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Hypoxia is a globally pressing environmental problem in aquatic ecosystems. In the present study, a comprehensive analysis was performed to evaluate the effects of hypoxia on physiological responses (hematology, cortisol, biochemistry, hif gene expression and the HIF pathway) of hybrid sturgeons (Acipenser schrenckii ♂ × Acipenser baerii ♀). A total of 180 hybrid sturgeon adults were exposed to dissolved oxygen (DO) levels of 7.00 ± 0.2 mg/L (control, N), 3.5 ± 0.2 mg/L (moderate hypoxia, MH) or 1.00 ± 0.1 mg/L (severe hypoxia, SH) and were sampled at 1 h, 6 h and 24 h after hypoxia. The results showed that the red blood cell (RBC) counts and the hemoglobin (HGB) concentration were significantly increased 6 h and 24 h after hypoxia in the SH group. The serum cortisol concentrations gradually increased with the decrease in the DO levels. Moreover, several serum biochemical parameters (AST, AKP, HBDB, LDH, GLU, TP and T-Bil) were significantly altered at 24 h in the SH group. The HIFs are transcription activators that function as master regulators in hypoxia. In this study, a complete set of six hif genes were identified and characterized in hybrid sturgeon for the first time. After hypoxia, five out of six sturgeon hif genes were significantly differentially expressed in gills, especially hif-1α and hif-3α, with more than 20-fold changes, suggesting their important roles in adaptation to hypoxia in hybrid sturgeon. A meta-analysis indicated that the HIF pathway, a major pathway for adaptation to hypoxic environments, was activated in the liver of the hybrid sturgeon 24 h after the hypoxia challenge. Our study demonstrated that hypoxia, particularly severe hypoxia (1.00 ± 0.1 mg/L), could cause considerable stress for the hybrid sturgeon. These results shed light on their adaptive mechanisms and potential biomarkers for hypoxia tolerance, aiding in aquaculture and conservation efforts. [ABSTRACT FROM AUTHOR]

Purpose: Guselkumab is a highly effective biologic agent for treating psoriasis. This study aimed to explore potential transcription factors involved in psoriasis pathogenesis and response to guselkumab treatment, aiming to provide new therapeutic strategies for psoriasis. Patients and Methods: We analyzed gene expression and single-cell RNA-seq data from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) that upregulated in psoriasis and downregulated after guselkumab treatment were subjected to enrichment analyses. Single-cell regulatory network inference and clustering (SENIC) and regulon module analyses identified different regulon activities between the lesion and non-lesion skin of psoriasis. Cell-cell communication analysis revealed interactions among specific cell clusters. Transcription factor (TF) regulons were identified from the guselkumab-specific regulon network. Gene set enrichment analysis (GSEA) confirmed the IRF7 regulon in the validation cohort. Finally, the expression level of IRF7 was identified in plaque psoriasis before and after 12 weeks of guselkumab therapy by immunohistochemical experiment. Results: 799 DEGs were downregulated after guselkumab treatment. Enrichment analyses highlighted the interleukin-17 (IL-17) pathway in this gene set. The M2 module exhibited the primary difference in regulon activity. Strong cell-cell interactions were observed between keratinocytes and immune cells. IRF7 regulon had significant roles in psoriasis and treatment response, as validated by GSEA analysis using the IL-17 signaling pathway as a reference. The immunohistochemical analysis unveiled substantial differences in the expression levels of IRF7 in psoriatic skin samples before and after 12 weeks of guselkumab treatment. Conclusion: IRF7 may be the key player in psoriasis pathogenesis and the therapeutic process involving guselkumab. Targeting IRF7 might offer new therapeutic strategies for psoriasis. [ABSTRACT FROM AUTHOR]

Hypoxia serves a critical role in the pathogenesis of liver fibrosis. Hypoxia-inducible factor 1α (HIF1-α) is induced when cells are exposed to low O2 concentrations. Recently, it has been suggested that Rho-associated coiled-coil-forming kinase 1 (ROCK1) may be an important HIF1-α regulator. In the present study, it was analyzed whether crosstalk between HIF1-α and ROCK1 regulates cell proliferation and collagen synthesis in hepatic stellate cells (HSCs) under hypoxic conditions. For this purpose, a rat hepatic HSC line (HSC-T6) was cultured under hypoxic or normoxic conditions, and HIF1-α and ROCK1 expression was measured at different time points. Additionally, HSC-T6 cells were transfected with HIF1-α small interfering RNA (siHIF1-α), and measured protein expression and mRNA transcript levels of α-smooth muscle actin, collagen 1A1 and ROCK1. Collagen 3A1 secretion was also measured by ELISA. Cell proliferation was assessed by the MTT assay under these hypoxic conditions. The results indicated that a specific ROCK inhibitor, Y-27632, increased HIF1-α and ROCK1 expression over time in HSC-T6 cells in response to hypoxia. In addition, knockdown of HIF1-α inhibited HSC-T6 proliferation, suppressed collagen 1A1 expression, decreased collagen 3A1 secretion and attenuated ROCK1 expression. Notably, ROCK1 inhibition caused HSC-T6 quiescence, suppressed collagen secretion and downregulated HIF1-α expression. Collectively, these findings indicated that the interplay between HIF1-α and ROCK1 may be a critical factor that regulates cell proliferation and collagen synthesis in rat HSCs under hypoxia. [ABSTRACT FROM AUTHOR]