Frigid Zone Medicine

Correlation of PM_2.5 pollution and daily mortality rate of cardiovascular and cerebrovascular diseases in Northeast China through PM_2.5 sources analysis

Qianqi Hong, Yang Zhao, Jing Wang, Hongyan Sun, Lanxin Deng, Jingjing Cao, Cheng Wang

2024, 4(4): 193-201. doi: 10.1515/fzm-2024-0019

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Abstract:
Objective This study aims to evaluate the relationship between PM_2.5 concentration and daily mortality rate from cardiovascular and cerebrovascular diseases (CCVD) in cold regions of northern China, as well as to identify the primary sources of PM_2.5. Methods A time series analysis model was used to calculate the exposure-response relationship between PM_2.5 and CCVD mortality in Harbin. Positive matrix factorization (PMF) was employed to analyze the sources of PM_2.5. Results After adjusting for multiple pollutant combinations, the maximum excess risk of cardio-cerebrovascular death on the day of PM_2.5 exposure was 0.42% (95% CI: 0.15%-0.70%). Stratification by gender and age revealed that the elderly individuals and men were particularly susceptible to PM_2.5 exposure. The source analysis identified seven major pollution sources contributing to PM_2.5 in Harbin. Conclusion Our findings strengthen the evidence that PM_2.5 is an independent risk factor for daily CCVD mortality, identify vulnerable populations that require special attention, and pinpoint the primary sources of PM_2.5 in Harbin. These findings provide reference points for effectively reducing the health risks associated with PM_2.5 exposure.

Small ubiquitin-like modifiers inhibitors lower blood pressure via ERK5/KLF2-dependent upregulation of the eNOS/NO pathway

Nannan Tang, Jiatong Li, Zhuo Wang, Jinlu Zuo, Zifeng Zhang, Di Huang, Yannan Han, Yuqing Chen, Yilin Sun, Xiang Li, Ruxue Mu, Qingxue Ma, Jie Zhang, Jiaying Wu, He Wang, Hongxia Zhao, Xingli Dong, Zhiguo Wang, Yu Liu, Dan Zhao, Baofeng Yang

2024, 4(4): 202-211. doi: 10.1515/fzm-2024-0020

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Abstract:
Background Small ubiquitin-like modifiers (SUMO)ylation is a dynamic and reversible post-translational modification playing pivotal roles in the regulation of cancer, diabetes, heart failure, and neurological diseases. However, whether SUMO inhibitors also have anti-hypertension effect remains yet to be explored. Methods Blood pressure was monitored in spontaneously hypertensive rats (SHR) after Tannic acid (TA) administration for 4 weeks. The contents of nitric oxide (NO) and endothelin-1 (ET-1) in the serum of SHR were measured. Isolated endothelium-intact mesenteric artery rings were used to study relaxation effect of SUMO inhibitors. ERK5 SUMOylation was determined using coimmunoprecipitation (co-IP) and immunofluorescence (IF). NO levels were analyzed by IF. The expression levels of KLF2 and p-eNOS were semiquantified by Western blot analysis. The transcriptional activity of eNOS promotor was assayed using ChIP-PCR. Results Three SUMO inhibitors all reduced the phenylephrine (PE)-induced contraction of mesenteric artery rings in a concentration-dependent manner. Co-IP revealed that ponatinib promoted ERK5 SUMOylation, which was nulled following pretreatment with the SUMO inhibitors. IF displayed that TA increased ERK5 accumulation and its co-localization with SUMO-1 in the nucleus. ChIP-PCR unveiled TA-induced enhancement of KLF2-dependent eNOS promoter activity and upregulation of eNOS/NO expression in HUVECs. In vivo, TA significantly lowered the blood pressure and improved the vascular reactivity by activating the KLF2/eNOS/NO pathway. Additionally, the level of NO was elevated along with decreased ET-1 levels in the serum of SHR. Conclusions SUMO inhibitors inhibit ERK5 SUMOylation to promote KLF2-eNOS/NO signaling, indicating their therapeutic potential for the treatment of hypertension.

GDF11 restores the impaired function of EPCs-MA by promoting autophagy: GDF11 ameliorates endothelial progenitor cell aging by promoting autophagy

Donghua Liu, Yang Zhang, Xin Liu, Qihe Huang, Xiaofang Zhang, Rui Yang, Yue Zhao, Penghui Li, Jiayi He, Kexiao Zhang, Zhenwei Pan, Huiwen Liu, Baofeng Yang

2024, 4(4): 212-223. doi: 10.1515/fzm-2024-0021

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Abstract:
Objective Our study aimed to assess the effects of Growth and differentiation factor 11 (GDF11) on the function of endothelial progenitor cells in middle-age individuals (EPCs-MA) isolated from mouse bone marrow and to explore the mechanistic relationship between GDF11 and age-related ALP impairment. Methods Bone marrow-derived EPCs were isolated, culture and GDF11 treatment. In vivo, the mice model of myocardial ischemia (MI) was induced by permanent ligation of the left anterior descending coronary artery (LAD) and mice were randomly divided into MI group and EPCs transplantation group (EPCs-Y, EPCs-MA, EPCs-MA/GDF11). The positive effect of GDF11 treatment of EPCs-MA on MI was verified by echocardiography and the average ratio of fibrotic area to left ventricular (LV) area. In vitro, the effect of GDF11 on ameliorating EPCs aging by promoting autophagy was confirmed by transwell assay, immunofluorescence staining, characterization of EPCs ultrastructure through transmission electron microscope (TEM), lysosome imaging and Western blot. Result Our findings demonstrate that GDF11 enhances the migration capacity of EPCs-MA and improves recovery of impaired cardiac function after myocardial infarction (MI) in mice, with EPCs isolated from young mice (EPCs-Y) as controls. Moreover, GDF11 restored functional phenotypes of EPCs-MA to levels akin to EPCs-Y, promoting the expression of CD31, endogenous NO synthase, and the restoration of von Willebrand factor (vWF) and CDH5 expression patterns, as well as the formation of Weibel-Palade bodies—key organelles for storage and secretion in endothelial cells and EPCs. Furthermore, GDF11 significantly enhanced the autophagic clearance capability of EPCs-MA by promoting ALP. Conclusions Our results suggest that GDF11 ameliorates cardiac function impairment by restoring the activities of EPCs from aging mice through enhanced ALP. These findings suggest that GDF11 may hold therapeutic potential for improving aging-related conditions associated with declined autophagy.

ISG15 promotes M5-induced hacat cell proliferation through Wnt signaling in psoriasis

Xianqi Sun, Yuzhen Li, Huiwen Yu, Jiaying Lin, Chen Wang, Quanlin Liu, Bingxue Bai

2024, 4(4): 224-232. doi: 10.1515/fzm-2024-0022

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Abstract:
Objective Psoriasis is a common chronic, recurrent, immune-mediated inflammatory skin disease, which tends to occur in cold areas. Its pathogenesis is currently unclear. This study aims to screen differentially expressed genes in the psoriasis dataset, identify the central genes, detect the expression of central genes in psoriasis lesions of patients in the cold regions and then conduct further research. Methods Differential genes associated with psoriasis in the GEO database were analyzed, and functional enrichment analysis and protein-protein interaction network analysis. The expression results of the identified genes were validated in psoriasis cell models. The ISG15 gene, which showed the most significant difference in expression, was further studied. The expression level of ISG15 protein in psoriasis was examined. Then, we knocked out ISG15 in psoriasis cell models and detected keratinocyte proliferation by MTT, Real-Time PCR and Western Blot. Western Blot showed the expression of β-catenin after ISG15 gene knockout. Results We detected the protein expression of ISG15 in the cold area of Northeast China, and found that the expression of ISG15 increased in patients with psoriasis, and the proliferation of keratinocytes and the expression of β-catenin decreased in psoriasis cell model after ISG15 was knocked down. ISG15 regulates keratinocyte proliferation through Wnt signaling pathway in psoriasis. Conclusions ISG15 expression is increased in psoriatic cells and skin lesions of patients with psoriasis. In psoriasis, ISG15 promotes keratinocyte proliferation through the Wnt signaling pathway.

Identification of hub genes and pathways in mouse with cold exposure

Xu Wang, Hongbo Hu, Ying Zhang

2024, 4(4): 233-241. doi: 10.1515/fzm-2024-0023

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Abstract:
Background Cold exposure is linked to numerous diseases, yet the changes in key genes and pathways in mice under cold exposure remain unexplored. Understanding these alterations could offer insights into the mechanisms of cold resistance and contribute valuable ideas for treating cold-related diseases. Methods The dataset GSE148361 was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the "limma" package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on DEGs. The STRING (Search Tool for the Retrieval of Interacting Genes) database was used to construct a protein-protein interaction (PPI) network. Additionally, gene set enrichment analysis (GSEA) was conducted to identify pathways associated with key genes. miRNAs and upstream transcription factors (TFs) were predicted using the miRNet database. Results A total of 208 DEGs were identified, with 137 upregulated and 71 downregulated. In biological processes, DEGs were enriched in nucleotide and purine-containing compound metabolism. For cellular components, DEGs were involved in condensed chromosomes and mitochondrial protein complexes. In molecular functions, proton transmembrane transporter activity was enriched. KEGG pathway analysis showed significant enrichment in biosynthesis of unsaturated fatty acids, fatty acids, and pyruvate metabolism. From the PPI network, 12 hub genes were identified using MCODE. Four hub genes (Col3a1, fi203, Rtp4, Vcan) demonstrated similar trends in a validation set (GSE110420) and were significantly differentially expressed. GSEA analysis indicated that these four genes were enriched in pathways such as ECM-receptor interaction and cytokinecytokine receptor interaction. The hub gene network included 93 miRNAs and one TF. Conclusion This study identified four hub genes as potential diagnostic biomarkers for cold exposure, providing insights for further research on the effects of cold on gene expression and disease.

The function and effect on prognosis of ANXA2 in gastric cancer peritoneal metastasis patients in cold region

Shiyang Jin, Longxu Liang, Xiaoyi Huang, Kuan Wang

2024, 4(4): 242-251. doi: 10.1515/fzm-2024-0024

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Abstract:
Objective Heilongjiang Province is part of the northern cold areas of China, where gastric cancer is one of the most common gastrointestinal malignancies. Peritoneal metastases (PM) are the leading cause of mortality among patients. This study conducted bioinformatics and basic research on the gene ANXA2 (Annexin A2), which may influence the prognosis of patients. Methods Genome sequencing was performed on patients from Heilongjiang to identify potential genes impacting survival time. The function of ANXA2 in gastric cancer was analyzed using multiple bioinformatics databases, focusing on its pathways and mechanisms. ANXA2-knockout gastric cancer cell lines were constructed, and in vitro assays, including CCK-8, flow cytometry, scratch, and Transwell experiments, were conducted. A nude mouse tumorigenesis model was also developed to analyze in vivo effects. Results ANXA2 was found to be expressed at higher levels in gastric cancer tissue than in normal gastric tissue, and its mRNA levels were associated with short overall survival (OS). Enrichment analysis indicated that ANXA2 is primarily localized on the cell membrane and primarily influences the PI3K-AKT signaling pathway. Cytological experiments demonstrated that knockdown of ANXA2 suppresses the growth and migration of gastric carcinoma cells, an effect that was also observed in vivo. Conclusions ANXA2 is essential for gastric cancer growth and may represent a potential risk factor affecting the survival probability of patients in cold regions.

Arthroscopic patellar denervation with microfracture for treating patellofemoral arthritis in cold weather conditions: a retrospective clinical analysis

Xinnan Ma, Xin Zhang, Yingkai Ma, Yonghou Zhao, Kai Liu

2024, 4(4): 252-256. doi: 10.1515/fzm-2024-0025

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Abstract:
Objective To evaluate the clinical efficacy of combining arthroscopic patellar denervation with microfracture in the treatment of patellofemoral arthritis under cold weather conditions. Methods A total of 134 patients with patellofemoral arthritis who underwent treatment between June 2019 and June 2021 were included in this study. Patients were randomly divided into two groups: the control group, which received standard arthroscopic debridement and conventional therapy, and the study group, which underwent additional peripatellar denervation and microfracture procedures. Clinical outcomes, including Tegner scores, hospital for special surgery (HSS) scores, and treatment-related adverse events, were evaluated and compared between the two groups. Results The study group achieved a significantly higher excellent treatment rate (95.52%, 64/67) compared to the control group. Posttreatment Tegner scores (5.48 ± 1.86) and HSS scores (86.37 ± 11.25) were also significantly better in the study group than in the control group. Furthermore, the incidence of adverse reactions was lower in the study group (4.48%, 3/67), with statistically significant differences observed (P < 0.05). Conclusions Arthroscopic patellar denervation combined with microfracture markedly improves clinical outcomes, including Tegner and HSS scores, in the treatment of patellofemoral arthritis, particularly under cold weather conditions. The procedure is effective and safe, supporting its broader clinical application.

2024 Vol. 4, No. 4

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