Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
The immune system, composed of innate and adaptive immunity, orchestrates a complex network of responses to maintain immune equilibrium. Central to this balance are regulatory T cells (Tregs), particularly CD4+ regs, which preserve self-tolerance and prevent autoimmunity. Advances in immunoregulation have elucidated key pathways governing Tregs function, including forkhead box P3 (FOXP3) regulation, metabolic dependencies, and interactions with signaling molecules like interleukin (IL)-2 and Notch-1. In addition to CD4+ Tregs, emerging research highlights the critical role of Qa-1-restricted CD8+ Tregs in promoting transplant tolerance and modulating autoimmune responses. Therapeutic strategies leveraging Tregs, from IL-2-based therapies to genetically engineered chimeric antigen receptor (CAR)-Tregs, have shown promise in modulating allo- and autoimmune responses. This review explores (1) the historical development of immunoregulation, (2) the role of innate and adaptive immune cells in immunoregulation, and (3) the most recent innovations in Treg-based therapies, emphasizing their potential for clinical application in transplantation, autoimmune disorders, and cancer immunotherapy.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Leukotrienes are a group of eicosanoids that are synthesised from arachidonic acid by 5-lipoxygenase (5-LOX) pathway and perform normal and pathological roles. Both leukotriene B4 (LTB4) and cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have membrane receptors. Diabetes mellitus and its complications have complex pathogenic mechanisms, including increased leukotriene synthesis. The implications of leukotrienes and other eicosanoids in the pathogenesis of diabetes are multiple. They are only partially known and frequently completely ignored in medical practice. This review emphasizes the intricate interactions between leukotrienes and other factors in the pathogenesis of diabetes complications. In individuals with diabetes and its complications, the serum and urinary concentration of leukotrienes is significantly higher than in normal individuals. LTB4 and LTC4 inhibit insulin secretion. Leukotrienes are involved in the pathogenesis of diabetic inflammation and stimulate the synthesis of proinflammatory cytokines, in the production of atheromatosis, retinopathy, nephropathy, obesity and various other diabetes complications. Existing data strongly suggest the use of montelukast and other cys-LT1 receptor antagonists in combination with antidiabetic drugs for the treatment of diabetes and its complications. These drugs may prevent or postpone the development of complications of diabetes. This review highlights the involvement of leukotrienes in the pathogenesis of diabetes and its complications. Additionally, various viewpoints on the therapeutic application of leukotriene antagonists are discussed.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: End-stage heart and kidney failure is constrained by donor organ scarcity. This study aimed to establish a standardized protocol for combined heart–kidney xenotransplantation using multi-gene–edited porcine grafts in a non-human primate (NHP) model and to evaluate their short-term functional outcomes, providing a basis for future clinical translation.
Methods: Genetically modified Bama miniature pigs carrying five gene edits (GTKO/SdaKO/CD46/CD55/TBM) were used as organ donors, and healthy male rhesus macaques served as recipients. Donor hearts and kidneys were harvested using a standardized protocol and preserved via cold perfusion. Cardiac transplantation was performed using an intra-abdominal heterotopic approach, with end-to-side anastomosis between the donor ascending aorta and the recipient abdominal aorta, as well as between the donor pulmonary artery and the recipient inferior vena cava. Renal transplantation involved orthotopic end-to-end anastomosis of the donor renal artery and vein to the recipient's left renal vasculature. A combined immunosuppressive regimen was administered perioperatively, alongside anticoagulation, anti-infective prophylaxis, and supportive care. Recipient vital signs and cardiorenal function were continuously monitored throughout the perioperative period. Experimental endpoints were defined as cessation of renal graft perfusion or irreversible cardiac graft failure.
Results: The recipient survived 7 days and 4 hours post-transplant with stable vital signs. Both grafts demonstrated good intraoperative perfusion. The heart graft resumed beating immediately upon reperfusion, with left ventricular ejection fraction peaking at 35% on postoperative day (POD) 5 before declining. Echocardiography revealed myocardial hypertrophy and reduced contractility, but no complete cardiac failure. The kidney graft showed perfusion by POD 1, and urine output by POD 5 confirmed initial function. However, increased vascular resistance and reversed flow between POD 6 and POD 7 indicated acute graft failure. Laboratory assessments showed persistent anemia, lymphopenia, and intermittent prolongation of activated partial thromboplastin time (APTT). At necropsy, the heart graft retained structural integrity and partial function, whereas the kidney graft exhibited hemorrhagic infarction. Notably, vascular anastomoses remained intact throughout the study. Additionally, the heart graft maintained its function despite renal rejection, suggesting greater resilience to immune injury.
Conclusion: This combined xenotransplantation model demonstrated short-term graft survival, with the cardiac graft showing greater resistance to rejection than the renal graft. It offers a platform for optimizing clinically viable strategies for long-term functional xenotransplantation.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Rapid and precise imaging is critical for timely therapeutic interventions that minimize brain damage in ischemic stroke. Conventional iodine-based contrast agents (ICA) enhance vascular visibility but fail to delineate cellular and molecular alterations in ischemic tissues. To bridge this gap, we developed Transferrin-Conjugated Iodine Contrast Agent Liposomes (TICA), a novel targeted agent designed to bind transferrin receptors upregulated in ischemic brain regions.
Methods: TICA was synthesized to target transferrin receptors overexpressed during ischemic injury. Its efficacy was evaluated using a comprehensive set of imaging and histological techniques in a rat Middle Cerebral Artery Occlusion (MCAO) model. Serial Computed Tomography (CT) imaging was conducted to evaluate the clarity and extent of ischemic regions. Triphenyltetrazolium chloride (TTC) staining was performed to verify the extent of ischemic damage, while immunohistochemical analysis quantified transferrin receptor expression in brain tissue. Additionally, Terminal deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining was employed to quantify cellular apoptosis in ischemic regions. Results obtained with TICA were compared against those from standard ICA to demonstrate the enhanced capability of TICA in identifying and characterizing ischemic damage.
Results: Initial CT imaging demonstrated that TICA provided clearer and more comprehensive visualization of ischemic regions than ICA. Longitudinal imaging further showed that TICA consistently delineated ischemic areas with greater spatial precision, findings corroborated by histopathological analysis. Collectively, these findings indicate that TICA improves both the initial identification and temporal monitoring of ischemic injury.
Conclusion: TICA represents a significant advancement in ischemic stroke imaging by offering a targeted, pathophysiology-aligned visualization of ischemic tissue. Its application improves diagnostic accuracy and may enhance treatment planning, potentially improving clinical outcomes in stroke management.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Diabetic Kidney Disease (DKD) is a leading cause of chronic kidney disease (CKD) and end-stage renal failure. The complement component 5a (C5a)-C5a Receptor 1 (C5aR1) signaling axis plays a critical role in these pathological processes by activating inflammatory pathways, including signal transducer and activator of transcription 3 (STAT3) signaling, exacerbating kidney injury. As the current treatments for DKD fail to address the underlying inflammatory and fibrotic processes, targeting the C5a-C5aR1 pathway may be a novel therapeutic approach.
Methods: High-throughput virtual screening (HTVS) was conducted to screen C5a-C5aR1 inhibition. Selected compounds were further validated through molecular dynamics (MD) simulations, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, followed by in vitro target evaluations using a cell-free C5aR1 inhibition assay. Apoptosis, downstream assessment was carried out by flow cytometry using the HK-2 cells.
Results: The in silico screening and ADMET analysis identified C5R-131 as a promising C5aR1 antagonist with favorable pharmacokinetic properties. MD simulations revealed stable binding of C5R-131 to C5aR1, with strong hydrogen bonding interactions, with a binding value of –9.4 kcal/mol. Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA)-based binding free energy calculation from the 100 ns simulation trajectories shows C5R-131 has –21.11 kcal/mol when bound to C5aR1. In vitro assays demonstrated that C5R-131 significantly inhibited C5aR1 activity with a half-dose inhibitory concentration (IC50) value of 53.75 nM. The compound reduced apoptosis, necrosis, STAT3 phosphorylation, and modulated CD31 expression in high-glucose-exposed HK-2 cells, indicating its potential to protect against renal cell injury and inflammation in DKD.
Conclusion: Through a combination of in silico screening and in vitro validation, we demonstrate that C5R-131 effectively modulates STAT3 activation, reduces renal cell apoptosis, and protects endothelial cells from dysfunction in high glucose (HG) conditions. These findings offer a new therapeutic strategy for developing targeted therapies for DKD and other diseases associated with C5a receptor activation.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Parkinson's disease (PD) is marked by dopaminergic neuron loss and motor deficits. Impaired autophagy and mitophagy contribute to PD, and α-synuclein (α-Syn) may worsen neurodegeneration by disrupting these pathways. This study investigates α-Syn's role in aggravating motor deficits and dopaminergic neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, focusing on its inhibition of autophagy and mitophagy via mechanistic target of rapamycin (mTOR).
Methods: The MPTP-induced PD mouse model was used to study α-Syn's role in PD. Motor function was assessed using the tail suspension, pole, and traction tests, while cognitive function was evaluated with the Morris water maze. α-Syn and tyrosine hydroxylase (TH) levels in the substantia nigra were measured using Western blotting and immunohistochemistry. Autophagy and mitochondrial autophagy markers were analyzed via Western blotting. SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium ion (MPP+) to model PD in vitro, followed by interventions α-Syn and rapamycin (Rapa). Cell viability and apoptosis were assessed using 5-ethynyl-2′-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, while autophagy and mitochondrial autophagy markers, reactive oxygen species (ROS) levels, and mitochondrial/lysosomal activity were analyzed using fluorescence staining and co-localization with MitoTracker and LysoTracker.
Results: The tail suspension, pole, and traction tests showed that MPTP treatment significantly impaired motor function, with α-Syn further exacerbating deficits (p < 0.05). However, Rapa improved motor function. The Morris water maze test revealed increased escape latency and reduced swimming speed in the MPTP group, indicating spatial learning impairment, which worsened with α-Syn but improved with α-Syn+Rapa (p < 0.05). The spatial probe test showed decreased spatial memory in the MPTP + α-Syn group, with significant improvement in the α-Syn+Rapa group. Western blotting and immunohistochemistry showed that α-Syn enhanced MPTP-induced dopaminergic neuron degeneration and inhibited autophagy and mitophagy (p < 0.05). In vitro, α-Syn worsened SH-SY5Y cell viability and apoptosis, and inhibited autophagy and mitophagy by activating the mTOR pathway (p < 0.05).
Conclusions: α-Syn induces dopaminergic neuron degeneration and worsens PD by inhibiting autophagy and mitophagy, but Rapa can partially reverse this by restoring these processes. Targeting autophagy and mitophagy may offer a promising strategy for PD treatment.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Abnormal DNA methylation has been detected in breast cancer (BC). Downregulation of F-box protein 31 (FBXO31) in BC and its upregulated methylation level have been initially confirmed via bioinformatic analyses. Likewise, DNA methyltransferase 3 beta (DNMT3B) is highly expressed in BC. Accordingly, this study is engineered to fathom out whether DNMT3B can affect the progression of BC (Luminal A type) by regulating FBXO31 methylation.
Methods: DNMT3B/FBXO31 expression and FBXO31 methylation level in BC were predicted by the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. 5-methylcytosine (5mC) site of FBXO31 was analyzed with RMBase database. After human BC cells were collected and transfected, viability, apoptosis and migration/invasion were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, flow cytometry, and Transwell assay, respectively. FBXO31 methylation level was determined by methylation-specific polymerase chain reaction (MSP). Expression levels of FBXO31, DNMT3B, and apoptosis/proliferation-associated proteins were evaluated using quantitative real-time reverse transcription polymerase chain reaction or Western blotting.
Results: DNMT3B expression was upregulated while FBXO31 expression was downregulated (p = 1.62 × 10-12), and FBXO31 methylation level was elevated in breast invasive carcinoma (p < 1 × 10-12). DNMT3B was highly expressed in MCF-7, MDA-MB-231 and MDA-MB-453 cells (p < 0.001). DNMT3B silencing inhibited viability, migration and invasion (p < 0.05), enhanced apoptosis (p < 0.001), upregulated expression levels of Bax and FBXO31 (p < 0.001), downregulated expression levels of B cell leukemia/lymphoma 2 (Bcl-2), Ki67 and proliferating cell nuclear antigen (PCNA) (p < 0.001), and diminished FBXO31 methylation level in MCF-7 cells. FBXO31 silencing showed the opposite effects in MCF-7 cells (p < 0.001), whereas DNMT3B silencing reversed the effects of FBXO31 silencing in MCF-7 cells (p < 0.01).
Conclusions: DNMT3B silencing alleviates malignant behaviors in Luminal A BC cells by suppressing FBXO31 methylation, indicating a novel mechanism of DNA methylation in Luminal A type BC.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Lung adenocarcinoma (LUAD) is characterized by a high propensity for metastasis and poor patient outcomes, along with reduced survival rates. This study aims to investigate the role of pleckstrin-homology-like domain family-A member 2 (PHLDA2) in the progression of LUAD and its transcriptional regulation by the ETS-like-1 protein (ELK1).
Methods: PHLDA2 expression was analyzed in The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) (gene expression profiling interactive analysis (GEPIA)) and validated in LUAD cell lines using Western blot (WB) analysis. Functional analyses, including the counting kit-8 (CCK-8) proliferation curves, Transwell migration/invasion, apoptosis, and cisplatin half-maximal inhibitory concentration (IC50) determination, were performed after silencing PHLDA2 (siPHLDA2). Additionally, chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) and dual-luciferase reporter assays were used to evaluate ELK1's binding and promoter activation.
Results: PHLDA2 was significantly upregulated in LUAD tumors compared to normal lung tissues (p < 0.05), and high PHLDA2 expression was associated with shorter overall survival (Kaplan–Meier, p = 0.02). Silencing PHLDA2 reduced proliferation, reversed epithelial-mesenchymal transition (EMT), diminished migration/invasion, and increased cisplatin sensitivity (IC50 ≈ 16 μM vs. ≈ 36 μM in controls). ELK1 bound a –420 bp motif in the PHLDA2 promoter and enhanced its transcription (≈3-fold).
Conclusion: These results suggest that the ELK1-PHLDA2 axis promotes LUAD malignancy and chemoresistance and may represent a potential therapeutic target, warranting in vivo and clinical validation.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Doxorubicin (DOX), although widely employed in cancer therapy, induces significant cardiotoxicity primarily via oxidative stress and DNA damage. Pachymic acid (PA), a natural triterpenoid with established antioxidative and anti-inflammatory properties, has not yet been fully investigated for its protective actions against DOX-induced injury. This study aimed to explore the cardioprotective role of PA in mitigating DOX-induced cardiotoxicity, focusing on oxidative stress, inflammatory responses, DNA damage, and apoptosis.
Methods: H9c2 cardiomyocytes were treated with various concentrations of DOX and PA, either individually or in combination. The experimental groups consisted of control, DOX alone, PA alone, and PA plus DOX. A range of assays (CCK-8, TUNEL, ELISA, comet assay, Western blot) were performed to evaluate cell viability, apoptosis, inflammatory cytokine production, oxidative stress, and DNA damage. In vivo, the cardioprotective potential of PA was further evaluated in a rat model using histopathological analysis and serum biomarker evaluation.
Results: In vitro, PA pretreatment significantly improved cell viability and inhibited apoptosis in DOX-exposed H9c2 cells (p < 0.01), as demonstrated by modulation of Bcl-2, cleaved-PARP, Bax, and cleaved-caspase-3 expression (p < 0.01). PA suppressed oxidative stress by reducing reactive oxygen species (ROS) and Malondialdehyde (MDA) levels while enhancing Superoxide dismutase (SOD) and Glutathione (GSH) activities (p < 0.01). Additionally, PA mitigated DNA damage and downregulated DNA damage response proteins (p-ATR, γH2AX, P53, and P21) (p < 0.01). Proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-1β were significantly decreased following PA treatment (p < 0.01). In vivo, serum concentrations of lactate dehydrogenase (LDH), cardiac troponin I (cTnI), brain natriuretic peptide (BNP), and creatine kinase-MB (CK-MB) were markedly reduced, and myocardial histopathology revealed alleviated structural damage (p < 0.01). These protective effects were accompanied by decreased oxidative damage, inflammatory responses, and cardiomyocyte loss in cardiac tissue (p < 0.01).
Conclusion: PA attenuated DOX-induced cardiotoxicity through the inhibition of oxidative stress, inflammatory responses, DNA damage, and apoptosis, highlighting its potential as a novel cardioprotective agent.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: B-cell lymphoma is a highly prevalent malignancy of the hematopoietic system. Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy is increasingly being used to treat hematologic malignancies. However, relatively few studies have explored the feasibility of combining CAR-NK therapy with PD-1 inhibitors for lymphoma treatment. This study aimed to investigate the feasibility and therapeutic efficacy of combining CAR-NK cells with a programmed death-1 (PD-1) inhibitor for the treatment of B-cell lymphoma.
Methods: Umbilical cord blood (CB)-derived NK cells were transduced with a retroviral vector encoding CAR-19, interleukin-15 (IL-15), and an inducible caspase-9 (iC9)-based suicide gene. The impact of iC9/CAR-19/IL-15 CAR-NK cell therapy combined with PD-1 inhibitor treatment on lymphoma cell cytotoxicity was evaluated separately through in vitro cell-based assays and in vivo animal experiments.
Results: iC9/CAR-19/IL-15 CAR-NK cells combined with PD-1 inhibitors (a combined therapy) selectively killed primary chronic lymphocytic leukemia (CLL) cells in vitro. The cytokines CD107a, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were increased in iC9/CAR-19/IL-15 CAR-NK cells, but were barely changed under the influence of PD-1 inhibitors. Compared to monotherapy, the combined therapy significantly elevated IL-22, IL-6 and IL-15 secretion levels (p < 0.05), and more importantly, greatly extended the survival of model mice (p < 0.001). Furthermore, a decrease in TNF-α, IL-6 and IL-10 levels was observed in the serum of model mice (p < 0.05).
Conclusions: The combined therapy of iC9/CAR-19/IL-15 CAR-NK cells with PD-1 inhibitors exhibits remarkable antitumor activity and prolongs survival, providing a potential novel treatment route for B-cell lymphoma.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Lumbar disc herniation is a common cause of low-back and radicular leg pain, often resulting from degeneration or protrusion of the intervertebral disc that compresses adjacent nerve roots. This study aims to explore the impact of combining diclofenac sodium with eperisone on the treatment of lumbar disc herniation.
Methods: This retrospective study evaluated the clinical data from 200 lumbar disc herniation patients treated at Wuxi Ninth People's Hospital, between January 2023 and January 2024. Based on therapeutic regimen, patients were categorized into the combination group (n = 95) and the diclofenac sodium monotherapy group (n = 105). Both groups underwent treatment for 2 weeks and followed up for 6 months. Basic characteristics, pain intensity, degree of pain relief, lumbar function, and adverse drug events were analyzed and compared between groups.
Results: At rest or during exercise, the visual analogue scale (VAS) score was progressively reduced in both groups in contrast to the previous time point (p < 0.05). However, the decrease was more pronounced in the combination group at 2 weeks post-treatment (p < 0.05). Both at rest and during exercise, the rate of pain relief during the treatment stage and overall stage was greater in the combination group (p < 0.05). Furthermore, the Japanese Orthopaedic Association (JOA) score progressively increased in both groups (p < 0.05), with the combination group demonstrating a significantly greater JOA score 2 weeks after treatment (p < 0.05). Additionally, adverse drug events did not differ significantly between the two groups.
Conclusion: A 2-week combined treatment of diclofenac sodium and eperisone significantly attenuates pain and improves lumbar function in lumbar disc herniation patients compared with a diclofenac sodium monotherapy regimen, showing a superior safety profile.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Aurora kinase A (AURKA) has been reported to play an oncogenic role in non-small cell lung cancer (NSCLC). However, its specific role in regulating mitochondrial function and reactive oxygen species (ROS) in NSCLC cells remains unclear. This study aimed to investigate the function of AURKA in NSCLC, with a particular focus on its regulation of mitochondrial activity and ROS levels in A549 and H1299 cell lines.
Methods: AURKA expression and protein localization in lung adenocarcinoma (LUAD) were analyzed using publicly available gene expression and immunohistochemistry datasets. Small interfering RNA (siRNA) was used to knock down AURKA expression in A549 and H1299 cell lines. To evaluate cellular proliferation, migration, and invasion capabilities, a series of assays were performed, including cell counting kit-8 (CCK-8), colony formation, 5-ethynyl-2′-deoxyuridine (EdU) incorporation, Transwell migration/invasion, and wound healing assays. Mitochondrial function was assessed by measuring mitochondrial membrane potential, nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD⁺/NADH) ratio, adenosine triphosphate (ATP) levels, and ROS generation. Apoptosis was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling staining, western blot analysis, and caspase activity assays. N-acetylcysteine (NAC) was used in rescue experiments to further investigate the role of oxidative stress.
Results: AURKA was significantly upregulated in LUAD tissues with higher protein expression confirmed by immunohistochemistry data, correlating with poor prognosis (p < 0.05). Targeted inhibition of AURKA expression resulted in diminished proliferative, migratory, and invasive behaviors in NSCLC cells (p < 0.05). AURKA silencing induced mitochondrial dysfunction, decreased NAD⁺/NADH ratio and ATP production, and increased ROS levels, resulting in enhanced apoptosis (p < 0.05). NAC treatment partially reversed these effects (p < 0.05).
Conclusion: AURKA maintains mitochondrial integrity and redox homeostasis in NSCLC cells, thereby suppressing ROS-mediated apoptosis. Targeting AURKA and oxidative stress pathways may represent a promising therapeutic strategy for NSCLC.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: IgA nephropathy (IgAN), a common glomerulonephritis, is characterized by glomerular deposition of IgA-containing immune complexes, which drive mesangial cell proliferation and extracellular matrix synthesis through transforming growth factor beta 1 (TGF-β1) overexpression. Previous studies demonstrated abundant plasma gelsolin (pGSN) deposition in IgAN glomeruli, which promoted TGF-β1 expression. However, the molecular mechanisms by which pGSN modulates TGF-β1-mediated fibrosis in mesangial cells remain unclear. This study aimed to elucidate these mechanisms and identify potential therapeutic targets for inhibiting glomerular fibrosis in IgAN.
Methods: Human glomerular mesangial cells (HMCs) were stimulated with pGSN. Transcriptome sequencing was applied to screen for key regulators of TGF-β1. Identified factors and TGF-β1 expression were validated by quantitative polymerase chain reaction (qPCR), western blot (WB), and immunofluorescence (IF). The functional role of the candidate regulator, adrenoceptor beta 2 (ADRB2), was further investigated using protein–protein interaction prediction and ADRB2 overexpression assays, including under co-stimulation with polymeric IgA1 (pIgA1).
Results: Transcriptome sequencing revealed the cyclic adenosine monophosphate (cAMP) pathway gene ADRB2 as a potential fibrosis regulator. Stimulation of HMCs with pGSN reduced ADRB2 (p < 0.01) and cAMP dependent protein kinase (PKA) (p < 0.01) expression, while significantly increasing TGF-β1 (p < 0.001). Conversely, ADRB2 overexpression increased ADRB2 (p < 0.001) and PKA (p < 0.001) levels while decreasing TGF-β1 (p < 0.001). Notably, ADRB2 overexpression reversed the TGF-β1 upregulation induced by combined pGSN and pIgA1 stimulation.
Conclusion: pGSN synergizes with pIgA1 to enhance TGF-β1 expression and glomerular fibrosis in IgAN by suppressing the ADRB2/cAMP signaling pathway. ADRB2 may represent a promising therapeutic target for antifibrotic strategies in IgAN.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Stem cell transplantation has emerged as a widely recognized therapeutic approach for myocardial infarction (MI). The primary objective of this study was to investigate the specific role of suppressor of cytokine signaling 3 (SOCS3) in regulating the differentiation potential of mesenchymal stem cells (MSCs) into functional cardiomyocytes. This research lays important groundwork for the development of novel therapeutic strategies aimed at post-injury cardiac regeneration.
Methods: Isolated from human umbilical cord tissue, MSCs were characterized through confirmation of positive expression of surface markers (CD90, CD73, CD44) in flow cytometry. Their multipotency was verified by demonstrating osteogenic and adipogenic differentiation potential, which was confirmed using Alizarin red and oil red O staining approaches, respectively. To elucidate the role of SOCS3, its expression was knocked down using shRNA (shSOCS3). Subsequently, cell morphological changes and expression of key cardiomyocyte-specific genes and proteins were analyzed. Furthermore, STAT3 knockdown (siSTAT3) and GATA binding protein 4 (GATA4) overexpression plasmids were constructed and employed in vitro to explore the underlying mechanism. Putative binding interaction between the transcription factor STAT3 and the promoter of GATA4 was predicted via the JASPAR database and subsequently validated experimentally by means of chromatin immunoprecipitation (ChIP).
Results: ShSOCS3 promoted cardiomyocyte-like morphological alterations in MSCs. Upregulation in the expression of connexin-43, myosin heavy chain (MHC), cardiac troponin T, NK2 homeobox 5 (NKX-2.5), and GATA4 was also detected following the transfection of shSOCS3. These effects attributable to shSOCS3 were partially reversed by siSTAT3. GATA4, which was bound to STAT3, partially counteracted the effect of siSTAT3.
Conclusion: SOCS3 plays an inhibitory role in the cardiomyogenic differentiation of MSCs, which is mechanistically mediated by the STAT3/GATA4 signaling axis, wherein SOCS3 modulates STAT3 activity, which in turn directly influences the expression of the critical cardiac transcription factor GATA4.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Accurate etiological diagnosis of community-acquired pneumonia (CAP) is essential for guiding targeted therapy. However, conventional bronchoalveolar lavage (cBAL) is susceptible to contamination by commensal or background microorganisms, potentially compromising diagnostic accuracy. This study aimed to evaluate the clinical value of hand-drawn navigation-guided transbronchial precision bronchoalveolar lavage (TB-PBAL) combined with metagenomic next-generation sequencing (mNGS) in enhancing the etiological diagnosis of CAP.
Methods: A total of 50 CAP patients were enrolled in the study. Each patient underwent TB-PBAL under hand-drawn navigation guidance and cBAL. The lavage fluids obtained by these two techniques were designated as the experimental group (TB-PBAL) and the control group (cBAL), respectively. All samples were analyzed using mNGS, and detection rates of pathogens, pathogenic bacteria, and background bacteria were compared. Differences in pathogen detection rate, relative abundance of pathogenic bacteria, background bacterial detection rate, mixed infection rate, pathogenic bacteria signal-to-noise ratio (S/N ratio), and clinician preference for test reports were statistically analyzed.
Results: The overall pathogen detection rates showed no significant difference between the two groups (95.70% vs. 93.20%, p > 0.05). Notably, TB-PBAL demonstrated a significantly higher relative abundance of pathogenic bacteria compared with cBAL (67.42% ± 11.28% vs. 31.25% ± 9.46%, p < 0.001), with predominant pathogens including Haemophilus influenzae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. TB-PBAL yielded significantly lower background microbial interference, as evidenced by reduced background bacterial detection rates (38% vs. 64%, p = 0.009) and sequence counts (25.30 ± 10.60 vs. 82.70 ± 15.40, p < 0.001). Consequently, the signal-to-noise ratio for pathogenic bacteria was markedly higher in the TB-PBAL group (6.50 ± 2.12 vs. 3.23 ± 1.45, p < 0.001). In blinded clinical assessments, physicians demonstrated significantly greater preference for TB-PBAL-derived mNGS reports (50% vs. 30%, p = 0.041).
Conclusion: Hand-drawn navigation-guided TB-PBAL combined with mNGS significantly improves etiological diagnosis of CAP by enriching the relative abundance of true pathogens, minimizing background microbial interference, enhancing the signal-to-noise ratio, and increasing clinician confidence in sequencing results.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: N,N,N-trimethyl-5-aminovaleric acid (TMAVA), a lysine-derived metabolite generated by gut microbiota, has been associated with metabolic disorders. However, its role in cardiovascular disease remains unclear. This study aimed to investigate whether TMAVA promotes atherosclerosis progression by disrupting mitochondrial metabolism through inhibition of γ-butyrobetaine hydroxylase (BBOX), a key enzyme in carnitine biosynthesis.
Methods: In vivo, ApoE⁻/⁻ mice were fed a high-fat diet and treated with TMAVA, with or without concurrent BBOX overexpression, for eight weeks. In vitro, human umbilical vein endothelial cells (HUVECs) were exposed to TMAVA, with or without BBOX overexpression, or left untreated. Molecular, metabolic, and functional assays were conducted to evaluate lipid metabolism, mitochondrial function, inflammation, and endothelial function.
Results: TMAVA accumulated in the aortic tissue of ApoE⁻/⁻ mice (p < 0.05) and was associated with aggravated lipid profiles (p < 0.05), increased inflammatory cytokine expression (p < 0.05), and impaired mitochondrial function (p < 0.05). In HUVECs, TMAVA further exacerbated ox-LDL-induced mitochondrial damage, oxidative stress, and inflammation (p < 0.05), accompanied by significant reductions in carnitine levels, ATP production, and fatty acid oxidation markers (AMPK, CPT1α) (p < 0.05). BBOX overexpression restored mitochondrial function and reversed TMAVA-induced metabolic and inflammatory abnormalities in both models (p < 0.05).
Conclusion: TMAVA accelerates atherosclerosis by suppressing BBOX expression, impairing carnitine biosynthesis, and disrupting mitochondrial fatty acid oxidation, ultimately leading to endothelial dysfunction and vascular inflammation. Targeting the TMAVA-BBOX-carnitine pathway may represent a promising therapeutic strategy for cardiovascular disease.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Persistent inflammation contributes to the progression of rheumatoid arthritis (RA); however, the exact molecular mechanisms underlying inflammation in RA are yet to be fully elucidated. Interleukin-25 plays a crucial role in host defense and the pathogenesis of inflammatory diseases. Its specific contribution to RA progression requires further investigation.
Methods: RA-FLSs were treated with tumor necrosis factor-α (TNF-α) to simulate the inflammatory response in the synovium. Furthermore, changes in inflammatory response and bone destruction indicators were assessed after Interleukin-25 (IL-25) intervention. The collagen-induced arthritis (CIA) mouse model was successfully constructed to evaluate the impact of IL-25 on joint inflammation and erosion.
Results: The expression levels of IL-25 were significantly elevated in the synovial tissues of both RA patients and CIA mouse models compared to controls (p < 0.05). In vitro, IL-25 pretreatment substantially suppressed TNF-α-induced upregulation of interleukin-1β (IL-1β), interleukin-6 (IL-6), high mobility group box-1 protein (HMGB1), matrix metalloproteinase-3 (MMP-3), toll-like receptors 4 (TLR4), and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) in RA-FLSs (p < 0.05, p < 0.01, p < 0.001), and suppressed nuclear factor kappa-B (NF-κB) signaling pathway by reducing p-P65 and p-IκBα protein levels (p < 0.001). In vivo, IL-25 negatively regulated joint inflammation and reduced the degree of bone erosion in mice (p < 0.01, p < 0.0001).
Conclusion: Elevated IL-25 levels exert anti-inflammatory effects both in vitro and in vivo and alleviate RA progression by inhibiting the TLR4/NF-κB/ NLRP3 signaling pathway.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Atrial fibrillation (AF) is the most prevalent sustained arrhythmia, whose clinical management faces numerous challenges, including high recurrence rates and significant adverse effects associated with current therapies. Myricetin, a natural flavonoid compound, has shown unique therapeutic potential due to its multitarget cardioprotective properties and favorable safety profile. This study aimed to elucidate the specific molecular mechanisms through which myricetin mitigates AF.
Methods: Human atrial fibroblasts (hAFs) were transfected with or without short hairpin RNA (shRNA) targeting estrogen receptor 1 (ESR1) and subsequently exposed to various concentrations of myricetin and/or angiotensin II (Ang II). To examine the involvement of autophagy and oxidative stress, specific groups were treated with the autophagy inhibitor 3-methyladenine (3-MA) and the antioxidant N-acetyl cysteine (NAC). Then efficacy evaluation was performed employing 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays for cell viability, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, flow cytometry, and co-immunoprecipitation (Co-IP) analyses.
Results: Myricetin effectively reversed Ang II-induced reductions in cell viability and increases in apoptosis (p < 0.05). It significantly stabilized ESR1 by attenuating reactive oxygen species (ROS)-dependent ubiquitination (p < 0.001), leading to marked decreases in endoplasmic reticulum (ER) stress markers (glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein (CHOP)), as well as autophagy indicators (Beclin and microtubule-associated proteins 1A/1B light chain 3B (LC3II/LC3I)) (p < 0.01).
Conclusion: Myricetin emerges as a promising therapeutic candidate for AF management by reducing ESR1 ubiquitination and suppressing ER stress-related autophagy, thereby enhancing cellular resistance to stress-induced injury. These findings suggest that myricetin could be incorporated into existing AF therapeutic strategies to improve efficacy and safety outcomes.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Liver cancer represents a major global health burden, and targeted therapy combined with immune checkpoint inhibitors (ICIs) has become an essential systemic treatment. However, treatment-related symptom clusters may markedly impair quality of life (QOL). This study aimed to examine the longitudinal evolution of symptom clusters and their impact on QOL in patients with malignant liver tumors across the first to fourth treatment phases.
Methods: A prospective cohort of 150 patients receiving combined targeted-ICI therapy was recruited at a tertiary hospital in Qingyuan, China, between January and August 2025. The Chinese version of the Memorial Symptom Assessment Scale (MSAS-C) and the Quality of Life–Liver Cancer (QOL-LC) V2.0 questionnaire were distributed and collected on Day 7 of each treatment phase. The symptom-onset timeline was provided to patients at the initiation of therapy and retrieved on Day 7 of the first phase. Factor analysis, Apriori association rule mining, repeated-measures analysis of variance (ANOVA), correlation analysis, and stepwise multiple regression were applied to identify the dynamic structure of symptom clusters and their associations with QOL outcomes.
Results: The final cohort comprised 150 patients with a mean age of 53.62 years; 67.33% were diagnosed with hepatocellular carcinoma (HCC), and most were in advanced stages. Symptom burden increased progressively during treatment, with high-frequency symptoms, such as fatigue, dry mouth, weight loss, and sleep disturbance, affecting more than 70% of patients by Phase 4. Factor analysis identified 5, 4, 4, and 5 significant symptom clusters at T1–T4, respectively, while Apriori analysis further revealed key antecedent symptoms such as nausea, pain, and nervousness. All five symptom clusters demonstrated significant increases in severity over time (p < 0.001), especially those involving emotional-psychological and gastrointestinal symptoms. QOL scores declined markedly during Phases 3 and 4, with significant impairments in physical, psychological, and social functioning (all p < 0.01), and an overall score reduction exceeding 20 points (p < 0.001). Self-reported evaluations also revealed a substantial decline. The symptom clusters exhibited moderate to strong negative correlations with QOL, with the psychiatric symptom cluster showing a progressively stronger negative association with overall QOL scores from T1 to T4 (r = –0.51 to –0.64). Regression analyses identified psychiatric and emotional–psychological clusters as the strongest predictors of reduced QOL across all treatment stages (p < 0.001). In later phases, liver function-metabolic and gastrointestinal clusters also emerged as significant contributors. Demographic variables, including gender and treatment phase, exerted additional effects. The regression model demonstrated a good fit and stable residuals.
Conclusions: Combined targeted-ICI therapy is associated with a progressive increase in symptom cluster burden among patients with liver cancer, leading to a significant decline in QOL. Emotional and psychological symptom clusters exert the most persistent and profound effects, while liver function–metabolic and gastrointestinal symptom clusters become increasingly prominent in later stages.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Silicosis is a chronic, irreversible occupational pulmonary disorder characterized by persistent inflammation and fibrotic remodeling, with endoplasmic reticulum (ER) stress implicated in its pathogenesis. Fluorofenidone (AKF-PD), an anti-fibrotic agent, has shown protective properties in pulmonary fibrosis. This study aimed to evaluate the therapeutic effects of AKF-PD on silica-induced pulmonary fibrosis and elucidate its underlying molecular mechanisms.
Methods: A murine silicosis model was established through intratracheal instillation of a silica suspension. Mice were randomly divided into three groups: control, silica, or silica + AKF-PD (24 mice per group). Lung tissues were collected at 7, 14, and 28 days for histopathological analysis (hematoxylin and eosin (HE) and Masson staining), inflammation and fibrosis scoring, enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative real-time PCR (RT-qPCR), and western blotting. In vitro, MLE-12 cells were treated with silica in the presence or absence of AKF-PD or the ER stress inhibitor 4-PBA (4-PBA). Oxidative stress indices (malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione (GSH)), inflammatory cytokines (interleukin (IL)-6, IL-1β), fibrosis markers (α-SMA, Fibronectin 1, Collagen IV), and ER stress-related proteins (Grp78, Chop, Xbp1, phospho-Ire1a, phospho-Eif2a) were quantified.
Results: In vivo, AKF-PD significantly attenuated alveolitis and fibrosis scores compared with the silica group, with Masson staining confirming reduced collagen deposition (p < 0.001). ELISA and RT-qPCR analyses showed decreased IL-6 (Il6) and IL-1β (Il1b) expression, while western blotting revealed downregulation of α-SMA, Fibronectin 1, and Collagen IV. ER stress markers (Grp78, Chop, Xbp1, phospho-Ire1a, phospho-Eif2a) and oxidative stress indices (MDA, ROS) were suppressed, accompanied by elevated GSH levels and SOD activity (p < 0.05). In vitro, AKF-PD reduced silica-induced production of inflammatory cytokines, fibrotic proteins, and ER stress mediators in MLE-12 cells (p < 0.05). These effects were comparable to those of 4-PBA, indicating that modulation of ER stress and oxidative stress contributed to the observed protection.
Conclusions: AKF-PD alleviates silica-induced pulmonary inflammation and fibrosis in vivo and in vitro. Its protective effects are associated with the regulation of ER stress and oxidative stress pathways, highlighting AKF-PD as a promising therapeutic candidate for silicosis.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Parkinson's disease (PD) is a neurodegenerative disorder that affects motor and non-motor functions. However, the molecular mechanisms underlying PD remain unclear, and effective treatments are limited. Recent advances in single-cell RNA sequencing provide new insights into PD. Therefore, this study aims to explore cellular and molecular changes in PD using high-dimensional transcriptomic analysis.
Methods: This study analyzed single-cell RNA sequencing data (GSE157783) and gene expression data from the substantia nigra (GSE20292 and GSE20333). Dimensionality reduction and clustering identified 17 cell populations, and differential gene expression analysis identified signal transducer and activator of transcription 6 (STAT6) as a key regulator, which was further examined in PD model cells.
Results: Single-cell analysis revealed significant differences (p < 0.05) in specific cell populations between PD and control samples. STAT6 was identified as a key gene upregulated in both single-cell and tissue-level datasets. In vitro experiments showed that the overexpression of STAT6 in PD model cells reduced apoptosis and α-synuclein aggregation, while improving cell viability and migration (p < 0.05) by activating the mechanistic target of rapamycin (mTOR) signaling pathway. Conversely, STAT6 knockdown significantly increased apoptosis and aggregation of α-synuclein, and reduced cell viability and migration (p < 0.05). Additionally, the neuroprotective effect of STAT6-overexpression was significantly inhibited by the mTOR inhibitor, Rapamycin (p < 0.05).
Conclusion: This study highlights STAT6 as a key molecular regulator in PD, suggesting that targeting the STAT6-mTOR axis could be a promising therapeutic strategy in managing this disease. Future research should focus on further elucidating the role of STAT6 in the progression of PD and evaluating its therapeutic potential.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide, with a high mortality rate that is closely associated with chronic inflammation and aberrantly activated signaling pathways in the tumor microenvironment. As a central regulator of inflammatory responses, the IκB kinase (IKK)/nuclear factor-κB (NF-κB) signaling pathway plays a critical role in the proliferation, invasion, and immune escape of HCC. This study analyzes the clinical significance of the IKK/NF-κB pathway in predicting the prognosis of HCC patients.
Methods: A total of 206 HCC patients from 2022 to 2025 were included in this study and divided into the death group (n = 117) and the survival group (n = 89) according to their survival status. The content of IKK, NF-κB p65 and downstream proteins interleukin-6 (IL-6) and cyclin D1 were analyzed using enzyme-linked immunosorbent assay (ELISA). Combined with the clinicopathological characteristics, Kaplan–Meier survival analysis and Cox proportional hazards model were used to evaluate the association between pathway activity and the risk of patient death.
Results: There was no significant difference in the baseline data between the two groups of patients (p > 0.05). The serum content of IKK and NF-κB p65 in the death group was significantly higher than that in the survival group (p < 0.05). Survival analysis showed that the high expression of IKK and NF-κB p65 was significantly associated with reduced overall survival (OS) in patients (p < 0.05). Multivariate Cox regression showed that IKK, NF-κB p65 and IL-6 were independent predictors of poor prognosis (p < 0.05).
Conclusion: Aberrant activation of the IKK/NF-κB signaling pathway is associated with death risk in HCC patients, serving as an independent prognostic marker.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by immune dysregulation, particularly the imbalance between T helper 1 (Th1) and regulatory T (Treg) cells, which plays a crucial role in its pathogenesis. Members of the protein tyrosine phosphatase (PTP) family are involved in immune regulation, and the protein tyrosine phosphatase receptor-type O (PTPRO) is significantly upregulated in inflamed tissues. However, the specific role of PTPRO in UC remains unclear. This study aimed to investigate the role and mechanisms of PTPRO in UC to identify new therapeutic targets.
Methods: A mouse model of UC was induced using dextran sulfate sodium (DSS), and PTPRO expression was examined in the colonic tissues of both mice and UC patients. PTPRO knockout (PTPRO-/-) mice were used to assess the impact of PTPRO deficiency on UC severity and the regulation of Th1/Treg cell balance. Primary T cells were isolated from mice to explore the signaling pathways regulated by PTPRO.
Results: PTPRO expression was significantly elevated in inflamed colonic tissues from both DSS-treated mice and UC patients (p < 0.05). PTPRO-/- mice exhibited attenuated colitis, manifesting as reduced body weight loss, lower Disease Activity Index (DAI) scores, and markedly improved histopathology compared to wild-type (WT) mice (all p < 0.05). Knockout of PTPRO reduced colonic levels of pro-inflammatory cytokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)) while increasing anti-inflammatory mediators (interleukin-10 (IL-10) and Forkhead box P3 (Foxp3)) (p < 0.05). Consistently, flow cytometry analysis demonstrated that PTPRO-/- mice had fewer Th1 cells and more Tregs in the colon, suggesting the restoration of immune homeostasis (p < 0.05). Mechanistically, PTPRO was found to interact with Janus kinase 2 (JAK2) and function as a negative regulator of JAK2–signal transducer and activator of transcription 5 (STAT5) signaling. Loss of PTPRO led to increased phosphorylation of JAK2 and STAT5, thereby promoting Treg differentiation, whereas in vivo JAK2 inhibition reversed these effects.
Conclusion: PTPRO regulates the Th1/Treg balance via the JAK2-STAT5 pathway, and its absence shifts the immune response toward anti-inflammatory Tregs, highlighting PTPRO as a potential therapeutic target for UC.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Colorectal cancer (CRC) is one of the highly prevalent malignancies worldwide and a leading cause of cancer-related mortality, with limited therapeutic options, particularly in advanced stages. This study investigates the role of the FOS-like antigen 1 (FOSL1)/ankyrin repeat domain 22 (ANKRD22) axis in regulating CRC through mitochondrial function.
Methods: ANKRD22 expression patterns in CRC tissues and adjacent normal tissues were analyzed using The Cancer Genome Atlas (TCGA) data. In vitro experiments were performed using CRC cell lines, where FOSL1 and ANKRD22 expression was manipulated via plasmid-mediated overexpression or short hairpin RNA (shRNA)-based silencing. Stemness was assessed using sphere formation assays, cloning assays, and Western blotting to profile expression of stemness-related proteins. FOSL1 binding to the ANKRD22 promoter was validated by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Mitochondrial status was evaluated by measuring reactive oxygen species (ROS), calcium levels, and membrane potential.
Results: TCGA data and in vitro analyses revealed that both FOSL1 and ANKRD22 were highly expressed in CRC cells (p < 0.05). Overexpression of FOSL1 or ANKRD22 in CRC cells significantly enhanced cell proliferation, sphere formation capacity, clonogenic potential, and expression of stemness-related proteins (p < 0.05). FOSL1 directly bound to the ANKRD22 promoter and transcriptionally upregulated its expression (p < 0.05). FOSL1 overexpression decreased mitochondrial ROS, calcium, and membrane potential (p < 0.05). Crucially, silencing ANKRD22 reversed the effects of FOSL1 overexpression on stemness (sphere formation, clonogenicity, stemness-related proteins) and mitochondrial parameters (ROS, calcium, membrane potential) (p < 0.05).
Conclusion: FOSL1 transcriptionally activates ANKRD22, which regulates mitochondrial function by controlling ROS, calcium, and membrane potential, to modulate CRC development. Targeting the FOSL1/ANKRD22 axis may represent a strategy to impede CRC progression.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Sickle cell anemia (SCA) is an inherited disorder characterized by chronic hemolysis and persistent hematological abnormalities. This study investigated the association of the hypoxia-inducible factor-1 alpha (HIF-1α) C1772T genetic variant, a key regulator of the hypoxic response, with hematological indices in SCA patients.
Methods: This case-control study included 100 adult SCA patients and 100 age- and gender-matched healthy controls in Taif. Hematological parameters were measured, and HIF-1α C1772T genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analyses were performed using Student's t-test or the Mann-Whitney U test, Chi-square (χ2) test, and odds ratio (OR) calculations with confidence intervals (CI).
Results: SCA patients exhibited markedly reduced hemoglobin (t = 27.59, p < 0.0001) and hematocrit levels (t = 41.54, p < 0.0001), and elevated white blood cell (t = 7.45, p < 0.0001) and platelet counts (t = 9.22, p < 0.0001). The CT genotype occurred more frequently in SCA patients (18%) than in controls (7%) (χ2 = 5.5, p = 0.019; OR = 2.91, 95% CI: 1.16–7.33). Similarly, the T allele frequency was higher among SCA patients (9%) than controls (3.5%) (χ2 = 5.2, p = 0.023; OR = 2.72, 95% CI: 1.11–6.68). Among SCA patients, carriers of the CT genotype had significantly higher hemoglobin (t = 2.83, p = 0.005), hematocrit (t = 3.05, p = 0.002), and fetal hemoglobin levels (p = 0.047), but lower serum ferritin levels (p = 0.026) than CC carriers.
Conclusions: The HIF-1α C1772T polymorphism is associated with SCA in this population. The presence of the T allele, particularly in the heterozygous CT genotype, may increase susceptibility to SCA. Additionally, CT carriers exhibited a more favourable hematological profile than those with the CC genotype. These findings suggest that this polymorphism may influence susceptibility to SCA, pathophysiology, and clinical severity of SCA.
Abstract (
)
Download PDF (
)
HTML
(
)
Knowledge map
Save
Background: Ischemic stroke remains a leading cause of disability and mortality worldwide, with limited therapeutic options beyond acute reperfusion. Promoting angiogenesis and collateral circulation in ischemic penumbra is crucial for neurological recovery, yet the underlying mechanisms are not fully understood. This study investigates the regulatory role of hydrogen sulfide (H2S) in angiogenesis and its associated molecular mechanisms in ischemic penumbra following transient focal cerebral ischemia in rats, with particular focus on examining the potential involvement of the Sonic hedgehog (SHH) signaling pathway.
Methods: Focal cerebral ischemia was induced via middle cerebral artery occlusion, with 90-minute reperfusion, in Sprague–Dawley rats. The rats were grouped as sham-7d, sham-14d, model-7d, model-14d, morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate (GYY4137)-7d, and GYY4137-14d, according to the treatment method and length of observation. Neurofunctional assessments included Longa scale and beam walking tests. Plasma H2S levels, cerebral blood flow, infarct volume, microvessel density, and expression of relevant proteins were measured using microassay, laser speckle imaging, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Ki67/CD31 co-immunofluorescence, double immunofluorescence, and Western blotting, respectively.
Results: In GYY4137-treated rats, neurobehavioral performance improved significantly and plasma H2S levels also significantly increased, compared to those of the model group (p < 0.05). Furthermore, cerebral blood flow showed substantial recovery, infarct volumes were significantly reduced, and microvessel density was augmented (p < 0.05). Immunofluorescence analysis revealed colocalization of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and angiopoietin 1 (ANG1) with CD31-positive endothelial cells. Western blot analysis demonstrated that ANG1, FGF2, VEGF, and SHH proteins were upregulated while cystathionine-β-synthase was downregulated in response to GYY4137 treatment (p < 0.05).
Conclusion: H2S upregulates the expression of VEGF, ANG1, and FGF2 proteins in the peri-infarct tissue of rats, accompanied by activation of the SHH signaling pathway, promoting angiogenesis and collateral circulation, thereby significantly improving neurological function. These findings suggest that the SHH signaling pathway may be involved in H2S-mediated pro-angiogenic effects, although further mechanistic validation is warranted.
