Galande Sheethal, Ravikanth V V, Tokala Ranjeet K, Satyanarayana Singh Surya, Rao G V, Talukdar Rupjyoti, Peddapulla Chandan, Reddy D Nageshwar, Sasikala Mitnala
Translational Research Centre, Asian Healthcare Foundation, AIG Hospitals, Hyderabad, India.
Department of Biochemistry, University College of Science, Osmania University, Hyderabad, India.
Gene. 2025 Mar 10;940:149200. doi: 10.1016/j.gene.2024.149200. Epub 2024 Dec 26.
A comprehensive understanding of the molecular pathogenesis of chronic pancreatitis (CP), a fibroinflammatory disorder of the pancreas, is warranted for the development of targeted therapies. The current study focused on comparing the transcriptomes of pancreatic tissues obtained from patients with CP with those of two rodent models of chemically induced CP to identify dysregulated genes/signaling pathways.
Pancreatitis was induced in mice using cerulein and L-arginine. Pancreatic tissues were obtained from humans and mice. The RNA was isolated, and the transcriptomes were generated using the GeneChip Human Transcriptome Array 2.0 and Clariom D Mouse Array respectively. Differentially expressed genes with log2-fold changes ≥ +2 and ≤ -2 were considered for functional and signaling pathway enrichment analysis. The expression of NUCB2, which plays a role in β-cell function, was validated by ELISA in acute pancreatitis (AP) and immune cell responses in AP and CP using flow cytometry.
The current study identifies L-arginine-induced CP as a better model for investigating the pathogenesis of human CP, with greater similarity in dysregulated genes (22%), transcription factors (34%) and enriched pathways (58%) compared to cerulein model (2%, 11% and 9%) respectively. Nesfatin-1, encoded by NUCB2, was decreased in patients with AP (12% nondiabetic, 41% post pancreatitis diabetes). The Th1 immune cell response was greater in the patients with AP (44%), whereas Th17 immune response was greater in patients with CP (18%).
Our study highlights potential novel and unexplored pathways involved in inflammation, fibrosis, and pain in CP and paves the way for testing them as putative drug targets using a severe disease model.
慢性胰腺炎（CP）是胰腺的一种纤维炎性疾病，全面了解其分子发病机制对于开发靶向治疗方法至关重要。本研究聚焦于比较CP患者胰腺组织的转录组与两种化学诱导的CP啮齿动物模型的转录组，以鉴定失调的基因/信号通路。
用雨蛙肽和L-精氨酸诱导小鼠胰腺炎。从人和小鼠获取胰腺组织。分离RNA，分别使用基因芯片人类转录组阵列2.0和Clariom D小鼠阵列生成转录组。将log2倍数变化≥ +2和≤ -2的差异表达基因用于功能和信号通路富集分析。通过酶联免疫吸附测定（ELISA）验证在β细胞功能中起作用的NUCB2的表达，并使用流式细胞术分析急性胰腺炎（AP）中的免疫细胞反应以及AP和CP中的免疫细胞反应。
本研究确定L-精氨酸诱导的CP是研究人类CP发病机制的更好模型，与雨蛙肽模型相比，其失调基因（分别为22%和2%）、转录因子（分别为34%和11%）和富集通路（分别为58%和9%）具有更高的相似性。由NUCB2编码的Nesfatin-1在AP患者中降低（非糖尿病患者中为12%，胰腺炎后糖尿病患者中为41%）。AP患者中Th1免疫细胞反应更强（44%），而CP患者中Th17免疫反应更强（18%）。
我们的研究突出了CP中炎症、纤维化和疼痛所涉及的潜在新的未探索通路，并为使用严重疾病模型将它们作为假定药物靶点进行测试铺平了道路。
