Siyu Hao

Objective: This study aimed to investigate the role of endoplasmic reticulum stress (ERS) in atopic dermatitis (AD) and its comorbid mental disorders and evaluate the therapeutic potential of mesencephalic astrocyte-derived neurotrophic factor (MANF). Methods: Clinical samples from patients with AD and comorbidities were analyzed for ERS and apoptosis markers using quantitative polymerase chain reaction and western blotting. Mouse models of depression were developed using 28 days of chronic unpredictable mild stress (CUMS), and dermatitis was induced using 0.2% 2,4-dinitrofluorobenzene. Adenovirus-mediated MANF overexpression was induced via local injection to develop comorbidities, comorbidities + negative control overexpression, and comorbidities + MANF overexpression groups. Further, the ERS inhibitors of 4-phenylbutyric acid were employed for the comorbidities + inhibitors group. Dermatitis scoring, the sucrose preference test for behavioral changes, and ERS and apoptosis assessments using transmission electron microscopy, terminal deoxynucleotidyl transferase dUTP Nick-End labeling staining, hematoxylin and eosin staining, and immunohistochemistry were conducted. Results: Clinical data demonstrated significant increases in ERS-related markers (GRP78, P-IRE1, and Caspase-12) and apoptosis marker of Bax, whereas Bcl-2 was decreased in comorbidities compared with those with AD alone. In mouse models, increased Bax and decreased Bcl-2 indicated apoptotic pathway activation in the comorbidities group. MANF overexpression reduced ERS-related factors and skin pathology while improving behavioral indicators. Further, MANF reduced skin cell apoptosis by downregulating Bax and upregulating Bcl-2. ERS inhibitors similarly alleviated cell apoptosis, thereby confirming the critical role of ERS in disease progression. Conclusion: MANF overexpression reduces ERS and apoptosis, which improves AD symptoms and comorbid mental disorders, thereby highlighting its therapeutic target potential.

The locus at 17q12 erb‐b2 receptor tyrosine kinase 2 (ERBB2) has been heavily amplificated and overexpressed in gastric cancer (GC), but it remains to be elucidated about the clinical significance of the co‐amplification and co‐overexpression of PGAP3 gene located around ERBB2 in GC. The profile of PGAP3 and ERBB2 in four GC cell lines and tissue microarrays containing 418 primary GC tissues was assessed to investigate the co‐overexpression and clinical significance of the co‐amplified genes, and to evaluate the impact of the co‐amplified genes on the malignancy of GC. Co‐amplification of PGAP3 and ERBB2 accompanied with co‐overexpression was observed in a haploid chromosome 17 of NCI‐N87 cells with double minutes (DMs). PGAP3 and ERBB2 were overexpressed and positively correlated in 418 GC patients. Co‐overexpression of the PGAP3 and ERBB2 was correlated with T stage, TNM stage, tumour size, intestinal histological type and poor survival proportion in 141 GC patients. In vitro, knockdown of the endogenous PGAP3 or ERBB2 decreased cell proliferation and invasion, increased G1 phase accumulation and induced apoptosis in NCI‐N87 cells. Furthermore, combined silencing of PGAP3 and ERBB2 showed an additive effect on resisting proliferation of NCI‐N87 cells compared with targeting ERBB2 or PGAP3 alone. Taken together, the co‐overexpression of PGAP3 and ERBB2 may be crucial due to its significant correlation with clinicopathological factors of GC. Haploid gain of PGAP3 co‐amplified with ERBB2 is sufficient to facilitate the malignancy and progression of GC cells in a synergistic way.

Zhang L, et al. Allergy Asthma Immunol Res. 2022 Jan;14(1):131-142. https://doi.org/10.4168/aair.2022.14.1.131