Zinc gluconate improves atopic dermatitis by modulating CXCL10 release of keratinocytes via PPARα activation.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex causes involving immune factors. The presence of essential trace elements that support immune system function can influence the development of this condition. This study investigated how serum trace elements impact the pathogenesis of atopic dermatitis. Upon analyzing serum microelements in AD patients and control subjects, it was observed that patients with AD had notably lower zinc levels. Genomic analysis of AD skin revealed distinct gene expression patterns, specifically the increased expression of CXCL10 in the epidermis. The heightened levels of CXCL10 in AD skin lesions were found to correlate with reduced serum zinc levels. Treatment with zinc gluconate showed reduced chemotactic response and CXCL10 release, suggesting its potential to regulate CXCL10 expression of keratinocytes in AD. The mechanism behind this involved the downregulation of STAT phosphorylation through activating PPARα. In the AD-like dermatitis mouse model, zinc gluconate therapy decreased serum IgE levels, alleviated skin lesion severity, reduced skin thickness, and lowered CXCL10 expression, demonstrating its efficacy in managing AD-like skin conditions. These findings indicate that zinc gluconate can reduce inflammation in keratinocytes by activating PPARα, inhibiting STAT signaling, and decreasing CXCL10 release, thus highlighting its potential as a therapeutic target for AD.

The role of dermal fibroblasts in autoimmune skin diseases.

Fibroblasts are an important subset of mesenchymal cells in maintaining skin homeostasis and resisting harmful stimuli. Meanwhile, fibroblasts modulate immune cell function by secreting cytokines, thereby implicating their involvement in various dermatological conditions such as psoriasis, vitiligo, and atopic dermatitis. Recently, variations in the subtypes of fibroblasts and their expression profiles have been identified in these prevalent autoimmune skin diseases, implying that fibroblasts may exhibit distinct functionalities across different diseases. In this review, from the perspective of their fundamental functions and remarkable heterogeneity, we have comprehensively collected evidence on the role of fibroblasts and their distinct subpopulations in psoriasis, vitiligo, atopic dermatitis, and scleroderma. Importantly, these findings hold promise for guiding future research directions and identifying novel therapeutic targets for treating these diseases.

Exosomes containing miR-1469 regulate natural killer cells by targeting CD122 in non-segmental vitiligo.

BACKGROUND: Plasma exosomal microRNAs (miRNAs) have been used as potential biomarkers for various diseases and have been investigated for their possible involvement in the pathogenesis of vitiligo. However, the miRNA expression profile of plasma exosomes in patients with non-segmental vitiligo (NSV) has not been determined yet. OBJECTIVE: To screen differentially expressed microRNAs in plasma exosomes derived from patients with NSV and explore their roles in the pathogenesis of NSV. METHODS: High-throughput sequencing was performed to determine the expression profiles of exosomal miRNAs in NSV. The effect of upregulated miR-1469 in NSV circulating exosomes on natural killer (NK) cells was further investigated using various molecular biological techniques. RESULTS: MiR-1469 was identified as a candidate biomarker whose expression was significantly increased in circulating exosomes of NSV patients. Circulating exosomes were internalized by NK cells and increased NK cell proliferation viability and IFN-γ secretion capacity delivering miR-1469. Further studies revealed that the upregulation of CD122, the predicted target of miR-1469, could partially reverse the effect of miR-1469 on natural killer cells. CONCLUSION: Alterations in plasma exosomal cargo occur in NSV and appear to contribute to NK cell dysfunction. Exosomal miR-1469 may be a biomarker of disease activity and could be used as a therapeutic drug target against innate immunity in NSV patients. The present study provides new insights into the role of exosomal miRNAs in NSV and suggests a novel miR-1469-CD122-IFN-γ pathway of NK cell underlying pathogenesis of NSV.

Clinical features and biomarker differences of severe intrinsic and extrinsic atopic dermatitis.

OBJECTIVES: Atopic dermatitis (AD) can be classified into intrinsic AD(IAD) and extrinsic AD(EAD). However, the differences in clinical features and pathogenesis between these two subtypes of AD are currently unclear. This study aimed to analyse the differences in clinical features and peripheral blood biomarkers between Chinese patients with severe IAD and EAD in order to elucidate the physiopathogenesis of AD. MATERIALS AND METHODS: A total of 316 hospitalised patients definitively diagnosed with severe AD were included in this study. There were 72 cases of severe IAD and 244 cases of severe EAD. The clinical features of the patients were recorded in details. Serum total IgE, IgA, IgG, IgM, complementC3/C4, peripheral blood cell counts, lactate dehydrogenase (LDH), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IL-2R, IL-6, IL-8, and TNF-α in AD patients and 60 age-matched healthy controls were analysed. IAD and EAD had similar severity/Scoring Atopic Dermatitis (SCORAD) scores. RESULTS: Compared with healthy controls, IAD patients had significantly higher total IgE, eosinophils, monocytes, LDH, CRP, IL-2R, IL-6, IL-8 and TNF-α, and lower IgM and C4. EAD patients had significantly higher total IgE, IgA, eosinophils, white blood cell (WBC) counts, neutrophils, monocytes, basophils, LDH, CRP, IL-2R, IL-6, IL-8, TNF-α and lower IgM than healthy controls. IAD patients had a higher percentage of rural/urban living and female/male, a shorter course of disease and lower total IgE, eosinophils, WBC counts, neutrophils, monocytes, basophils, LDH, IgG and C4 than EAD patients. SCORAD scores, eosinophils, LDH expression levels increased with total IgE uniquely in patients with EAD. CONCLUSIONS: IAD and EAD exhibit specific clinical features and molecular changes. IAD has a more complex physiopathogenesis, and deserves further investigation.

Exosomal miRNAs in autoimmune skin diseases.

Exosomes, bilaterally phospholipid-coated small vesicles, are produced and released by nearly all cells, which comprise diverse biological macromolecules, including proteins, DNA, RNA, and others, that participate in the regulation of their biological functions. An increasing number of studies have revealed that the contents of exosomes, particularly microRNA(miRNA), play a significant role in the pathogenesis of various diseases, including autoimmune skin diseases. MiRNA is a class of single-stranded non-coding RNA molecules that possess approximately 22 nucleotides in length with the capability of binding to the untranslated as well as coding regions of target mRNA to regulate gene expression precisely at the post-transcriptional level. Various exosomal miRNAs have been found to be significantly expressed in some autoimmune skin diseases and involved in the pathogenesis of conditions via regulating the secretion of crucial pathogenic cytokines and the direction of immune cell differentiation. Thus, exosomal miRNAs might be promising biomarkers for monitoring disease progression, relapse and reflection to treatment based on their functions and changes. This review summarized the current studies on exosomal miRNAs in several common autoimmune skin diseases, aiming to dissect the underlying mechanism from a new perspective, seek novel biomarkers for disease monitoring and lay the foundation for developing innovative target therapy in the future.

1,25-Dihydroxyvitamin D3 Provides Benefits in Vitiligo Based on Modulation of CD8+ T Cell Glycolysis and Function.

Vitiligo is a common autoimmune skin disease caused by autoreactive CD8+ T cells. The diverse effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on immune cell metabolism and proliferation have made it an interesting candidate as a supporting therapeutic option in various autoimmune diseases. This study aimed to elucidate the immunomodulatory effects of 1,25(OH)2D3 in vitiligo. Cross-sectional relationships between serum 1,25(OH)2D3 levels and disease characteristics were investigated in 327 patients with vitiligo. The immunomodulatory and therapeutic effects of 1,25(OH)2D3 were then investigated in vivo and in vitro, respectively. We found that 1,25(OH)2D3 deficiency was associated with hyperactivity of CD8+ T cells in the vitiligo cohort. In addition, 1,25(OH)2D3 suppressed glycolysis by activating the AMP-activated protein kinase (AMPK) signaling pathway, thereby inhibiting the proliferation, cytotoxicity and aberrant activation of CD8+ T cells. Finally, the in vivo administration of 1,25(OH)2D3 to melanocyte-associated vitiligo (MAV) mice reduced the infiltration and function of CD8+ T cells and promoted repigmentation. In conclusion, 1,25(OH)2D3 may serve as an essential biomarker of the progression and severity of vitiligo. The modulation of autoreactive CD8+ T cell function and glycolysis by 1,25(OH)2D3 may be a novel approach for treating vitiligo.

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators.

Inflammation plays a crucial role in the initiation and development of a wide range of systemic illnesses. Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid (AA) metabolized by CYP450 epoxygenase (CYP450) and are subsequently hydrolyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs), which are merely biologically active. EETs possess a wide range of established protective effects on many systems of which anti-inflammatory actions have gained great interest. EETs attenuate vascular inflammation and remodeling by inhibiting activation of endothelial cells and reducing cross-talk between inflammatory cells and blood vessels. EETs also process direct and indirect anti-inflammatory properties in the myocardium and therefore alleviate inflammatory cardiomyopathy and cardiac remodeling. Moreover, emerging studies show the substantial roles of EETs in relieving inflammation under other pathophysiological environments, such as diabetes, sepsis, lung injuries, neurodegenerative disease, hepatic diseases, kidney injury, and arthritis. Furthermore, pharmacological manipulations of the AA-CYP450-EETs-sEH pathway have demonstrated a contribution to the alleviation of numerous inflammatory diseases, which highlight a therapeutic potential of drugs targeting this pathway. This review summarizes the progress of AA-CYP450-EETs-sEH pathway in regulation of inflammation under different pathological conditions and discusses the existing challenges and future direction of this research field.

Single-case metanalysis of fat embolism syndrome.

BACKGROUND: Only one large series has been reported on fat embolism syndrome (FES), a condition caused by fat globules release into the circulation, primarily as consequence of bone fracture. Thus, more data on clinical features, therapies, and prognosis are needed. METHODS AND RESULTS: The study screened 1090 manuscripts in PubMed and Web of Science on cases of FES published from June 2010 to June 2020. The authors identified 124 studies and included in the pooled-analysis 135 patients (>14 years), plus one additional unpublished case managed in Tongji hospital. All had confirmed diagnosis of FES with complete clinical data. The median age at presentation was 39 years, and 82 (61.8%) were men. FES was predominantly associated with bone fractures (78, 57.4%), particularly femur fracture (59, 43.4%). The most common clinical finding at the onset was respiratory abnormalities in 34.6% of all clinical presentations. Therapies included respiratory supportive care in 127 (93.4%) patients, application of corticosteroids in 22 (16.2%) and anticoagulant in 5 (3.7%) cases. Overall mortality was 30.2% (N = 41), and logistic regression analysis showed that corticosteroid therapy was significantly associated with reduced mortality with an OR of 0.143 (95%CI 0.029-0.711), while age ≥ 65 years and non-orthopedic conditions were significantly associated with increased mortality with an OR of 4.816 (95%CI 1.638-14.160) and 4.785 (95%CI 1.019-22.474). CONCLUSIONS: FES has been associated with a larger mortality rate than previously observed, although publication bias can have led to overestimation of mortality. Finally, a potential protective effect of corticosteroid therapy has been suggested by the current analysis.

N-Acetyl Cysteine Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Intracellular Triglyceride Accumulation by Preserving Mitochondrial Function.

Rationale: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic disease characterized by liver steatosis. Excessive reactive oxygen species (ROS) originating from dysfunctional mitochondria is the major pathophysiological contributor in the development of NAFLD and is thought to be a promising therapeutic target. A few reports demonstrate the antioxidative treatments for NAFLD. Methods: Male C57 mice were fed on a normal chow diet (ND) or high-fat diet (HFD) for 8 weeks. PBS or N-acetyl cysteine (NAC) was gavaged to mice. LO2 human liver cell line treated with palmitic acid (PA) was applied as a cellular model. Western blot, immunofluorescence, biochemistry assay, and pathological staining were used to investigate the mechanism of suppressing lipid accumulation of NAC. Results: NAC treatment was able to prevent HFD-induced NAFLD, as evidenced by less hepatic triglyceride accumulation and lipid droplet formation compared with that of mice in the HFD group. NAC could preserve mitochondrial function by inhibiting excessive mitophagy and promoting mitochondria biogenesis to prevent ROS production. NAC also activated Sirt1 and preserved its protein level and subsequently promoted mitochondria biogenesis via deacetylating PGC1a. Conclusion: We demonstrated that NAC may be an effective drug to treat NAFLD, which was related to its antioxidative and mitochondrial protective effect.

[Endogenous protective effects of arachidonic acid epoxygenase metabolites, epoxyeicosatrienoic acids, in cardiovascular system].

The morbidity and mortality of cardiovascular diseases are increasing annually, which is one of the primary causes of human death. Recent studies have shown that epoxyeicosatrienoic acids (EETs), endogenous metabolites of arachidonic acid (AA) via CYP450 epoxygenase, possess a spectrum of protective properties in cardiovascular system. EETs not only alleviate cardiac remodeling and injury in different pathological models, but also improve subsequent hemodynamic disturbances and cardiac dysfunction. Meanwhile, various studies have demonstrated that EETs, as endothelial-derived hyperpolarizing factors, regulate vascular tone by activating various ion channels on endothelium and smooth muscle, which in turn can lower blood pressure, improve coronary blood flow and regulate pulmonary artery pressure. In addition, EETs are protective in endothelium, including inhibiting inflammation and adhesion of endothelial cells, attenuating platelet aggregation, promoting fibrinolysis and revascularization. EETs can also prevent aortic remodeling, including attenuating atherosclerosis, adventitial remodeling, and aortic calcification. Therefore, it is clinically important to study the physiological and pathophysiological effects of EETs in the cardiovascular system to further elucidate the mechanisms, as well as provide new strategy for the prevention and treatment of cardiovascular diseases. This review summarizes the endogenous cardioprotective effects and mechanisms of EETs in order to provide a new insight for research in this field.

Hierarchically urchin-like hollow NiCo2S4 prepared by a facile template-free method for high-performance supercapacitors.

Hollow structures draw much attention for high energy density supercapacitors due to their large hollow cavities, high specific surface area, and low interfacial contact resistance. However, constructing hierarchical hollow structures remains a challenge. Herein, we reported a facile template-free method for a novel urchin-like hollow nickel cobalt sulfide (NiCo2S4). The hollow interior and urchin exterior remarkably improved the specific capacitance and accommodated structural collapse caused by electrochemical reactions. Owing to these features, the urchin-like hollow NiCo2S4 spheres exhibited an impressive capacitance of 1398F g-1 at 1 A g-1 and maintained 1110F g-1 with a large current density of 10 A g-1. The hybrid supercapacitor fabricated by NiCo2S4 and active carbon possesses an energy density of 39.3 Wh kg-1 at a power density of 749.6 W kg-1 and an outstanding cycling stability of 74.4% retention after 5000 cycles. Our work presents a facile method of constructing a hollow structure of binary sulfide materials and also makes progress on highly efficient supercapacitors.