Pediatric asthma is a common respiratory condition in children, characterized by a complex interplay of environmental and genetic factors. Evidence shows that the airways of stimulated asthmatic patients have increased oxidative stress, but the exact mechanisms through which this stress contributes to asthma progression are not fully understood. Oxidative stress originates from inflammatory cells in the airways, producing significant amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS). External factors such as cigarette smoke, particulate matter, and atmospheric pollutants also contribute to ROS and RNS levels. The accumulation of these reactive species disrupts the cellular redox balance, leading to heightened oxidative stress, which activates cellular signaling pathways and modulates the release of inflammatory factors, worsening asthma inflammation. Therefore, understanding the sources and impacts of oxidative stress in pediatric asthma is crucial to developing antioxidant-based treatments. This review examines the sources of oxidative stress in children with asthma, the role of oxidative stress in asthma development, and the potential of antioxidants as a therapeutic strategy for pediatric asthma.
Phages have exerted severe evolutionary pressure on prokaryotes over billions of years, resulting in major rearrangements. Without every enzyme involved in the phage–bacterium interaction being examined; bacteriophages cannot be used in practical applications. Numerous studies conducted in the past few years have uncovered a huge variety of bacterial antiphage defense systems; nevertheless, the mechanisms of most of these systems are not fully understood. Understanding the interactions between bacteriophage and bacterial proteins is important for efficient host cell infection. Phage proteins involved in these bacteriophage–host interactions often arise immediately after infection. Here, we review the main groups of phage enzymes involved in the first stage of viral infection and responsible for the degradation of the bacterial membrane. These include polysaccharide depolymerases (endosialidases, endorhamnosidases, alginate lyases, and hyaluronate lyases), and peptidoglycan hydrolases (ectolysins and endolysins). Host target proteins are inhibited, activated, or functionally redirected by the phage protein. These interactions determine the phage infection of bacteria. Proteins of interest are holins, endolysins, and spanins, which are responsible for the release of progeny during the phage lytic cycle. This review describes the main bacterial and phage enzymes involved in phage infection and analyzes the therapeutic potential of bacteriophage-derived proteins.
The accurate diagnosis of regional lymph node metastasis is critical for guiding treatment decisions in head and neck cancer patients. Despite advances in imaging techniques, detecting nodal metastasis using radiology remains challenging, leading to potential undertreatment or overtreatment. This review aims to identify molecular markers associated with occult metastasis in head and neck squamous cell carcinoma (HNSCC) patients. We divided the results by subsite for markers: lymph node analysis (microRNAs, myosin-5a (MYO5A), ring finger protein 145 (RNF145), F-box only protein 32 (FBXO32), CTONG2002744, cytokeratin 14 (CK14), eukaryotic initiation factor 4E (eIF4E), desmoglein-3 (DSG3), microsatellite D9S171, squamous cell carcinoma antigen, cytokeratin, tumor budding score, human papillomavirus-DNA (HPV-DNA), tumor infiltrating lymphocytes, sentinel lymph node analysis techniques, single fiber reflectance spectroscopy, radiological techniques), tumor tissue analysis (activin A, carcinoma-associated fibroblasts, cyclins, β-catenin, histopathology, genetic amplifications, DNA methylation, ecotropic viral integration site 1, CC-chemokine receptor 7, melanoma associated-A antigens, vascular endothelial growth factor-C (VEGF-C), panitumumab, epidermal growth factor receptor (EGFR), cornulin, total protein analysis, CD133, NANOG homeobox, neurogenic locus notch homolog protein 1 (NOTCH1), metastasis-associated protein 1, 14-3-3-zeta, E-cadherin, focal adhesion kinase, p-epithelial-mesenchymal transition (EMT), small proline rich protein 1B (SPRR1B), transcription factor NKX3-1, DNA copy number aberrations, microfibril-associated protein 5 (MFAP5), troponin C1, slow skeletal and cardiac type (TNNC1), matrix Gla protein (MGP), fibroblast growth factor binding protein 1 (FBFBP1), F-box protein 32 (FBXO32), fatty acid binding protein 5, B cell-specific Moloney murine leukemia virus integration site 1, podoplanin, p53, Bcl-2, epidermal growth factor receptor (EGFR), Ki67, cyclin D1, cox-2, semaphorin-3F, neuropilin-2, histologic features, cellular dissociation grade, prospero homeobox protein 1, radiologic features, Ki-67, poly (ADP-ribose) polymerase (PARP), Bcl-2 associated agonist of cell death (BAD), caspase-9, vascular endothelial growth factor A (VEGF-A), HPV, p16, methylation status of long interspersed element 1 (LINE-1) and Alu elements, mesenchymal-epithelial transition (MET), gene expression analyses, molecular subtypes) and blood markers (standard blood analysis indexes and ratios, circulating tumor cells, HPV-DNA, CD-31, bone marrow analysis). Several promising markers were identified, including miR-205, desmoglein 3 (DSG3), pan-cytokeratin (CK) AE1/AE3, HPV-16, activin-A, cyclin D1, E-cadherin, and neural progenitor lineage (NPL) that demonstrated effectiveness across multiple studies. Future research should focus on exploring combination scoring systems to improve diagnostic precision and optimize treatment selection in HNSCC patients.
Over the past decade, new technologies have emerged to increase intrinsic potency, enhance bioavailability, and improve targeted delivery of drugs. Most pharmaceutical formulations require multiple dosing due to their fast release and short elimination kinetics, increasing the risk of adverse events and patient non-compliance. Due to these limitations, enormous efforts have focused on developing drug delivery systems (DDSs) for sustained release and targeted delivery. Sustained release strategies began with pioneering research using silicone rubber embedding for small molecules and non-inflammatory polymer encapsulation for proteins or DNA. Subsequently, numerous DDSs have been developed as controlled-release formulations to deliver systemic or local therapeutics, such as small molecules, biologics, or live cells. In this review, we discuss the latest developments of DDSs, specifically nanoparticles, hydrogels, and microgrippers for the delivery of systemic or localized drugs to the gastrointestinal (GI) tract. We examine innovative DDS design and delivery strategies tailored to the GI tract’s unique characteristics, such as its extensive length and anatomical complexity, varying pH levels and enzymatic activity across different sections, and intrinsic peristalsis. We particularly emphasize those designed for the treatment of inflammatory bowel disease (IBD) with in vivo preclinical studies.
Dental follicle cells (DFCs) are dental stem cells that can only be obtained from tooth germs or after extraction of unerupted wisdom teeth. For many years, DFCs have been studied in basic research and preclinical studies in regenerative dentistry, as they are involved in both the development of the periodontium and tooth eruption. Since the first isolation, the number of studies with DFCs has increased. This article summarizes the most important articles of the last five years to provide an overview of current research topics. The focus was on basic research and preclinical research. Basic research includes articles on tooth development and tooth eruption, as well as research into molecular mechanisms during osteogenic differentiation. In addition, articles on preclinical research with DFCs focused on regenerative therapies and immunotherapies are also discussed. These new studies show that DFCs have improved our understanding of periodontal development and regeneration. DFC research is important for the regenerative dentistry of the future; however, preclinical studies indicate that significant progress is still needed before DFCs can be integrated into routine clinical practice.
The expression profiles and function of exosomal long RNAs (exoLRs) in ischemic stroke remain unknown. This study aimed to investigate the pathophysiologic responses reflected by exoLRs.
The expression profile of exosomal messenger RNA, long non-coding RNA and circular RNA in 9 patients with ischemic stroke and 12 healthy individuals were analyzed by sequencing. We assessed the immune cell landscape to reveal the pathophysiologic responses reflected by exoLRs and performed biological process and pathway enrichment analyses. Competing endogenous RNA networks were constructed to explore the molecular functions of exoLRs.
A total of 321 up- and 187 down-regulated messenger RNAs, 31 up- and 9 down-regulated long non-coding RNAs, and 67 up- and 48 down-regulated circular RNAs were identified. The immune cell landscape analysis identified that the proportions of exhausted and gamma delta T cells were statistically higher in patients with ischemic stroke. Bioinformatics analyses, including enrichment and competing endogenous RNA network analyses, also indicated that exoLRs were associated with T- cell-mediated inflammatory responses.
The expression patterns of exoLRs highlighted the association between ischemic stroke and inflammatory responses mediated by T cells.
Metastasis is a major cause of prostate cancer (PCa)-related deaths in men. Recent studies have indicated that VGF nerve growth factor inducible (VGF) affects tumor invasion and metastasis. The present study investigated whether VGF is abnormally expressed in PCa and affects PCa progression and investigated the specific regulatory mechanisms by which VGF affects PCa invasion and metastasis.
The sh- hypoxia-inducible factor1 alpha (HIF-1α) plasmid was transfected into human cell lines 22Rv1 and C4-2 to create cell lines with stable low expression and overexpression of VGF. Quantitative PCR (qPCR) was performed to detect VGF mRNA. Western blot was performed to detect invasive migration-related proteins. Akt activator SC79 (4 μg/mL) was added. After adding docetaxel (4 nM) to cells transfected with sh-NC and sh-VGF, the capacity of the cells to migrate invasively was assessed using the Transwell and scratch assays. Nude mice were injected with cells stably transfected with sh-NC or sh-VGF and the metastasis of the cancer cells was detected by live imaging and HE staining after the injection of docetaxel (10 mg/kg).
Abnormal levels of VGF in PCa tissue and plasma samples were detected, and VGF knockdown suppressed PCa metastasis. VGF was also shown to affect the invasion and metastasis of PCa cells via PI3K/Akt signaling. VGF knockdown limited PCa metastasis and the inhibitory impact was higher when paired with docetaxel (p < 0.001). After hypoxia induction, both the mRNA and protein levels of VGF and HIF-1α increased, which is associated with a poor prognosis for PCa.
By stimulating the PI3K/Akt pathway, VGF encourages the invasive metastasis of PCa. As a result, targeting VGF may be a potential treatment approach for metastatic PCa therapy.
Infectious diseases caused by fungi, viruses, or bacteria can have a profound impact on human cognition. This can be due to either direct spread to the central nervous system (CNS) or indirect neuroinflammation. Ultimately causing neuronal damage and even neurodegeneration. Deteriorations in cognition, such as poor encoding and attention deficits, have been reported secondary to infectious diseases. Preclinical studies have identified the underlying mechanisms of these infection-related cognitive effects, such as through blood-brain barrier (BBB) disruption and M1 microglial polarization. These mechanisms are spearheaded by inflammatory markers that are released/initiated by the pathogens over the course of the infection. Among them, the high mobility group box 1 (HMGB1) protein is a common biomarker implicated across several infection-related cognitive deficits. Understanding these effects and mechanisms is crucial for the development of strategies to prevent and treat infection-related cognitive impairment. This review will thus consolidate and elucidate the current knowledge on the potential role of HMGB1 as a therapeutic target for infection-related cognitive impairments. This review will not only advance scientific understanding but also have significant clinical and public health implications, especially considering recent global health challenges. Based on the selected articles, extracellular HMGB1, as opposed to intracellular HMGB1, acts as damage-associated molecular patterns (DAMPs) or alarmins when released in the peripheries secondary to inflammasome activation. Due to their low molecular weight, they then enter the CNS through routes such as retrograde transport along the afferent nerves, or simple diffusion across the impaired BBB. This results in further disruption of the brain microenvironment due to the dysregulation of other regulatory pathways. The outcome is structural neuronal changes and cognitive impairment. Given its key role in neuroinflammation, HMGB1 holds promise as both a biomarker for diagnostic detection and a potential therapeutic target candidate for preventing infection-related cognitive impairment.
Alzheimer’s disease (AD) is the most prevalent cause of dementia and a significant contributor to health issues and mortality among older individuals. This condition involves a progressive deterioration in cognitive function and the onset of dementia. Recent advancements suggest that the development of AD is more intricate than its underlying brain abnormalities alone. In addition, Alzheimer’s disease, metabolic syndrome, and oxidative stress are all intricately linked to one another. Increased concentrations of circulating lipids and disturbances in glucose homeostasis contribute to the intensification of lipid oxidation, leading to a gradual depletion of the body’s antioxidant defenses. This heightened oxidative metabolism adversely impacts cell integrity, resulting in neuronal damage. Pathways commonly acknowledged as contributors to AD pathogenesis include alterations in synaptic plasticity, disorganization of neurons, and cell death. Abnormal metabolism of some membrane proteins is thought to cause the creation of amyloid (Aβ) oligomers, which are extremely hazardous to neurotransmission pathways, especially those involving acetylcholine. The interaction between Aβ oligomers and these neurotransmitter systems is thought to induce cellular dysfunction, an imbalance in neurotransmitter signaling, and, ultimately, the manifestation of neurological symptoms. Antioxidants have a significant impact on human health since they may improve the aging process by combating free radicals. Neurodegenerative diseases are currently incurable; however, they may be effectively managed. An appealing alternative is the utilization of natural antioxidants, such as polyphenols, through diet or dietary supplements, which offer numerous advantages. Within this framework, we have extensively examined the importance of oxidative stress in the advancement of Alzheimer’s disease, as well as the potential influence of antioxidants in mitigating its effects.
The term inherited retinal dystrophies (IRDs) refers to a diverse range of conditions characterized by retinal dysfunction, and mostly deterioration, leading to a gradual decay of the visual function and eventually to total vision loss. IRDs have a global impact on about 1 in every 3000 to 4000 individuals. However, the prevalence statistics might differ significantly depending on the exact type of dystrophy and the demographic being examined. The cellular pathophysiology and genetic foundation of IRDs have been extensively studied, however, knowledge regarding associated refractive errors remain limited. This review aims to clarify the cellular and molecular processes that underlie refractive errors in IRDs. We did a thorough search of the current literature (Pubmed, accession Feb 2024), selecting works describing phenotypic differences among genes-related to IRDs, particularly in relation to refractive errors. First, we summarize the wide range of IRDs and their genetic causes, describing the genes and biological pathways connected to the etiology of the disease. We then explore the complex relationship between refractive errors and retinal dysfunction, including how the impairment of the vision-related mechanisms in the retina can affect ocular biometry and optical characteristics. New data about the involvement of aberrant signaling pathways, photoreceptor degeneration, and dysfunctional retinal pigment epithelium (RPE) in the development of refractive errors in IRDs have been examined. We also discuss the therapeutic implications of refractive defects in individuals with IRD, including possible approaches to treating visual impairments. In addition, we address the value of using cutting-edge imaging methods and animal models to examine refractive errors linked to IRDs and suggest future lines of inquiry for identifying new targets for treatment. In summary, this study presents an integrated understanding of the cellular and molecular mechanisms underlying refractive errors in IRDs. It illuminates the intricacies of ocular phenotypes in these conditions and offers a tool for understanding mechanisms underlying isolated refractive errors, besides the IRD-related forms.
Polycystic ovary syndrome (PCOS) is a prevalent gynecological endocrine and metabolic disorder in women, with an incidence rate of 10–13%. The etiology of PCOS is multifaceted, involving genetic predisposition, environmental influences, lifestyle factors, and endocrine metabolic dysregulation. Iron, a critical mineral, not only plays a role in regulating female physiological functions and the progression of PCOS but also requires careful management to avoid deficiency. However, excess iron can trigger ferroptosis, a form of nonapoptotic cell death characterized by the accumulation of lipid peroxides. While numerous studies have explored ferroptosis in patients with PCOS and animal models, the precise mechanisms and therapeutic implications remain inadequately understood. This review seeks to elucidate the pathophysiology of PCOS and the contributory factors of ferroptosis. Additionally, we examine the diverse manifestations of ferroptosis in PCOS and evaluate its role. Furthermore, we introduce ferroptosis-related traditional Chinese medicines that may enhance the understanding of PCOS pathogenesis and aid in the development of targeted therapies for ferroptosis in PCOS.
Hypertrophic cardiomyopathy (HCM) is a hereditary disease of the myocardium characterized by asymmetric hypertrophy (mainly the left ventricle) not caused by pressure or volume load. Most cases of HCM are caused by genetic mutations, particularly in the gene encoding cardiac myosin, such as MYH7, TNNT2, and MYBPC3. These mutations are usually inherited autosomal dominantly. Approximately 30–60% of HCM patients have a family history of similar cases among their immediate relatives. This underscores the significance of genetic factors in the development of HCM. Therefore, we summarized the gene mutation mechanisms associated with the onset of HCM and potential treatment directions. We aim to improve patient outcomes by increasing doctors’ awareness of genetic counseling, early diagnosis, and identification of asymptomatic patients. Additionally, we offer valuable insights for future research directions, as well as for early diagnosis and intervention.
Gliomas are aggressive brain tumors known for their poor prognosis and resistance to standard treatment options. Ferroptosis is an iron-dependent form of regulated cell death that has emerged as a promising target for cancer treatment. This study examined how the methyltransferase-like 3/YTH domain family protein 1 (METTL3/YTHDF1) axis influences ferroptosis and glioma progression by stabilizing mitochondrial carrier homolog 2 (MTCH2) messenger RNA (mRNA).
MTCH2 expression in glioma tissues and cell lines was evaluated through quantitative real-time polymerase chain reaction (PCR) and western blot analyses. To assess the effects of MTCH2 knockdown and overexpression on glioma cell functions, we performed a series of functional assays, including cell viability, colony formation, and measurements of lipid reactive oxygen species (lipid ROS) and malondialdehyde (MDA) levels. Additionally, we conducted RNA immunoprecipitation (RIP) and RNA stability assays to explore the underlying mechanisms governing the interaction between METTL3, YTHDF1, and the stability of MTCH2 mRNA.
MTCH2 was significantly upregulated in glioma tissues and cell lines. Silencing of MTCH2 resulted in decreased glioma cell proliferation and induced ferroptosis, as evidenced by increased lipid peroxidation and ROS accumulation. Conversely, overexpression of MTCH2 enhanced glioma cell survival and reduced ferroptosis. METTL3-mediated N6-methyladenosine (m6A) modification enhanced MTCH2 mRNA stability by enabling YTHDF1 to bind and protect the modified mRNA from degradation.
The METTL3/YTHDF1/MTCH2 axis plays a critical role in glioma progression by inhibiting ferroptosis and promoting tumor cell survival. Targeting this pathway may provide a new and effective treatment strategy for glioma patients.
A number of association studies have linked ribosomal DNA gene copy number (rDNA CN) to aging and pathology. Data from these studies are contradictory and depend on the quantitative method.
The hybridization technique was used for rDNA quantification in human cells. We determined the rDNA CN from healthy controls (HCs) and patients with schizophrenia (SZ) or cystic fibrosis (CF) (total number of subjects N = 1124). For the first time, rDNA CN was quantified in 105 long livers (90–101 years old). In addition, we conducted a joint analysis of the data obtained in this work and previously published by our group (total, N = 3264).
We found increased rDNA CN in the SZ group (534 ± 108, N = 1489) and CF group (567 ± 100, N = 322) and reduced rDNA CN in patients with mild cognitive impairment (330 ± 60, N = 93) compared with the HC group (422 ± 104, N = 1360). For the SZ, CF, and HC groups, there was a decreased range of rDNA CN variation in older age subgroups compared to child subgroups. For 311 patients with SZ or CF, rDNA CN was determined two or three times, with an interval of months to several years. Only 1.2% of patients demonstrated a decrease in rDNA CN over time. We did not find significant rDNA CN variation in eight different organs of the same patient or in cells of the same fibroblast population.
The results suggest that rDNA CN is a relatively stable quantitative genetic trait statistically associated with some diseases, which however, can change in rare cases under conditions of chronic oxidative stress. We believe that age- and disease-related differences between the groups in mean rDNA CN and its variance are caused by the biased elimination of carriers of marginal (predominantly low) rDNA CN values.
This review presents a comprehensive overview of single-cell RNA sequencing (scRNA-seq) analyses used to study tooth and periodontal tissues. The intricate cellular composition of both teeth and periodontium are revealed, leading to the identification of new cell types and tracing lineage profiles for each cell type. Herein, we summarize the progression of dental and periodontal tissue formation, tooth homeostasis, and regenerative mechanisms. scRNA-seq analyses have demonstrated that the cellular constituent ratio of dental and periodontal tissues transforms homeostasis or injury repair. Importantly, single-cell data in the diseased tissue demonstrated a change in both cell types and intercellular communication patterns compared to the normal state. These findings provide valuable insights into the underlying disease mechanisms at the cellular level in the context of single-cell vision, thereby facilitating the investigation of potential therapeutic interventions.
Enhanced cardiac sympathetic activity contributes to chronic heart failure (CHF). Interventions targeting the stellate ganglion (SG) can reduce this activity, potentially slowing the progression of cardiovascular diseases. This study examined the effects and mechanisms of stellate ganglionectomy on myocardial hypertrophy and cardiac dysfunction caused by pressure overload.
A rat model of pressure overload was created using abdominal aortic constriction. Four groups were studied: the sham surgery, abdominal aortic coarctation (AB), aortic constriction plus left stellate ganglionectomy (LSG), and aortic constriction plus right stellate ganglionectomy (RSG) groups. Cardiac function was assessed via echocardiography, and myocardial hypertrophy and fibrosis were evaluated using hematoxylin-eosin staining (H&E) and Masson staining. Serum atrial natriuretic peptides (ANP) and norepinephrine (NE) levels were measured using enzyme linked immunosorbent assay (ELISA), and the levels of the molecular markers tyrosine hydroxylase (TH) and growth-associated protein-43 (GAP43) were analyzed using Western blotting and PCR. Calcium calmodulin dependent protein kinase II (CaMKII) and phosphorylated Ryanodine Receptor 2 (p-RyR2) expression were also investigated.
Stellate ganglionectomy significantly reduced myocardial hypertrophy and improved cardiac function, as indicated by decreased left ventricular posterior wall thickness (LVPWD) (p < 0.01), left ventricular end-diastolic diameter (LVEDD) and volume (p < 0.001), left ventricular end-diastolic volume (LVEDV) (p < 0.001), increased left ventricular ejection fraction (LVEF) (p < 0.001) and left ventricular fractional shortening (LVFS) (p < 0.001). Histological analysis confirmed reduced myocardial dilation. Molecular analysis revealed decreased CaMKII/RyR2 signaling (p < 0.001) and lower NE levels (p < 0.01), suggesting reduced neurohormonal stress.
Stellate ganglionectomy alleviates hypertrophy and cardiac dysfunction caused by pressure overload, likely through inhibition of the CaMKII/RyR2 pathway, underscoring its potential as a therapeutic approach.
Dysregulated metabolic pathways, including glycolysis and a compromised DNA damage response (DDR), are linked to the progression of colorectal cancer (CRC). The mitotic arrest deficient-like 2 (MAD2L2) and aurora kinase B (AURKB) genes play roles in cell cycle regulation and the DDR, making them potential targets for CRC therapy.
Differential expression analysis was performed using The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) and GSE47074 datasets. A predictive model was established, and gene expression levels were further analyzed. The Gene Expression Profiling Interaction Analysis database and co-immunoprecipitation experiments assessed the correlation between AURKB and MAD2L2. Knockdown experiments in CRC cell lines further investigated the role of AURKB, followed by analyses of cell behavior, oxidative stress, glycolysis, DDR, and interaction with MAD2L2.
The risk model identified six prognostic genes (BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), AURKB, aurora kinase A (AURKA), exonuclease 1 (EXO1), topoisomerase II alpha (TOP2A), cyclin A2 (CCNA2)) associated with CRC, which were significantly expressed in tumor samples from the TCGA-COAD and GSE47074 datasets. In vitro assays confirmed that AURKB knockdown inhibited CRC cell behavior, induced G1 cell cycle arrest, and increased oxidative stress and apoptosis. AURKB knockdown also impaired glycolysis, reducing lactate production, glucose uptake, and ATP levels. Overexpression of MAD2L2 partially reversed these effects, restored glycolytic activity, and mitigated the cell cycle arrest and DDR caused by AURKB knockdown.
AURKB regulates CRC progression by modulating glycolysis and DDR pathways. Targeting the AURKB-MAD2L2 axis offers a promising therapeutic strategy for disrupting fundamental metabolic and DNA repair mechanisms in CRC.
Salsolinol (SAL) is a dopamine metabolite and endogenous neurotoxin that exerts neurotoxicity to dopaminergic neurons and is involved in the genesis of Parkinson’s disease (PD). However, the machinery underlying SAL-induced neurotoxicity in PD is still being elucidated.
In the present study, we first used RNA-seq and KEGG analysis to examine differentially expressed genes in SAL-challenged SH-SY5Y cells. PD animal models were established and treated with acteoside. Cell viability assays, lipid peroxidation assessments (malondialdehyde [MDA] and 4-Hydroxynonenal [4-HNE]), immunoblot, and transmission electron microscopy were used to confirm acteoside-mediated inhibition of ferroptosis and its neuroprotective effect on dopaminergic (DA) neurons.
We found that ferroptosis-related pathway was enriched by SAL. SAL inducing ferroptosis through upregulating long-chain acyl-CoA synthetase family member 4 (ACSL4) in SH-SY5Y cells, which neurotoxic effect was reversed by ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO). Acteoside, a phenylethanoid glycoside of plant origin with a neuroprotective effect, attenuates SAL-induced neurotoxicity by inhibiting ferroptosis in in vitro and in vivo PD models through downregulating ACSL4.
The present study revealed a novel molecular mechanism underlying SAL-induced neurotoxicity via induction of ferroptosis in PD, and uncovered a new pharmacological effect against PD through inhibiting ferroptosis. This study highlights SAL-induced neurotoxicity via ferroptosis as a potential therapeutic target in PD.
N-acetyltransferase 10 (NAT10) mediates N4-acetylcytidine (ac4C) mRNA modification and promotes malignant tumor progression. However, there has been limited research on its role in cervical cancer. This study aimed to decipher the role of NAT10 in cervical cancer.
The prognostic value of NAT10 was explored using the cancer genome atlas (TCGA) database and immunohistochemistry of cervical cancer tissue. The biological actions of NAT10 in cervical cancer were investigated by cell proliferation, transwell, wound healing, and chicken chorioallantoic membrane assays. The therapeutic action of remodelin (a NAT10 inhibitor) was verified in a nude mouse model. Mechanistic analyses were conducted by RNA sequencing, ac4C dot blotting, acetylated RNA immunoprecipitation, quantitative PCR, and RNA stability experiments.
NAT10 was overexpressed in cervical carcinoma and its overexpression was associated with poor prognosis. NAT10 knockout impaired proliferative and metastatic potentials of cervical cancer cells, while its overexpression had the opposite effects. Remodelin impaired cervical cancer proliferation in vivo and in vitro. NAT10 acetylated solute carrier family 7 member 5 (SLC7A5) enhanced mRNA stability to regulate SLC7A5 expression.
NAT10 exerts a critical role in cervical cancer progression via acetylating SLC7A5 mRNA and could represent a key prognostic and therapeutic target in cervical cancer.
The neuropeptide B/W signalling system (NPB/W) has been identified in multiple body regions and is integral to several physiological processes, including the regulation of food intake and energy homeostasis. Recently, it has also been detected in human skin; however, its specific functions in this context remain to be thoroughly investigated. This study aims to identify the expression of neuropeptides B/W receptor 1 (NPBWR1) and neuropeptides B/W receptor 2 (NPBWR2) in human dermal fibroblasts of mesenchymal origin using genomic and proteomic techniques. We will also investigate the role of these receptors in cell proliferation and calcium signalling.
The mRNAs for NPBWR1 and NPBWR2 were detected using quantitative PCR (qPCR) analysis and further validated by western blot and immunofluorescence analyses. Additionally, we synthesised ligands for these receptors, specifically hNPB (25–53) and hNPW (33–62), to investigate their effects on cell proliferation and intracellular calcium levels in human fibroblasts.
Our results demonstrated that hNPW (33–62) has anti-proliferative effect on human dermal fibroblasts and concentration of 0.1-μmol/L can significantly decrease intracellular calcium levels (p < 0.05).
This finding suggests a potential role for the NPB/W signalling system in pathologies associated with impaired calcium handling, such as fibrosis. Furthermore, we observed that the proliferation of human fibroblasts was not affected by hNPB (25–53). Our findings could lead to the development of new therapeutic strategies for various skin conditions and improved wound healing.
Vascular smooth muscle cells(VSMCs) phenotypic switching under hyperglycemic conditions accelerates atherosclerotic progression. Notch receptor 3(NOTCH3), a critical stabilizer of VSMC homeostasis implicated in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) pathogenesis, ensures vascular integrity; however, its interplay with RAN Binding Protein 1(RANBP1) during pathological hyperglycemia remains uncharacterized. We hypothesize that hyperglycemia-induced autophagic dysregulation is mechanistically governed by theNotch receptor 3 (NOTCH3)/RANBP1 axis, proliferative capacity, and apoptotic signaling in high glucose (HG)-stimulated VSMCs. The aim of this study was to elucidate the regulatory mechanisms of autophagy in VSMCs under HG conditions, with a focus on the NOTCH3/RANBP1 axis and its implications for vascular health.
Bioinformatics analysis was performed on NOTCH3 sequencing data, including weighted gene co-expression network analysis (WGCNA), screening of differentially expressed genes (DEGs), and construction of a protein-protein interaction (PPI) network, to identify the key gene, RANBP1. In vitro experiments, including cell counting kit-8 (CCK-8) assays, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting (WB), and flow cytometry, were conducted to examine the effects of NOTCH3 knockdown combined with RANBP1 overexpression on glucose-induced autophagy marker expression and cell viability in VSMCs.
NOTCH3 knockdown suppressed VSMC proliferation and induced apoptosis, and the cell cycle was stopped at the S phase. Analysis of VSMC sequencing data revealed 38 overlapping genes between the turquoise module and DEGs, 11 (HPF1, RANBP1, CRNKL1, LGALS3, RDX, ECM1, CXCL5, PA2G4, CENPS, ZNF830, and HIST1H4L) of which were significantly underexpressed in VSMC samples with si-NOTCH3. In a dose-dependent manner, HG therapy altered the expression of autophagy-related markers, upregulated NOTCH3, and downregulated phosphorylated mammalian target of rapamycin (p-mTOR). Downregulation of NOTCH3 aggravated the effects of HG on cell viability and autophagy, whereas overexpression of RANBP1 reversed these effects, suggesting an offsetting effect on HG-induced autophagy.
On the basis of sequencing technology, bioinformatics analysis and cell experiments, we conclude that the RANBP1/NOTCH3 axis is essential for the control of autophagy and survival of VSMCs under hyperglycemic stress and could provide new insight for the clinical treatment of VSMC-related diseases.
Heart failure with preserved ejection fraction (HFpEF) is a systemic syndrome primarily associated with fibrosis, oxidative stress, inflammation, and cellular apoptosis. Growth differentiation factor 15 (GDF15), a biomarker commonly used in clinical studies, exhibits protective effects on the myocardium. Therefore, the focus of the present study is to determine the mechanism by which GDF15 protects cardiac function in HFpEF.
We conducted functional enrichment analysis and protein-protein interaction network analysis on genes highly expressed in HFpEF but lowly expressed in normal samples. We established an HFpEF rat model by feeding the rats with a high-fat diet and administering N-omega-nitro-l-arginine-methyl ester (L-NAME) in their drinking water and silenced GDF15 by tail vein injection of lentivirus (L3110). After 12 weeks of feeding, echocardiographic examinations were performed. Following euthanasia of the rats, blood and heart tissue samples were collected. Heart tissue sections were stained using Masson’s trichrome and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining methods. Western blot (WB) analysis was employed to determine the concentrations of relevant proteins.
The echocardiographic results showed that compared with the HFpEF + MOCK group, the HFpEF+silencing GDF15 (siGDF15) group exhibited more severe cardiac dysfunction, with significant decreases in ejection fraction (p < 0.05) and E/A ratio (p < 0.001). WB results demonstrated that, compared with the HFpEF + MOCK group, the HFpEF+siGDF15 group exhibited increased expression of cardiac fibrosis-associated proteins, including collagen I (p < 0.01), collagen III (p < 0.01), and α-smooth muscle actin (α-SMA) (p < 0.01). Additionally, oxidative stress-associated biomarkers such as myeloperoxidase (MPO) (p < 0.01) and oxidized low-density lipoprotein (ox-LDL) (p < 0.01), inflammation-associated biomarkers, including interleukin-1 beta (IL-1β) (p < 0.01), interleukin-6 (IL-6) (p < 0.01), interleukin-8 (IL-8) (p < 0.01), and tumor necrosis factor α (TNFα) (p < 0.01), and apoptosis-associated biomarkers like cleaved caspase-3 (p < 0.01) and BCL2-associated X (BAX) (p < 0.01) were also upregulated in HFpEF+siGDF15 group.
Our research indicates that GDF15 preserves cardiac function by inhibiting myocardial fibrosis, reducing myocardial cell oxidative stress, alleviating cardiac inflammation, and suppressing myocardial cell apoptosis.
Psoriasis is an enduring inflammatory skin disorder defined by recurring attacks, distinguished primarily by red patches and scaly skin. Quercetin, a kind of natural flavonoid compound, is widely found in various vegetables, fruits, and Chinese herbs. Quercetin is a multifaceted compound with a wide range of potential health benefits. In addition to antioxidant, cardiovascular protection, and anti-tumor effects, quercetin has shown potential in regulating immune and inflammation effects. In the initial stages, in vivo studies have demonstrated that quercetin positively affects psoriasis and is connected with the phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (AKT)/glucose transporter 1 (GLUT1) signaling. Nevertheless, the precise mechanism by which quercetin influences the PI3K/AKT/GLUT1 signaling cascade in the context of psoriasis remains uncertain.
The aim of this study was to investigate the potential therapeutic influence of quercetin on psoriasis and the relationship with the PI3K/AKT/GLUT1 signaling pathway.
A mouse model for psoriasis induced by imiquimod was employed to assess alterations in the morphology of skin lesions and their histopathological characteristics. Cell Counting kit-8 (CCK-8) assay was used to assess the impact of proliferation of HaCaT human keratinocyte cells. HaCaT cells were examined using flow cytometry for the influence of quercetin on apoptosis. Additionally, Western blot analysis was used to evaluate the protein expression levels in the PI3K/AKT/GLUT1 signaling pathway.
concerning pathological alterations, the mice in the model group exhibited characteristic alterations associated with psoriasis. The extent of excessive keratinization in the epidermis and hypertrophy of the spinous layer observed in each quercetin dosage group was less pronounced compared to the model group. The CCK-8 assay laid out that quercetin can suppress the proliferation of HaCaT cells. Furthermore, it was found that quercetin facilitates the apoptosis of these cells. Analysis of immunoblotting demonstrated that the intervention of quercetin in HaCaT cells led to modifications in the proteins related to the PI3K/AKT/GLUT1 signaling pathway.
Through in vivo and in vitro experiments, this study shows that quercetin may play a therapeutic role in psoriasis and inhibit the PI3K/AKT/GLUT1 signaling pathway.
Chronic wounds, such as diabetes-related foot ulcers, arise from delayed wound healing and create significant health and economic burdens. Macrophages regulate healing by shifting between pro- and anti-inflammatory phenotypes, known as macrophage polarization. Sex and diabetes can impair wound healing, but their influence on macrophage phenotype in skin tissue during wound healing remains unclear, which was investigated in this study using a novel two-sex diabetic mouse model.
Diabetes was induced in male and female C57BL/6J mice using low-dose streptozotocin injections and high-fat diet feeding, with chow-fed mice as controls. After 18 weeks, each mouse received four circular full-thickness dorsal skin wounds. The macrophage phenotypes in wounded skin tissues at Day 0 and Day 10 post-wounding were analyzed using mass cytometry with manual gating and automated computational clustering.
Male diabetic mice exhibited more severe hyperglycemia and insulin resistance compared to females. Although diabetic mice did not display delayed wound healing, male mice had a greater proportion of total macrophages than females, especially a higher proportion of pro-inflammatory matrix metalloproteinase-9 (MMP-9)+ macrophages and a lower proportion of anti-inflammatory adiponectin receptor 1 (AdipoR1)+ macrophages in male diabetic mice compared to females, indicating an imbalanced polarization towards a pro-inflammatory phenotype that could result in poorer wound healing. Interestingly, computational clustering identified a new pro-inflammatory, pro-healing phenotype (Ly6C+AdipoR1+CD163–CD206–) more abundant in females than males, suggesting this phenotype may play a role in the transition from the inflammatory to the proliferative stage of wound healing.
This study demonstrated a significant sex-based difference in macrophage populations, with male diabetic mice showing a pro-inflammatory bias that may impair wound healing, while a unique pro-inflammatory, pro-healing macrophage population more abundant in females could facilitate recovery. Further research is needed to investigate the role of these newly identified phenotypes in regulating impaired wound healing.
Regulated forms of necrosis-like cell death (e.g., necroptosis) have been shown to contribute to cardiac ischemia/reperfusion (I/R) injury. However, pro-inflammatory necroptosis is unlikely to be involved during early reperfusion and little is known about the associated molecular changes. Thus, this study aimed to provide an in-depth protein screening with a particular focus on pro-pyroptotic and mitochondrial damage-related pathways.
Langendorff-perfused rat hearts were subjected to 30-minute global ischemia followed by 10-minute reperfusion. Liquid chromatography coupled with mass spectrometry (LC-MS/MS) and immunoblotting techniques were used to study the complex cardiac proteome. In addition, calcium-induced mitochondrial swelling and lactate dehydrogenase (LDH) release were examined to assess mitochondrial stress and necrosis phenotype, respectively.
Approximately 160 proteins linked to cell death signaling, cellular metabolism, and post-translational modifications were significantly differentially expressed in I/R hearts compared to controls. Conventional proteins of pyroptosis, either of canonical or non-canonical signaling, were not affected during the short reperfusion. Notably, this type of I/R was associated with increased expression of p25 cleaved form of poly [ADP-ribose] polymerase 1 (PARP1 p25) and mature apoptosis-inducing factor (AIF), alongside nitrosative stress and mitochondrial swelling. Conversely, a receptor-interacting protein kinase 3 (RIP3) inhibitor (GSK′872, 250 nM) reversed mitochondrial swelling and plasma membrane rupture and mitigated the increase in the expression of PARP1 p25 and AIF.
This study shows for the first time that necrosis-like injury during early I/R of the isolated heart is associated with mitochondrial events, rather than pro-inflammatory pyroptotic cell death. Furthermore, the inhibition of RIP3 mitigates this injury independent of targeting pro-inflammatory signaling.
Globally, ischemic stroke is a major cause of mortality and disability, posing a significant challenge in clinical practice and public health. Recent studies have reported that stroke leads to the impairment of the intestinal barrier and the migration of intestinal bacteria to multiple organs. This process exacerbates neurological damage by further impairing intestinal barrier function and leading to bacterial translocation. Dexmedetomidine (Dex), an α2-adrenoceptor (α2AR) agonist, has proven anti-cerebral ischemic effects, yet its effects in post-stroke intestinal dysfunction remain unclear. This study aimed to determine whether Dex mitigates intestinal dysfunction and brain injury following cerebral ischemia-reperfusion.
A C57BL/6J mouse model of middle cerebral artery occlusion (MCAO) was used for in vivo experiments, while lipopolysaccharide (LPS)-induced Caco-2 monolayers served as an in vitro model of intestinal barrier dysfunction. Neuronal apoptosis was evaluated using neuronal nuclei (NeuN) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) double labeling. Reverse transcription-quantitative PCR (RT-qPCR) was performed to measure pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Intestinal permeability was assessed using histological score, serum fluorescein isothiocyanate (FITC)-dextran fluorescence, and endotoxin levels. The expression levels of epithelial cadherin (E-cadherin), zonula occludens-1 (ZO-1), and occludin were analyzed by western blot and immunofluorescence. Statistical analyses included analysis of variance with Tukey’s post-hoc test.
Dex treatment significantly reduced cerebral infarct volume (p < 0.001) and improved neurological scores compared to MCAO controls. Neuronal apoptosis was significantly inhibited (p < 0.01), as evidenced by reduced TUNEL-positive cells in Dex-treatment MCAO mice. TNF-α, IL-1β and IL-6 were markedly downregulated (p < 0.05). While MCAO increased intestinal permeability (elevated serum FITC-dextran and endotoxin levels, p < 0.01), Dex treatment restored barrier integrity. Dex upregulated E-cadherin expression significantly (p < 0.05) but did not restore the decreased levels of ZO-1 and occludin following MCAO. Dex promoted intestinal permeability repair and alleviated brain injury via the α2AR/focal adhesion kinase (FAK) pathway in MCAO mice. Similarly, Dex mitigated LPS-induced barrier dysfunction in Caco-2 monolayers by restoring FAK expression and improving intestinal barrier integrity.
Dex alleviates post-stroke intestinal barrier dysfunction and mitigates brain injury, possibly through activating the α2AR/FAK pathway. These findings underscore a potential therapeutic strategy for addressing secondary complications of ischemic stroke and improving patient outcomes.
Macrophages (Mφ) are innate immune cells known for their different activation phenotypes, classically described as falling within two broad categories, M1 and M2. The latter were originally described as alternatively activated M2 cells to differentiate them from classically activated M1 cells. M2 cells were later classified into M2a (interleukin (IL)-4), M2b (immune complex), M2c (IL-10) and M2d (5-(N-ethylcarboxamido) adenosine (NECA) + lipopolysaccharide (LPS)) based on their inducing stimuli. Considering the established role of M2d/tumour-associated macrophage (TAM) cells within cancer initiation and proliferation, expanding on the knowledge of M2d characteristics can provide fundamental information for Mφ targeted immunotherapy. The precise characterization of M2d cells derived from tissues has not been described in detail.
Our study focused on spleen-derived macrophages (SpM), which were also compared to bone marrow-derived macrophages (BMDMs).
By investigating different conditions for M2d-specific stimulation and employing various assays including functional tests, we show how Mφ M2d (NECA + LPS) polarization can be affected by prolonged culture conditions to induce a phenotype that was clearly different from M2a cells.
This work offers new insights into the properties of primary M2d Mφ following extended stimulation with LPS and NECA.
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, resulting in progressive motor neuron loss and muscle atrophy. The urotensin 2 (UTS2) gene, located on chromosome 9q34.2, plays a significant role in cellular activities such as proliferation, apoptosis, and inflammatory responses. Notably, elevated expression levels of UTS2 have been observed in SMA patients. However, its precise contribution to disease pathogenesis remains unclear. This study aimed to investigate the effects of UTS2, which is overexpressed in SMA patients, in SMA cell models using a UTS2 inhibitor.
We conducted genomic sequencing and bioinformatics analysis on clinical samples to identify proteins highly expressed in association with SMA. Using RNA interference technology, we suppressed SMN1 gene expression in bone marrow mesenchymal stem cells (MSCs) to establish an in vitro cellular model of SMA. To assess the biological consequences of SMN1 gene knockdown, we employed molecular biological techniques such as immunofluorescence, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting. Furthermore, we treated the SMA cellular model with the urantide UTS2 receptor inhibitor and examined its effects on cell proliferation, apoptosis, and the expression of relevant proteins.
UTS2 was successfully identified as a highly expressed protein associated with SMA. A stable MSC model with SMN1 gene knockdown was established. RNA interference (RNAi) technology effectively suppressed SMN1 gene expression, leading to changes in cellular morphology and neuron-specific marker expression. Urantide intervention significantly affected both proliferation and apoptosis in the SMA cell model in a dose-dependent manner. Techniques such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, TUNEL fluorescence staining, and flow cytometry analysis revealed that uride decreased cell viability while increasing the proportion of apoptotic cells. Following urantide intervention, there was a notable increase in caspase-3 messenger ribonucleic acid (mRNA) levels, as well as an increase in caspase-3 protein expression, as demonstrated by immunofluorescence analysis.
We elucidated the role of the UTS2 gene in an SMA cell model, emphasizing its dysregulation and identifying potential therapeutic targets. Urantide, a UTS2 inhibitor, had significant biological effects on the SMA cell model, indicating that it is a promising therapeutic strategy for SMA. These findings provide valuable insights for advancing drug development and clinical treatment of SMA.
The human DNA double helix is wrapped around proteins known as histones, which play a critical role in regulating gene expression. The goal of this opinion piece is to provide an overview of how histone sensing drives Alzheimer’s disease (AD). Histones are proteins enriched in basic amino acids. Histone acetylation plays an important role in the progression of AD as its dysregulation can lead to neuroinflammation and neurodegenerative diseases. Specifically, abnormal histone acetylation, a post-translation modification, is a key factor in AD as it contributes to brain cell inflammatory pathology. Thus, higher levels of histone acetylation could potentially serve as important biomarkers for the progression of AD. Here, we report that increased levels of acetylation of histones H2B, H3, and H4 in the promoter regions of Tip60 lysine acetyltransferase protein, p300/CREB-binding protein (CBP), GCN5-related N-acetyltransferases, p300/CBP-associated factor, elongator protein 3, brain-derived neurotrophic factor, and Tau genes in the hippocampus and temporal lobe are associated with the development of AD-associated learning and memory impairment.
Subarachnoid hemorrhage (SAH), a severe cerebrovascular disorder, is principally instigated by the rupture of an aneurysm. Early brain injury (EBI), which gives rise to neuronal demise, microcirculation impairments, disruption of the blood-brain barrier, cerebral edema, and the activation of oxidative cascades, has been established as the predominant cause of mortality among patients with SAH. These pathophysiological processes hinge on the activation of inflammasomes, specifically the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)and absent in melanoma 2 (AIM2) inflammasomes. These inflammasomes assume a crucial role in downstream intracellular signaling pathways and hold particular significance within the nervous system. The activation of inflammasomes can be modulated, either by independently regulating these two entities or by influencing their engagement at specific target loci within the pathway, thereby attenuating EBI subsequent to SAH. Although certain clinical instances lend credence to this perspective, more in-depth investigations are essential to ascertain the optimal treatment regimen, encompassing dosage, timing, administration route, and frequency. Consequently, targeting the ensuing early brain injury following SAH represents a potentially efficacious therapeutic approach.
Atherosclerosis (AS), with a profound inflammatory response, is the basis of cardiovascular diseases. Previous reports showed that heat shock protein family B member 1 (HSPB1) has a protective effect against AS, but the specific mechanism is still unclear. In this study, we aim to explore the functions and downstream targets of HSPB1 in human umbilical vein endothelial cells (HUVECs).
Expression of the HSPB1 gene was knocked down in HUVECs. Cellular phenotype was then assessed and transcriptome data (RNA-seq) was analyzed to identify the potential targets regulated by HSPB1. Moreover, RNA-seq data for human fibroatheroma (GSE104140) from the gene expression omnibus (GEO) database was re-analyzed to verify the targets of HSPB1 in AS.
Silencing of HSPB1 significantly reduced apoptosis (p < 0.0001) and increased the proliferation (p < 0.05) of HUVECs. The 608 differentially expressed genes (DEGs) were identified after HSPB1 knockdown, including 423 upregulated genes. DEGs, including CXCL1, CXCL8, CXCL2, TRIB3, GAS5, SELE, and TNIP1, were enriched in inflammatory and immune response pathways. HSPB1 was also shown to affect alternative splicing patterns of hundreds of genes, especially those enriched in apoptotic processes, including ACIN1, IFI27, PAK4, UBE2D3, and FIS1. An overlapping gene set was found between the HSPB1-regulated and AS-induced transcriptome. This included 171 DEGs and 250 alternatively spliced genes that were also enriched in inflammatory/immune response- and apoptosis-associated pathways, respectively.
In summary, HSPB1 knockdown modulates the proliferation and apoptosis of HUVECs by regulating RNA levels and alternative splicing patterns. HSPB1 plays an important role in AS pathogenesis by modulating the inflammatory and immune response. This study provides novel insights for the investigation of future AS therapeutic strategies.
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood.
We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis.
Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins (IL1B, IL8, and IL15) and interferon G (IFNG). Multiple pattern recognition receptors involved in proinflammatory signaling were also upregulated in patients, including NOD-like receptors (NLRs) (NLRP1, NLRP3, and NLRC5), RNA helicases (DDX58, IFIH1, DHX9, and DHX36), cGAS (cyclic GMP-AMP synthase) and IFI16 (interferon gamma inducible protein 16). Additionally, human leukocyte antigen molecules HLA-DQA1 and HLA-DRB1 enriched in memory B cells were upregulated in patients. More importantly, we found that the genes for antiviral defense response were significantly elevated in high-risk patients relative to the low-risk group. More than twenty genes were negatively correlated with estimated glomerular filtration rate (eGFR), such as BST2 (bone marrow stromal cell antigen 2) and SLC35F1 (solute carrier family 35 member F1). Their predicted values were confirmed in a larger population with nephrotic syndrome or other chronic kidney diseases from a public database. Furthermore, we developed a series of scoring systems for distinguishing high-risk patients from low- and moderate-risk individuals.
Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN.