m Akap1+/- mice compared to Akap1+/+. Through the analysis of the microbial signature, we observed the different bacterial species present in the microbiota of the experimental groups. FMT of bacteria species from old Akap1+/− to young Akap1+/+ mice induced gut abnormalities and cardiac dysfunction, while FMT from young Akap1+/+ donors ameliorated cardiac dysfunction in old Akap1+/+ mice. Conclusions MitoAKAPs play a crucial role in the maintenance of intestinal barrier function, gut microbiota composition and cardiac function during aging. Modulation of the composition of the intestinal microbiota influences intestinal permeability and cardiac function. MitoAKAPs could represent an important diagnostic and therapeutic target for cardiac and intestinal dysfunction.

Renal Semaphorin 3C mediates cardiac adaptive response

Abstract Cardiorenal syndrome, characterized by reciprocal heart-kidney interactions that progressively promote dysfunction in both organs, is associated with a high mortality rate. However, the mechanisms linking the two organs are insufficiently understood. Here we report that semaphorin 3C (SEMA3C) is a novel cardioprotective mediator secreted from the kidney. SEMA3C was highly expressed in the renal proximal tubules in mice. Renal Sema3c expression and circulating SEM3C were reduced by the left ventricular pressure overload that induced renal remodeling. Proximal tubule-specific secretory Sema3c deletion exacerbated cardiac hypertrophy, fibrosis and dysfunction after the pressure overload, suggesting renal SEMA3C is important for the proper cardiac adaptive response. Mechanistically, SEMA3C inhibits pathological cardiac remodeling at least partly by inhibiting Akt, ERK and Wnt/β-catenin signaling in cardiomyocytes. In heart failure patients, the plasma SEMA3C level was decreased and the low plasma SEMA3C was associated with poor cardiac outcomes. Collectively, our results show that SEMA3C produced by the kidney pivotally contributes to the cardiac stress response and its reduction contributes to the progression of heart failure. SEMA3C signaling appears to be an attractive therapeutic and diagnostic target for cardiorenal syndrome.

Engineering exosomes from fibroblast growth factor 1 pre-conditioned adipose-derived stem cells promote ischemic skin flaps survival by activating autophagy

BackgroundThe recovery of ischemic skin flaps is a major concern in clinical settings. The purpose of this study is to evaluate the effects of engineered exosomes derived from FGF1 pre-conditioned adipose-derived stem cells (FEXO) on ischemic skin flaps. Method6 patients who suffered from pressure ulcer at stage 4 and underwent skin flaps surgery were recruited in this study to screen the potential targets of ischemic skin flaps in FGF family. FGF1 was co-incubated with adipose stem cells, and ultracentrifugation was applied to extract FEXO. Transcriptome sequencing analysis was used to determine the most effective microRNA in FEXO. Animal skin flaps models were established in our study to verify the effects of FEXO. Immunofluorescence (IF), western blotting (WB) and other molecular strategy were used to evaluate the effects and mechanism of FEXO. ResultsFGF1 was expected to be the therapeutic and diagnostic target of ischemic skin flaps, but there is still some deficiency in rescuing skin flaps. FEXO significantly improved the viability of RPSFs and endothelial cells by inhibiting oxidative stress and alleviating apoptosis and pyroptosis through augmenting autophagy flux. In addition, FEXO inhibited the over-activated inflammation responses. Transcriptome sequencing analysis showed that miR-183-5p was significantly elevated in FEXO, and inhibiting miR-183-5p resulted in impaired protective effects of autophagy in skin flaps. The exosomal miR-183-5p markedly enhanced cell viability, inhibited oxidative stress and alleviated apoptosis and pyroptosis in endothelial cells by targeting GPR137 through Pi3k/Akt/mTOR pathway, indicating that GPR137 could also be a therapeutic target of ischemic skin flap. It was also notabale that FGF1 increased the number of exosomes by upregulating VAMP3, which may be a promising strategy for clinical translation. ConclusionFEXO markedly improved the survivial rate of ischemic skin flaps through miR-183-5p/GPR137/Pi3k/Akt/mTOR axis, which would be a promising strategy to rescue ischemic skin flaps.

Immunohistochemical Localization of Fibroblast Activation Protein in Coronary Arteries with Different Forms of Atherosclerosis

Background: Fibroblast activation protein (FAP) is a cell surface glycoprotein expressed by myofibroblasts in areas of active tissue remodeling. It plays a potentially important role in cardiac remodeling, atherosclerotic plaque formation, and plaque rupture. Given the distinct pathophysiology and morphology of different forms of atherosclerosis, we analyzed FAP expression in human coronary vessels with no coronary artery disease, atherosclerotic plaques at different levels of progression, and other distinct forms of coronary disease in post bypass vein grafting and cardiac allograft vasculopathy after a heart transplant. Methods: Immunohistochemical staining with monoclonal F19 mouse anti-human FAP antibody was performed to identify FAP in human atherosclerotic plaques, coronary bypass atherosclerosis, and post-transplant arteriosclerosis. The presence and distribution of FAP in different types and stages of human atherosclerosis were compared. Results: There was no FAP staining in patients with no significant coronary disease. All different types of human atherosclerotic lesioning lesions showed the presence of FAP expression, with different staining patterns in advanced atherosclerotic plaque, vein graft atherosclerosis lesions, and arteriosclerosis after a heart transplant. Conclusions: These data suggest that FAP may be a potential diagnostic marker and target for interventions, not only in coronary atherosclerotic plaque, but also in other forms of coronary disease, which have distinct pathophysiologies and currently limited treatment options.

Dysregulation of the 3β-hydroxysteroid dehydrogenase type 2 enzyme and steroid hormone biosynthesis in chronic kidney disease.

Chronic kidney disease (CKD) presents a critical global health challenge, marked by the progressive decline of renal function. This study explores the role of the 3β-hydroxysteroid dehydrogenase type 2 enzyme (HSD3B2) and the steroid hormone biosynthesis pathway in CKD pathogenesis and progression. Using an adenine-induced CKD mouse model, we conducted an untargeted metabolomic analysis of plasma samples to identify key metabolite alterations associated with CKD. Immunohistochemistry, Western blotting, and qPCR analyses were performed to confirm HSD3B2 expression in both human and mouse tissues. Additionally, Nephroseq and Human Protein Atlas data were utilized to assess the correlation between HSD3B2 and kidney function. Functional studies were conducted on HK2 cells with HSD3B2 knockdown to evaluate the impact on cell proliferation and apoptosis. Metabolic characteristics revealed significant shifts in CKD, with 61 metabolites increased and 65 metabolites decreased, highlighting the disruption in steroid hormone biosynthesis pathways influenced by HSD3B2. A detailed examination of seven key metabolites underscored the enzyme's central role. HSD3B2 exhibited a strong correlation with kidney function, supported by data from Nephroseq and the Human Protein Atlas. Immunohistochemistry, Western blotting, and qPCR analyses confirmed a drastic reduction in HSD3B2 expression in CKD-affected kidneys. Suppressed proliferation and increased apoptosis rates in HSD3B2 knocked down HK2 cells further demonstrated the enzyme's significance in regulating renal pathophysiology. These findings underscore the potential of HSD3B2 as a clinical diagnostic and therapeutic target in CKD. While further studies are warranted to fully elucidate the mechanisms, our results provide valuable insights into the intricate interplay between steroid hormone biosynthesis and CKD. This offers a promising avenue for precision medicine approaches and personalized treatment strategies.

Dual Roles of microRNA-122 in Hepatocellular Carcinoma and Breast Cancer Progression and Metastasis: A Comprehensive Review

microRNA-122 (miR-122) plays crucial yet contrasting roles in hepatocellular carcinoma (HCC) and breast cancer (BC), two prevalent and aggressive malignancies. This review synthesizes current research on miR-122’s functions in these cancers, focusing on its potential as a diagnostic, prognostic, and therapeutic target. A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus databases. In HCC, miR-122 is downregulated in most cases, suppressing oncogenic pathways and reducing tumor growth and metastasis. Restoring miR-122 levels has shown promising therapeutic potential, increasing sensitivity to treatments like sorafenib. In contrast, in BC, miR-122 plays a pro-metastatic role, especially in triple-negative breast cancer (TNBC) and metastatic lesions. miR-122′s ability to influence key pathways, such as the Wnt/β-catenin and NF-κB pathways in HCC, and its role in enhancing the Warburg effect in BC underline its significance in cancer biology. miR-122, a key factor in breast cancer radioresistance, suppresses tumors in radiosensitive cells. Inhibiting miR-122 could reverse resistance and potentially overcome radiotherapy resistance. Given its context-dependent functions, miR-122 could serve as a potential therapeutic target, where restoring or inhibiting its expression may help in treating HCC and BC, respectively. The dual roles of miR-122 underscore its significance in cancer biology and its potential in precision medicine.

A photosensitive modification of recombinant Salmonella carrying shRNA-PD-L1 promotes host immunity against poorly immunogenic tumors

The tumor microenvironment (TME) exists as a hypoxic, non-inflammatory “cold” state, it is difficult for many drugs to target the aggregation and activation of the immune system. The attenuated facultative anaerobe Salmonella can be used as a tumor-targeting vector to overcome osmotic limitations and exhibit immune effects against the hypoxic characteristics of the tumor region, maximizing the diagnostic and therapeutic targeting. Here, we genetically modified the ΔphoPΔphoQ knockout strain of attenuated Salmonella enterica serovar typhimurium LH430 to carry programmed cell death ligand 1 (PD-L1) short hairpin RNA (shRNA) on a plasmid to solve the current problem of therapeutic antibodies targeting immune checkpoints in the clinic. In addition, combining the attenuated Salmonella with the photosensitizer IR780 not only allows the bacteria to aggregate and target hypoxia at the tumor site, but also the photothermal therapy for an effective tumor ablation. This approach provides a promising strategy for photothermal therapy and immunotherapy targeting deep-seated tumors.

Emerging roles of noncoding RNAs in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with limited treatment options and efficacy. Evidence suggests that IPF arises from genetic, environmental, and aging-related factors. The pathogenic mechanisms of IPF primarily involve dysregulated repeated microinjuries to epithelial cells, abnormal fibroblast/myofibroblast activation, and extracellular matrix (ECM) deposition, but thus far, the exact etiology remains unclear. Noncoding RNAs (ncRNAs) play regulatory roles in various biological processes and have been implicated in the pathophysiology of multiple fibrotic diseases, including IPF. This review summarizes the roles of ncRNAs in the pathogenesis of IPF and their potential as diagnostic and therapeutic targets.

Novel therapeutic targets for major depressive disorder related to oxidative stress identified by integrative multi-omics and multi-trait study.

Oxidative stress (OS) is strongly implicated in the pathophysiology of major depressive disorder (MDD) but the molecular mechanisms remain largely unknown. The purpose of this study is to identify genes related to both OS and MDD, and further to evaluate the utility of these genes as diagnostic markers and potential treatment targets. We searched datasets related to MDD from the Gene Expression Omnibus (GEO) database for differentially expressed genes (DEGs) also related to OS according to GeneCards. Bioinformatics analyses and machine learning algorithms were used to identify hub genes mediating OS-MDD interactions. A summary data-based Mendelian randomization (SMR) approach was employed to identify possible causal genes for MDD from blood tissue eQLT data. These investigations identified 32 genes mediating OS-MDD interactions, while SMR analysis identified KCNE1 (OR = 1.057, 95%CI = 1.013-1.102, P value = 0.010), MAPK3 (OR = 1.023, 95%CI = 1.004-1.043, P value = 0.020), and STIP1 (OR = 0.792, 95%CI = 0.641-0.979, P value = 0.031) as OS-related causal genes for MDD. These genes may thus serve as useful diagnostic markers and potential therapeutic targets.

Immunoregulatory role of AC007278.3 and HOTAIR long non-coding RNAs in lupus nephritis: potential biomarkers and therapeutic targets.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various biological processes, including immune regulation and autoimmune pathologies. However, their specific significance in modulating the cytokine network in systemic lupus erythematosus (SLE) remains largely unexplored. This study assessed the expression patterns of immune-related lncRNAs, HOTAIR, and AC007278.3, along with their related protein-coding genes, TNF-α and IL18RAP, in nephritic SLE patients. Additionally, the potential of selected genes as diagnostic biomarkers for SLE was evaluated. Blood samples were obtained from SLE patients (n = 30) and age-sex-matched healthy controls (HCs) (n = 60). Subsequently, RNA was isolated from peripheral blood mononuclear cells (PBMCs), and cDNA was synthesized to analyze the expression levels of the target genes using real-time PCR. The correlation analysis between the relative expressions of different genes was examined in both the patient and HC groups. The diagnostic potential of the lncRNAs was determined by calculating the Area Under the Curve of the Receiver Operating Characteristics (AUC of ROC), Cut-off, sensitivity, and specificity. Our results indicated a significant upregulation of lncRNAs AC007278.3 (fold change [FC] = 14.13, p-value < 0.0001) and HOTAIR (FC = 14.1, p-value < 0.0001). Correspondingly, their associated target genes, TNF-α and IL18RAP, were also overexpressed in patients (FC = 2.66 and FC = 5.18, respectively, p-value < 0.001). Notably, a strong positive correlation was observed between IL18RAP and AC007278.3 in SLE patients. Moreover, the AUC of ROC analyses underscored the diagnostic efficacy of AC007278.3 alone and combined with HOTAIR, yielding values of 0.89 and 0.86, respectively. These findings highlight the potential immunoregulatory roles of lncRNAs AC007278.3 and HOTAIR, emphasizing their significance as promising diagnostic biomarkers and potential therapeutic targets for SLE. Additionally, they provide valuable insights into the molecular mechanisms underpinning the disease's pathogenesis.

Blood Protein Ratios Reveal New Diagnostic Biomarkers for Prostate Cancer: A Study from the Perspective of Mendelian Randomization

Prostate cancer (PCa) is a leading malignancy affecting men globally, contributing significantly to cancer-related morbidity and mortality. Our study aims to explore causal relationships between blood protein ratios (BPR) and PCa using a Mendelian randomization (MR) approach, potentially identifying new diagnostic and therapeutic targets. Methods: A two-sample MR method was employed, utilizing genetic variants as instrumental variables (IVs) to infer causality between circulating BPR and PCa. Data on BPR were obtained from a proteomics study of the UK Biobank, while PCa data were sourced from FinnGen, the PRACTICLE Consortium, and the GWAS Catalog. Stringent criteria were applied for IV selection, and statistical analyses included the inverse-variance weighted (IVW) method with sensitivity analyses to address pleiotropy and heterogeneity. Results: Significant causal associations were identified between several BPR and PCa. Notably, the ratios of CEBPB/PXN, APBB1IP/NCF2, APP/EGF, and CRKL/ EGF were found to be protective against PCa, while the ratios of ARHGAP1/RAD23B, EGF/ TNFSF14, and GOLM2/STC1 were identified as risk factors. Reverse MR analysis suggested that PCa might act as a protective factor for the GOLM2/STC1 ratio. Sensitivity analyses confirmed the robustness of these findings. Conclusions: This study elucidates significant causal relationships between 7 BPR and PCa, offering new insights for diagnosis, treatment evaluation, and personalized therapeutic strategies. Future research should focus on validating these findings and exploring the underlying biological mechanisms to improve PCa management.

Impact of SCN10A Polymorphism on Abdominal Pain Perception and Visceral Hypoalgesia in Crohn's Disease and Ulcerative Colitis.

Hypoalgesic inflammatory bowel disease (IBD) may provide critical insights into human abdominal pain. This condition was previously associated with homozygosity for a polymorphism (rs6795970,A1073V;1073val/val) related to Nav1.8, a voltage-gated sodium channel preferentially expressed on nociceptors. It was unclear whether this relationship existed for both Crohn's disease (CD) and ulcerative colitis (UC). This study evaluated a larger, carefully phenotyped IBD cohort to investigate this question. Allelic and genotypic frequencies of rs6795970 were compared among study cohorts characterized by concomitant assessment of intestinal inflammatory status and abdominal pain experience. Visceral sensory perception was performed in healthy individuals using rectal balloon distension(RBD). We analyzed 416 IBD patients (261CD:155UC) and 142 healthy controls. In the IBD cohort, 84 individuals (43CD:41UC) were determined to have hypoalgesic disease. The allelic frequency of rs6795970 was significantly higher in hypoalgesic IBD patients when compared to other IBD patients and healthy controls. Hypoalgesic IBD patients were also more likely to be homozygous for this polymorphism when compared to other IBD patients and healthy controls. Hypoalgesic CD (30%vs.12%,p=0.004) and hypoalgesic UC (32%vs.15%,p=0.036) were each significantly more likely to be associated with homozygosity for the rs6795970 polymorphism. In a cohort of healthy individuals(n=50), rs6795970 homozygotes(n=11) also demonstrated reduced abdominal discomfort to RBD. These findings indicate that Nav1.8 plays a key role in human visceral pain perception, and could serve as a novel diagnostic target in the management of hypoalgesic CD and UC, and potential therapeutic target for conditions associated with chronic abdominal pain.

Potential liquid biopsy markers of exosomal microRNAs in renal interstitial fibrosis blood and urine

ABSTRACT Objective: To explore more and better liquid biopsy markers of exosomal microRNAs (exo-miRNAs) in renal interstitial fibrosis (RIF) and to preliminary investigate the biological functions and signaling pathways involved in these markers. MATERIALS AND METHODS: High-throughput miRNA sequencing was performed on blood and urine exo-miRNAs from three RIF patients and three healthy volunteers, and differential expression analysis and bioinformatic processing were performed. Results: There were 13 differentially expressed exo-miRNA (DEexo-miRNA) between RIF and healthy blood, and 20 DEexo-miRNAs in urine. These were various DEexo-miRNAs in different specimens, and the former included PC-3p-213532_58, hsa-miR-338-5p_R-1, PC-5p-34127_410, pal-miR-9993a-3p_L+2R-1, and hsa-miR-26a-1-3p with intermediate expression levels; the latter involved hsa-miR-126-3p, hsa-miR-217-5p, hsa-miR-199b-3p_R-1, mmu-miR-5106_R-4_1ss1AG, and PC-5p-39041_356, and others, while hsa-miR-378a-3p, hsa-miR-143-3p_R+1, hsa-miR-183-5p, hsa-miR-126-3p, hsa-miR-155-5p_R-1, mmu-miR-5106_R-4_1ss1AG, hsa-miR-126-5p, and hsa-miR-199b-3p_R-1 had high expression levels. Bioinformatics analysis of the up-regulated DEmiRNA with high expression in urine showed that there are 291 target corresponding mRNAs for six of eight DEexo-miRNAs, with mmu-miR-5106_R-4_1ss1AG and hsa-miR-199b-3p_R-1 having no target gene found in TargetScan and miRanda. GO annotation revealed that GO:0005515 (protein binding) had the lowest P value, involving the most genes. KEGG analysis revealed that the signaling included the mTOR signaling pathway, autophagy - animal, etc., and hsa05200 (pathways in cancer) had a lower P value, involving the most genes. Conclusions: Urine is a better sample for RIF exo-miRNA detection than blood. Urinary exosomal hsa-miR-143-3p_R+1, hsa-miR-183-5p, hsa-miR-126-3p, mmu-miR-5106_R-4_1ss1AG, hsa-miR-126-5p, and hsa-miR-199b-3p_R-1 are novel liquid biopsy markers for RIF. These DEexo-miRNA may be associated with the occurrence and development of RIF and may participate in specific biological processes by regulating the expression of their target mRNA. Further research may require exploring the specific functions and mechanisms of these miRNAs in RIF, as well as whether they can serve as diagnostic or therapeutic targets for RIF.

Association of aging related genes and immune microenvironment with major depressive disorder

ObjectiveTo study the relationship between aging related genes (ARGs) and Major Depressive Disorder (MDD). MethodsThe datasets GSE98793, GSE52790 and GSE39653 for MDD were obtained from the GEO database, and ARGs were obtained from the Human Aging Genome Resources database. Differential expression genes (DEGs) screening and GO, KEGG enrichment analysis were performed to uncover the underlying mechanisms. To identify key ARGs associated with MDD (key ARG-DEGs), we employed machine learning methods such as LASSO, SVM, and Random Forest, as well as the plug-ins CytoHubba-MCC and MCODE methods. SsGSEA was used to analyze the immune infiltration of MDD and healthy controls. Furthermore, we created risk prediction nomograms model and ROC curves to assess not only the ability of key ARG-DEGs to diagnose MDD, but also predicted miRNAs and transcription factors (TFs) that might interact. Finally, a two-sample Mendelian randomization (MR) study was performed to confirm the association of identified key ARG-DEGs with depression. ResultsDEGs of ARGs between MDD and healthy controls led to the identification of eight ARG-DEGs. GO and KEGG analysis revealed that the pathways associated with these eight ARG-DEGs were primarily concentrated in Foxo pathway, JAK-STAT pathway, Pl3K-AKT pathway, and metabolic diseases. A comprehensive analysis further narrowed down the 8 ARG-DEGs to 4 key ARG-DEGs: MMP9, IL7R, S100B, and EGF. Immune infiltration analysis indicated significant differences in CD8(+) T cells, macrophages, neutrophils, Th2 cells, and TIL cells between MDD and control groups, correlating with these four key ARG-DEGs. Based on these four key ARG-DEGs, a risk prediction model for MDD was developed. The miRNA-TF-mRNA interaction network of the key ARG-DEGs highlights the complexity of the regulatory process, providing valuable insights for future related research. The MR study suggested a potential causal relationship between MMP9 and the risk of depression. ConclusionThe process of aging, immune dysregulation, and MDD are closely interconnected. MMP9, IL7R, S100B, and EGF may be used as novel diagnostic biomarkers and potential therapeutic targets for MDD, especially MMP9.

Eight novel diagnostic markers differentiate lineages of the highly invasive myrtle rust pathogen Austropuccinia psidii.

Austropuccinia psidii is the causal agent of myrtle rust in over 480 species within the family Myrtaceae. Lineages of A. psidii are structured by their hosts in the native range, and some have success in infecting newly encountered hosts. For example, the pandemic biotype has spread beyond South America, and proliferation of other lineages is an additional risk to biodiversity and industries. Efforts to manage A. psidii incursions, including lineage differentiation, relies on variable microsatellite markers. Testing these markers is time-consuming, complex, and requires reference material that is not always readily available. We designed a novel diagnostic approach targeting eight selectively chosen loci including the fungal mating-type HD (homeodomain) transcription factor locus. The HD locus (bW1/2-HD1 and bE1/2-HD2) is highly polymorphic, facilitating clear biological predictions about its inheritance from founding populations. To be considered as potentially derived from the same lineage, all four HD alleles must be identical. If all four HD alleles are identical six additional markers can further differentiate lineage identity. Our lineage diagnostics relies on PCR amplification of eight loci in different genotypes of A. psidii followed by amplicon sequencing using Oxford Nanopore Technologies (ONT) and comparative analysis. The lineage-specific assay was validated on four isolates with existing genomes, uncharacterized isolates, and directly from infected leaf material. We reconstructed alleles from amplicons and confirmed their sequence identity relative to their reference. Genealogies of alleles confirmed the variations at the loci among lineages/isolates. Our study establishes a robust diagnostic tool for differentiating known lineages of A. psidii based on biological predictions and available nucleotide sequences. This tool is suited to detecting the origin of new pathogen incursions.

Unlocking the Potential of Circulating miRNAs as Biomarkers in Glioblastoma

Using microRNAs (miRNAs) as potential circulating biomarkers in diagnosing and treating glioblastoma (GBM) has garnered a lot of scientific and clinical impetus in the past decade. As an aggressive primary brain tumor, GBM poses challenges in early detection and effective treatment with significant current diagnostic constraints and limited therapeutic strategies. MiRNA dysregulation is present in GBM. The intricate involvement of miRNAs in altering cell proliferation, invasion, and immune escape makes them prospective candidates for identifying and monitoring GBM diagnosis and response to treatment. These miRNAs could play a dual role, acting as both potential diagnostic markers and targets for therapy. By modulating the activity of various oncogenic and tumor-suppressive proteins, miRNAs create opportunities for precision medicine and targeted therapies in GBM. This review centers on the critical role and function of circulating miRNA biomarkers in GBM diagnosis and treatment. It highlights their significance in providing insights into disease progression, aiding in early diagnosis, and potential use as targets for novel therapeutic interventions. Ultimately, the study of miRNA would contribute to improving patient outcomes in the challenging landscape of GBM management.

Long Non-coding RNAs: Potential Diagnostic and Treatment Targets for Non-small Cell Lung Cancer

Abstract: Lung cancer is the leading cause of cancer-related deaths globally, necessitating ongoing scientific research to understand its detection, treatment, and prevention. Long non-coding RNAs (lncRNAs) are a diverse group of non-coding RNAs that play crucial roles in regulating tumorigenic processes, such as cell proliferation, invasion, and metastasis in non-small cell lung cancer (NSCLC). Despite not encoding proteins, lncRNAs have significant impacts on the development and progression of NSCLC. Recent evidence suggests that lncRNAs may serve as valuable biomarkers for diagnosing and prognosticating NSCLC through tissue or blood analysis, and as potential therapeutic targets. This review provides a comprehensive overview of recent advancements in lncRNA research for NSCLC, offering new insights into their mechanisms of action and potential therapeutic applications. It also explores promising avenues for therapeutic development. By elucidating the complex roles of lncRNAs in NSCLC, this article aims to contribute to the development of innovative diagnostic and therapeutic strategies that can significantly enhance patient outcomes. Understanding the multifaceted functions of lncRNAs in lung cancer has the potential to lead to substantial progress in early disease detection, targeted treatments, and personalized medicine, ultimately improving the prognosis and quality of life for individuals affected by this devastating disease.

Unraveling Mitochondrial Reactive Oxygen Species Involvement in Psoriasis: The Promise of Antioxidant Therapies.

Psoriasis is a chronic inflammatory skin disorder characterized by immune dysregulation and aberrant keratinocyte proliferation. Despite tremendous advances in understanding its etiology, effective therapies that target its fundamental mechanisms remain necessary. Recent research highlights the role of reactive oxygen species dysregulation and mitochondrial dysfunction in psoriasis pathogenesis. Mitochondrial reactive oxygen species mediate cellular signaling pathways involved in psoriasis, such as proliferation, apoptosis, and inflammation, leading to oxidative stress, exacerbating inflammation and tissue damage if dysregulated. This review explores oxidative stress biomarkers and parameters in psoriasis, including myeloperoxidase, paraoxonase, sirtuins, superoxide dismutase, catalase, malondialdehyde, oxidative stress index, total oxidant status, and total antioxidant status. These markers provide insights into disease mechanisms and potential diagnostic and therapeutic targets. Modulating mitochondrial reactive oxygen species levels and enhancing antioxidant defenses can alleviate inflammation and oxidative damage, improving patient outcomes. Natural antioxidants like quercetin, curcumin, gingerol, resveratrol, and other antioxidants show promise as complementary treatments targeting oxidative stress and mitochondrial dysfunction. This review aims to guide the development of personalized therapeutic methods and diagnostic techniques, emphasizing the importance of comprehensive clinical studies to validate the efficacy and safety of these interventions, paving the way for more effective and holistic psoriasis care.

RGS22 maintains the physiological function of ependymal cells to prevent hydrocephalus.

Ependymal cells line the wall of cerebral ventricles and ensure the unidirectional cerebrospinal fluid (CSF) flow by beating their motile cilia coordinately. The ependymal denudation or ciliary dysfunction causes hydrocephalus. Here, we report that the deficiency of regulator of G-protein signaling 22 (RGS22) results in severe congenital hydrocephalus in both mice and rats. Interestingly, RGS22 is specifically expressed in ependymal cells within the brain. Using conditional knock-out mice, we further demonstrate that the deletion of Rgs22 exclusively in nervous system is sufficient to induce hydrocephalus. Mechanistically, we show that Rgs22 deficiency leads to the ependymal denudation and impaired ciliogenesis. This phenomenon can be attributed to the excessive activation of lysophosphatidic acid receptor (LPAR) signaling under Rgs22-/- condition, as the LPAR blockade effectively alleviates hydrocephalus in Rgs22-/- rats. Therefore, our findings unveil a previously unrecognized role of RGS22 in the central nervous system, and present RGS22 as a potential diagnostic and therapeutic target for hydrocephalus.

Dysregulated GLUT1 results in the pathogenesis of preeclampsia by impairing the function of trophoblast cells

Preeclampsia (PE) is a common placental-origin complication of pregnancy and a major cause of morbidity and mortality among pregnant women and fetuses. However, its pathogenesis has not been elucidated. Effective strategies for prevention, screening, and treatment are still lacking. Studies have indicated that dysfunction of placental trophoblast cells, such as impaired syncytialization, proliferation, and epithelial-mesenchymal transition processes, plays a crucial role in the development of PE. Glucose transporter 1 (GLUT1) is a key protein regulating glucose transport in placental tissues. However, the effect of GLUT1 on the function of trophoblast cells in PE is not well understood. In this study, we found that GLUT1 expression is reduced in PE placental tissues. GLUT1 promotes the syncytialization process by increasing the glucose uptake ability of BeWo cells. Additionally, GLUT1 promotes the proliferation, migration, and invasion capabilities of HTR-8/SVneo cells by regulating MAPK and PI3K/AKT signaling pathways. Overall, these findings provide a new insight into understanding the biological functions of GLUT1, clarifying the pathogenesis of PE, and identifying diagnostic and therapeutic targets for PE.