Biology subjects

Kai, H.

Publications and source records attributed to Kai, H..

4 recordsLinked to original sources

bioRxiv2026

Early apelin receptor activation attenuates elastase-induced emphysema and preserves endothelial apelin receptor signaling in mice

Alveolar capillary endothelial cells are positioned adjacent to the alveolar epithelium and contribute to lung homeostasis and injury responses. Single-cell studies have identified aerocyte capillary endothelial cells (aCap), which are specialized for gas exchange, and general capillary endothelial cells (gCap), which contribute to endothelial maintenance and inflammatory signaling. Apelin and its receptor are differentially enriched across these endothelial compartments, but their roles in emphysema development remain incompletely understood. Using an elastase-induced emphysema model in male C57BL/6J mice, we combined bulk RNA sequencing, CIBERSORTx-based cell-type deconvolution, histology, inflammatory assays, pulmonary function testing, and pharmacologic activation of the apelin receptor with [Pyr1]-Apelin-13. At 24 hours after elastase exposure, the inferred fraction of gCap was reduced, and lung expression of apelin and the apelin receptor was decreased. Early [Pyr1]-Apelin-13 administration reduced lung inflammatory mediator expression, Ly6G-positive neutrophil accumulation, bronchoalveolar lavage neutrophil counts, and matrix metalloproteinase-9 activity. Early treatment also attenuated subsequent airspace enlargement, whereas treatment initiated after emphysema was established did not improve physiological or histological outcomes. In a chronic {beta}ENaC-transgenic mouse model, the inferred gCap fraction was maintained, the aCap fraction was reduced, and apelin receptor activation did not improve disease phenotypes. These findings suggest that early activation of the apelin receptor modifies acute inflammatory and endothelium-associated responses following elastase injury and limits emphysematous remodeling in mice. Together, these results support a time-sensitive role for apelin-APJ signaling during the early phase of emphysema development.

molecular biology↗

bioRxiv2026

Dietary lipids attenuate IGF-1-Akt and injure epithelial-endothelial injury program that accelerates obstructive lung disease

Background Altered lipid metabolism is increasingly implicated in chronic obstructive pulmonary disease (COPD), but it remains unclear how a pre-existing obstructive lung state modifies the response to systemic lipid excess. We investigated whether high-fat diet (HFD) amplifies COPD-relevant lung injury and examined epithelial and vascular programs associated with this response. Methods Male wild-type (WT) and beta-epithelial sodium channel-transgenic ({beta}ENaC-Tg) mice were fed control diet or HFD for 10-11 weeks. Lung structure and function, whole-lung transcriptomes, Akt-FOXO1 signaling, apoptosis-related responses, and pulmonary vascular profiles were assessed. Streptozotocin-induced insulin-deficient diabetes and pharmacological IGF-1 receptor inhibition were used as mechanistic comparators. Palmitate responses were examined in human bronchial epithelial cells, ENaC-hyperactive epithelial cells, and endothelial cells, including conditioned-medium transfer. HFD preconditioning was also evaluated in an elastase-induced emphysema model. Statistical analyses included unpaired two-tailed Student's t tests, one-way ANOVA with Tukey-Kramer or Dunnett multiple-comparison testing, Pearson correlation, and Benjamini-Hochberg correction for RNA-sequencing analyses. Results HFD produced similar increases in body weight, glycemia, and adiposity in WT and {beta}ENaC-Tg mice, while further increasing distal-airspace enlargement and reducing FEV0.1/FVC in {beta}ENaC-Tg mice. Lung transcriptomics revealed coordinated remodeling of lipid metabolic, PI3K-Akt, and vascular programs. HFD reduced Akt phosphorylation, increased FOXO1 and Fasl, and increased TUNEL-positive cells in epithelial regions. Palmitate attenuated IGF-1-induced Akt activation in bronchial epithelial cells, whereas IGF-1 receptor inhibition reproduced Akt suppression and apoptosis-related responses without fully reproducing the HFD phenotype. HFD preconditioning also increased elastase-induced airspace enlargement, accompanied by parallel upregulation of FOXO1 and TUNEL positivity. HFD reduced pulmonary CD34-positive vascular profiles, and palmitate activated endothelial cells directly and through conditioned media from ENaC-hyperactive epithelium. In men with airflow obstruction, hepatic steatosis coincided with lower percent-predicted FEV1. Conclusions Dietary lipid stress amplifies obstructive lung injury and engages complementary epithelial and vascular responses. Impaired epithelial IGF-1-Akt signaling and epithelial-endothelial crosstalk provide a mechanistic framework linking systemic metabolic stress to reduced resilience of the obstructive lung.

molecular biology↗

bioRxiv2021

Alternations of fecal microbes and lung tissue microbes in Lung Cancer patients is more consistent than that of sputum.

Microbiome in the human body environment is related to the occurrence of a variety of disease phenotypes. Recent studies discovered that lung is an open organism with in touch of air and microbe in it, and the presence of some microbes in lung cancer tissues proved that there are many microbes in lungs. In this project, we collected lung tissue, feces and sputum from three Bioprojects of NCBI related to lung cancer (LC). Each project contains LC cases and lung normal (LN) controls. Those three projects contain a total of 339 samples of 16s rRNA sequencing data. By analyzing the composition of microbes in the three environments, and predicting their functions we found that compared with sputum, the ecological environment of fecal microbe is closer to tissue microbes in terms of evolutionary relationship, indicating that the impact of feces on tissue microbes is greater than that of the sputum. We used Picrust2 to predict the differential microbe function of lung cancer (LC) and the control (Lung Normal, LN) groups in the three environments, and found that at the microbe genetic level, compared to feces and sputum, sputum and tissues, feces and tissues have more common Differential genes, at the level of differential enzyme genes and differential pathways, feces and tissues have more common differences compared to feces and sputum, sputum and tissues. Our results showed that the similarity of feces and tissue microbiome is closer than the similarity of sputum and feces microbe. Through Spearman correlation analysis based on the relative abundance of predicted pathways and the relative abundance of genus classified by LDA analysis as marker diseases and healthy samples. The results indicated that the activation of marker genus in sputum and feces and significantly changed pathways has an opposite trend, and there are many pathways contributing to glycolysis are correlated with marker genus. Patients with LC has potential to regulate the microbe composition of feces, tissues and sputum by regulating metabolism.

microbiology↗

bioRxiv2021

Aminoglycoside-induced premature termination codon readthrough of COL4A5 nonsense mutations that cause Alport syndrome

Alport syndrome (AS) is characterized by glomerular basement membrane (GBM) abnormalities leading to progressive glomerulosclerosis. Mutations in the COL4A3, COL4A4 or COL4A5 genes encoding type IV collagen 345 cause AS. Truncated 3, 4, and 5 chains lacking an intact COOH-terminal noncollagenous domain due to a premature termination codon (PTC) cannot assemble into heterotrimers or incorporate into the GBM. Therefore, achieving full-length protein expression is a potential therapy for AS caused by truncating nonsense mutations. Small molecule-based PTC readthrough (PTC-RT) therapy has been well studied in other genetic diseases, but whether PTC-RT is applicable to AS is unexplored. To investigate the feasibility of PTC-RT therapy in AS, we made a cDNA to express COL4A5 fused to a C-terminal NanoLuc luciferase (NLuc) to monitor full-length translation. Full-length COL4A5-NLuc produces luminescence, but mutants truncated due to a PTC do not. To screen for COL4A5 nonsense mutants susceptible to PTC-RT, we introduced 49 individual nonsense mutations found in AS patients into the COL4A5-NLuc cDNA. Luciferase assays revealed that 11 mutations (C29X, S36X, E130X, C1521X, R1563X, C1567X, W1594X, S1632X, R1683X, C1684X and K1689X) were susceptible to PTC-RT induced by G418, which is known to have high readthrough activity. Moreover, we found that some next-generation "designer" PTC-RT drugs induced RT, and RT enhancer compounds increased the efficacy of PTC-RT in a G418-susceptible PTC mutant. These results suggest that PTC-RT therapy is a feasible approach for some patients with AS. Our luciferase-based COL4A5 translation reporter system will contribute to further development of PTC-RT therapies in a personalized medicine approach to treating AS.

genetics↗