Search Results (2,184)

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Background/Objectives: Atherosclerotic plaque instability is driven by complex interactions among inflammatory, structural, and cellular remodeling programs. While bulk RNA sequencing provides insight into tissue-level transcriptional states and single-cell RNA sequencing (scRNA-seq) defines cellular heterogeneity, integration across these transcriptomic layers remains limited. We aimed to identify coordinated transcriptional programs associated with stable and unstable plaque phenotypes and map these programs to specific cellular compartments and regulatory networks. Methods: Paired bulk RNA-seq data from stable and unstable human carotid plaques (GSE120521) and scRNA-seq data from human coronary atherosclerotic lesions (GSE131778) were analyzed. Differential expression and Hallmark gene set enrichment analyses were performed using limma and clusterProfiler. Bulk-derived inflammatory and structural signatures were projected onto single-cell data using Seurat module scoring. Compartment-level transcriptional scores, an inflammatory–structural endotype index, and transcription factor activity inference using decoupleR and DoRothEA were used to characterize plaque-associated transcriptional states. Results: Unstable plaques demonstrated enrichment of inflammatory pathways, including interferon gamma response, inflammatory response, TNFα/NF-κB signaling, IL6/JAK/STAT3 signaling, complement activation, and reactive oxygen species pathways. In contrast, stable plaques demonstrated relative enrichment of myogenesis and structural remodeling programs. Projection of bulk-derived signatures onto single-cell data localized inflammatory programs predominantly to TREM2hi and inflammatory macrophage populations, whereas structural programs localized to smooth muscle cell and fibromyocyte-like compartments. Compartment-level analyses showed increased myeloid and adaptive immune signatures in unstable plaques and increased smooth muscle cell/fibro-remodeling signatures in stable plaques. Transcription factor activity analysis identified increased SPI1, NFKB1, RELA, and STAT1 activity in unstable plaques and higher SRF and TEAD1 activity in stable plaques. Conclusions: Integrative analysis of bulk and single-cell transcriptomic data identified distinct inflammatory and structural plaque transcriptional states associated with unstable and stable plaque phenotypes, respectively. These findings support a systems-level framework linking tissue-level plaque behavior to specific cellular and regulatory programs and provide evidence for inflammatory and structural plaque endotypes in human atherosclerosis. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

The JAK/STAT pathway is a conserved signaling pathway involved in insect immune regulation. Although its antibacterial role has been investigated in some aphids, evidence is lacking for Aphis glycines. In this study, we identified JAK/STAT pathway-related genes in A. glycines and examined their roles in antibacterial defense. Candidate genes were identified and characterized through sequence, domain, and phylogenetic analyses. Developmental expression and transcriptional responses to bacterial infection were determined by qRT-PCR, and gene function was evaluated by RNA interference followed by bacterial challenge. Six putative JAK/STAT pathway-related genes were identified, including AglyJak, AglyDome-1, AglyDome-2, AglyDome-3, AglyStat92E-1, and AglyStat92E-2. Conserved domain architecture and phylogenetic analysis confirmed these genes as A. glycines JAK/STAT orthologs. Expression profiling showed that, except for AglyJak and AglyDome-2, most genes were most highly expressed in early nymphal stages, particularly in first-instar nymphs. After injection with Escherichia coli or Staphylococcus aureus, the transcript levels of AglyJak, AglyDome, and AglyStat genes increased significantly. Gene silencing significantly reduced aphid survival following bacterial infection. These results indicate that JAK/STAT pathway-related genes participate in the antibacterial defense of A. glycines and provide candidate targets for further studies on immune regulation and biologically based management of this pest. Full article

Muscle wasting associated with gastric cancer represents a complex, multifactorial systems disorder involving inflammatory, anabolic, mechanosensory, calcium-regulatory, mitochondrial, and proteostatic disruption. This review synthesizes current evidence regarding the cellular and physiological mechanisms involved in skeletal muscle dysfunction in gastric cancer and provides a unifying framework centered on loss of signaling coherence. Specifically, it examines IL-6/STAT3 and NF-κB inflammatory signaling, the myostatin–activin–ACVR2B–SMAD pathway, PI3K/Akt/mTOR signaling, mechanotransduction, excitation–metabolism coupling, calcium homeostasis, mitochondrial function, and proteostasis. Although individual components of these pathways have been implicated in muscle wasting associated with chronic disease, current evidence suggests that they interact through positive feedback loops. Inflammation, anabolic resistance, impaired force-to-signal conversion, mitochondrial stress, altered intracellular calcium homeostasis, and disrupted protein quality control may reinforce one another, contributing to metabolic, structural, and transcriptional instability. Within this context, muscle wasting reflects not only loss of muscle mass or strength, but also loss of functional integrity resulting from disrupted integration of mechanical, metabolic, inflammatory, and anabolic signals. Given the systemic nature of these effects, this review proposes kinesitherapy as a potentially useful nonpharmacological adjunctive strategy that may modulate inflammation, restore responsiveness to mechanical stimuli, support calcium homeostasis and mitochondrial function, improve anabolic sensitivity, and maintain protein quality control. Overall, this review presents a systems-biology model of gastric cancer-associated muscle wasting and supports further investigation of exercise-based therapies for this condition. Full article

Cancer stem cells (CSCs) drive therapeutic resistance and tumor relapse by exploiting redundant regulatory networks that integrate Wnt/β-catenin, Notch, and Hedgehog signaling with metabolic reprogramming, epigenetic plasticity, and tumor microenvironment crosstalk, a network architecture that renders single-pathway inhibition strategies insufficient. This review systematically examines evidence that natural compounds (curcumin, sulforaphane, resveratrol, EGCG, berberine, and quercetin) act as multitarget modulators of CSC plasticity, analyzing their molecular mechanisms of action in specific cancer models. Each compound engages distinct regulatory nodes: curcumin suppresses β-catenin nuclear translocation and STAT3 phosphorylation in lung cancer CSC models; sulforaphane represses ΔNp63α-driven stemness transcription in colorectal cancer and reduces CSC self-renewal in prostate and head and neck models; resveratrol dissociates the β-catenin–GLI-1 interaction in oral and lung CSC populations and induces Wnt/β-catenin-dependent autophagy in breast CSCs; EGCG inhibits DNMT and HDAC activity in glioblastoma and colorectal models; berberine activates AMPK-mediated suppression of mTORC1 in colorectal cancer; and quercetin suppresses PI3K/AKT/mTOR signaling while downregulating EMT transcription factors in breast and colorectal systems. We critically assess persistent methodological limitations, including bulk cell-line models, supraphysiological concentrations, and the absence of functional tumor-initiating validation, that currently prevent stronger translational conclusions. Natural compounds from Latin American biodiversity are identified as an underexplored source of CSC-active molecules. We conclude by defining the experimental standards required to reposition natural compounds as clinically relevant network-level modulators of CSC plasticity. Full article

Background: High body mass index (BMI) is a causal risk factor for endometrial cancer, but the tumor molecular mechanisms affected by adiposity remain poorly understood. Here, we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic liability to elevated BMI. Methods: We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to test for associations between the BMI germline PGS and endometrial cancer tumor genome-wide genomic, transcriptomic, proteomic, epigenomic and immune traits in TCGA. Results: High BMI germline PGS was associated with (i) upregulated tumor gene expression in IL6-JAK-STAT3 signaling (FDR = 4.2 × 10⁻⁷) and in other immune/inflammatory pathways; (ii) increased estimated intra-tumor activated mast cell infiltration (FDR = 0.008); and (iii) increased single base substitution (SBS) mutational signature 1 (FDR = 0.03), implicating age-related mutagenesis. In contrast, BMI at diagnosis associated with elevated progesterone receptor expression and alterations in estrogen and androgen signaling. Conclusions: Thus, we integrated germline, somatic and clinical data to identify associations between genetically predicted lifelong liability to higher BMI and endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development of this cancer, shaping endometrial tumor biology differentially over the long term. Full article

Background/Objectives: Essential Oils (EO), complex mixtures of organic compounds, exhibit a wide range of properties useful in the pharmaceutical, cosmetic, perfumery and agri-food fields. In particular, well-recognized EO anti-inflammatory properties push towards the investigation of the mechanisms underlying them. One of the signaling pathways targeted by EOs is the Janus Kinase Signal of Transducer and Activator of Transcription (JAK/STAT), whose hyperactivation is associated with inflammation, immune diseases and tumor progression. Methods: A comprehensive search on the major bibliographic databases was conducted; current findings and recent insights about the role of EOs in modulating the JAK/STAT Signaling Pathway were collected. Results: EOs derived from different plant species showed efficacy in attenuating the release of pro-inflammatory cytokines and mediators and in inhibiting phosphorylation of both JAK and STAT proteins. These results could be due to the EO’s multi-component nature and to the synergistic interaction occurring within these complex mixtures, both reflecting multi-target effects and modulations. Limitations concerning formulations, lack of standardization, efficacy and safety profiles, sustainable and eco-friendly approaches, and the gap between the literature and translation to the clinic were addressed. Conclusions: EOs represent emergent, promising and high-value candidates able to modulate the JAK/STAT Signaling Pathway. Full article

Background/Objectives: TGFB2 is the dominant TGF-β isoform in glioma, and isolated experimental studies have implicated it in immunosuppressive signaling; however, its prognostic value and systematic association with the tumor immune microenvironment across the diffuse glioma spectrum have not been comprehensively characterized in large clinical cohorts. Methods: A multi-cohort transcriptomic study was conducted using TCGA (n = 667) as discovery and CGGA (n = 404) as validation, integrating survival analysis, functional enrichment, immune deconvolution by ssGSEA and MCP-counter, immune checkpoint correlation, and TISCH2-based single-cell localization. Results: TGFB2 was consistently overexpressed in glioma relative to normal brain at both mRNA and protein levels, with expression highest in GBM (median 10.60 vs. 8.45 in LGG; p < 2.2 × 10⁻¹⁶) and increasing across WHO grade. High TGFB2 predicted worse overall survival in both cohorts (TCGA: 648 vs. 2907 days; CGGA: 863 vs. 3107 days; both p < 0.0001), with 3-year AUCs of 0.823 and 0.714, and retained independent prognostic significance in the CGGA multivariate model (HR = 1.343; p = 3.2 × 10⁻⁴). Hallmark GSEA identified consistent enrichment of interferon signaling, epithelial–mesenchymal transition, TNFα/NF-κB, and IL-6/JAK/STAT3 pathways. ssGSEA and MCP-counter concordantly demonstrated significantly expanded myeloid, monocytic, and stromal populations across both cohorts. TGFB2 correlated positively with PD-L1, TIM-3, ICOS (ρ = 0.449), IL2RA (ρ = 0.397), CTLA4 (ρ = 0.375), and TIGIT (ρ = 0.170) in TCGA, with all associations replicated in CGGA. Conclusions: TGFB2 is an adverse prognostic biomarker in diffuse glioma coupled to a myeloid-enriched, multi-checkpoint-activated tumor microenvironment, supporting its evaluation as a stratification biomarker in TGF-β/checkpoint combination immunotherapy trials. Full article

Ankylosing Spondylitis (AS) is a chronic inflammatory autoimmune rheumatic disease that primarily affects the spine and sacroiliac joints. This study aimed to investigate the expression levels of immune response-related genes, including IRF7, NFKB1A, TNFAIP3, STAT1, TRIM21, TRIM22, and TRIM25, as well as the serum levels of CXCL10 and SIRPA proteins in patients with AS. In addition, the potential diagnostic performance of these molecular and serum biomarkers in distinguishing patients with AS from healthy controls was evaluated. A total of 45 patients with AS and 44 healthy controls were included in the study. Immune-related gene expression levels were analyzed using RT-PCR. In addition, serum CXCL10 and SIRPA protein levels were evaluated using ELISA. The expression levels of NFKB1A, TNFAIP3, IRF7, STAT1, and TRIM21 were significantly increased in patients with AS compared to healthy controls (p < 0.05). In contrast, no significant differences were detected in the expression levels of TRIM22 and TRIM25. In the ROC analysis, the highest diagnostic performance was obtained for NFKB1A (AUC = 0.741), TNFAIP3 (AUC = 0.720), and TRIM21 (AUC = 0.722). Serum CXCL10 and SIRPA levels were not significantly different between the groups. In AS, genes particularly associated with NF-κB and interferon signaling pathways (NFKB1A, TNFAIP3, IRF7, STAT1, and TRIM21) were found to be significantly altered, and these genes may serve as potential molecular biomarkers for AS. In contrast, the diagnostic power of serum protein biomarkers is limited. These findings indicate that the potential of these genes as biomarkers for AS pathogenesis should be further supported by advanced studies evaluating their expression levels. Full article

Heat and Cd²⁺ stress are major environmental challenges for marine benthic invertebrates. This study examined their combined effects on growth, physiology, and transcriptomic responses in the peanut worm (Sipunculus nudus). After 30 days, Cd²⁺ reduced survival at 26 °C without significantly affecting growth, whereas at 32 °C, both survival and growth declined with increasing Cd²⁺ concentration, indicating that heat stress exacerbates Cd²⁺ toxicity. Cd accumulation increased with exposure concentration but was not affected by temperature. Heat stress increased immune (AKP) and antioxidant (SOD, CAT) enzyme activities, although significant increases in SOD and CAT were observed only under Cd²⁺ exposure. AKP activity rose at low Cd²⁺ concentrations and fell at high Cd²⁺ concentrations at 26 °C, whereas no significant difference occurred at 32 °C between 0 and 0.25 mg/L Cd²⁺. At the same temperature, SOD and CAT activities were significantly higher under high Cd²⁺ exposure than under low Cd²⁺ exposure. Transcriptome analysis showed that Cd²⁺ exposure activated longevity-related pathways, protein processing, and translation initiation. Heat stress activated Jak-STAT signaling and endoplasmic reticulum protein processing while inhibiting the ribosome pathway. Under combined stress, pathways related to xenobiotic metabolism, nutrient digestion and absorption, and amino acid derivative metabolism were broadly suppressed. These results highlight that heat stress exacerbates Cd²⁺ toxicity, affecting growth, enzyme activity, and transcriptomic responses, and provide insights into the adaptive strategies of marine benthic organisms under the combined pressures of climate change and heavy metal pollution. Full article

Obesity exhibits pronounced sex-dependent differences in susceptibility and progression; however, the molecular mechanisms coordinating central energy sensing with peripheral thermogenic responses remain incompletely defined. Selenoprotein F (SELENOF), an endoplasmic reticulum (ER)-resident member of the selenoprotein family involved in protein quality control and redox-sensitive metabolic regulation, has not previously been investigated in the context of diet-induced obesity. In the present study, WT and SELENOF-deficient mice subjected to a 16-week high-fat diet (HFD) were combined with primary brown adipocyte experiments to determine the role of SELENOF in systemic metabolic homeostasis. SELENOF deficiency markedly aggravated HFD-induced weight gain, adipose tissue expansion, dyslipidemia, and hyperleptinemia selectively in female mice, whereas no genotype-dependent effects were observed in males. Mechanistically, SELENOF deficiency intensified hypothalamic ER stress and leptin resistance, as reflected by increased GRP78, p-IRE1α, and p-PERK expression together with SOCS3 upregulation, reduced STAT3 phosphorylation, and activation of the IKK/NF-κB inflammatory pathway. In parallel, SELENOF deficiency reduced circulating free triiodothyronine (FT₃) levels and the ratio of free triiodothyronine to free thyroxine (FT₃/FT₄ ratio), and suppressed DIO2 and UCP1 expression in brown adipose tissue (BAT). Experiments in primary brown adipocytes further showed that SELENOF deficiency did not disrupt proximal β3-adrenergic signaling but attenuated the downstream induction of DIO2 and UCP1. Collectively, these findings provide preliminary evidence that SELENOF is associated with sex-dependent metabolic adaptation during HFD-induced stress by linking hypothalamic proteostasis with the thyroid hormone-related thermogenic signaling program in BAT. Full article

In patients with myocardial infarction (MI), the level of sphingolipids, such as ceramide (Cer), is elevated and is associated with an increased risk of progression towards heart failure (HF). Dihydroceramide desaturase 1 (DES1) catalyses the conversion of dihydroceramide (dhCer) into Cer in the de novo sphingolipid pathway. While pharmacological inhibition of DES1 has shown therapeutic benefits in metabolic disease and cancer models, its role in cardiac remodelling remains unclear. This study aimed to determine whether pharmacological inhibition of DES1 using the novel compound, CIN038, attenuates cardiac remodelling following ischemia–reperfusion (I/R) injury. Three-month-old male C57Bl/6 mice underwent I/R or sham surgery (n = 8) and were treated with vehicle or CIN038 (50 mg/kg/day, i.p.) for 28 days. Cardiac function, molecular changes, and lipid profiles in circulation and liver were assessed at the endpoint. CIN038 reduced infarct size and cardiac myocyte hypertrophy compared to the I/R + vehicle group. Profibrotic signalling was reduced in the infarcted hearts, as evidenced by reduced expression of Col1a1, Col3a1, and Tgfb mRNA and decreased levels of α-SMA and TGFβ1 protein expression. Inflammatory signalling was attenuated with reduced ERK and NFkB phosphorylation and suppression of Il-6-STAT axis. Despite these structural and molecular improvements, no changes were observed in cardiac function. Lipidomic analysis revealed selective alterations in circulating and hepatic lipid species, including plasmalogen phosphatidylethanolamines and ether-linked triglycerides, suggesting modulation of lipid metabolism. Collectively, these findings indicate that CIN038 attenuates post-ischemic cardiac remodelling by suppressing inflammatory and profibrotic signalling, highlighting DES1 as a potential therapeutic target following MI. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited actionable targets, early recurrence, metastatic propensity, and variable responses to immune checkpoint blockade. Therapeutic resistance is closely associated with myeloid immunosuppression, in which tumor-associated macrophages (TAMs) promote T-cell exclusion, stromal remodeling, angiogenesis, metabolic dysfunction, and resistance to cytotoxic and immune-based therapies. Anthraquinone compounds, including emodin, aloe-emodin, rhein, and chrysophanol, may support TAM reprogramming by regulating tumor-cell stress responses, endoplasmic reticulum stress, immunogenic cell death-associated signaling, redox balance, immunometabolism, and STAT3/NF-κB-related inflammatory pathways. However, poor aqueous solubility, heterogeneous biodistribution, unstable systemic exposure, and potential off-target toxicity limit their translational development. Liposomal delivery offers a formulation strategy to improve solubilization, biodistribution, TAM-associated uptake/engagement, intracellular release, and therapeutic exposure windows. This review discusses anthraquinone-loaded liposomes for TAM reprogramming in TNBC by integrating mechanistic rationale, evidence boundaries, delivery logic, formulation determinants, and translational challenges, with particular attention to stress chaperone proteins, lipid composition, vesicle lamellarity, membrane phase state, responsive release, clinically relevant liposomal formulations, and clinical developability. Overall, anthraquinone-loaded liposomes are better positioned as immune microenvironment recalibration platforms or synergistic modulators in combination therapy rather than as standalone cytotoxic agents for TNBC. Full article

Bisphenol A (BPA) is a common industrial chemical primarily used in the manufacture of plastics, and it has been found in more than 90% of people worldwide. As an endocrine disruptor, BPA can impair reproduction, development, immunity, metabolism, and cognition; it also disturbs immune balance and thus fosters chronic inflammation. A number of population-based studies have indicated a link between environmental BPA exposure and atopic dermatitis (AD). Nevertheless, the detailed molecular pathways connecting BPA to AD remain poorly understood. AD is the leading chronic recurrent inflammatory skin disorder, characterized by severe itching and repeated eczema-like lesions. Its prevalence is roughly 13% among children and 5% among adults, and its global incidence continues to rise, imposing heavy health and economic burdens on societies. To clarify whether and how BPA may promote or worsen AD, we carried out a comprehensive computational study that integrated network toxicology, transcriptomic data, machine learning, molecular docking, and molecular dynamics simulations. From the CTD, ChEMBL, and SwissTargetPrediction databases, we collected 5701 potential BPA targets; from GeneCards and OMIM, we obtained 3270 genes linked to AD. The overlap between these two gene sets gave a group of common candidate genes. Enrichment analyses using GO and KEGG showed that these common genes were significantly overrepresented in the PI3K-Akt signaling pathway, Th17 cell differentiation, and the JAK-STAT signaling pathway—all central to immune and inflammatory regulation. We then built a protein–protein interaction (PPI) network by submitting the common genes to the STRING database and employed Cytoscape to extract hub genes from that network. By integrating human AD transcriptomic profiles with the hub genes and applying two machine learning techniques (LASSO and SVM), we identified six core toxic targets of BPA in AD: TIGIT, JAK3, IL22, S100A8, CCL2, and FCER1G. These six targets fall into two main functional categories: immune dysregulation and inflammatory cell infiltration. Subsequent molecular docking and molecular dynamics simulation experiments confirmed that BPA binds well to all six targets and can form stable complexes with them. Collectively, our findings offer a preliminary experimental foundation for future investigations into the pathogenesis of BPA-induced AD and provide important molecular evidence for understanding how environment–gene interactions contribute to complex inflammatory skin diseases such as AD. Full article