Zinc deficiency increases lung inflammation and fibrosis in obese mice by promoting oxidative stress.

BACKGROUND: Zinc deficiency can lead to multiple organ damage. In this study, we investigated the effects of zinc deficiency on obesity-related lung damage. METHODS: C57BL/6 J mice were fed a diet with differing amounts of zinc and fat over a 6-month period. Palmitic acid was used to stimulate A549 cells to construct a high-fat alveolar epithelial cell model. Western blotting and histopathological staining were performed on animal tissues. Nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was detected in cultured cells. A reactive oxygen species (ROS) assay kit was used to detect intracellular ROS. Furthermore, Nrf2 siRNA was used to examine zinc deficiency effects on A549 cells. RESULTS: Pathological results showed significant damage to the lung structure of mice in the high-fat and low-zinc diet group, with a significant increase in the expression of inflammatory (IL-6, TNF-α) and fibrosis (TGFß1, PAI-1) factors, combined with a decrease in the expression of Nrf2, HO-1 and NQO1 in the antioxidant pathway. In A549 cells, high fat and low zinc levels aggravated ROS production. Western blot and immunofluorescence results showed that high fat and zinc deficiency inhibited Nrf2 expression. After Nrf2-specific knockout in A549 cells, the protective effect of zinc on oxidant conditions induced by high fat was reduced. Phosphorylated Akt and PI3K levels were downregulated on the high-fat and low-zinc group compared with the high-fat group. CONCLUSIONS: Zinc attenuated lung oxidative damage in obesity-related lung injury and Nrf2 activation is one of the important mechanisms of this effect. GENERAL SIGNIFICANCE: Regulating zinc homeostasis through dietary modifications or supplemental nutritional therapy can contribute to the prevention and treatment of obesity-related lung injury.

Prognostic significance of peripheral blood S100A12, S100A8, and S100A9 concentrations in idiopathic pulmonary fibrosis.

BACKGROUND: S100A12, S100A8, and S100A9 are inflammatory disease biomarkers whose functional significance in idiopathic pulmonary fibrosis (IPF) remains unclear. We evaluated the significance of S100A12, S100A8, and S100A9 levels in IPF development and prognosis. METHODS: The dataset was collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes were screened using GEO2R. We conducted a retrospective study of 106 patients with IPF to explore the relationships between different biomarkers and poor outcomes. Pearson's correlation coefficient, Kaplan-Meier, Cox regression, and functional enrichment analyses were used to evaluate relationships between these biomarkers' levels and clinical parameters or prognosis. RESULTS: Serum levels of S100A12, S100A8, and S100A9 were significantly elevated in patients with IPF. The two most significant co-expression genes of S100A12 were S100A8 and S100A9. Patients with levels of S100A12 (median 231.21 ng/mL), S100A9 (median 57.09 ng/mL) or S100A8 (median 52.20 ng/mL), as well as combined elevated S100A12, S100A9, and S100A8 levels, exhibited shorter progression-free survival and overall survival. Serum S100A12 and S100A8, S100A12 and S100A9, S100A9 and S100A8 concentrations also displayed a strong positive correlation (rs2 = 0.4558, rs2 = 0.4558, rs2 = 0.6373; P < 0.001). S100A12 and S100A8/9 concentrations were independent of FVC%, DLCO%, and other clinical parameters (age, laboratory test data, and smoking habit). Finally, in multivariate analysis, the serum levels of S100A12, S100A8, and S100A9 were significant prognostic factors (hazard ratio 1.002, P = 0.032, hazard ratio 1.039, P = 0.001, and hazard ratio 1.048, P = 0.003). CONCLUSIONS: S100A12, S100A8, and S100A9 are promising circulating biomarkers that may aid in determining IPF patient prognosis. Multicenter clinical trials are needed to confirm their clinical value.

Anti­PD­1/PD­L1 and anti­CTLA­4 associated checkpoint inhibitor pneumonitis in non­small cell lung cancer: Occurrence, pathogenesis and risk factors (Review).

Immune checkpoint inhibitors (ICIs) play a significant anti­tumor role in the management of non­small cell lung cancer. The most broadly used ICIs are anti­programmed death 1 (PD­1), anti­programmed cell death­ligand 1, and anti­cytotoxic T lymphocyte­associated antigen­4 monoclonal antibody. Compared with traditional chemotherapy, ICIs have the advantages of greater efficiency and more specific targeting. However, the resulting immune­related adverse events limit the clinical application of ICIs, especially checkpoint inhibitor pneumonitis (CIP). CIP chiefly occurs within 6 months of administration of ICIs. Excessive activation and amplification of cytotoxic T lymphocytes, helper T cells, downregulation of regulatory T cells, and over­secretion of pro­inflammatory cytokines are the dominant mechanisms underlying the pathophysiology of CIP. The dysregulation of innate immune cells, such as an increase in inflammatory monocytes, dendritic cells, neutrophils and M1 polarization of macrophages, an increase in IL­10 and IL­35, and a decrease in eosinophils, may underlie CIP. Although contested, several factors may accelerate CIP, such as a history of previous respiratory disease, radiotherapy, chemotherapy, administration of epidermal growth factor receptor tyrosine kinase inhibitors, PD­1 blockers, first­line application of ICIs, and combined immunotherapy. Interestingly, first­line ICIs plus chemotherapy may reduce CIP. Steroid hormones remain the primary treatment strategy against grade ≥2 CIP, although cytokine blockers are promising therapeutic agents. Herein, the current research on CIP occurrence, clinical and radiological characteristics, pathogenesis, risk factors, and management is summarized to further expand our understanding, clarify the prognosis, and guide treatment.

Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease; although the recent introduction of two anti-fibrosis drugs, pirfenidone and Nidanib, have resulted in a significant reduction in lung function decline, IPF is still not curable. Approximately 2-20% of patients with IPF have a family history of the disease, which is considered the strongest risk factor for idiopathic interstitial pneumonia. However, the genetic predispositions of familial IPF (f-IPF), a particular type of IPF, remain largely unknown. Genetics affect the susceptibility and progression of f-IPF. Genomic markers are increasingly being recognized for their contribution to disease prognosis and drug therapy outcomes. Existing data suggest that genomics may help identify individuals at risk for f-IPF, accurately classify patients, elucidate key pathways involved in disease pathogenesis, and ultimately develop more effective targeted therapies. Since several genetic variants associated with the disease have been found in f-IPF, this review systematically summarizes the latest progress in the gene spectrum of the f-IPF population and the underlying mechanisms of f-IPF. The genetic susceptibility variation related to the disease phenotype is also illustrated. This review aims to improve the understanding of the IPF pathogenesis and facilitate his early detection.

Protective role of zinc in the pathogenesis of respiratory diseases.

Respiratory diseases remain a major cause of morbidity and mortality worldwide. An imbalance of zinc, an essential trace element, is associated with a variety of lung diseases. We reviewed and summarized recent research (human subjects, animal studies, in vitro studies) on zinc in respiratory diseases to explore the protective mechanism of zinc from the perspective of regulation of oxidative stress, inflammation, lipid metabolism, and apoptosis. In the lungs, zinc has anti-inflammatory, antioxidant, and antiviral effects; can inhibit cancer cell migration; can regulate lipid metabolism and immune cells; and exerts other protective effects. Our comprehensive evaluation highlights the clinical and experimental effects of zinc in the pathogenesis of respiratory diseases. Our analysis also provides insight into the clinical application of zinc-targeted therapy for respiratory diseases.

The protective effect of natural medicines against excessive inflammation and oxidative stress in acute lung injury by regulating the Nrf2 signaling pathway.

Acute lung injury (ALI) is a common critical disease of the respiratory system that progresses into acute respiratory distress syndrome (ARDS), with high mortality, mainly related to pulmonary oxidative stress imbalance and severe inflammation. However, there are no clear and effective treatment strategies at present. Nuclear factor erythroid 2-related factor 2(Nrf2) is a transcription factor that interacts with multiple signaling pathways and regulates the activity of multiple oxidases (NOX, NOS, XO, CYP) related to inflammation and apoptosis, and exhibits antioxidant and anti-inflammatory roles in ALI. Recently, several studies have reported that the active ingredients of natural medicines show protective effects on ALI via the Nrf2 signaling pathway. In addition, they are cheap, naturally available, and possess minimal toxicity, thereby having good clinical research and application value. Herein, we summarized various studies on the protective effects of natural pharmaceutical components such as polyphenols, flavonoids, terpenoids, alkaloids, and polysaccharides on ALI through the Nrf2 signaling pathway and demonstrated existing gaps as well as future perspectives.

Urinary exosomal circular RNAs of sex chromosome origin are associated with gender-related risk differences of clinicopathological features in patients with IgA nephropathy.

BACKGROUND: There are arguments for individualized treatments and the necessity of non-invasive biomarkers for patients with IgA nephropathy (IgAN) according to gender, but the rationale remains unclear. We aimed to investigate the relationship between urine exosomal circular RNA (circRNA) levels, related genes, clinical features, and renal pathological features in IgA nephropathy patients of different genders. METHODS: Clinicopathological data from patients of different genders from a multicenter cohort were retrospectively analyzed. We used the Oxford classification to examine the severity of pathological damage in these patients. We compared clinical features and renal pathologies between IgAN patients of different genders. Using findings of urine exosomal circRNAs from male IgAN patients, we analyzed the relationship between this factor, the regulated genes located on the sex chromosomes, and renal pathologies. RESULTS: A total of 502 IgAN patients were included. The proportion of male patients with crescent formation was higher than that of females (p = 0.019). Multivariate logistic regression analysis showed that proteinuria was an independent marker for crescent formation in male and female patients with IgAN, while smoking and higher low-density lipoprotein cholesterol (LDL-C) levels were independent risk factors for crescent formation in males alone. Urine exosomal circRNA chrY:15478147-15481229- located on the Y chromosome in male patients was negatively correlated with the expressions of UTY in specific regions of the Y chromosome. CONCLUSION: Compared with female patients, males with IgAN had more severe renal dysfunction and a higher probability of glomerular crescent formation. Urine exosomal circRNA chrY:15478147-15481229- might participate in the pathogenesis of IgAN in male patients by altering UTY expressions.

The role of Elabela in kidney disease.

Elabela, also known as Toddler or Apela, is a recently discovered hormonal peptide containing 32 amino acids. Elabela is a ligand of the apelin receptor (APJ). APJ is a G protein-coupled receptor widely expressed throughout body, and together with its cognate ligand, apelin, it plays an important role in various physiological processes including cardiovascular functions, angiogenesis and fluid homeostasis. Elabela also participates in embryonic development and pathophysiological processes in adulthood. Elabela is highly expressed in undifferentiated embryonic stem cells and regulates endoderm differentiation and cardiovascular system development. During differentiation, Elabela is highly expressed in pluripotent stem cells and in adult renal collecting ducts and loops, where it functions to maintain water and sodium homeostasis. Other studies have also shown that Elabela plays a crucial role in the pathogenesis of kidney diseases. This review addresses the role of Elabela in kidney diseases including renal ischemia/reperfusion injury, hypertensive nephropathy, diabetic nephropathy, and cardiorenal syndrome.

Differential expression analysis of urinary exosomal circular RNAs in patients with IgA nephropathy.

AIMS: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease to cause end-stage kidney disease. This study investigated the difference in urinary exosomal circular RNA (circRNA) expression profiles between patients with IgAN and healthy controls (HCs), for better understanding of gene regulation in exosomes of IgAN patients. METHODS: A pairwise comparison of urinary circRNA expression profiles between IgAN patients and HCs was performed using methods, including high-throughput sequencing and quantitative polymerase chain reaction. Moreover, the potential functions of differentially expressed circRNAs (DECs) in IgAN were investigated by gene ontology (GO) enrichment analysis; Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis; and the circRNA-miRNA-mRNA network. RESULTS: We identified 450 upregulated and 26 downregulated circRNAs in the IgAN patients. GO analysis showed that these enriched circRNAs might regulate primary miRNA processing, the ability of angiotensin receptor binding, and stress fibre function. KEGG analysis suggested these DECs may be closely associated with the phosphoinositide-3-kinase-protein kinase B/Akt (PI3K-Akt) signalling pathways. Network analysis revealed the relationship between circRNAs and their target genes. CONCLUSION: The identified DECs may be useful for both researches on molecular aetiology of IgAN and development of potentially novel non-invasive biomarkers of IgAN.

Serum elabela and apelin levels during different stages of chronic kidney disease.

PURPOSE: The association of serum elabela (ELA) and apelin with the progression of chronic kidney disease (CKD) is unknown. We determined if serum ELA and apelin levels were associated with CKD stage. METHODS: This observational study involved 60 CKD patients and 20 healthy, age-, race-, and gender-matched controls. The participants were grouped according to renal function as follows: normal control group, CKD1 group (stage-1 CKD, 20 patients), CKD3 group (stage-3 CKD, 20 patients), and CKD5 group (stage-5 CKD, 20 patients) in accordance with the Kidney Disease Outcomes - Quality Initiative criteria. We recorded the demographic, clinical, and biochemical data of all participants. Serum ELA and apelin levels were measured using commercially available enzyme-linked immunosorbent assays. RESULTS: Serum ELA levels gradually and significantly declined with decreases in the estimated glomerular filtration rate (eGFR). Serum ELA showed significant negative correlations with serum creatinine (r = -0.529, p < .001), blood urea nitrogen (r = -0.575, p < .001), systolic blood pressure (r = -0.455, p < .001), and diastolic blood pressure (r = -0.450, p < .001), and significant positive correlations with hemoglobin (r = 0.523, p < .001) and eGFR (r = 0.728, p < .001). Multiple regression analysis showed that eGFR independently influenced serum ELA levels. No significant association was found between serum apelin levels and CKD progression. CONCLUSION: In CKD patients, serum ELA levels decreased with decreasing eGFR. This finding may provide a new target for the prediction, diagnosis, and staging of CKD.