Currently, limited research exists on the relationship between osteoarthritis (OA) and Benzophenone-3 (BP-3). This study aims to explore the potential molecular pathways involved, using both in vivo and in vitro biological experiments. In vivo experiments revealed that exposure to BP-3 leads to cartilage damage in the knee joints of rats, suggesting that BP-3 may be a significant risk factor in the development and progression of osteoarthritis. Proteomic sequencing of knee cartilage tissue revealed alterations in multiple inflammatory pathways in the BP-3 group. In vitro cellular experiments further demonstrated the toxic effects of BP-3 on chondrocytes, including inflammatory changes and increased transcriptional levels of IL-6. Cellular transcriptomics sequencing revealed significant changes in multiple intracellular inflammatory pathways, particularly the JAK-STAT pathway. Additional experiments demonstrated that BP-3 enhances STAT3 phosphorylation, promoting the degradation of extracellular matrix (ECM) proteins. Silence of STAT3 alleviated the impaired effects of BP-3 on chondrocytes. Overall, our data suggest that BP-3 exposure may be a significant risk factor for OA development. This study provides substantial evidence and a comprehensive understanding of the impact of BP-3 on OA development.

Cervical spondylosis is a prevalent ailment characterized by chronic wear and degenerative changes affecting the cervical spine, leading to various clinical syndromes such as axial neck pain, cervical myelopathy, and cervical radiculopathy. The pathophysiology of the development of cervical alterations is multifaceted, with alterations in the normal physiology and pathogenesis of intervertebral disc degeneration. The involvement of pro-inflammatory mediators, such as interleukin-1, tumor necrosis factor-α, interleukin-4, interleukin-6, and interleukin-10, in the pathological processes associated with intervertebral disc degeneration offers potential therapeutic targets. The review also introduces kinase inhibitors as potential treatments for cervical spondylosis. Protein kinase inhibitors, including mitogen-activated protein kinase (MAPK), Janus kinase (JAK), and spleen tyrosine kinase (SYK), are explored for their anti-inflammatory properties. The article discusses their potential in modulating inflammatory signaling cascades and presents them as attractive candidates for treating immune-mediated disorders. Inhibitors of Nuclear Factor-κB, p38 MAPK, Jun-N terminal kinase (JNK), and Extracellular signal-regulated kinase (ERK) have shown efficacy in suppressing inflammatory responses, offering potential avenues for intervention in this prevalent condition. Organogels are semi-solid materials formed by trapping an organic solvent within a three-dimensional cross-linked network. They hold considerable potential in drug delivery, especially in enhancing drug solubility, facilitating controlled release, and improving skin penetration. These properties of organogels can help treat or alleviate the symptoms of cervical spondylosis.

Calcitonin gene-related peptide (CGRP) biases Langerhans cell (LC) Ag presentation to CD4+ T cells towards Th17-type immunity through actions on endothelial cells (ECs). We now report further evidence that IL-6 signalling at responding T cells mediates this effect. This CGRP effect was absent with ECs from IL-6 KO mice. Exposure of LCs, but not T cells, to IL-6 enhanced IL-6 and IL-17A production and reduced IFN-γ in the T-cell response. Pretreatment of LCs with IL-6 receptor α-chain (IL-6Rα) antibodies prior to IL-6 exposure significantly inhibited these responses. However, T-cell pretreatment with an IL-6/IL-6Rα chimera mimicked the effect of IL-6 pretreatment of LCs on T-cell responses. When this experiment was performed in the presence of the ADAM17 and ADAM10 inhibitor TAPI-1 during LC pretreatment of LCs and during the Ag presentation culture, release of soluble IL-6Rα chains into the medium was very significantly reduced, but this did not affect levels of T-cell cytokine release. Interestingly, LC exposure to IL-6 significantly increased LC IL-6 expression. Furthermore, pretreatment of T cells with antibodies against the IL-6 receptor β-chain significantly inhibited the IL-6 effect. CGRP may stimulate ECs in lymphatics and/or lymph nodes to produce IL-6 which likely results in migrating LCs nonclassically presenting IL-6. Furthermore, we found that IL-6 induces IL-6 production by LCs, suggesting an autocrine amplification pathway for this effect.

The differentiation of Th17 and iTreg is tightly associated with fatty acid metabolism. TGFβ1-induced iTreg differentiation from Th0 relies on fatty acid oxidation (FAO), whereas IL-6 with TGFβ1 shifts metabolism to Th17-preferred fatty acid synthesis (FAS). However, how IL-6 reprograms fatty acid metabolism remains unclear. Here, we unveiled that TGFβ1-activated JNK is recruited to the Klhl25 promoter by NF-YA. JNK then phosphorylates histone H3 at Ser10 to activate Klhl25 transcription, leading to the ubiquitination-dependent degradation of ATP-citrate lyase (ACLY) and the switch from FAS to FAO, which supports iTreg generation. Whereas, upon IL-6 signaling, NF-YA is phosphorylated by ERK, losing its DNA binding ability, which shuts off TGFβ1-JNK-mediated Klhl25 transcription and ACLY ubiquitination, thereby increasing FAS and supporting Th17 differentiation. This study demonstrated that KLHL25-ACLY module functions as a switch in response to TGFβ1 and IL-6 signals, playing a decisive role in the fate determination of iTreg/Th17 differentiation.

Blood orange peel flour (BO-pf)-a by-product of the citrus supply chain-still contains bioactive molecules with known health benefits, such as antiradical scavenging activity or an antiproliferative activity regarding tumors. In vitro studies have demonstrated that orange polyphenols showed potential involvement in necroptosis. In addition to previous research, we tested BO-pf on two colorectal cancer cell lines. Using HT29 and Caco2 cells, our experiments confirmed the regulation of inflammasome expression. They provided valuable insights into how BO-pf influences the cancer cell features (i.e., viability, proliferation, and pro- and anti-inflammatory activity). Notably, BO-pf extract is a rich source of polyphenolic compounds with antioxidant properties. Western blot and real-time PCR analyses showed that treatment with BO-pf extract demonstrated beneficial effects by influencing the expression of both pro-inflammatory cytokines (IL-1β, IL-6) through the modulation of the TLR4/NF-kB/NLRP3 inflammasome signaling. Moreover, the results of this study demonstrate that BO-pf extracts can enhance the expression of anti-inflammatory cytokines, such as IL-10 and TGFβ, suggesting that BO-pf extracts may represent a promising functional ingredient to counteract the intestinal inflammatory responses involved in IBD.

Sepsis, a life-threatening condition arising from a dysregulated immune response to infection, is a significant health burden globally. Interleukin-6 (IL-6), an inflammatory cytokine produced by immune cells as a response to infection and tissue damage, plays a key role in the pathogenesis of sepsis. This systematic review and meta-analysis aimed to investigate the association of the baseline plasma levels of IL-6, and the dynamic change in these levels over a timespan of 96 h, with short-term mortality. A systematic literature search was conducted across multiple databases. Studies were included if they assessed the independent prognostic value of IL-6 in adult sepsis patients, used well-defined sepsis criteria, and reported at least one IL-6 measurement. Pooled effect estimates for the association between IL-6 and 28-30-day mortality were determined using logistic regression and AUROC analysis. Thirty-one studies, encompassing 4566 patients, were included. While baseline IL-6 levels and 96 h IL-6 clearance were not significantly associated with mortality risk (pooled OR 1.001, 95% CI 0.999-1.003 and 1.019, 95% CI 0.925-1.112, respectively), AUROC analysis indicated moderate-to-good discriminatory power for both baseline (0.701, 95% CI 0.660-0.742) and 96 h IL-6 clearance (0.828, 95% CI 0.736-0.919) in predicting 28-day mortality. While not a strong independent predictor, IL-6 demonstrates some discriminatory ability, suggesting its potential value in conjunction with other biomarkers.

Interleukin-6 (IL-6) is a critical cytokine involved in immune regulation, inflammation, and the pathogenesis of various diseases, including autoimmune disorders, cancer, and the cytokine storm associated with severe COVID-19. Identifying IL-6 inducing epitopes, the short peptide fragments that trigger IL-6 production, is crucial for developing epitope-based vaccines and immunotherapies. However, traditional methods for epitope prediction often lack accuracy and efficiency. This study presents RAG_MCNNIL6, a novel deep learning framework that integrates Retrieval-augmented generation (RAG) with multiwindow convolutional neural networks (MCNNs) for accurate and rapid prediction of IL-6 inducing epitopes. RAG_MCNNIL6 leverages ProtTrans, a state-of-the-art pretrained protein language model, to generate rich embedding representations of peptide sequences. By incorporating a RAG-based similarity retrieval and embedding augmentation strategy, RAG_MCNNIL6 effectively captures both local and global sequence patterns relevant for IL-6 induction, significantly improving prediction performance compared to existing methods. We demonstrate the superior performance of RAG_MCNNIL6 on benchmark data sets, highlighting its potential for advancing research and therapeutic development for IL-6-mediated diseases.

The connection between intestine microbiota and lung disease is described as the gut-lung axis, these organ systems are somehow interrelated in both homeostasis and disease development. In newborns, the most important gastrointestinal complications are necrotizing enterocolitis (NEC), and the pulmonary complication both cause significant systemic morbidity. In this study, sildenafil administered at varying doses in neonatal rat model of experimental necrotizing enterocolitis and focused on both mRNA expression and histopathological alterations. 15-day-old Wistar Albino rat pups were randomly divided into six groups; Control, NEC, DMSO, Sil_1mg, Sil_5mg, Sil_10mg (n = 5). NEC induction was performed using hypoxia/asphyxia and cold stress. At the end of the experiment, lung tissues were harvested, molecular and histopathological alterations were analysed. Histopathological examination was performed with hematoxylin&eosin and masson trichrome staining in lung samples of neonatal rats and the mRNA expression levels of TNF-α, IL-6 and HSPa5 genes were analyzed. The mRNA expression levels of TNF-α, IL-6 and HSPa5 were increased in the NEC group compared to the control group and sildenafil treatment could significantly reduced the levels of the genes and inflammation (*p < 0.05 and **p ≤ 0.0001). Alveolar edema and hemorrhage findings were observed in the lung tissue of the NEC group. Interstitial edema and hemorrhage findings were reduced in the groups treated with sildenafil compared to the NEC group. The data we obtained indicate that sildenafil administering at different doses has therapeutic effect on NEC induced lung tissue inflammation both at the mRNA expression and tissue levels.

Abdominal aortic aneurysm (AAA) is a severe aortic disease for which no pharmacological interventions have yet been developed. This investigation focused on identifying protein-based therapeutic targets and assessing how proteins mediate the interplay between modifiable risk factors and AAA development.

Causal inferences between plasma proteins and AAA were drawn using 2-sample Mendelian randomization, followed by comprehensive sensitivity testing, colocalization, and replication efforts. Further analyses included database interrogation, single-cell RNA data analysis, enrichment analysis, protein-protein interaction networks, and immunohistochemistry to map the tissue-specific expression of these proteins, their expression within AAA tissues, and their biological roles. Mediation Mendelian randomization was employed to evaluate the mediating effects of AAA-related proteins on the associations between AAA and 3 risk factors: hypertension, smoking, and obesity.

A total of 43 proteins were identified as having causal links to AAA. Colocalization analysis pinpointed 13 proteins with strong evidence of colocalization with AAA. Of these, the causal involvement of 10 proteins was substantiated by external validation data. Consistent evidence for PCSK9 (proprotein convertase subtilisin/kexin type 9), IL6R (interleukin-6R), ECM1 (extracellular matrix protein 1), and ANGPTL4 (angiopoietin-related protein 4) was further validated through tissue immunohistochemistry and blood data. Moreover, Mendelian randomization analysis identified 10 proteins as mediators of the influence of hypertension, smoking, and obesity on AAA development.

This analysis identifies 4 proteins (PCSK9, IL6R, ECM1, and ANGPTL4) as high-priority therapeutic targets for AAA and emphasizes the intermediary role of plasma proteins in linking hypertension, smoking, obesity, and AAA. Further investigations are needed to clarify the specific roles of these proteins in AAA pathology.

Neonatal sepsis (NS) remains a significant cause of morbidity and mortality in newborns, particularly in preterm and low-birthweight infants. It has been shown previously that interleukin-6 (IL-6) can predict sepsis, and its non-invasive determination can be performed quickly, leading to the diagnosis and appropriate treatment for each case. Elevated IL-6 levels have been associated with early and late-onset NS, showing potential as an early indicator of infection before the onset of clinical symptoms. IL-6, in conjunction with other biomarkers such as C-reactive protein (CRP) and procalcitonin, may improve the accuracy of sepsis diagnosis and help guide antibiotic therapy.  We conducted a retrospective study to assess the validity of IL-6 in predicting NS. The optimal IL-6 cutoff was 181 pg/ml, yielding a sensitivity of 80.1%, a specificity of 85.7%, a positive predictive value of 84.6%, and a negative predictive value of 81.8%. Among culture-positive cases, IL-6 sensitivity was 90%, while in culture-negative cases, sensitivity was 71.4%. Our study showed that IL-6 is a new biomarker with high sensitivity and good specificity for identifying sepsis, and it has been linked with a better diagnostic value than CRP.

Interleukin-6 (IL-6) is a key parameter and critical role in cancer progression. However, for detection of IL-6 in colorectal cancer diagnosis, developing a sensitive biosensor is necessary and very important. In this paper, to enhance the sensitivity of IL-6 electrochemical biosensor, the electric field was used to orient arrangement of silver nanowires (AgNWs) to be free-standing AgNWs electrode. Gold nanoparticles (AuNPs) were electro-reduced around the surface of each AgNWs to solve the rapid oxidization problem of the AgNWs at very low potential (<70 mV) during the electrochemical detection. Oxidation peak current of the free-standing AgNWs/AuNPs electrode only decreased by 5% after 500 scanning cycles, while the free-standing AgNWs electrode without AuNPs decreased by 90.7% after 8 CV scanning cycles. The oxidation peak current of free-standing AgNWs/AuNPs electrode was 500 times of bare electrode. This biosensor showed a wide linear range from 0.001 ng ml-1 to 100 ng ml-1 and a low detection limit of 0.322 pg ml-1 for IL-6. In the end, IL-6 secreted by Caco-2 cell was detected by the fabricated biosensor which integrated into the gut-on-a-chip. IL-6 secretion achieved 11.3 pg ml-1 during 10-days culturing.

Fatty degenerative osteonecrosis of the jaw (FDOJ) is a chronic, aseptic inflammatory condition that is characterized by molecular disruptions in bone metabolism and necrotic bone marrow within the jawbone cavities. In contrast to the overt clinical signs typically observed in osteopathies, FDOJ frequently presents with a "silent inflammation" phenotype. The electronic databases PubMed, Scopus, and Embase were searched using appropriate search terms, and the methodology was performed according to PRISMA-ScR guidelines. The elevated expression of inflammatory mediators, particularly C-C motif Chemokine Ligand-5/Regulated on Activation, Normal T Cell Expressed and Secreted (CCL5/RANTES), fibroblast growth factor-2, and interleukin-1 receptor antagonist, distinguishes FDOJ at the molecular level and links it to systemic inflammatory and autoimmune diseases. These immunohistochemical markers play a pivotal role in the pathogenesis of chronic inflammation, immune response regulation, and abnormal bone remodeling. Advanced diagnostic tools, such as conebeam computed tomography and trans-alveolar ultrasonography, facilitate the detection of pathological changes that are not easily discernible with conventional radiography. Surgical intervention remains the primary treatment modality, often complemented by therapies that target these molecular pathways to modulate chronic inflammation. This article underscores the importance of integrating molecular diagnostics, advanced imaging, and clinical data for effective FDOJ detection and management.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas with varying severity. The mortality rate varies from 20% to 40% among severe acute pancreatitis (SAP). Interleukin-6 (IL-6) is a pro- and anti-inflammatory cytokine that involves various infections, inflammations, and systemic disorders. Injury to acinar cells leads to necrosis, releasing proinflammatory cytokines, including IL-6, which peaks earlier. The lack of extensive data regarding the association of IL-6 with AP influences us to do this meta-analysis for early detection and treatment of AP to prevent multiorgan failure.

We searched the PubMed, Cochrane Library, and Google Scholar databases for relevant articles published from inception to June 2024. We examined the positive and negative likelihood ratios, diagnostic odds ratios, and pooled sensitivity and specificity. We used the QUADAS-2 tool to evaluate the risk of bias.

This meta-analysis included 13 studies involving 1386 patients with AP, of which 343 had SAP and 1043 had mild and moderately severe AP. The positive and negative likelihood ratios were 3.5 (95% CI 2.6 to 4.5) and 0.25 (95% CI 0.16 to 0.40). The diagnostic odds ratio of IL-6 to diagnose SAP is 14 (95% CI: 7 to 27), and the summary receiver operating characteristic curve is 0.85 (95% CI: 0.82-0.88).

Based on the results of this meta-analysis, serum IL-6 is a promising biomarker for diagnosing SAP in the early stage. However, a larger-scale study involving a more extensive population is necessary due to the considerable variation between the studies.

Metabolism alteration is a common complication of rheumatic arthritis (RA). This work investigated the reason behind RA-caused triglyceride (TG) changes.

Fresh RA patients' whole blood was transfused into NOD-SCID mice. Metabolism-regulatory tissues were examined after sacrifice. To verify the findings, tissues of the rats with long-lasting adjuvant-induced arthritis (AIA) were analyzed. Some rats were injected with human plasma and GPIHBP1, and their blood TG was monitored. Various cells were stimulated by cytokines or rheumatic subjects' serum. Some pre-adipocytes were cultured by human serum or in the presence of HUVEC cells and GPIHBP1.

TG decrease occurred in blood and white adipose tissues (WAT) of the RA blood-transfused NOD-SCID mice and chronic AIA rats. Fatty acids (FA) oxidation in muscles was accelerated a bit, while TG catabolism status in their livers was varied. TNF-α, IL-1β, IL-6 and RA/AIA serum promoted expression of TG utilization-related enzymes and FA uptake transporters in pre-adipocytes, but barely affected LPL. Mild IL-6 stimulus promoted GPIHBP1 release of HUVEC cells. GPIHBP1 was increased in RA serum. This change can decrease blood TG in rats, which was overshadowed by an injection of excessive GPIHBP1. RA serum slightly inhibited LPL secretion in pre-adipocytes. Both HUVEC cells co-culture and GPIHBP1 supplement reduced LPL distribution on pre-adipocytes, and eliminated LPL activity difference between normal and RA serum-treated cells. No TG uptake difference was observed in these circumstances.

RA-associated inflammation induces GPIHBP1 secretion of endothelial cells, which facilitates blood TG hydrolysis and uptake to compensate the loss in WAT.

Endometriosis is a chronic inflammatory disorder characterized by presence of endometrial tissue outside the uterine cavity. Immunohistochemical analysis (IHC) revealed markedly elevated expression of IL6ST in endometrial tissue of patients with ovarian endometriosis. Level of methylation of IL6ST is diminished in patients with endometriosis, whereas level of mRNA expression is markedly elevated by RT-PCR. Cell Counting Kit-8, Transwell, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays substantiated endometrial stromal cells stably transfected with 3*FLAG-IL6ST plasmid exhibited enhanced viability, augmented invasive capacity, and notable reduction in apoptosis rates. Furthermore, IL6ST facilitated progression of endometriosis by activating mitogen-activated protein kinase 9/Signal Transducer and Activator of Transcription 3 signaling pathway. Western blot analysis revealed significantly elevated protein levels of p-JAK2/JAK2, p-STAT3/STAT3, HIF-1α, and VEGF in IL6ST overexpression group. Conversely, JAK2/STAT3 inhibitor WP1066 had markedly reduced p-JAK2 and p-STAT3 protein levels in IL6ST overexpression group. Inhibiting JAK2/STAT3 signaling pathway had mitigating effect on proliferative and invasive enhancement of endometrial stromal cells, as well as inhibition of apoptosis induced by IL6ST. These findings offer novel potential targets and strategies for the treatment of endometriosis.

Oxaliplatin-induced hypersensitivity reactions (HSRs) are commonly encountered in first-line therapies for various malignancies. Recent research indicates that these reactions can include cytokine release reactions (CRRs), which are characterized by a marked increase in interleukin-6 (IL-6) levels, sometimes rising as much as 40-fold. Standard management strategies for HSRs typically involve desensitization protocols and routine treatments. However, these conventional approaches may be insufficient for managing CRRs. Preliminary studies suggest that tocilizumab, an IL-6 receptor (IL-6R) antagonist, may play a crucial role in mitigating CRRs. In our case, a 65-year-old male with stage IV extranodal NK/T-cell lymphoma developed a severe HSR on day 1 following the infusion of oxaliplatin during his fourth chemotherapy cycle. This reaction was marked by a substantial increase in IL-6 levels. Despite the administration of standard treatments, including epinephrine and corticosteroids, the patient required ventilatory support and vasopressors on day 1. On day 2, tocilizumab was administered, resulting in a rapid and significant reduction in IL-6 levels. Subsequently, the patient's symptoms, including fever, dyspnea, and hypotension, resolved, and he was discharged on day 5. This case demonstrates that tocilizumab can be an effective intervention in managing severe HSRs associated with CRRs. To our knowledge, this is the first reported instance of tocilizumab successfully salvaging a patient experiencing oxaliplatin-induced HSR. Nevertheless, further research is required to validate the efficacy of tocilizumab in treating oxaliplatin-induced HSRs.

Cancer-associated fibroblasts have been reported to play a central role in driving cancer progression, promoting metastasis, and conferring resistance to therapy in HNSCC.

Indirect and direct co-culture models of HPV-positive and HPV-negative HNSCC cells with fibroblasts were developed to study the effect of fibroblasts on cancer cells. ELISA was used to measure IL-6 secretion in these models. To dissect the underlying signalling mechanisms, the effects of IL-6, an IL-6 receptor (IL-6R) inhibitor, a MAPK/ERK inhibitor, and a JAK/STAT inhibitor were evaluated. Epithelial-to-mesenchymal transition (EMT) was assessed by measuring EMT markers and conducting scratch assays and spheroid assays. Radioresistance was evaluated using clonogenic assays. Additionally, radioresistant (RR) cell lines were established from parental cells to examine the correlation between radioresistance and EMT.

Fibroblasts were found to drive EMT-like changes and heightened radioresistance in HNSCC cells through IL-6 secretion. Remarkably, these Fb-driven effects were robustly reversed using IL-6R and MAPK/ERK inhibitors in both HPV-positive and HPV-negative cell lines, whereas JAK/STAT inhibitors proved effective only in HPV-negative cells. RR cell lines exhibit a more aggressive phenotype than their parental counterparts, marked by pronounced EMT features and heightened resistance to radiotherapy. Importantly, these aggressive characteristics were substantially attenuated by targeting IL-6R or MAPK/ERK pathways.

This study highlights the critical role of fibroblast-secreted IL-6 in driving and maintaining EMT and radioresistance in HNSCC, resulting in a more aggressive tumour phenotype. Targeting the IL-6/IL-6R/ERK pathway emerges as a promising therapeutic approach for combating CAF-driven tumour progression and improving clinical outcomes in patients with aggressive, therapy-resistant HNSCC.

Characterize C-reactive protein (CRP) within 72 postnatal hours in early-onset sepsis (EOS).

Secondary analysis of a prospective surveillance study of neonates with EOS 2015-2017. We examined CRP use by center and neonatal characteristics, and CRP levels by time, neonatal characteristics, clinical signs, and pathogen.

CRP was obtained for 96/235 neonates with EOS, which varied by center (p < 0.001). 71/95 had CRP > 10 mg/L (1 missing). Neonatal characteristics with and without CRP did not differ. There was no relationship between CRP level and timing (p = 0.41) or neonate characteristics. Median CRP was higher with ≥5 vs <5 clinical signs (56, 23 mg/L; p = 0.002), and was not different in Gram-positive vs Gram-negative sepsis (43, 51 mg/L; p = 0.37) or preterm neonates who died vs survived (38, 28 mg/L; p = 0.37).

Among neonates with EOS, CRP use varied by center. CRP levels did not differ by time, neonate characteristics, pathogen, or death.

ClinicalTrials.gov ID Early-Onset Sepsis an NICHD/CDC Surveillance Study (EOSII): NCT02410486.

Drug toxicity is an important cause of chronic liver damage, which in the long term can lead to impaired bone homeostasis through an imbalance in the liver-bone axis. For instance, non-steroidal anti-inflammatory drugs (e.g., diclofenac), which are commonly used to control pain during orthopaedic interventions, are known to reduce bone quality and are the most prevalent causes of drug-induced liver damage. Therefore, we used human cell lines to produce a stable, reproducible, and reliable in vitro liver-bone co-culture model, which mimics the impaired bone homeostasis seen after diclofenac intake in vivo. To provide the best cell culture conditions for the two systems, we tested the effects of supplements contained in liver and bone cell culture medium on liver and bone cell lines, respectively. Additionally, different ratios of culture medium combinations on bone cell scaffolds and liver spheroids' viability and function were also analysed. Then, liver spheroids and bone scaffolds were daily exposed to 3-6 µM diclofenac alone or in co-culture to compare and evaluate its effect on the liver and bone system. Our results demonstrated that a 50:50 liver:bone medium combination maintains the function of liver spheroids and bone scaffolds for up to 21 days. Osteoclast-like cell activity was significantly upregulated after chronic exposure to diclofenac only in bone scaffolds co-cultured with liver spheroids. Consequently, the mineral content and stiffness of bone scaffolds treated with diclofenac in co-culture with liver spheroids were significantly reduced. Interestingly, our results show that the increase in osteoclastic activity in the system is not related to the main product of diclofenac metabolism. However, osteoclast activation correlated with the increase in oxidative stress and inflammation associated with chronic diclofenac exposure. In summary, we established a long-term stable liver-bone system that represents the interaction between the two organs, meanwhile, it is also an outstanding model for studying the toxicity of drugs on bone homeostasis.

Cancer-associated fibroblasts (CAFs) can interact with macrophages in the tumor microenvironment by secreting extracellular vesicles (EVs), thereby affecting tumor progression. However, the mechanisms of CAF-secreted EVs in gastric cancer (GC) remain not well understood. Here, we investigated the effect of CAF-EVs on macrophage polarization in GC and the underlying mechanisms. Macrophage polarization was evaluated using flow cytometry and quantitative real-time polymerase chain reaction. GC cell proliferation was determined using cell counting kit-8, EdU, and colony formation assays. The molecular mechanism was explored using microarray analysis, dual-luciferase reporter assay, and RNA pull-down analysis. The results showed that CAFs secreted EVs that inhibit macrophage M1 polarization and promote M2 polarization. Moreover, miR-4253 expression was increased in CAF-EVs, and inhibition of miR-4253 reversed the macrophage polarization induced by EVs. IL6R was identified as the target of miR-4253. Additionally, macrophages treated with EVs that encapsulated miR-4253 promote GC cell proliferation. In conclusion, CAF-secreted EVs packaging miR-4253 facilitate macrophage polarization from M1 to M2 phenotype by targeting IL6R, thereby accelerating GC cell proliferation. The findings suggest that EV-encapsulated miR-4253 may be a promising therapeutic target of GC.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes associated with high mortality and disability rates. Inflammation has emerged as a key pathological mechanism in DKD, prompting interest in novel therapeutic approaches targeting inflammatory pathways. Interleukin-6 (IL-6), a well-established inflammatory cytokine known for mediating various inflammatory responses, has attracted great attention in the DKD field. Although multiple in vivo and in vitro studies highlight the potential of targeting IL-6 in DKD treatment, its exact roles in the disease remains unclear. This review presents the roles of IL-6 in the pathogenesis of DKD, including immunoinflammation, metabolism, hemodynamics, and ferroptosis. In addition, we summarize the current status of IL-6 inhibitors in DKD-related clinical trials and discuss the potential of targeting IL-6 for treating DKD in the clinic.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of progesterone and estrogen receptors and low (or absent) HER2 expression. TNBC accounts for 15-20% of all breast cancers. It is associated with younger age, a higher mutational burden, and an increased risk of recurrence and mortality. Standard treatment for TNBC primarily relies on cytotoxic agents, such as taxanes, anthracyclines, and platinum compounds for both early and advanced stages of the disease. Several targeted therapies, including bevacizumab and sunitinib, have failed to demonstrate significant clinical benefit in TNBC. The emergence of immune checkpoint inhibitors (ICI) has revolutionized cancer treatment. By stimulating the immune system, ICIs induce a durable anti-tumor response across various solid tumors. TNBC is a particularly promising target for treatment with ICIs due to the higher levels of tumor-infiltrating lymphocytes (TIL), increased PD-L1 expression, and higher mutational burden, which generates tumor-specific neoantigens that activate immune cells. ICIs administered as monotherapy in advanced TNBC yields only a modest response; however, response rates significantly improve when ICIs are combined with cytotoxic agents, particularly in tumors expressing PD-L1. Pembrolizumab is approved for use in both early and advanced TNBC in combination with standard chemotherapy. However, more research is needed to identify more potent biomarkers, and to better elucidate the synergism of ICIs with other targeted agents. In this review, we explore the challenges of immunotherapy in TNBC, examining the mechanisms of tumor progression mediated by immune cells within the tumor microenvironment, and the signaling pathways involved in both primary and acquired resistance. Finally, we provide a comprehensive overview of ongoing clinical trials underway to investigate novel immune-targeted therapies for TNBC.

Neuroinflammation, triggered by aberrantly activated microglia, is widely recognized as a key contributor to the initiation and progression of Alzheimer's disease (AD). Microglial activation in the central nervous system (CNS) can be classified into two distinct phenotypes: the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. In this study, we investigated the effects of a non-invasive rotating magnetic field (RMF) (0.2T, 4Hz) on cognitive and memory impairments in a sporadic AD model of female Kunming mice induced by AlCl3 and D-gal. Our findings revealed significant improvements in cognitive and memory impairments following RMF treatment. Furthermore, RMF treatment led to reduced amyloid-beta (Aβ) deposition, mitigated damage to hippocampal morphology, prevented synaptic and neuronal loss, and alleviated cell apoptosis in the hippocampus and cortex of AD mice. Notably, RMF treatment ameliorated neuroinflammation, facilitated the transition of microglial polarization from M1 to M2, and inhibited the NF-кB/MAPK pathway. Additionally, RMF treatment resulted in reduced aluminum deposition in the brains of AD mice. In cellular experiments, RMF promoted the M1-M2 polarization transition and enhanced amyloid phagocytosis in cultured BV2 cells while inhibiting the TLR4/NF-кB/MAPK pathway. Collectively, these results demonstrate that RMF improves memory and cognitive impairments in a sporadic AD model, potentially by promoting the M1 to M2 transition of microglial polarization through inhibition of the NF-кB/MAPK signaling pathway. These findings suggest the promising therapeutic applications of RMF in the clinical treatment of AD.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, and inflammatory signaling is involved in its pathogenesis. Cytokines exert a robust effect on the progression of AML and affect survival outcomes. The dysregulation in the cytokine network may foster a pro-tumorigenic microenvironment, increasing leukemic cell proliferation, decreasing survival and driving drug resistance. The dominance of pro-inflammatory mediators such as IL-11β, TNF-α and IL-6 over anti-inflammatory mediators such as TGF-β and IL-10 has been implicated in tumor progression. Additionally, inflammatory cytokines have favored certain populations of hematopoietic stem and progenitor cells with mutated clonal hematopoiesis genes. This article summarizes current knowledge about inflammatory cytokines and signaling pathways in AML, their modes of action and the implications for immune tolerance and clonal hematopoiesis, with the aim of finding potential therapeutic interventions to improve clinical outcomes in AML patients.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Vestibular schwannomas (VSs) exhibit a range of tumor behaviors, such as growth patterns and auditory dysfunction. Recent research has offered insights into the inflammatory microenvironment in modulating tumor dynamics. This study investigates the role of inflammatory genes and immune infiltration in VS pathogenesis.

We retrieved mRNA microarray data of VSs and normal nerves from the GEO database (GSE141801, GSE108524, and GSE56597), focusing on bioinformatic analysis of inflammatory response genes. Based on the evidence provided by bioinformatics analysis, we assessed the expression levels of Iba-1, IL-10, IL-10RA, and IL-18 in 31 VS patients via immunohistochemistry and delved into their association with tumor size and auditory dysfunction.

We identified 1117 differentially expressed genes (DEGs) in VSs compared to normal nerves, showing an upregulation in inflammatory pathways. Intersection with inflammatory response genes (IRG) yielded 41 significant IRG-DEGs. Network analysis identified a core module of 10 IRG-DEGs and 11 hub genes, most of which were inflammatory cytokines. Immune infiltration analysis showed macrophage activation and M2 polarization. These findings were validated in an independent dataset (GSE39645). To further explore the association between inflammation and tumor behaviors, immunohistochemistry analysis was conducted on VS samples and the results exhibited notable associations between the macrophage marker (Iba1) and inflammatory cytokines (IL-10, IL-10RA, and IL-18) with both tumor size and auditory dysfunction. In particular, the multiple regression analysis of inflammatory cytokines demonstrated that IL-10 and IL-10RA were statistically significant predictors of tumor size, while IL-18 was associated with hearing loss.

Our study underscores the role of inflammation in VS pathogenesis, showing that macrophage activation with M2 polarization and the expression of inflammatory cytokines, especially IL-10/IL-10RA and IL-18, are linked to tumor size and auditory function. This study highlights the inflammatory landscape's impact on VS behaviors, providing a basis for targeted therapeutic strategies.

Uveitis is a prevalent inflammatory eye disease that primarily affects working-age individuals and can lead to blindness if untreated. Interleukin-10 (IL-10) is a multifunctional cytokine with broad immunosuppressive properties and plays a significant role in various pathological and physiological processes. However, its specific role and underlying mechanisms in uveitis remain incompletely understood. This review aims to shed light on the biological characteristics of IL-10, its involvement in the uveitis pathophysiology, and its potential as a novel therapeutic target. By examining existing literature, the review analyzes IL-10 expression levels and regulatory mechanisms in different types of uveitis, discussing its role in immune regulation. Despite IL-10 being expressed variably across various forms of autoimmune uveitis, studies consistently highlight its protective role, prompting research into ways to enhance its bioavailability in the eye. IL-10 is often upregulated in infectious uveitis, contributing to pathogen immune evasion. Furthermore, primary intraocular lymphoma (PIOL), which shares clinical similarities with uveitis, also shows upregulated IL-10 levels, whereas IL-6 is more commonly elevated in uveitis. This differential expression suggests that IL-6 and IL-10 could be diagnostic markers to distinguish between PIOL and uveitis. Future research should continue to focus on elucidating the molecular mechanisms of IL-10 in uveitis, exploring its potential therapeutic applications, and developing targeted treatments that leverage the immunomodulatory effects of IL-10 to prevent and manage this sight-threatening condition.

Oclacitinib is a novel Janus kinase (JAK) inhibitor that potently inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus (IL-2, IL-4, IL-6, IL-13, and IL-31). Oclacitinib (Apoquel®, Zoetis Inc, Parsippany, NJ) is approved for the treatment/control of pruritus associated with allergic dermatitis and treatment/control of clinical manifestations of atopic dermatitis in dogs at least 12 months of age. To evaluate the effectiveness of oclacitinib in dogs with flea allergy dermatitis, the JAK1 selective inhibitor was tested in a placebo-controlled, masked, single-dose (0.4 mg/kg) or repeat-dose (0.4 mg/kg, twice daily for 2 weeks) study. Pruritic behaviors were quantitated by video recording, and erythema and skin lesions were assessed using a 10-cm visual analog scale (VAS). Results showed that oclacitinib reduced pruritus by 61% as early as 1.5 h after a single oral dose compared to placebo, with an average reduction (compared to placebo) of 85% 1-5 h after dosing (0.4 mg/kg; p < .0001). Oclacitinib also significantly reduced erythema (p < .0001) and skin lesion (p < .0005) VAS scores on Day 14 compared to placebo in a repeat dose study. No adverse events were noted during the conduct of these studies. IL-31 concentrations were elevated in the majority of dogs after flea infestation, suggesting JAK1-dependent cytokines may drive clinical signs of flea allergy dermatitis. These findings show that oclacitinib, an inhibitor of JAK1-dependent cytokines involved in allergy and inflammation can rapidly reduce clinical signs associated with flea allergic dermatitis in dogs.

Host genetic variation has been recognized as a key predictor of diverse clinical sequelae among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. Insights into the link between the Interleukin-6 receptor (IL-6R) and Interleukin-1 beta (IL-1β) genetic variation and severe coronavirus disease 2019 (COVID-19) are crucial for developing new predictors and therapeutic targets. We aimed to investigate the association of IL-6R rs12083537, IL-1β rs16944, and IL-1β rs1143634 SNPs with the severity of COVID-19. Our study was conducted on 300 COVID-19-negative individuals (control group) and 299 COVID-19-positive cases, classified into mild, moderate, and severe subgroups. Analyses of IL-1β (rs16944, rs1143634) and IL-6R (rs12083537) SNPs' genotypes were performed using qPCR genotyping assays. The IL-1β (rs16944) CC genotype and IL-6R (rs12083537) GG genotype were substantially related to COVID-19 severity, which was also associated with comorbidities and some laboratory parameters (p < 0.001). The IL-1β (rs1143634) TT genotype was found to be protective. Likewise, the IL-1β (rs16944) CC genotype was associated with increased mortality. IL-1β rs16944 and IL-6R rs12083537 SNPs are promising potential predictors of SARS-CoV-2 disease severity. Meanwhile, the rs1143634 SNP T allele was protective against severity and mortality risk.

Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP.

We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function.

We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha).

Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Severely ill patients with coronavirus disease 2019 (COVID-19) show an increased risk of new-onset atrioventricular blocks (AVBs), associated with high rates of short-term mortality. Recent data suggest that the uncontrolled inflammatory activation observed in these patients, specifically interleukin (IL)-6 elevation, may play an important pathogenic role by directly affecting cardiac electrophysiology. The aim of our study was to assess the acute impact of IL-6 changes on electrocardiographic indices of atrioventricular conduction in severe COVID-19.

We investigated (1) the behavior of PR-interval and PR-segment in patients with severe COVID-19 during active phase and recovery, and (2) their association with circulating IL-6 levels over time.

During active disease, COVID-19 patients showed a significant increase of PR-interval and PR-segment. Such atrioventricular delay was transient as these parameters rapidly normalized during recovery. PR-indices significantly correlated with circulating IL-6 levels over time. All these changes and correlations persisted also in the absence of laboratory signs of cardiac strain/injury or concomitant treatment with PR-prolonging drugs, repurposed or not.

Our study provides evidence that in patients with severe COVID-19 and high-grade systemic inflammation, IL-6 elevation is associated with a significant delay of atrioventricular conduction, independent of concomitant confounding factors. While transient, such alterations may enhance the risk of severe AVB and associated short-term mortality. Our data provide further support to current anti-inflammatory strategies for severe COVID-19, including IL-6 antagonists.

Parkinson's disease (PD) is a prevalent neurodegenerative disease in which treatment often includes an exercise regimen. Exercise is neuroprotective in animal models of PD, and, more recently, human clinical studies have verified exercise's disease-modifying effect. Aerobic exercise and resistance training improve many of PD's motor and non-motor symptoms, while neuromotor therapy and stretching/flexibility exercises positively contribute to the quality of life in people with PD. Therefore, understanding the role of exercise in managing this complex disorder is crucial. Exerkines are bioactive substances that are synthesized and released during exercise and have been implicated in several positive health outcomes, including neuroprotection. Exerkines protect neuronal cells in vitro and rodent PD models in vivo. Aerobic exercise and resistance training both increase exerkine levels in the blood, suggesting a role for exerkines in the neuroprotective theory. Many exerkines demonstrate the potential for protecting the brain against pathological missteps caused by PD. Every person (people) with Parkinson's (PwP) needs a comprehensive exercise plan tailored to their unique needs and abilities. Here, we provide an exercise template to help PwP understand the importance of exercise for treating PD, describe barriers confronting many PwP in their attempt to exercise, provide suggestions for overcoming these barriers, and explore the role of exerkines in managing PD. In conclusion, exercise and exerkines together create a powerful neuroprotective system that should contribute to slowing the chronic progression of PD.

Depression is a common neuropsychiatric disease which brings an increasing burden to all countries globally. Baicalin, a flavonoid extracted from the dried roots of Scutellaria, has been reported to exert anti-inflammatory, antioxidant, and neuroprotective effects in the treatment of depression. However, the potential biological mechanisms underlying its antidepressant effect are still unclear. In the present study, we conducted extensive research on the potential mechanisms of baicalin's antidepressant effect using the methods of network pharmacology, including overlapped terms-based analysis, protein-protein interaction (PPI) network topology analysis, and enrichment analysis. Moreover, these results were further verified through molecular docking, weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and subsequent animal experiments. We identified forty-one genes as the targets of baicalin in the treatment of depression, among which AKT1, IL6, TP53, IL1B, and CASP3 have higher centrality in the more core position. Meanwhile, the roles of peripheral genes derived from direct potential targets were also observed. Our study suggested that biological processes, such as inflammatory reaction, apoptosis, and oxidative stress, may be involved in the therapeutic process of baicalin on depression. These mechanisms were validated at the level of structure, gene, protein, and signaling pathway in the present study. Taken together, these findings propose a new perspective on the potential mechanisms underlying baicalin's antidepressant effect, and also provide a new basis and clarified perspective for its clinical application.

Anti-IL-6 receptor antibodies are clinically efficacious in the management of RA with an associated increase in Tregs; however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyse the relationship between these Treg subsets and the clinical outcome of RA.

We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52.

The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period.

Blocking the IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favourable treatment course and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

There is growing interest in evaluating the safety and therapeutic potential of existing treatments such as tocilizumab (TCZ), an IL-6 receptor antagonist used to treat inflammatory diseases. However, there have been reports of increased inflammation in patients with HTLV-1 uveitis after TCZ treatment, and its ocular safety in the HTLV-1 infected state remains unknown. This study focused on assessing the impact of TCZ on HTLV-1-infected ocular cells using an in vitro model in which retinal pigment epithelial cells were cocultured with irradiated HTLV-1-infected T-cell lines. TCZ did not significantly affect cellular viability, inflammatory markers, or HTLV-1 proviral loads at various concentrations (25/50/100 µg/ml), indicating no increased risk of HTLV-1 viral infection and no exacerbation of the inflammatory aspects of HTLV-1 infection in the ocular cells. These promising results support the potential of TCZ as a safe treatment option for HTLV-1-infected patients, particularly those with eye infections.

Vitiligo is a persistent autoimmune disease characterized by progressive depigmentation of the skin caused by the selective destruction of melanocytes. Although its etiopathogenesis remains unclear, multiple factors are involved in the development of this disease, from genetic and metabolic factors to cellular oxidative stress, melanocyte adhesion defects, and innate and adaptive immunity. This review presents a comprehensive summary of the existing knowledge on the role of different cellular mechanisms, including cytokines and chemokines interactions, in the pathogenesis of vitiligo. Although there is no definitive cure for vitiligo, notable progress has been made, and several treatments have shown favorable results. A thorough understanding of the basis of the disease uncovers promising drug targets for future research, providing clinical researchers with valuable insights for developing improved treatment options.

Vascular adhesion protein-1 (VAP-1) is a type 2 transmembrane sialoglycoprotein with oxidative deamination functionality, encoded by the amine oxidase copper-containing 3 (AOC3) gene. VAP-1 is widely expressed across various tissues, particularly in highly vascularized tissues and organs essential for lymphocyte circulation. In the vascular system, VAP-1 is predominantly found in vascular smooth muscle cells and endothelial cells, with higher expression levels in vascular smooth muscle cells. Under inflammatory conditions, VAP-1 rapidly translocates to the endothelial cell surface, facilitating leukocyte adhesion and migration through interactions with specific ligands, such as sialic acid-binding immunoglobulin-type lectins (Siglec)-9 on neutrophils and monocytes, and Siglec-10 on B cells, monocytes, and eosinophils. This interaction is crucial for leukocyte transmigration into inflamed tissues. Furthermore, VAP-1's enzymatic activity generates hydrogen peroxide and advanced glycation end-products, contributing to cytotoxic damage and vascular inflammation. In this context, the soluble form of VAP-1 (sVAP-1), produced by matrix metalloproteinase cleavage from its membrane-bound counterpart, also significantly influences leukocyte migration. This review aims to elucidate the multifaceted pathophysiological roles of VAP-1 in vascular inflammation, particularly in giant cell arteritis (GCA) and associated polymyalgia rheumatica (PMR). By exploring its involvement in immune cell adhesion, migration, and its enzymatic contributions to oxidative stress and tissue damage, we investigate the importance of VAP-1 in GCA. Additionally, we discuss recent advancements in imaging techniques targeting VAP-1, such as [68Ga]Ga-DOTA-Siglec-9 PET/CT, which have provided new insights into VAP-1's role in GCA and PMR. Overall, understanding VAP-1's comprehensive roles could pave the way for improved strategies in managing these conditions.