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Multiple myeloma (MM) is a hematological disease that remains largely incurable. The introduction of proteasome inhibitors (PIs) at the turn of the century led to prolonged survival of patients, though most will inevitably develop resistance over successive treatments. It is of great clinical interest, then, to resensitize MM cells to PIs. This review discusses some of the most well-established resistance pathways, such as alterations in the proteostasis network and the bone marrow microenvironment. Novel targets are highlighted and placed in the context of potential treatment strategies where applicable.
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This descriptive review synthesizes mechanistic and clinical evidence on the periodontal disease (PD)–atherosclerotic cardiovascular disease (ASCVD) axis to clarify how oral inflammation, bacterial translocation, immune dysregulation, and oxidative stress may influence vascular pathology and to identify where causal inference and interventional evidence remain insufficient. We searched PubMed, Web of Science, ScienceDirect, and Google Scholar for studies on microbial translocation, systemic inflammation, endothelial dysfunction, and interventional outcomes. Evidence supports a robust epidemiological association between PD and ASCVD; proposed mechanisms prominently involve Porphyromonas gingivalis-driven immune modulation and endothelial injury. Periodontal therapy consistently reduces inflammatory biomarkers and improves surrogate vascular measures, while effects on hard cardiovascular outcomes are suggestive but not definitive. Recognizing PD as a modifiable oral inflammatory condition may refine cardiovascular risk assessment and motivate integrated prevention, while future work should prioritize well-designed randomized trials with standardized PD/ASCVD phenotyping.
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This review provides a comprehensive and up-to-date overview of viral skin diseases, integrating recent epidemiological findings, advances in pathophysiological and molecular mechanisms, and the latest diagnostic and therapeutic strategies, with the goal of informing both research and clinical practice. Relevant literature published between January 2015 and January 2025 was retrieved from PubMed, Web of Science, and official documents from the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC). Studies addressing epidemiology, molecular mechanisms, diagnostic approaches, therapeutic strategies, and clinical guidelines for viral skin diseases were systematically reviewed, analyzed, and summarized. Recent epidemiological evidence demonstrates persistent regional disparities in the prevalence of major viral skin infections caused by human papillomavirus (HPV) and herpes simplex virus (HSV). Advances in molecular research have elucidated key mechanisms, including viral immune evasion, latency, and reactivation, which are closely associated with diagnostic refinement and therapeutic development. Diagnostic precision has improved through nucleic acid amplification techniques, while novel therapeutic approaches, including targeted immunomodulatory agents and expanded vaccination programs, offer potential to overcome longstanding treatment bottlenecks. This review highlights the integration of epidemiological trends, molecular insights, and standardized clinical guidelines to provide a comprehensive reference for clinicians and researchers. We propose that elucidating molecular mechanisms underlying viral skin diseases, particularly those involving viral immune evasion and host immune regulation, will facilitate the development of targeted immunomodulatory strategies to enhance patient outcomes.
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Influenza A virus (IAV) is an obligatory intracellular microbial pathogen. It causes seasonal epidemics, occasional pandemics, and zoonotic outbreaks of an acute febrile respiratory disease called influenza, commonly known as flu, in humans. IAV is an enveloped virus and possesses a single-stranded, negative-sense RNA genome which has a linear but segmented configuration and is composed of eight gene segments. The non-structural 1 (NS1) protein is encoded by the eighth gene segment and, as the name suggests, is not packaged into IAV particles but found only in infected cells. NS1 is an IAV virulence factor, and the IAV mutants lacking NS1 exhibit attenuated phenotype. NS1 is composed of two major domains—the N-terminal RNA-binding domain and the C-terminal effector domain, which are joined by a small linker region, and the effector domain is flanked by a C-terminal tail. NS1 is truly a multi-functional protein and exploits or subverts multiple host pathways, e.g., mRNA splicing, nuclear export and translation, innate antiviral response, phosphatidylinositol-3-kinase signaling, to facilitate IAV multiplication and pathogenesis. This review summarizes the targeting of those host pathways and their components by NS1 and highlights the potential of NS1 as an antiviral drug target and the development of IAV NS1 mutants as a flu vaccine.
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In preclinical drug development, the success rate of carrying candidates from phase I trials to final approval is as low as ~10%. Initially, compounds hitting specific molecular targets are selected via testing on permanent cell lines, xenotransplants, and animal experimentation. However, numerous failed clinical trials demonstrate that these models lack sufficient predictive power. In contrast to established cell lines altered by extended periods in tissue culture, freshly isolated cancer cells may represent original characteristics. For typical solid tumors, access to representative tumor cells is difficult, although pleura-derived tumor cells of advanced lung cancer patients may provide a notable exception to obtain original cell suspensions. These lung cancer cells can be used directly or upon the establishment of cell lines, which can be obtained rapidly at a high take rate due to the aggressive nature of these tumors. In contrast to established permanent cell lines, freshly isolated cells exhibit higher resistance and may more accurately predict responses. Furthermore, these cell lines can be validated within the framework of functional precision medicine for personalized chemotherapy by comparing the in vitro chemosensitivity profile of cells to clinical responses for specific inhibitors directed at mutated drivers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1, receptor tyrosine kinase (ROS1), and neurotrophic tropomyosin receptor kinase (NTRK) oncogenes in non-small cell lung cancer (NSCLC). This review discusses the use of freshly cultivated lung cancer cells from pleural effusions and highlights their value in generating clinically relevant predictive data, in contrast to permanent cell lines.
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Migraine is a common neurological condition that may be caused by changes in the weather, stress, trouble sleeping, changing hormones, and not eating for a long time. These causes can affect how the brain works, making the nerves active, changing blood flow, and making the brain more excitable, which can lead to initiation of migraines and how irritating they feel. Identifying underlying environmental factors is important for figuring out how to potentially prevent and manage these health issues. In general, medical strategies like computed tomography (CT) scan and magnetic resonance imaging (MRI) can find out if there are any changes even very small in the brain structure and hence improved the overall diagnosis, but they are not fully accurate in determining migraines. Advanced machine learning and deep learning methods were created to help doctors find out about and treat diseases more accurately and quickly, since the traditional tests are not always perfect. These treatment methods include both treating right away when someone needs it and steps that try to prevent illnesses from happening. Beta-blockers, some seizure medicines, antidepressants, and a new class of medicines like calcitonin gene-related peptide (CGRP) antibodies all help prevent migraines and can be used as a treatment. Chronic medications like triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and CGRP receptor antagonists can help with the pain patients feel. Furthermore, non-medication methods like talking therapy, changing daily habits, and using electrical devices can help manage migraine. With advanced tools like artificial intelligence (AI) and machine learning, doctors are now able to find out what might be causing migraines in patients in ways that go past just using regular scans. AI-driven tools look at things like medical history, gene information, and scans to help find certain patterns of migraines, guess when an attack might happen, and suggest ways to help manage the condition. These technologies help doctors perform surgery with more precision, find diseases early, come up with better treatment plans, and help patients recover more successfully. As with each passing day, AI is put into more use in healthcare, it will help make migraine research and management better by giving a more accurate and individualized way to care for people with migraines.
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Lipids are a broad group of hydrophobic macromolecules that play critical roles in cell physiology, specifically in metabolism, membrane synthesis and signaling, which also includes the physiology of cancer cells. Due to the metabolic changes in cancer cells, lipids are used as an important energy source and signaling intermediates, which support the progression and survival of the transformed cells. Cholesterol is also an important part of these mechanisms, since it is an essential component of lipid rafts, which act as membrane platforms for signal transduction. Apart from the metabolism and signaling implication of lipids in cancer cells, these molecules may also affect histone modifications and the tumor microenvironment, modifying gene expression, cytokines secretion and the infiltration of white blood cells in the tumor, impeding tumor detections and clearance by the immune system. Due to the preponderant role of lipids in malignant cells, enzyme lipid uptake and synthesis represent potential therapeutic targets that are being studied to provide a complete treatment that focuses on different mechanisms to kill malignant cells. This review aims to provide a metabolic explanation about the influence of lipids in the survival of cancer cells, the immune response evasion, as well as some potential therapeutic targets that regulate these processes.
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Background: Autophagy is essential for effective bacterial clearance, in which the E3 ubiquitin ligase beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) participates. Herein, investigation was performed regarding the role of BTRC in post-traumatic brain injury (TBI)-associated bacterial pneumonia, alongside elucidation of the downstream mechanisms involving Unc-51 like autophagy activating kinase 1 (ULK1).
Methods: Using post-TBI mouse models and primary alveolar macrophages (PAM), we examined the effects of Pseudomonas aeruginosa K-strain (PAK) infection and BTRC silencing on pulmonary inflammation and bacterial clearance. Inflammatory cytokines, lung pathology and PAM viability were analyzed. Bacterial clearance in lung tissues, as well as intracellular killing and phagocytosis in PAM, was evaluated by colony-forming assays. Expressions of autophagy-related markers were measured employing western blot and immunofluorescence. ULK1 ubiquitination was assessed via immunoprecipitation. To confirm the involvement of ULK1, experiments with both BTRC and ULK1 knockdown were performed.
Results: PAK infection impaired bacterial clearance, suppressed autophagy and increased inflammatory cytokine levels in both lung tissues and PAMs, while these pathological changes were significantly reversed by BTRC knockdown (p < 0.01). Mechanistically, PAK infection promoted ULK1 ubiquitination in PAMs, which was offset by BTRC silencing; however, ULK1 knockdown neutralized the effects of BTRC silencing, as indicated by repressed autophagy activity and bacterial clearance, and enhanced inflammatory responses (p < 0.05).
Conclusion: BTRC silencing alleviates PAK-induced bacterial pneumonia after TBI by enhancing macrophage-mediated bacterial clearance through inhibition of ULK1 ubiquitination and activation of autophagy, a process critically dependent on ULK1 stability.
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Background: Innovative therapies are urgently required for treating insomnia, a prevalent neurological disorder associated with multisystem comorbidities. This study aims to explore the neuroprotective potential of right-sided stellate ganglion block (SGB) against insomnia-induced neuronal damage and cognitive dysfunction, focusing on ferroptosis modulation through the nuclear factor-erythroid 2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) pathway.
Methods: A rat model of insomnia was established through para-chlorophenylalanine (PCPA) induction. Interventions tested in this study included right-sided SGB (1% lidocaine), ferroptosis modulators (RAS-Selective Lethal 3 (RSL3), ferrostatin-1 (Fer-1)), and an NRF2 inhibitor (ML385). Cognitive performance of the rats was evaluated using the Morris water maze. Neuronal integrity was examined through histopathologic assessments (HE/Nissl staining), evaluation of synaptic markers (synuclein (SYN)/postsynaptic density protein 95 (PSD-95) immunohistochemistry), and detection of glial activation (ionized calcium-binding adaptor molecule 1 (Iba-1)/glial fibrillary acidic protein (GFAP) immunofluorescence). Neurotransmitters (serotonin (5-HT)/γ-aminobutyric acid (GABA)/dopamine (DA)/noradrenaline (NE)), brain redox status (malondialdehyde (MDA)/glutathione (GSH)/reactive oxygen species (ROS)), and neuroinflammation (tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/interleukin-6 (IL-6)) were assessed by means of ELISA. Western blotting was used to analyze the expression of proteins related to iron metabolism (ferritin heavy chain (FTH1)/ferritin light chain (FTL)/transferrin receptor 1 (TFR1)) and the NRF2/GPX4 pathway.
Results: SGB treatment reversed PCPA-induced cognitive deficits, as evidenced by reduced escape latency and increased target quadrant dwell time (p < 0.05). Histologic staining revealed that SGB rescued synaptic density and attenuated neuronal loss (p < 0.05). Mechanistically, SGB suppressed ferroptosis by normalizing iron homeostasis, suppressing lipid peroxidation, and inhibiting ROS overproduction, while mitigating neuroinflammation (both p < 0.05). Treatment with ML385 negated SGB's benefits, indicating that these effects can be mediated by NRF2/GPX4 pathway activation, whereas Fer-1 restored the neuroprotective effects of SGB (p < 0.05).
Conclusion: Right-sided SGB alleviates cognitive deficits and neuronal injury in insomniac rats by activating the NRF2/GPX4 pathway to inhibit ferroptosis and neuroinflammation, offering a novel neuromodulatory therapy for insomnia-related neurodegeneration.
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Background: Several studies have explored the association between alkaline phosphatase (ALP) and venous thromboembolism (VTE), yet the findings remain inconclusive and inconsistent. The correlation between them has yet to be definitively established. We conducted a multicenter cohort study and a two-sample Mendelian randomization (MR) analysis with the aim of investigating the association between serum ALP levels and acute VTE in East Asian populations.
Methods: We collected data on VTE patients from Taizhou Municipal Hospital and Taizhou Hospital of Zhejiang Province between January 2019 and October 2024, alongside data from routine health check-up participants as the control group. Employing propensity score matching (PSM) and cubic spline model analysis, we investigated the relationship between ALP levels and VTE. Additionally, we performed a bidirectional two-sample MR analysis using genome-wide association study (GWAS) data to assess the potential causal effect between them.
Results: The retrospective cohort study involving 720 VTE patients and 1000 healthy controls found significantly lower ALP levels in the VTE group, which remained consistent after propensity score matching, with a non-linear relationship between ALP levels and VTE risk. Two-sample MR analysis confirmed a negative causal effect of ALP on VTE, with no evidence of pleiotropy in the results.
Conclusions: Our study suggested a negative association between ALP levels and the risk of VTE in the East Asian population. This finding may provide valuable insights into the role of ALP as a potential biomarker for VTE risk assessment.
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Background: Immunoglobulin A nephropathy (IgAN) is a common primary glomerular disease characterized by the deposition of IgA or its complexes in the renal mesangium. Despite the availability of medications for treating IgAN, finding more effective treatment methods remains a critical need. Angelicin has shown potential therapeutic effects on IgAN due to its unique anti-inflammatory and antioxidative properties.
Methods: Immunofluorescence, Western blotting and enzyme-linked immunosorbent assay (ELISA) approaches were employed to investigate the therapeutic efficacy of angelicin in a rat model with IgAN. The hTFtarget database was used to predict estrogen receptor 1 (ESR1) targets, while analysis of the GSE35489 dataset through the Gene Expression Omnibus (GEO) database was conducted to identify the role of Fos proto-oncogene (FOS) in fibrosis regulation.
Results: Treatment with angelicin significantly reduced IgA deposition, improved kidney tissue structure, decreased the rate of cell apoptosis, alleviated renal fibrosis (p < 0.01), and suppressed the expression of inflammation markers interleukin (IL)-1β, IL-6, and IL-18 (p < 0.001). Moreover, the expression of ESR1, FOS, phosphorylated c-Jun (p-c-Jun) and phosphorylated mitogen-activated protein kinase (p-MAPK) was downregulated by angelicin in a dose-dependent manner (p < 0.05).
Conclusions: Angelicin can effectively mitigate renal fibrosis and inflammation in IgAN via the ESR1-FOS signaling pathway, highlighting its potential as a viable therapeutic agent for IgAN. This discovery provides new molecular targets and a theoretical basis for the pharmacological treatment of IgAN.
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Background: Chronic stress-related disorders, such as cardiovascular neurosis, are frequently associated with elevated cortisol levels, which can impair mitochondrial function and contribute to cardiomyocyte injury. Fibroblast growth factor 19 (FGF19), a metabolic regulator with known cytoprotective properties, has been implicated in the maintenance of mitochondrial homeostasis. However, its role in mitigating cortisol-induced cardiac stress remains poorly understood. This study aimed to investigate whether FGF19 confers protection to cardiomyocytes against cortisol-induced mitochondrial dysfunction and apoptosis, and to elucidate the underlying molecular mechanisms.
Methods: Human AC16 cardiomyocytes were treated with cortisol and subjected to either FGF19 overexpression or knockdown. Cell viability, apoptosis, and mitochondrial function were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), adenosine triphosphate (ATP) quantification, mitochondrial DNA (mtDNA) copy number analysis, and mitochondrial membrane potential assessment using JC-1 dye, and reactive oxygen species (ROS) measurement. Western blot analysis was performed to examine the expression of proteins involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM), as well as proteins regulating mitochondrial dynamics, such as Mitofusin 1 and 2 (Mfn1/2) and dynamin-related protein 1 (Drp1).
Results: Cortisol treatment significantly downregulated FGF19 expression, impaired mitochondrial function, and increased apoptosis (p < 0.01). Overexpression of FGF19 enhanced mitochondrial biogenesis, preserved mitochondrial membrane potential, and reduced oxidative stress, thereby mitigating mitochondrial dysfunction and apoptosis (p < 0.01). Conversely, FGF19 knockdown aggravated mitochondrial damage, elevated ROS levels, further reduced cell viability, and promoted apoptosis (p < 0.01). The opposing phenotypes observed with FGF19 overexpression and silencing underscore its critical role in preserving mitochondrial integrity and promoting cell survival under cortisol-induced stress.
Conclusion: This study demonstrates that FGF19 mitigates cortisol-induced cardiomyocyte injury by improving mitochondrial function and reducing apoptosis. These findings provide experimental evidence supporting FGF19 as a potential therapeutic target for the treatment of cardiovascular neurosis and related stress-induced cardiac disorders.
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Background: Gestational diabetes mellitus (GDM), a common complication during pregnancy, is associated with impaired metabolism and endocrine dysfunction, thereby compromising maternal and fetal health. LIM and SH3 protein 2 (LASP2) has been reported to play regulatory roles in several diseases and has been found to be upregulated in the placental tissues of preeclampsia. However, the specific role of LASP2 and underlying signaling pathways in the progression of GDM largely remains uninvestigated. Therefore, this study aims to assess the impact of LASP2 on the high glucose-induced suppression of trophoblast cell proliferation and migration in GDM patients.
Methods: Placental tissue samples were obtained from women with normal pregnancies (n = 15) and those diagnosed with GDM (n = 15). The GDM cell model was successfully established by exposing HTR-8/SVneo cells to high glucose (30 mM). Furthermore, HTR-8/SVneo cells were transfected with siRNAs targeting LASP2 (si-LASP2#1 and si-LASP2#2), along with a negative control (si-NC). The expression levels of LASP2 were evaluated using RT-qPCR and Western blot analysis, and cell proliferation was determined using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Additionally, cell migratory capability was evaluated using wound healing and Transwell assays, and their angiogenic ability was assessed using the tube formation assay.
Results: LASP2 was upregulated in the placental tissues of patients with GDM (p < 0.001). Moreover, the cell viability of HTR-8/SVneo cells was significantly alleviated under high glucose conditions, an effect that was counteracted by LASP2 knockdown (p < 0.05). Similarly, cell migration ability was substantially suppressed under high glucose treatment; this impairment was effectively rescued by LASP2 silencing (p < 0.01). Additionally, angiogenic ability significantly decreased after high glucose treatment, an effect that was neutralized by LASP2 suppression (p < 0.001). LASP2 knockdown effectively provoked the Wingless-related integration site (Wnt)/β-catenin signaling pathway.
Conclusion: LASP2 knockdown effectively reverses high glucose-induced suppression of proliferation and migration in trophoblast cells by modulating the Wnt/β-catenin signaling pathway, providing novel insights into the role of LASP2 in GDM.
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Background: Arachidonate 5-lipoxygenase (ALOX5), a key enzyme in lipid metabolism and inflammation, has been linked to the progression of various cancer types. However, its specific function in thyroid cancer and the tumor immune microenvironment remains unclear.
Methods: ALOX5 expression in thyroid cancer tissues and cell lines was analyzed using The Cancer Genome Atlas (TCGA) and GTEx databases, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blotting. A series of cellular assays—namely cell counting kit-8 (CCK-8), 5-Ethynyl-2′-Deoxyuridine (EdU) incorporation, colony formation, wound closure, and Transwell invasion tests—were conducted to assess the impact of ALOX5 knockdown on cell proliferation, migration, and invasion. The expression levels of cytokines (C-C motif chemokine ligand 2 (CCL2) and colony-stimulating factor 1 (CSF1)) and M2 macrophage surface markers (Cluster of Differentiation 163 (CD163) and Cluster of Differentiation 206 (CD206)) were evaluated using RT-qPCR and Western blot analyses in both conditioned medium and co-culture models. Flow cytometry was performed to quantify the expression of CD163 and CD206 in THP-1–derived macrophages following exposure to conditioned medium from thyroid cancer cells or direct co-culture. Furthermore, expression levels of proteins associated with the Notch signaling pathway were evaluated, and rescue experiments with Jagged canonical Notch ligand 1 (Jagged1) overexpression were conducted to validate the specific role of this pathway.
Results: ALOX5 was significantly upregulated in thyroid cancer tissues and cell lines (p < 0.001). Silencing ALOX5 suppressed cell proliferation, migration, and invasion. Additionally, ALOX5 knockdown reduced CCL2 and CSF1 expression and inhibited M2 macrophage polarization. Mechanistically, ALOX5 positively regulated the Jagged1-Notch signaling pathway, as evidenced by decreased expression of Jagged1, Notch intracellular domain (NICD), Hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1), and Hairy and enhancer of split-1 (HES1) upon ALOX5 silencing. Additionally, overexpression of Jagged1 reversed the inhibitory effects of ALOX5 knockdown on tumor cell behavior and the production of immunosuppressive cytokines.
Conclusion: ALOX5 promotes thyroid cancer progression and the polarization of immunosuppressive tumor-associated macrophage polarization through activation of the Jagged1-Notch signaling cascade. Inhibiting ALOX5 could represent a promising therapeutic avenue for managing thyroid cancer by concurrently restraining tumor progression and reshaping the immune landscape of the tumor microenvironment.
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Background: Spinal cord injury (SCI) results in profound neurological dysfunction, involving calcium dysregulation, mitochondrial impairment, and lysosomal dysfunction. Transient receptor potential mucolipin 1 (TRPML1), a lysosomal calcium-permeable channel, plays a pivotal role in cellular homeostasis and lysosome–mitochondria crosstalk. Therefore, this study aims to elucidate the functional role and regulatory mechanisms of TRPML1 in SCI repair.
Methods: A T9–T10 contusive SCI model was established in C57BL/6 mice. TRPML1 was overexpressed via adeno-associated virus (AAV9), and its effects were assessed through behavioral assessments, histopathological examination, and molecular analyses. Furthermore, a hydrogen peroxide (H2O2)-induced NSC-34 motor neuron-like cell injury model was employed to validate the mechanisms in vitro.
Results: In vivo, TRPML1 overexpression significantly enhanced the expression of mitochondrial and lysosomal functional proteins (transcription factor EB [TFEB], lysosomal-associated membrane protein 1 [LAMP1], ATP synthase-α 1 [ATP5A1]), suppressed Cytochrome C levels, restored mitochondrial membrane potential, and alleviated both calcium overload and reactive oxygen species (ROS) accumulation (p < 0.01). Furthermore, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining revealed decreased apoptosis, whereas histological analysis showed preserved spinal cord architecture and diminished inflammatory infiltration. Additionally, basso mouse scale (BMS) scores demonstrated improved locomotor recovery. In vitro, TRPML1 was found to alleviate H2O2-induced NSC-34 cell damage, as evidenced by restored calcium homeostasis, reduced ROS, enhanced mitochondrial function, and attenuated apoptosis, indicating its consistent neuroprotective effects across models.
Conclusion: TRPML1 exerts neuroprotective effects by modulating calcium signaling and coordinating mitochondrial and lysosomal function, highlighting its therapeutic potential as a promising target for managing SCI repair.
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Background: Allicin has demonstrated promoting effects on the sensitivity of non-small cell lung cancer (NSCLC) cells to radiotherapy. Herein, we further explore the mechanism by which allicin improves NSCLC immunotherapy.
Methods: NSCLC cells were subjected to different concentrations of allicin, where protein levels of lysine demethylase 5B (KDM5B) and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) were measured. To unveil the mechanism of allicin, KDM5B overexpression plasmid and short hairpin RNA for SETDB1 (shSETDB1) were first constructed, and transfected into cells. The basic function and molecular expressions of NSCLC cells were examined. In vivo studies were performed through constructing hormonal tumour mice model. After administration of allicin and/or anti-programmed death receptor 1 (PD-1), changes in tumour growth, KDM5B and SETDB1 expressions, and immune cell infiltration were analyzed by tumour volume measurement, differentiation assays, immunohistochemical staining, and flow cytometry.
Results: Allicin down-regulated KDM5B and SETDB1 protein expressions in NSCLC cells (p < 0.05). Allicin inhibited NSCLC cell viability, migration and invasion, while promoting apoptosis (p < 0.05). Overexpression of KDM5B counteracted the therapeutic effect of allicin, while shSETDB1 reversed the effect of KDM5B (p < 0.05). In vivo, allicin significantly inhibited the growth of transplanted tumours, repressed the expressions of KDM5B and SETDB1, promoted CD8+ T-cell infiltration and reduced the proportion of tumour-associated macrophages (TAM) in the tumour (p < 0.05). With the addition of anti-PD-1 therapy, allicin showed synergistic adjuvant effects (p < 0.05).
Conclusion: Allicin inhibits the malignant function of NSCLC cells by regulating KDM5B/SETDB1 and potentiates the suppressing effect of anti-PD-1 therapy on tumour growth.
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Background: The practice of polypharmacy is prevalent among older adults and has been associated with mobility decline and cognitive impairment. However, its effects on gait performance in patients with cerebral small vessel disease (CSVD)—a population inherently vulnerable to gait disturbances—remain poorly understood. This study investigated the impact of polypharmacy on gait performance during single-task walking (STW) and dual-task walking (DTW) in patients with CSVD, and identified neuroimaging correlates associated with polypharmacy.
Methods: A total of 126 hospitalized individuals with CSVD were recruited. Based on the number of regularly used medications that had been in use for ≥2 weeks, patients were classified into three groups: non-polypharmacy (≤4 drugs, n = 47), polypharmacy (5–9 drugs, n = 49), or hyper-polypharmacy groups (≥10 drugs, n = 30). Gait speed and its coefficient of variation (CV) were recorded during STW and DTW. Magnetic resonance imaging was used to evaluate white-matter hyperintensities, lacunar infarcts, and cerebral microbleeds, which were integrated into a total CSVD burden score (0–3).
Results: During STW, the hyper-polypharmacy group had significantly slower gait speed (0.70 ± 0.20 m/s) compared to the non-polypharmacy and polypharmacy groups (both >0.91 m/s, p < 0.001). In DTW, gait speed decreased and CV increased across all groups, with the most pronounced impairments in the hyper-polypharmacy group (DTW speed: 0.59 ± 0.15 m/s; CV: 16.03%). Linear regression revealed that medication count was negatively associated with gait speed (STW β = –5.622, p < 0.001; DTW β = –8.484, p < 0.001) and positively with gait variability during DTW (β = 0.246, p < 0.001). The total CSVD score was independently associated with polypharmacy (p = 0.036).
Conclusion: The study confirmed a relationship between polypharmacy and locomotion in CSVD patients. Furthermore, total CSVD score—but not any single neuroimaging biomarker—is independently associated with the presence of polypharmacy.
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Background: Sepsis-induced myocardial injury, also known as septic myocardial injury (MI), significantly elevates mortality during life-threatening organ dysfunction. While 2,4-dienoyl-CoA reductase 1 (DECR1), a well-recognized gene signature in septic myocardium and blood, and catalase (CAT), which mitigates cardiac anomalies by suppressing ferroptosis, the interaction between them during septic MI pathogenesis remains unclear. Therefore, this study investigates the underlying mechanism by which DECR1 regulates catalase-mediated ferroptosis to confer cardio-protection.
Methods: We established in vivo septic MI rat models and in vitro human monocytic leukemia cells (THP-1) cell models using 10 mg/kg and 1 μg/mL lipopolysaccharide (LPS), respectively. DECR1 was overexpressed in both systems using lentiviral vectors. Rat serum and peripheral blood mononuclear cells (PBMCs) were isolated for subsequent analyses. Myocardial function was assessed through echocardiography (ejection fraction, fractional shortening). Histopathology (Hematoxylin-Eosin (H&E), Masson's trichrome), oxidative stress markers (MDA, 4-HNE) levels, and ferroptosis-related indicators (PTGS2, ACSL4) were evaluated. Furthermore, the apoptosis rate (Terminal deoxynucleotidyl-transferase-mediated dUTP-nick-end labeling (TUNEL), caspase-3) as well as levels of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6); Enzyme-linked immunosorbent assay (ELISA)) were assessed. Additionally, THP-1 ferroptosis (C11-BODIPY fluorescence), apoptosis levels (annexin V/PI), and antioxidant activities (CAT, superoxidase dismutase (SOD)) were also evaluated.
Results: In septic MI rats, DECR1 expression decreased in PBMCs, while its overexpression attenuated myocardial oxidative stress, accompanied by increased activities/expressions of CAT and SOD, reduced myocardial ferroptosis and histological anomalies, ameliorated cardiac dysfunction, and inhibited serous and myocardial inflammation and myocardial apoptosis (p < 0.05). Furthermore, DECR1 overexpression suppressed ferroptosis, enhanced CAT and SOD activities/expressions, and repressed apoptosis and inflammation in LPS-stimulated THP-1 cells (p < 0.05).
Conclusion: DECR1 deficiency in PBMCs exacerbates septic MI by promoting ferroptosis and inflammation. DECR1 overexpression activates CAT and SOD, thereby suppressing oxidative stress, macrophage ferroptosis, and apoptosis. This study is the first to demonstrate that PBMC-derived DECR1 regulates CAT activity to suppress ferroptosis and mitigate septic MI, offering a novel therapeutic approach for septic MI management.
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Background: Thrombospondin-1 (TSP-1) is a multifunctional glycoprotein involved in various physiological processes, including tissue repair and the regulation of angiogenesis. However, its role in bone regeneration remains unclear. This study aims to investigate the role of TSP-1 in promoting bone healing in a rat fracture model, with a particular focus on its effects on angiogenesis and the recruitment of mesenchymal stem cells (MSCs).
Methods: A stable femoral fracture model was established in rat. The experimental rat received treatment of TSP-1, MSCs, or a combination of both, and bone healing was assessed 2 weeks post-surgery. Micro-computed tomography (micro-CT) was used to evaluate bone regeneration by analyzing bone mineralization and trabecular parameters. Immunohistochemistry was performed to detect angiogenesis and bone formation markers (Cluster of Differentiation 105 (CD105), Cluster of Differentiation 31 (CD31), Bone Morphogenetic Protein-2 (BMP-2)). To investigate the mechanism by which TSP-1 promotes angiogenesis, 5-ethynyl-2′-deoxyuridine staining (EdU) staining was used to assess endothelial cell proliferation, and Western blotting was conducted to measure the protein expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF). A tube formation assay was used to evaluate the effect of TSP-1 on endothelial cell tube formation. Additionally, MSCs were co-cultured with TSP-1 for 7 days, and Transwell migration assays were performed to evaluate MSC migration. Tube formation assays were also used to assess vascular differentiation potential of MSCs. Immunofluorescence staining was performed to detect the expression of endothelial cell markers CD31, vascular endothelial growth factor receptor 1 (VEGFR1), and vascular endothelial growth factor receptor 2 (VEGFR2) in MSCs.
Results: Two weeks post-surgery, the TSP-1 and MSC groups exhibited significantly more callus, denser trabecular bone, and higher mineralization levels compared to the model group (p < 0.05). The TSP-1+MSC group showed superior fracture healing, bone mineralization, trabecular thickness, and bone density compared to the single-treatment TSP-1 and MSC groups (p < 0.05). Immunohistochemical analysis revealed that, compared to the model group, the expression of CD105, CD31, and BMP-2 was significantly increased in the TSP-1 and MSC groups (p < 0.05), with the TSP-1+MSC group showing higher expression levels than the single treatment groups (p < 0.05). Hematoxylin-eosin staining results showed that in the TSP-1 and MSC groups, fibrous tissue was gradually replaced by bone tissue, with mature bone formation observed. The TSP-1+MSC group exhibited more mature bone tissue. In vitro, TSP-1 treatment significantly promoted endothelial cell proliferation and tube formation, with higher protein expression levels of COX-2 and VEGF detected as compared to the control group (p < 0.05). Additionally, TSP-1 significantly enhanced MSC migration and tube formation, and upregulated the expression of endothelial cell markers CD31, VEGFR1, and VEGFR2 in MSCs (p < 0.05).
Conclusions: Both TSP-1 and MSCs, whether used alone or in combination, significantly promoted bone formation and angiogenesis during the fracture healing process. The combined treatment with TSP-1 and MSC showed the most significant effects, suggesting a synergistic role in accelerating fracture repair. These results provide new evidence for the potential applications of TSP-1 and MSCs in bone fracture healing and vascular regeneration.
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Background: Eicosapentaenoic acid (EPA) effectively modulates immune responses and reshapes the gut microbiota. Therefore, this study aims to investigate the role of EPA in modulating the composition of gut microbial and restoring mitochondrial and efferocytic function in atherosclerosis (AS).
Methods: Male apolipoprotein E knockout (ApoE-/-) mice were fed a high-fat diet to induce AS and then subjected to EPA treatment. Fecal microbiota transplantation (FMT) was performed using fecal samples from untreated AS mice. Histopathological changes in the aortic root were assessed using hematoxylin and eosin staining and Oil Red O staining approaches. Serum lipid profiles were quantified using corresponding biochemical assays. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were evaluated using 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) and 2′,7′-dichlorofluorescein diacetate (DCFH-DA) staining, respectively. Efferocytosis was analyzed using Diff-Quick staining, and the composition and functions of the gut microbiota were analyzed using 16S rRNA gene sequencing.
Results: EPA treatment attenuated AS progression and improved serum lipid profiles by reducing total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C). Furthermore, EPA treatment restored mitochondrial membrane potential, reduced ROS production, and enhanced macrophage efferocytosis in the aorta. Microbial analysis revealed that EPA reshaped the composition of gut microbiota by enriching beneficial bacterial taxa and altering metabolic pathways, including those related to carbohydrate metabolism and xenobiotic degradation. Notably, FMT from AS mice effectively reversed the protective effects of EPA on mitochondrial function, ROS levels, and efferocytosis.
Conclusion: This study demonstrates that EPA alleviates atherosclerotic pathology by modulating the composition of gut microbiota, restoring mitochondrial function, and enhancing efferocytosis. The findings support the therapeutic potential of EPA as a microbiota-targeting intervention for cardiovascular disease.
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Background: Bladder cancer is a prevalent malignancy of the urinary system, exhibiting extraordinarily complex pathogenesis involving multidimensional interactions between genetic and environmental factors. Substantial evidence confirms the pivotal role of genetic determinants in bladder carcinogenesis and progression. Although genome-wide association studies (GWAS) have successfully identified multiple genetic variants potentially associated with bladder cancer, the population-specific genetic architecture and its clinical implications in the Han Chinese patients remain to be elucidated.
Methods: This study developed a detection system for single nucleotide polymorphisms (SNPs) using multiplex polymerase chain reaction (PCR), single-base extension (SBE), and capillary electrophoresis technology, aimed at identifying potentially pathogenic variants. The method was applied to analyze 142 samples obtained from the Han Chinese individuals (aged 15–82, with an average age of 58 years) into a case group (n = 71) and a control group (n = 71).
Results: Statistical analysis revealed five SNPs with significant association in the case group. Binary Logistic regression analysis further validated its application for disease risk assessment and prediction. A predictive model integrating four significant SNPs, including rs8102137, rs7747724, rs1258767, and rs2042329, yielded an area under the curve (AUC) of 0.797 for predicting bladder cancer, while multifactor dimensionality reduction (MDR) analysis achieved a balanced accuracy of 0.7543.
Conclusion: This study demonstrates that these SNPs hold significant potential for application in genetic testing to predict bladder cancer risk; however, further research is needed to elucidate their functional mechanisms. Our analysis provides comprehensive insights into the association between bladder cancer-related genetic polymorphisms, hereditary susceptibility, and disease progression. These results establish a theoretical foundation for improving early diagnosis, preventive measures, and personalized treatment strategies in bladder cancer.
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Background: Age-related hearing loss (ARHL) is a common sensory disorder predominantly affecting older individuals, primarily caused by progressive degeneration of cochlear. While the toll-like receptor 4 (TLR-4)/nuclear factor kappa-B (NF-κB) signaling pathway plays a crucial role in inflammation, its precise role in cochlear inflammation and ARHL remains to be elucidated. Therefore, this study explored the role of TLR-4/NF-κB signaling axis in cochlear inflammation and its impact on ARHL pathogenesis.
Methods: HEI-OC1 cells were treated with lipopolysaccharide (LPS) to establish an inflammatory model, with TLR-4 and NF-κB inhibitors used as interventions. Similarly, male C57BL/6 mice (8 weeks and 24 months old) were treated with LPS to induce an ARHL model. Cellular viability and apoptosis rate were assessed using the cell counting kit-8 (CCK-8) assay. Furthermore, hearing function was determined using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR). Finally, the expression levels of TLR-4, NF-κB, and pro-inflammatory cytokines were assessed using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and enzyme-linked immunosorbent assay (ELISA).
Results: In vitro experiments revealed that TLR-4 and NF-κB inhibitors significantly restored cell viability and reduced LPS-induced apoptosis (p < 0.05). LPS treatment activated TLR-4/NF-κB signaling pathway and increased interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) expression levels, while these effects were suppressed through TLR-4 inhibition (p < 0.05). In vivo experiments showed that LPS-treated mice exhibited significant hearing impairment, which was alleviated through TLR-4 inhibitor (p < 0.05). Histopathological analysis revealed that LPS induced cochlear inflammation and cell damage, whereas TLR-4 inhibition mitigated these pathological changes. Furthermore, suppression of the TLR-4/NF-κB pathway significantly reduced the expression of pro-inflammatory cytokines in cochlear tissues, thereby alleviating inflammatory responses (p < 0.05).
Conclusion: The TLR-4/NF-κB pathway plays a crucial role in LPS-induced cochlear inflammation and ARHL progression. Inhibition of this pathway effectively alleviates age-related hearing loss by attenuating cochlear inflammation and protecting cochlear cells from apoptosis.
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Background: Smoking-induced glycocalyx significantly contributes to the pathogenesis of chronic obstructive pulmonary disease (COPD). Forkhead box protein 1 (Foxp1) reduces the expression of matrix metalloproteinase 9 (MMP9), thereby preventing glycocalyx injury. Therefore, we hypothesized that Foxp1 may maintain the integrity of the glycocalyx by inhibiting MMP9, thereby alleviating COPD.
Methods: We established COPD mouse models and intervened with Adeno-associated virus 9 (AAV9)-Foxp1. The mean linear intercept (MLI) and apoptosis of the lung tissue were analyzed using histological staining. Human pulmonary microvascular endothelial cells (hPMVECs) were transfected with Foxp1 plasmid and or MMP9 plasmid and then exposed to cigarette smoke extract (CSE) to establish in vitro cellular model. The expressions of glycocalyx-related proteins (Versican, syndecan-1 and MMP9) and Foxp1 were assessed using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Cellular viability, apoptosis, endothelial permeability, and tube formation capabilities were determined using the cell counting kit-8 (CCK-8) assay, flow cytometry, transwell assay, and tube formation assay, respectively.
Results: In vivo, AAV9-Foxp1 treatment significantly reduced MLI and endothelial apoptosis in COPD mice (p < 0.05). It also suppressed MMP9 expression while increasing Versican and syndecan-1 levels, indicating glycocalyx protection (p < 0.05). In vitro, Foxp1 overexpression counteracted CSE-induced damage by enhancing cell viability, reducing apoptosis, improving endothelial barrier function, and promoting tube formation (p < 0.05). Furthermore, Foxp1 upregulation restored glycocalyx integrity by increasing syndecan-1 and decreasing MMP9 expression. However, these protective effects were abolished when MMP9 was overexpressed simultaneously, confirming that Foxp1 acts through the inhibition of MMP9 (p < 0.05).
Conclusion: Foxp1 protects glycocalyx from injury to relieve COPD by downregulating MMP9, highlighting its potential as a promising therapeutic target.
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Background: Polycystic ovary syndrome (PCOS) is a highly prevalent and complex endocrine-metabolic syndrome, characterized by impaired folliculogenesis and follicular arrest. The marked clinical heterogeneity observed among PCOS patients is hypothesized to reflect variations in its etiopathogenesis, although the underlying mechanisms remain incompletely elucidated. This study was conducted employing individual-patient protein-protein interaction (PPI) network analysis to investigate key candidate genes and their associated signaling pathways in the granulosa cells (GCs) of PCOS patients at a single-patient resolution. The aim of this study was to provide novel insights and deepen the understanding of the pathogenic mechanisms and heterogeneity of PCOS.
Methods: Data were extracted from three mRNA expression datasets derived from high-throughput sequencing (GSE168404, GSE155489, and GSE138518) available in the Gene Expression Omnibus (GEO) database. These datasets included 24 samples, comprising 12 from individuals with PCOS and 12 controls. A gene correlation matrix was generated using control samples to assess global transcriptional alterations induced by data from individual PCOS patients. Individual-patient PPI networks were subsequently constructed to identify key candidate genes and molecular subtypes unique to each patient. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed via KOBAS-i to elucidate the underlying biological functions.
Results: A total of 7752 nodes (1978 unique) and 19,219 edges (13,626 unique) were mapped to construct the individual-patient PPI networks. These networks exhibited considerable variability in terms of nodes (median = 2128, range = 1141–3838) and edges (median = 2369, range = 903–6237). Despite some shared molecular features, the distinct network architectures observed in each patient underscored patient-specific variations in gene expression, thereby reflecting the intrinsic heterogeneity of the PCOS population. To identify key candidate genes, five overlapping nodes (fibronectin 1 (FN1), DNA ligase 3 (LIG3), vesicle associated membrane protein 2 (VAMP2), kinesin family member 23 (KIF23), pescadillo ribosomal biogenesis factor 1 (PES1)) were extracted from these networks, and KIF23, along with protein regulator of cytokinesis 1 (PRC1), were identified as common hub genes when analyses were restricted to more than 50% of patients. Furthermore, four signaling pathways, cyclic Guanosine Monophosphate-Protein Kinase G (cGMP-PKG), Wingless/Int-1 (Wnt), Relaxin, and Apelin, were differentially enriched across all individual-patient PPI networks. These pathways were distinct from those enriched with differentially expressed genes (DEGs) between the PCOS and control groups.
Conclusion: This study revealed patient-specific variations in gene expression by examining distinct network characteristics across individuals, highlighting the molecular heterogeneity inherent in PCOS. In addition to identifying candidate genes and signaling pathways enriched with DEGs, KIF23 emerged as a potential hub gene due to its ubiquitous presence. Additionally, the cGMP-PKG, Wnt, relaxin, and apelin signaling pathways were identified as potential core signaling pathways. However, these findings require further experimental validation through comprehensive in vivo and in vitro studies to establish their biological relevance.
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Objective: Macrophages and myeloid-derived suppressor cells (MDSCs) are key immune cells within the tumor microenvironment. Activation of the stimulator of interferon genes (STING) pathway and its downstream secretion of C-X-C motif chemokine ligand 10 (CXCL10) can suppress tumor development. This study investigated whether the STING–CXCL10 axis inhibits tumor progression by preventing macrophage M2 polarization and the differentiation of bone marrow cells (BMCs) into MDSCs.
Methods: Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used to assess the expression levels of STING and CXCL10. Lung cancer cell culture supernatants were collected and co-cultured with macrophages and bone marrow cells (BMCs). Flow cytometry was employed to evaluate macrophage polarization and the differentiation of MDSCs. Enzyme-linked immunosorbent assay (ELISA) was performed to measure CXCL10 levels in the lung cancer cell culture supernatant. To assess cell viability and invasion, BMCs or M0 macrophages were co-cultured with lung cancer cells, and the roles of STING and CXCL10 in these processes were analyzed.
Results: STING signal pathway is downregulated in lung cancer cell lines. Silencing of STING promotes macrophage M2 polarization and BMCs to MDSCs differentiation. In addition, knockdown of STING led to a downregulation of CXCL10 levels. Effects of STING overexpression were abolished by neutralizing antibody to CXCL10 (NAb-CXCL10). Co-culture of lung cancer cells with M0 macrophages or BMCs enhanced their viability and invasive capacity, whereas STING overexpression inhibited these effects by upregulating CXCL10.
Conclusions: This study suggests that the activation of the STING/CXCL10 axis inhibits macrophage M2 polarization and differentiation of BMCs to MDSCs. This study further suggests that the STING/CXCL10 axis is a potential target for lung cancer therapy.
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Background: With growing age and the development of metabolic diseases, the incidence of fundus diseases, including age-related macular degeneration (AMD), pathological myopia, and diabetic retinopathy, has risen sharply, often resulting in the formation of abnormal neovascularization and damage to normal fundus tissue. Anti-vascular endothelial growth factor (VEGF) therapy has emerged as the standard treatment for neovascular fundus diseases. Although the emergence of small interfering RNA (siRNA) drugs targeting VEGF offers a new treatment option for patients with ocular vascular diseases, the requirement of frequent injection and potential safety challenges associated with their administration impose substantial burdens and risks to patients.
Objective: This study aims to develop a simple and straightforward siRNA-based formulation for intraocular injection and assess its efficacy and safety profile.
Methods: This study developed siRNA-based formulations, evaluated the VEGF inhibitory effect, and Half-maximal Inhibitory Concentration (IC50) values at the mRNA level using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and proliferation activity were determined using the cell counting kit-8 (CCK-8). Furthermore, the angiogenic capability of the cells was assessed using a tube formation assay. Additionally, a laser-induced mouse choroidal neovascularization (CNV) model was applied to investigate the therapeutic effect of siRNA on retinal neovascularization in vivo, and intraocular safety was evaluated using slit lamp examination and hematoxylin and eosin (H&E) staining of retinal tissue sections.
Results: siRNA formulation effectively silenced VEGF expression in human umbilical vein endothelial cells (HUVECs), indicating an mRNA inhibition rate of >85%. The treatment substantially inhibited HUVEC proliferation (compared to the control group: at 24 hours post-administration, siRNA 75 nM and 100 nM groups, p < 0.05; at 48 hours, siRNA 50 nM group, p < 0.05, and siRNA 75 nM and 100 nM groups, p < 0.005; at 72 hours, siRNA 50 nM group, p < 0.01, siRNA 75 nM and 100 nM groups, p < 0.005). Furthermore, siRNA formulations significantly suppressed angiogenesis compared to the control group (siRNA 50 nM, p < 0.05; siRNA 75 nM and 100 nM, p < 0.01). Moreover, after a single intravitreal injection, VEGF expression suppressed for up to 5 weeks, along with reduction in neovascularization area compared to the negative control group: at day 7 after administration, medium dose, p < 0.05 and high dose, p < 0.01; at day 21 after administration, low-, p < 0.05, medium dose and high-dose, p < 0.005; at day 35 post-administration, low-dose, p < 0.05, medium dose, p < 0.01, and high-dose, p < 0.005. Notably, no significant retinal toxicity was observed in normal rabbits after 3 months of vitreous injection.
Conclusion: This study confirms the therapeutic potential of VEGF-targeting siRNA formulations for retinal diseases, emphasizing their significance in promoting the clinical translation of siRNA-based therapies in ophthalmology.
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Background: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, and its progression is closely associated with metabolic stress and epigenetic dysregulation under high-glucose conditions. Emerging evidence suggests that histone lactylation may play a pivotal role in gene transcription regulation during renal injury. This study aimed to elucidate the underlying mechanism by which histone lactylation of YTHDF2 exacerbates renal injury in a high-glucose environment, specifically through the enhancement of N6-methyladenosine (m6A) modification of growth differentiation factor 15 (GDF15), using both in vivo and in vitro models.
Methods: Histone lactylation and its role in renal injury were investigated in mouse renal tissues and in HK-2 tubular epithelial cells exposed to high glucose. Experimental approaches included immunofluorescence, ELISA, and immunoblotting. Autophagy and pyroptosis pathways were analyzed using markers such as LC3 and NLRP3. The histone lactylation on YTHDF2 transcription was evaluated using RT-qPCR, Chromatin immunoprecipitation (ChIP)-qPCR, and immunoblotting. Additionally, the impact of YTHDF2 on the m6A modification of GDF15 and its contribution to renal injury were examined using PAR-CLIP and MeRIP assays.
Results: Histone lactylation levels were significantly elevated in DN renal tissues and in HK2 cells exposed to high glucose (p < 0.01). Inhibition of histone lactylation alleviated high glucose-induced renal injury (p < 0.01). Interestingly, lactylation inhibition promoted autophagy while suppressing pyroptosis in both in vivo and in vitro DN models (p < 0.05). Histone acylation enhanced the transcriptional activation of YTHDF2, and YTHDF2 overexpression further aggravated renal injury (p < 0.05). Mechanistically, YTHDF2 facilitated the m6A modification of GDF15, leading to mRNA degradation and subsequent exacerbation of renal damage (p < 0.05).
Conclusion: Histone lactylation promotes the transcriptional activation of YTHDF2, which aggravates high glucose-induced renal injury by enhancing m6A-mediated degradation of GDF15 mRNA. Targeting the YTHDF2-GDF15 axis may represent a promising therapeutic strategy for DN.
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Background: Excessive inflammation and fibrosis during wound healing can cause delayed repair and pathological scar formation. This study aimed to investigate the effects of butorphanol on inflammation and fibrosis during wound healing and to explore the underlying molecular mechanisms.
Methods: A rat burn wound model was established and treated with varying doses of butorphanol. Wound closure rates were recorded on days 3, 7, 10, and 14 post-injury. Histological analyses were performed to assess tissue repair and fibrosis. Expression levels of pro-inflammatory cytokines, macrophage polarization markers, fibrosis-related proteins, and p38/c-Jun N-terminal kinase (JNK) signaling molecules were measured using real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, and Western blotting. Pharmacological inhibitors and agonists targeting the interleukin-6 (IL-6)/p38/JNK pathway were applied to validate mechanistic involvement.
Results: Butorphanol significantly accelerated wound healing, reduced inflammatory cell infiltration, and downregulated pro-inflammatory cytokines in the early stages (p < 0.05). It promoted macrophage polarization toward the anti-inflammatory M2 phenotype by increasing Cluster of Differentiation (CD)206 expression and suppressing CD86 expression (p < 0.05). Temporally, butorphanol enhanced the early expression of fibrosis-associated markers to support the transition to the proliferative phase, while suppressing their excessive late-stage expression to prevent pathological scarring (p < 0.05). Mechanistically, butorphanol inhibited activation of the IL-6/p38/JNK signaling pathway, as evidenced by altered pathway activity following pharmacological modulation, thereby regulating inflammation and fibrosis during healing (p < 0.05).
Conclusion: Butorphanol promotes orderly wound healing by modulating inflammation and fibrosis through regulation of the IL-6/p38/JNK signaling axis. These findings establish butorphanol as a promising therapeutic candidate for enhancing burn wound repair, and offer new perspectives on the IL-6/p38/JNK axis as a potential molecular target for regulating inflammation and fibrosis.
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Background: Atopic dermatitis (AD) is a chronic inflammatory disease characterized by immune dysregulation and skin barrier dysfunction. Recent evidence suggests that the monocyte chemotactic protein-1 (MCP-1)/C-C motif chemokine receptor 2 (CCR2) signaling pathway plays a crucial role in the recruitment of inflammatory cells and immune activation. This study aimed to investigate the role and underlying mechanisms of the MCP-1/CCR2 signaling pathway in AD pathogenesis.
Methods: A 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD mouse model and in vitro HaCaT cell-based experiments were employed. Clinical skin lesion scores, transepidermal water loss (TEWL), scratching bouts, and visceral indices were assessed. Histopathological changes were evaluated via hematoxylin and eosin (H&E) staining. The expression levels of inflammatory cytokines, skin barrier proteins, and components of the MCP-1/CCR2 pathway were determined using enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analyses. Furthermore, the MCP-1/CCR2 pathway was inhibited using Bindarit to evaluate its role in modulating inflammation and barrier function.
Results: AD mice exhibited severe skin lesions, with TEWL increased by ~3.5-fold (p < 0.05) and scratching bouts elevated by ~3-fold (p < 0.05) compared to controls. Serum levels of immunoglobulin E (IgE), interleukin (IL)-4, and IL-5 were significantly higher in AD mice than in controls (p < 0.05). Additionally, MCP-1 and its receptor CCR2 showed time-dependent upregulation at both the mRNA and protein levels (p < 0.05). Following Bindarit treatment, the expression levels of inflammation-related genes were significantly reduced (p < 0.05), and the levels of skin barrier-associated proteins tended to normalize.
Conclusion: The MCP-1/CCR2 signaling pathway contributes to AD pathogenesis by promoting inflammatory cell recruitment and activating downstream signaling, leading to skin barrier dysfunction. Targeted inhibition of this pathway may represent a promising therapeutic strategy for alleviating AD symptoms and restoring skin barrier integrity.
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Background: While existing pharmacotherapies for osteoporosis, such as bisphosphonates, reduce fracture risk, their long-term use remains limited by adverse effects, including gastrointestinal toxicity, osteonecrosis of the jaw, and atypical femoral fractures. Hydrogen sulfide (H2S), an endogenous gasotransmitter with anti-inflammatory properties, emerges as a potential alternative, but the role of its donor, sodium hydrosulfide (NaHS), in osteoporosis remains unexplored. Therefore, this study investigates NaHS-driven bone-protective mechanisms, emphasizing its ability to modulate the nuclear factor kappa-B (NF-κB)/ inhibitor of NF-κB alpha (IκB-α) axis—a crucial pathway in osteoclastogenesis.
Methods: Mice were divided into a sham control group (n = 6) and an ovariectomized (OVX) group (n = 6). Mice in the OVX group received varying doses of NaHS (0, 0.38, 0.75, 1.5 mg/kg/day) or vehicle for 4 weeks. Bone mineral density (BMD) was quantified using micro-computed tomography (micro-CT) analysis. Osteoclast differentiation was assessed in bone marrow-derived macrophages (BMMs) and RAW264.7 cells via tartrate-resistant acid phosphatase (TRAP) staining. Molecular mechanisms were deciphered using ubiquitination assays, nuclear/cytoplasmic fractionation, and immunofluorescence.
Results: NaHS treatment increased lumbar BMD and trabecular bone-to-tissue volume in OVX mice compared to untreated controls. In vitro, NaHS (0.15 mM) significantly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis (p < 0.05). Mechanistically, for the first time, NaHS was found to stabilize IκB-α by inhibiting its ubiquitination, thereby blocking the nuclear translocation of NF-κB p65.
Conclusions: NaHS mitigates OVX-induced bone loss via dual inhibition of osteoclast differentiation (through IκB-α/NF-κB blockade) and bone resorption. Its capacity to circumvent the limitations of current therapies positions NaHS as a novel candidate for osteoporosis management.
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Background: Lung adenocarcinoma (LUAD) is a major cause of cancer-related mortality worldwide. However, its key driver genes and molecular mechanisms remain insufficiently defined. This study aimed to identify novel oncogenic drivers in LUAD, focusing on leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4). We analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) and developed a prognostic model.
Methods: Differentially expressed genes between LUAD and normal lung tissues were identified using TCGA data. An initial analysis using DESeq2 with a fold-change threshold of ≥4 identified 3100 significantly differentially expressed genes (adjusted p < 0.05; 2671 upregulated and 429 downregulated). Univariate Cox regression (hazard ratio, HR) and least absolute shrinkage and selection operator (LASSO) regression were employed to construct a prognostic risk model, reducing the pool to 28 prognostic genes. Intersecting these with 19 genes both highly expressed and associated with poor prognosis yielded 10 key prognostic markers, including LGR4. Experimental validation was performed: LGR4 mRNA expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in clinical LUAD samples, and functional assays (cell counting kit-8 (CCK-8) proliferation, wound healing, and Transwell migration/invasion) as well as a nude mouse xenograft model were performed to assess the role of LGR4.
Results: In vitro assays demonstrated that LGR4 knockdown significantly suppressed proliferation, migration, and invasion of A549 and H1650 cells (all p < 0.05), whereas LGR4 overexpression in H1299 cells produced the opposite effect (p < 0.05). In vivo, a subcutaneous xenograft model in nude mice further confirmed that LGR4 promotes tumor growth (p < 0.05). Mechanistic analyses revealed that LGR4 activates the nuclear factor kappa-B (NF-κB) signaling pathway, leading to the upregulation of cyclin D1 (CCND1), matrix metalloproteinase 2 (MMP2), and vascular endothelial growth factor (VEGF) (p < 0.05), which regulate cell cycle progression, extracellular matrix remodeling, and angiogenesis, thereby facilitating LUAD progression.
Conclusion: Collectively, these findings demonstrate that LGR4 serves as a novel prognostic biomarker and potential therapeutic target in LUAD. This study provides a theoretical framework for further elucidating the molecular mechanisms underlying lung adenocarcinoma and advancing targeted therapeutic strategies.
