20 December 2022, Volume 36 Issue 6

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  • Review
    Ning Gao, Hui-Qing Lu, Ting-Ting Zou, Li-Ping Ren, Ke Cai, Yue Li, Xue-Hua Pu, Ji-Lu Ye
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1727-1734. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.181
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    Acute kidney injury (AKI) can result from a variety of etiologies (e.g., ischemia, toxicity, and sepsis) and is characterized by high rates of morbidity and mortality. As the diagnostic criteria for AKI, an increase in serum creatinine (SCr) concentration and/or a decrease in urine output often lags behind. However, early detection and timely treatment of AKI are crucial to reduce the mortality. AKI diagnosed only by elevated markers of tubular/glomerular injury is called “Subclinical AKI” means elevated markers of glomerular/tubular injury, but not accompanied by elevated SCr. In recent years, there have been many studies on biomarkers for early diagnosis of AKI, and several novel biomarkers have emerged. This manuscript discusses some important biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type FABP (L-FABP), proenkephalin (Penkid), metalloproteinase 2 (TIMP-2), insulin-like growth factor binding protein 7 (IGFBP7) and Dickkopf-3 (DDK3). We analyze their advantages, limitations and clinical application prospects in subclinical AKI.

  • Review
    Jing Ning, Shenyi Jiang, Shu Wang, Xuhong Deng, Zhiqiang Zhang, Lijie He, Daqing Wang, Youhong Jiang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1735-1740. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.182
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    Glypican 3 (GPC3) is a heparan sulfate proteoglycan whose gene is located on chromosome Xq26. GPC3 has different expression patterns in different cancer types, and its role remains controversial. GPC3 is overexpressed in hepatocellular carcinoma, melanoma, embryonic tumors, and hepatoblastoma but is under-expressed in mesothelioma, ovarian, and breast cancer. Reports of GPC3 in lung cancer remain limited and superficial. GPC3 expression is significantly higher in LUSC (lung squamous cell carcinoma) than in lung adenocarcinoma. GPC3 overexpression can accelerate the growth of lung squamous cells and the occurrence of LUSC, highlighting its role in LUSC progression. Owing to the expression of GPC3 in LUSC tissues, it has been tested as an immunotherapeutic (including chimeric antigen receptor (CAR)-GPC3 T cells), and clinical trials targeting GPC3 are ongoing. This article reviews the relationship between GPC3 and LUSC and recent clinical trials targeting GPC3 to provide a theoretical basis and reference for follow-up research.

  • Article
    Marco Zaffanello, Angelo Pietrobelli, Luana Nosetti, Giorgio Piacentini, Giuliana Ferrante, Michele Piazza, Alessandra Guzzo, Franco Antoniazzi
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1741-1747. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.183
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    Background: Besides its role in calcium homeostasis and bone mineralization, vitamin D may also reduce the risk of cancer, cardiovascular and autoimmune diseases. Excessive vitamin D intake can lead to life-threatening hypercalcemia and toxicity, however. Here, we wanted to determine the relative search volume (RSV) of interest in vitamin D and its adverse biological effects (hypercalcemia, renal failure, kidney stones, bone density).

    Methods: We used data from Google Trends to assess changes in RSV trends across the world’s regions. Data were extracted via the search terms “cholecalciferol”, “ergocalciferol, “hypercalcemia”, “acute renal failure”, “kidney stones”, and “bone density” from queries in English from 1 January 2004 to 1 October 2018 in the tool’s related query database. Statistical analysis was performed using SPSS® 22.0 for Windows (IBM Inc., Armonk, NY, USA, 10504-1722).

    Results: There was a correlation between the RSV of cholecalciferol and ergocalciferol (Spearman’s correlation) and the RSV of hypercalcemia, renal failure, kidney stones, and bone density. As measured by the change in RSV score, the trend for interest in kidney stones increased more rapidly than that for the other search terms. There was a positive correlation between the RSV score for cholecalciferol (or ergocalciferol) and renal failure and between the RSV score for cholecalciferol (or ergocalciferol) and kidney stones, whereas there was a negative correlation between cholecalciferol and hypercalcemia. The interest of ergocalciferol increased in parallel with the interest in bone density. The highest concentration of interest in cholecalciferol occurred in North America, Europe, India and Australia, whereas interest in ergocalciferol was greater in Central and South America, Spain, and Thailand. Interest in kidney stones was greater than cholecalciferol in North America, Brazil, India, and Australia, while interest in bone density was greater than cholecalciferol in North America, Brazil, Italy, Spain, South Africa, and Australia.

    Conclusions: In the pre-pandemic COVID-19 (COronaVIrus Disease 19) era, our preliminary results showed a positive correlation between global interest in cholecalciferol and kidney stones and renal failure, respectively. However, we found an unexpected negative correlation between global interest in cholecalciferol and hypercalcemia. Additionally, we found a positive correlation between global interest in ergocalciferol and bone density. These correlations can inform health interventions and education.

  • Article
    Wendian Yin, Liang Zhang, Meifang Qian
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1749-1757. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.184
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    Background: This study determined the function and the underlying mechanism of fibulin-5 in patients with lung infections.

    Methods: Serum was collected from patients with lung infections and healthy volunteers. Mice underwent cecal ligation and puncture surgery as served as a lung infection model. Serum expression of fibulin-5 was downregulated in patients and mice with lung infections.

    Results: Fibulin-5 attenuated inflammation and prevented lung injury in mice with lung infections via suppression of the calcitonin gene-related peptide (CGRP) pathway. Upregulation of fibulin-5 attenuated inflammation and suppressed the CREB/CGRP pathway in an in vitro model. Upregulation of the CREB/CGRP pathway weakened the anti-inflammation effects of fibulin-5 in an infection—induced lung injury model. These data demonstrated, for the first time, that serum fibulin-5 gene expression may be a clinical indicator in patients with lung infections.

    Conclusions: Furthermore, fibulin-t attenuated inflammation via the CREB/CGRP pathway.

  • Article
    Wei Wang, Can Du, Min Huang, Chao Cheng, Meng-lan Zhang, Xue-cheng Zhang, Yu-juan Qi
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1759-1766. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.185
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    Background: Polycomb chromobox 4 (CBX4) is a component of the polycomb complex and also a small ubiquitin-related modifier E3 ligase. CBX4 has been identified as a poor prognostic marker for various cancers, but its role in stomach adenocarcinoma (STAD) chemotherapy resistance remains unclear.

    Purpose: The aim of this study was to study the expression of CBX4 in STAD and its role in STAD chemotherapy resistance. Method: This study looked for CBX4 expression level in patients with STAD and adjacent normal tissues by immunohistochemistry generated CBX4 knockout (KO) STAD cell line with CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 technology, checked for CBX4-related transcriptional profile with RNA (Ribonucleic Acid)-seq technology and measured chemotherapy resistance with CCK8 (Cell Counting Kit-8) assay.

    Result: In this study, CBX4 was found to be highly expressed in STAD tumor tissues. CBX4-related transcriptional profile was illustrated in CBX4 KO STAD cell lines, showing that CBX4 regulated the alternative splicing involved in DNA (DeoxyriboNucleic Acid)-repair pathways. CBX4 KO STAD cells were found to be more vulnerable to 5-fluorouracil (5-FU) treatment.

    Conclusions: This study confirmed the high expression of CBX4 level in STAD tissues and revealed that CBX4 is a potential biomarker for predicting 5-FU sensitivity in STAD. Inhibition of CBX4 is a potential strategy to overcome the drug resistance of 5-FU in STAD treatment.

  • Article
    Rui Wang, Hui-Na Song, Wen-Chao Yang, Xi-Hua Liu, Li Wang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1767-1771. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.186
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    Objective: With the development of social material civilization, the change of living environment and diet structure, the number of allergic disease visits is increasing gradually. Seeking patient of medical treatment for allergen disease visits is necessary. To analyze the pattern of allergy-related hospital visits and the characteristics of allergen distribution in patients with suspected allergic diseases.

    Methods: A total of 1584 patients with suspected allergic diseases who underwent allergen testing in the outpatient clinic of the Third Medical Center of Chinese People’s Liberation Army (PLA) General Hospital between January 2018 and December 2020 were enrolled. Serum-specific immunoglobulin E (sIgE) antibodies to multiple allergens and total immunoglobulin E (TIgE) were determined in each patient’s serum using a domestic chemiluminescence instrument.

    Results: The number of allergic disease visits indicated a bimodal pattern for three consecutive years, with the highest number of visits being between March and May and between August and October. The results of the allergen tests were ranked as follows: Artemisia pollen was the most common seasonal inhalant allergen, dust mites were the most common perennial inhalant allergen, and the three most common food allergens were sea fish/sea crab, milk, and sea shrimp.

    Conclusions: Based on the distribution characteristics of allergens in this study, most of the allergic disease visits are currently in passive medical mode. It is planned to adjust the patient’s treatment mode to active treatment before the occurrence of allergic symptoms give preventive measures and medication guidance to reduce patients’ allergic symptoms.

  • Article
    Xiaohui Sun, Yuyan Shi, Nan Hua
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1773-1780. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.187
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    Background: Oxaliplatin (OXA) is used to treat patients with advanced gastric cancer (GC). However, due to the presence of drug resistance, GC patients often respond poorly to chemotherapy.

    Methods: Quantitative real-time PCR (RT-qPCR) to detect HOX (homeobox) transcript antisense intergenic RNA (HOTAIR) expression in GC patients and OXA-resistant SGC-7901 cells. After HOTAIR silencing, Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing test, and Transwell® assay respectively measure cell proliferation, cell cycle and apoptosis, cell migration, and invasion ability. The p-PI3K, PI3K (phosphatidylinositol 3 kinase), p-ATK, ATK (protein kinase B), E-cadherin and Vimentin protein expression and their mRNA expression levels were tested by Western blotting and RT-qPCR. In addition, a xenograft tumor experiment was conducted to further verify the role of HOTAIR in GC.

    Results: In this study, we observed that HOTAIR was highly expressed in GC patients and OXA-resistant SGC-7901 cells. HOTAIR silencing significantly reduced the proliferation, migration and invasion ability of SGC-7901 and OXA-resistant SGC-7901 cells, increased the apoptosis rate, and arrested cells at the G2 phase. In vivo research revealed that HOTAIR knockdown significantly inhibited tumor development. Silencing HOTAIR inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway while decreasing the expression of Vimentin, p-Akt and p-PI3K, and increasing the expression of E-cadherin. Overall, HOTAIR silencing inhibits epithelial-mesenchymal transition (EMT) through the PI3K/Akt pathway to inhibit OXA resistance in GC.

    Conclusions: HOTAIR might be a potential novel therapeutic target for GC that is OXA-resistant.

  • Article
    Lichao Zhang, Shaoxia Zi
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1781-1788. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.188
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    Background: Phosphoinositide 3-kinase/Protein kinase B (PI3K/AKT) pathway activation correlates with the clinical progress of melanoma. Previous research demonstrated the inhibitory effect of parthenolide on PI3K/AKT pathway. It was testified whether parthenolide could be utilized to inhibit PI3K-AKT pathway activation and relevant growth in melanoma in this study.

    Methods: Flow cytometry based on Annexin V/propidine iodide (PI) staining was used to measure cell apoptosis. A xenograft mouse model was constructed, and parthenolide was intraperitoneally injected to examine the effects of parthenolide in vivo. Parthenolide showed cytotoxicity on A375 and A2058 cells as revealed by diminishing viability, colony formation, and migration.

    Results: Increased apoptosis was found in A375 and A2058 cells induced by parthenolide treatment. Up-regulated Bax, and down-regulated B-cell lymphoma 2 (Bcl-2) expression was observed after parthenolide administration. Parthenolide also reduced the levels of phosphorylation of AKT and PI3K. In addition, parthenolide inhibited the growth of melanoma in the xenograft model.

    Conclusions: In summary, parthenolide inhibits cell viability and induces apoptosis in melanoma through the inhibition of PI3K/AKT signaling pathway, which could be considered an adjuvant therapy.

  • Article
    Rui Wang, Hongxia Yang, Yinglian Zhou, Xidong Zhu, Meihua Jin, Jin Fu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1789-1797. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.189
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    Background: Multiple sclerosis (MS) is a disease that is characterized by demyelination of the central nervous system. The pathogenesis is associated with heredity, the environment and autoimmunity. The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signalling pathway is mediated by a variety of cytokines, and may be involved in cell proliferation, differentiation, apoptosis and immune regulation. We aimed to study the association of genetic polymorphisms of molecules in the JAK-STAT signalling pathway with the susceptibility to MS.

    Methods: We collected 110 patients with MS and 110 healthy volunteers as negative controls. Venous blood was extracted from all patients with MS and healthy volunteers. Genes related to JAK-STAT signalling pathways associated with MS susceptibility were screened through literature retrieval and gene clustering database. The gene polymorphisms were genotyped using modified ligase reaction (iMLDR) technology. SPSS 16.0 software was used to compare the differences between MS patients and healthy controls.

    Results: The genotype frequencies of 10 polymorphisms of STAT3 (signal transducer and activator of transcription 3) (rs4796791, rs744166 and rs2293152), STAT4 (rs9967792), IL7R (interleukin 7 receptor) (rs6897932 and rs6881706), IL2RA (interleukin 2 receptor A) (rs12722489 and rs2104286), and IL12A (interleukin 12A) (rs1014486 and rs4680534) in the JAK-STAT signalling pathway were not significantly different between the patients with MS and the healthy controls (p > 0.05). When stratified by sex, the female subjects who carried STAT3 (rs2293152) CG had an increased risk of MS when compared to those who carried the GG allele (odds ratio (OR) = 2.596, 95% confidence interval (CI): 1.131 5.959, p = 0.023); The male subjects who carried IL7R (rs6881706) GT had a decreased risk of MS when compared to those who carried the GG allele (OR = 0.175, 95% CI: 0.034 0.892, p = 0.023).

    Conclusions: Polymorphisms in the STAT3 (rs4796791 and rs744166), STAT4 (rs9967792), IL7R (rs6897932), IL2RA (rs12722489 and rs2104286), and IL12A (rs1014486 and rs4680534) genes in the JAK-STAT signalling pathway were not associated with MS susceptibility in northern China. Females with the STAT3 (rs2293152) CG genotype may have an increased susceptibility to MS, and male with the IL7R (rs6881706) GT genotype may have a reduced MS susceptibility.

  • Article
    Yongjun Chen, Nian Shi, Hui Mao, Cuilin Xie
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1799-1808. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.190
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    Background: Psoriasis is a common and recurrent chronic inflammatory skin disease, which is characterized by high expression of Keratin 17 (K17) of keratinocytes and is considered a Th cell-mediated immune disease. As a major effector of Th cells, interleukin 6 (IL-6) has been found to play a significant role in developing psoriasis by promoting inflammation and keratinocyte proliferation. However, the mechanism has not been fully understood.

    Methods: In this study, we investigated the correlation between IL-6 and K17 expression in GEO datasets, psoriasis mouse model, and human keratinocytes, respectively. Using a label-free quantitative proteomic approach, we determined the effect of IL-6 stimulation on the proteomics profile of keratinocytes and identified the potential underlying signaling pathways. Further experimental validation was performed using inhibitors.

    Results: The expression levels of K17 and IL-6 were positively correlated. A total of 2876 proteins were quantified in IL-6-treated human keratinocyte HaCaT, of which 98 were downregulated, while 135 were upregulated. Bioinformatic analysis revealed a significant enrichment of inflammation-related biological functions and the JAK/PI3K pathway. Experimental validation using a specific antagonist of JAK and PI3K demonstrated that keratinocyte proliferation and Keratin 17 induction by IL-6 depended on the JAK/PI3K/AKT pathway.

    Conclusions: Our study demonstrated that IL-6 promoted psoriasis through the JAK/PI3K/AKT pathway, which might be a potential target for psoriasis.

  • Article
    Lan Gao, Nannan Yang, Li Shi
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1809-1820. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.191
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    Background: The role of long noncoding RNA (lncRNA) heart and neural crest derivatives expressed 2 anti-sense 1 (HAND2-AS1) in 5-fluorouracil (5-FU)-resistant colorectal cancer has been identified. Hence, this study explores whether and how HAND2-AS1 influences 5-FU-resistant esophageal squamous cell carcinoma (ESCC).

    Methods: ESCC and 5-FU-resistant ESCC cells were included in the study. HAND2-AS1 and miR-590-3p levels in ESCC/5-FU-resistant ESCC cells were compared. 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide, colony formation, flow cytometry and transwell assays were utilized to assess cell viability, proliferation, apoptosis, migration and invasion.

    Results: ESCC cells and 5-FU-resistant ESCC cells had a low HAND2-AS1 level. Cleaved caspase 3 and Bax protein levels and apoptosis were markedly decreased, while Bcl-2 (B-cell lymphoma-2) protein level, miR-590-3p expression, proliferation, migration and invasion were obviously increased in ESCC cells resistant to 5-FU. However, these changes were all reversed by HAND2-AS1 overexpression which also significantly promoted ESCC cell sensitivity to 5-FU. MiR-590-3p overexpression neutralized the impacts of HAND2-AS1 overexpression.

    Conclusions: HAND2-AS1 promotes ESCC cell sensitivity to 5-FU via inhibiting miR-590-3p expression.

  • Article
    Jiang-tao Zhang, Xiang-hua Wu, Hui-chao Ruan, Xiao-bing Fu, Rong-qian Yang, Dao-lai Huang, Jun Chen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1821-1831. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.192
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    Background: The downstream neighbor of SON (DONSON) plays a pivotal role in cell cycle regulation. To date, its role in cancer has been poorly studied.

    Methods: In the present study, the relationship between DONSON expression and various cancer prognoses and tumor subgroups was discussed using bioinformatics tools. The relative expression of DONSON in breast cancer cell lines and the normal breast cell line was measured via quantitative real-time polymerase chain reaction. The DEPMAP database was used to understand the effects of a DONSON knockdown on tumor cell line growth. The DONSON co-expression network and protein-protein interaction network were studied via LinkedOmics, Genemania, and Metascape. Finally, the comparative toxicogenomics database (CTD) was used to evaluate the correlation between the DONSON transcription level and drug treatment.

    Results: Data obtained from ONCOMINE, UALCAN, TNM plot, Gene Expression Profiling Interactive Analysis 2.0 (GEPIA 2.0), Kaplan–Meier plotter, PrognoScan, and Breast Cancer Gene-Expression Miner v 4.7 (BC-GenExMiner v 4.7) suggest that DONSON is highly expressed in cancer tissues, abnormally expressed in different tumor subgroups, and related to poor prognosis. The DONSON mRNA (messager ribonucleic acid) levels were increased in breast cancer cell lines (MCF-7, MDA-MB-231, T47D, and MDA-MB-468) compared with the normal breast cell line (MCF-10A). Decreased DONSON expression can inhibit the growth ability of many tumor cell lines analyzed by DEPMAP; DONSON may be involved in the development of tumors by regulating cell cycle progression.

    Conclusions: Overall, DONSON has the potential to serve as a novel prognostic biomarker in human tumors.

  • Article
    Zhangyong Yin, Zaiting Ye, Jiongwei Pan, Xiaoping Cai, Hao Zheng, Yuling Li, Zhuo Cao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1833-1843. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.193
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    Background: Long non-coding RNAs (lncRNAs) have been intensively expounded to be implicated in various cancers, including lung cancer (LC), where LINC02381 is highly expressed in lung adenocarcinoma, but its function on LC is poorly defined. Additionally, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) functions as a prominent pathogenic factor in NSCLC, one major subtype of LC. This paper is designed to investigate whether and how LINC02381 affects EML4-ALK+ LC progression.

    Methods: EML4-ALK+cells were transfected with small interfering RNA (siRNA) for LINC02381 (LIN-siRNA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was made to test ALK, miR-133b and LINC02381 expression levels. The targeting relationship between LINC02381 and miR-133b or miR-133b and ALK was predicted and verified through bioinformatics analysis and dual-luciferase reporter assay. The proliferative, migratory and invasive abilities of cells were evaluated by 5-ethynyl-2’-deoxyuridine (EdU), colony formation, wound healing and Transwell assays.

    Results: LINC02381 expression levels were upregulated in EML4-ALK+ LC cells. LINC02381 targeted miR-133b and miR-133b targeted ALK. LINC02381 silencing promoted miR-133b expression to down-regulate ALK levels in EML4-ALK+ LC cells. LINC02381 silencing repressed EML4-ALK+ LC cell proliferation, migration and invasion.

    Conclusions: LINC02381 silencing inhibits EML4-ALK+ LC cell proliferation, migration and invasion via the miR-133b/ALK axis.

  • Article
    Ming-Fang Weng, Wei Li, Wei Zhang, Rong Liu, Chun-Yu Guo, Rui Yang, Hu Zhao, Zhen Deng
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1845-1861. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.194
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    Background and Objectives: The diagnostic and therapeutic approaches to urothelial carcinoma of the bladder (UCB) have their limitations. The aim of this study was to explore whether microRNA-30a-5p (miR-30a-5p)/proliferating cell nuclear antigen clamp associated factor (PCLAF) can serve as biomarkers for diagnosis, predicting patient prognosis, and UCB treatment.

    Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine miR-30a-5p and PCLAF expressions in clinical UCB tissues and human UCB cell lines. Western blotting (WB) and immunohistochemistry (IHC) were used to quantify the levels of PCLAF protein in human UCB tissues and xenograft tumor tissues, respectively. The link between miR-30a-5p and PCLAF mRNA/protein level in human UCB tissues was examined a Spearman correlation analysis. miR-30a-5p/PCLAF’s function on human UCB cell proliferation was examined, using the cell counting kit-8 (CCK-8)/5-bro’o-2’-dexoyuridine (BrdU)/3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-ium bromide (MTT)/colony formation experiments, on migration with Transwell/Wound healing assays, and on invasion with Transwell assay. Tumor growth and cell metastasis models were established to evaluate the roles of miR-30a-5p/PCLAF on human UCB tumor development and metastasis, respectively.

    Results: MiR-30a-5p and PCLAF were significantly underexpressed and upregulated, respectively, in human UCB tissues and cells, and their expression patterns significantly and negatively correlated in human UCB tissues. MiR-30a-5p upregulation significantly suppressed while miR-30a-5p knockdown significntly stimulated cell proliferation, migration and invasion, tumor development and metastasis in human UCB, by regulating PCLAF expression. Moreover, downregulated miR-30a-5p or upregulated PCLAF expression were significantly associated with increased progression and poor prognosis of UCB sufferers.

    Conclusions: MiR-30a-5p significantly suppressed UCB malignant progression, by regulating PCLAF. MiR-30a-5p and PCLAF have a potential to be the possible biomarker for UCB’s diagnosis and prognosis.

  • Article
    Lixia Zhang, Weili Zhu, Shan Pan, Xuedong Tang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1863-1873. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.195
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    Backgrounds: To investigate the effect and its mechanism of homo sapiens-microRNA-128 (hsa-miR-128) on cervical cancer (CC) progression.

    Methods: Hsa-miR-128 level was measured in CC patients using RT-qPCR (reverse transcription quantitative PCR). CCK-8 (cholecystokinin octapeptide), colony formation, flow cytometry, western blotting, wound healing and transwell assay were used to investigate hsa-miR-128 effects on CC progression. The binding capacity between miR-128a and forkhead box protein 2 (FOXP2) was assessed using the luciferase reporter assay.

    Results: Hsa-miR-128 expression was significantly lower and FOXP2 level was significantly higher in CC tissues than adjacent normal tissues. Hsa-miR-128 sponged and negatively controlled FOXP2. Hsa-miR-128 targeted FOXP2 to repress proliferation and the cell cycle, while it facilitated apoptosis in TGF-β (transforming growth factor-β)-treated CaSki (a human cervical cancer cell line) cells. Additionally, hsa-miR-128 targeted FOXP2 in TGF-β-treated CaSki cells to decrease cell invasion and migration. Further studies revealed that hsa-miR-128 inactivated the TGF-β/Smad2/3 pathway by targeting FOXP2 in TGF-β-treated CaSki cells. Hsa-miR-128 suppressed the development of CC by silencing TGF-β/Smad2/3 signaling through targeting FOXP2.

    Conclusions: Hsa-miR-128 suppressed cell proliferation and metastasis of CC through targeting FOXP2, and expedited the apoptosis of CC cells by inhibiting the TGF-β/Smad2/3 signaling pathway.

  • Article
    Liufu Su, Shoufeng Wang, Yingtong Huang, Yao Feng, Tong Xie, Naiquan Mao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1875-1885. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.196
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    Background: Immune response in the context of lung adenocarcinoma affects patient prognosis and immunotherapy efficiency. Therefore, we aimed to identify an effective prognostic model for facilitating further treatment.

    Methods: First, T cell inflammatory and immune scores were calculated based on an online dataset. Second, optimal genes related to the T cell inflammatory and immune scores were screened using weighted gene co-expression network analysis, differential expression analysis, and survival analysis. Finally, an inflammatory immune-related risk model was established and evaluated. Immune cell infiltration, functional characteristics, mutation features, immune checkpoint blockage genes, human leukocyte antigen genes, immune cell marker genes, and drug sensitivity were analyzed between the high- and low-immune-related risk score groups.

    Results: An eight-gene immune-related risk model was established and determined to perform well in regard to predicting lung adenocarcinoma survival. Different immune-related risk groups exhibited different immune cell infiltration characteristics, mutation frequencies, tumor mutation burdens, immune checkpoint blockage genes, human leukocyte antigen genes, immune cell marker genes, and drug sensitivities. Moreover, the differentially expressed genes between the high- and low-immune-related risk groups were enriched in the functions and pathways related to immune response and cancer progression.

    Conclusions: The immune-related risk model established in this study possesses a potential predictive value for patient prognosis and immunotherapy response, thus indicating its potential applicability for use in clinical practice.

  • Article
    Xiaofan Chen, Hongtan Lin, Chunli Huang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1887-1896. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.197
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    Background: Autophagy is a key mechanism that contributes to the resistance to cisplatin (DDP), a natural bioactive medicinal compound extracted from traditional Chinese medicinal herb Tripterygium Wilfordii, in gastric cancer (GC). In this study, we assessed the effect of Triptonide to regulate autophagy and DDP resistance in GC.

    Method: DDP resistant GC cells was established to assess the effect of Triptonide alone or in combination with cisplatin on a variety of tumor assays. The cell viability and apoptosis/cell cycle were determined using Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Autophagy level and the effect of Triptonide were evaluated using fluorescence intensity of RFP (red fluorescent protein)-GFP (green fluorescent protein)-LC3 (tandem fluorescent-tagged)/GFP-LC3, western blot, and electron microscope. Finally, the effect of Triptonide on chemosensitivity of the cisplatin-resistant cell line was validated in vivo on 32 nude mice.

    Results: The results showed that Triptonide not only led to a dose-dependent reduction in GC cell proliferation, it also reversed the chemoresistance of DDP-resistant on GC cell lines. We also found that autophagy was activated in DDP-resistant GC cancer cells during chemotherapy and contributed to the adaptative protective effects against DDP. Non-toxic dose of Triptonide act synergistically with DDP. Triptonide could inhibit the protective autophagy activation and enhance the sensitivity of DDP to DDP-resistant on GC cells. Triptonide effect on GC cells was also observed in nude mice.

    Conclusions: Based on these findings, we conclude that DDP in combination with Triptonide could restore DDP sensitivity in DDP-resistant on GC cells by inhibiting autophagy. Clinically, this combination might be effective in reversing chemoresistance.

  • Article
    Ping Fu, Yang Xiang, Guangfu Bai, Jianping Wang, Haitao Sun
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1897-1905. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.198
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    Background: Oxidative stress and immune abnormalities in cardiac arrest (SCA) patients undergoing cardiopulmonary resuscitation (CPR) seriously threaten their survival. The mild hypothermia therapy has been applied in patients after successful cardiopulmonary resuscitation. However, the function of mild hypothermia therapy on oxidative stress and immune regulation in SCA patients remains unclear.

    Methods: A controlled clinical trial was performed to evaluate the effects of mild hypothermia therapy on the management of SCA patients in intensive care unit (ICU) post CPR. Participants diagnosed with SCA received CPR and were divided in to mild hypothermia (MH) group (n = 46) and control group (n = 46). They received standard ICU management or ICU management plus mild hypothermia therapy respectively. Glasgow coma scale (GCS) and sequential organ failure assessment (SOFA) were performed. The oxidative stress and immunological markers were examined.

    Results: Mild hypothermia therapy statistically inhibited the total incidence of complications in SCA patient post-CPR. Mild hypothermia therapy upregulated the GCS score and downregulated the SOFA score at 18 h and 36 h post CPR. Mild hypothermia therapy inhibited the oxidative stress of patients with SCA post-CPR. The IgA (immunoglobulins A), IgG (immunoglobulins G) and IgM (immunoglobulins M) were upregulated statistically post mild hypothermia.

    Conclusions: Mild hypothermia therapy has protective effects on oxidative stresses and immune functions of SCA patient post-CPR.

  • Article
    Jia Guo, Shimeng Li, Lu Qiao, Haifeng Zhao, Chengyan He
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1907-1920. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.199
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    Background: Colorectal cancer (CRC) is a common disease worldwide. Most patients are diagnosed at advanced stages, resulting in a poor prognosis. Therefore, early detection is essential for improving the prognosis of CRC and reducing social burden. In this study, the mechanisms underlying CRC development and progression were evaluated.

    Methods: Liquid chromatography-mass spectrometry was used to analyze proteins in grade 2 and grade 3 CRC tissues and their corresponding paracancerous tissues. Differentially expressed proteins (DEPs) between CRC tissues and paracancerous tissues as well as those between grade 2 and grade 3 tissues were identified. Functional and pathway enrichment analyses of the DEPs in each comparison were performed. Finally, western blotting was performed to validate the expression levels of critical proteins.

    Results: In total, 227, 103, and 181 DEPs were identified between grade 2 cancer tissues and paracancerous tissues, between grade 3 cancer tissues and paracancerous tissues, and between grade 2 and grade 3 cancer tissues, respectively. Functional analyses showed that these DEPs are involved in eukaryotic initiation factor 2 signaling, integrin-linked kinase signaling, the tricarboxylic acid cycle, liver X receptor/retinoid X receptor signaling, and phosphoinositol-3 kinase/AKT signaling pathways varied at different tumor stages. Western blotting showed that the protein expression levels of periostin and serpin H1 were significantly higher (p < 0.05) and calponin-1 levels were significantly lower (p < 0.05) in CRC tissues than in paracancerous tissues.

    Conclusions: Periostin, serpin H1, and calponin-1 are novel candidate diagnostic and prognostic targets for CRC.

  • Article
    Yan Lv, Yun-Feng Tian, Yi-Rui Zhao, Xiao-Qin Guo, Wei-Ming Yu, Xiao-Jun Ren, Jia Xu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1921-1927. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.200
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    Objective: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). This study retrospectively analyzed the clinical data of 30 renal anemia patients undergoing maintenance hemodialysis treated with Roxadustat to confirm its efficacy and safety.

    Methods: Patients who regularly underwent hemodialysis at the Blood Purification Center of the Third Hospital of Shanxi Medical University were screened from December 2019 to December 2020. All the included patients had failed to meet the hemoglobin standard after 12 weeks of erythropoiesis stimulants (ESAs) treatment. The starting dose of Roxadustat was determined according to body weight. The hemoglobin levels were monitored for 12 weeks, with 110–130 g/L as the target. Hemoglobin, hematocrits, iron metabolism indexes, C-reactive protein (CRP), blood lipids, electrolytes, blood pressure, and adverse reactions were recorded.

    Results: A total of 30 renal anemia patients who received maintenance hemodialysis were included. After 12 weeks, their hemoglobin levels significantly increased from 87.73 ± 14.52 g/L to 105.27 ± 14.27 g/L (p < 0.001). After Roxadustat treatment, triglycerides, total cholesterol, CRP and ferritin decreased, and the total iron-binding ability increased, showing a significant difference from the baseline values (p < 0.05). There were no significant changes in electrolytes, platelets, and blood pressure before and after treatment. No serious adverse reactions occurred in any of the patients during treatment.

    Conclusions: Roxadustat is effective in patients with renal anemia who have a poor response to erythropoietin therapy.

  • Article
    Tianyu Li, Youliang Shen, Wenru Ma, Zengshuai Han, Wenlian Song, Tengbo Yu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1929-1938. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.201
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    Purpose: The incidence of rotator cuff injury is as high as about 20% of shoulder joint diseases, causing functional limitations. Single-nucleotide polymorphism (SNP) of beta-defensin 1 gene (DEFB1) was shown to correlate with the presence of rotator cuff disease. The aim of this study was to investigate the regulatory effect of SNP on tendon regeneration and its molecular mechanism of action.

    Method: DEFB1 gene was constructed for rabbit tendon stem cell transfection. Differential binding proteins were screened for both different genotypes using DNA pull down and mass spectrometry, and the function of the binding proteins was further verified.

    Result: DEFB1-WT (GG) (wild-type DEFB1) and DEFB1-MUT (CC) (DEFB1 mutated) binding proteins were different, and the content of FUS RNA binding protein (FUS) protein in DEFB1-WT (GG) group was significantly higher than that in DEFB1-MUT (CC) group. Chromatin immunoprecipitation revealed that significantly more FUS protein was binding to DEFB1 (GG) than DEFB1 (CC). Subsequent validation tests at the cellular level showed that FUS gene significantly and positively regulated DEFB1 gene expression, and that after interfering with FUS expression, DEFB1 expression was significantly decreased, and tendon stem cell calcification and osteogenic differentiation were significantly enhanced.

    Conclusions: DEFB1-WT (GG) type might affect the prognostic repair of tendon rupture through the regulation of the non-tenogenic differentiation of tendon stem cells in the pathological state.

  • Article
    Jinxi Liang, Liang Chen, Ziqi Xu, Chao Sun, Wenfeng Peng, Xia Cao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1939-1946. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.202
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    Purpose: The current study evaluated treadmill and wheel exercise as potential treatments for osteoarthritis (OA) in an animal model, and investigated the reactive oxygen species (ROS)-mediated apoptosis pathway in knee osteoarthritis (KOA) models.

    Methods: We used male BALB/c mice to establish a KOA model, and divided the mice into four groups: (1) Control (normal saline); (2) KOA (monosodium iodoacetate (MIA) induced); (3) KOA with treadmill exercise (treadmill + KOA); And (4) KOA with wheel exercise (wheel + KOA). Safranin O staining, Tartrate-resistant acid phosphatase staining, western blot, and ELISA assays were utilized to explore the influence of treadmill and wheel exercise in KOA.

    Results: Our results revealed that, compared with the control group, the KOA groups showed severe damage to joint cartilage and enhanced numbers of osteoclasts as well as chondrocyte apoptosis-related protein levels of caspase-3 and Bcl-2-associated X protein (BAX), but downregulated the Bcl-2 protein expression. However, treatment with treadmill or wheel exercise alleviated chondrocyte apoptosis and decreased ROS production in mice with KOA.

    Conclusions: Our data showed that treadmill and wheel exercise protects against chondrocyte apoptosis by regulating the ROS-mediated apoptosis pathway in knee osteoarthritis (KOA) models.

  • Article
    Haiyan Gou, Yanmei Zhu, Jia He, Yan Chen, Jiahang Sun, Yulan Zhu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1947-1956. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.203
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    Background: Epileptic seizures negatively impact cognitive function and increase the levels of prostaglandins and nuclear transcription factor-κB (NF-κB) in the brain, leading to neuroinflammation. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to inhibit inflammatory mediators. This study aims to determine whether celecoxib reduces the production of inflammatory mediators in status epilepticus (SE) by regulating the NF-κB pathway and has a protective effect on neurons.

    Methods: Male Wistar rats received 35 mg/kg/day of pentylenetetrazole (PTZ) intraperitoneally (i.p.) for 28 days. The effects of pre-treatment with celecoxib (10 mg/kg) and celecoxib plus NF-κB/p65 (p65) inhibitor, caffeic acid phenethyl ester (CAPE; 15 mg/kg), against PTZ-kindled seizures were investigated. After treatment with celecoxib or celecoxib plus CAPE for 5, 10, 15 and 21 days, PTZ was injected and the seizure scores were analyzed. The hippocampus histopathology examination was completed after hematoxylin-eosin staining (H&E) staining and Nissl staining. The mRNA expression levels of PGE2 (Prostaglandin E2), PGI2 (Prostaglandin-I-2), and p65 were examined by real time quantitative PCR (RT-qPCR). The production of PGE2 and PGI2 were analyzed by enzyme linked immunosorbent assay (ELISA). The protein expression levels of nuclear p65, total p65, and total phosphorylated p65 were determined by western blot and immunofluorescence.

    Results: Celecoxib treatment or celecoxib plus CAPE co-treatment after SE seizure significantly reduced the seizure scores and protected hippocampal neurons from SE damage. Celecoxib also down-regulated the mRNA expression levels of PGE2, PGI2, and p65, as well as the reduction of PGE2 and PFI2 production. In addition, celecoxib significantly suppressed the protein expression levels of nuclear p65 and total phosphorylated p65. The therapeutic effects of celecoxib were more significant after CAPE down-regulated the NF-κB pathway.

    Conclusions: Celecoxib may inhibit the expression of PGE2 and PGI2 by regulating the NF-κB pathway and has a protective effect on neurons, which may appear as a promising antiepileptic drug.

  • Article
    Yan Li, Li Dong, Li-na Liu, Jia-lin Wang, Cui-cui Ma, Xiao-ye Bai, Hui Chi, Huan Wang, Rui-fang Guo
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1957-1967. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.204
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    Objective: To explore the impact of the gastric microbiota in the development of gastric mucosal lesions.

    Methods: Forty-one gastric antrum and corpus mucosal samples were collected from patients with gastritis or peptic ulcer, and were divided into chronic superficial gastritis (CSG, n = 21), chronic atrophic gastritis (CAG, n = 12) and peptic ulcer (PU, n = 8) groups. 16S rRNA gene amplicons were sequenced by Pacific Biosciences Single Molecule Real Time (Pacbio SMRT) sequencing technology. QIIME (Quantitative Insights Into Microbial Ecology) software was used to calculate the α diversity metrics. Principal coordinate analysis (PCoA) was used to detect unweighted and weighted UniFrac distance. Linear discriminant effect size (LEfSe) analysis was used to assess the abundance of strains among groups.

    Results: The α diversity of the gastric microbiota in PU group decreased compared to CSG and CAG groups. Abundance of Helicobacter pylori (HP) in PU group was increased (82.3%), while the abundance of Lactobacillus was decreased compared to CSG and CAG group. Microbial community structure in PU group was separated from CAG and CSG groups (p = 0.015 and 0.001). Microbial community structure in HP positive samples was separated from HP negative samples in CSG and CAG groups. Overall, 41 strains with different abundance were found and identified in the CSG, CAG and PU groups. The enrichment of Proteobacteria, Helicobacter and HP were observed in the PU group.

    Conclusions: Gastric mucosal lesions severity reduced the diversity of the gastric microbiota, and increased the abundance of HP.

  • Article
    Si-Yu Yu, Xiang-Yu Shan, Yu-Jie Wu, Cheng Ji
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1969-1976. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.205
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    Purpose: The aim of this study was to look into the effect and mechanism of action of oridonin (Ori) in carbon tetrachloride (CCL4)-induced liver injury in rats.

    Methods: 24 adult male Sprague Dawley (SD) rats were divided into four groups at random: Control, Ori, CCL4, and CCL4 + Ori. In addition to body and liver weights as well as blood tests, real-time quantitative reverse transcription PCR (qRT-PCR) was used to detect the mitochondrial deoxyribonucleic acid (DNA) level in the liver tissue of rats, and the protein expression levels of NAD (P) H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and the nuclear erythroid-2-related factor 2 (Nrf2) in the liver tissues of the rats were checked for using western blot.

    Results: Ori showed antioxidant and hepatoprotective effects in rats with CCL4-induced liver injury and significantly improved mitochondrial function in rats with CCL4-induced liver injury. Additionally, Ori significantly alleviated CCL4-induced liver injury in rats, by activating the Nrf2/HO-1/NQO1 pathway.

    Conclusions: Ori may attenuate CCL4-induced liver injury in rats via improving mitochondrial function and activating the Nrf2/HO-1/NQO1 pathway, as well as having hepatoprotective and anti-oxidative effects.

  • Article
    Weiqi Huang, Xiaoting Liu, Gaofeng Jiang, Yu Huang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1977-1988. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.206
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    Background: The overall cure and survival rates of non-small cell lung cancer (NSCLC) are still very low, and this disease has serious effects on patients’ quality of life. The aim of this study was to explore the role and possible mechanism of toll-like receptor 4 (TLR4) in NSCLC.

    Methods: This study screened the core differentially expressed genes (DEGs) related to cell adhesion molecules (CAMs), through bioinformatics methods. The TLR4 expression in A549 was knocked down by transfecting with shTLR4 (TLR4 shRNA). Scratch assay and flow cytometry were used to evaluate the effects of TLR4 knockdown on A549 cell migration and apoptosis, respectively. The binding of TLR4 and miR-20b-5p was proved by dual-luciferase reporter assay. The effect of TLR4 on tumor growth in vivo was investigated by establishing xenograft tumor mouse model. The quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect messenger ribonucleic acid (mRNA) and protein levels of CAMs-related genes.

    Results: miR-20b-5p and TLR4 are core differentially expressed miRNA (DEmiRNA) and DEG with targeted regulatory relationship in the interaction network through bioinformatics analysis. In vitro, shTLR4 transfection significantly inhibited A549 cell migration (p < 0.01) and promoted cell apoptosis (p < 0.001). In vivo, xenograft tumor growth in SH group mice was also significantly inhibited (p < 0.01). Dual luciferase reporter gene experiment also demonstrated the targeted regulation of miR-20b-5p on TLR4. In addition, qRT-PCR and Western blot also showed that TLR4 knockdown could significantly down-regulate the expression of syndecan-1 and intergrin β3, and up-regulate the expression of E-cadherin. These results above indicated that TLR4 was targeted and down-regulated by miR-20b-5p and promoted the proliferation, migration of NSCLC cells and inhibiting the apoptosis by regulating the levels of CAMs.

    Conclusions: TLR4 and miR-20b-5p can be used as meaningful biological targets to study the regulation of cell proliferation and migration by NSCLC.

  • Article
    Xiaolong Wang, Yan Huang, Hongmei Ding, Jing Dong, Qing Tong, Fenglei Gao, Deqin Geng
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 1989-2000. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.207
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    Background: Alzheimer’s disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by dementia and neuropsychiatric disorders. Although the pathogenesis of AD remains unclear, most scientists support the amyloid cascade hypothesis that metal ions imbalance accelerates amyloid β (Aβ) aggregation, ultimately resulting in Aβ-induced neurotoxicity. Therefore, metal chelate and Aβ-targeted therapy are considered to be effective strategies for the treatment of AD.

    Methods: In this study, we fabricated an original nanoparticle composite with the capability to chelate metal ions and disaggregate Aβ fibrils, which consisted of a gold nanoparticle (AuNP) core and a porous metal-organic framework (MOF) shell. In addition, benzothiazolinone (BTA), an ideal fluorescent probe for specific binding of Aβ fibrils, was chosen as a conjugate for the MOF.

    Results: Results from both in vitro and in vivo experiments revealed that AuNP@MOF-BTA nanocomposites could accurately detect the aggregation and fluorescence imaging of Aβ. Furthermore, it disaggregated Aβ fibrils locally in the near-infrared spectrum as well as inhibited the formation of Aβ aggregates by capturing Cu2+ through metal chelation. Therefore, the nanocomposites could, thus, reduce the toxic effects of Aβ aggregation, protect neurons, and improve memory disorders and depressive symptoms.

    Conclusions: These findings may provide a novel visualization therapy for Alzheimer’s disease guided by fluorescence imaging.

  • Article
    Tiechun Zhang, Qian Chen, Suifeng Zhang, Lirong Wu, Ke Sun, Xiaofang Lan, Xin Xie, Junfeng Yan
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2001-2012. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.208
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    Purpose: Depression is a mental disorder that severely impacts the body and spiritual health of patients. The main treatment methods are drugs and psychological counseling. However, drugs have a single route of action, and long-term use is prone to drug resistance. Chinese medicine has a moderate and stable effect, with fewer adverse effects; Making it more suitable for the long-term pharmacological management of depression. The disclosure of the microbe-gut-brain axis prompted researchers to investigate the effect of gut microbes on depression. The aim of this study was to explore the effect of Changyu Daotan Decoction (CDD) on the structure and metabolic function of intestinal flora in mice. This information belongs to the method.

    Methods: 30 mice were induced to establish depression model by P. Willner method and treated with CDD. The changes of genes and species in the blank group, model group, CDD group and SHT (Sertraline Hydrochloride Tablets) group were determined using metagenomic sequencing technology. The functional variability in different groups was analyzed by annotation of common functional databases.

    Results: There were variations in the number of genes and species in different groups. The predominant intestinal microflora of mice in each group was Bacteroides, Firmicutes, Actinobacteria, Proteobacteria, Ascomycota, and Spirochaetes, among which Bacteroides was the most abundant, followed by Firmicutes. The content of Actinobacteria and Proteobacteria in depression model mice increased, and CDD could reduce the abundance of Proteobacteria and Actinobacteria. CDD restored the intestinal flora diversity of depression model mice, and significantly increased the content of Lactobacillus. Significant differences in KEGG Orthology (KO), Non-Supervised Orthologous Groups (NOG), Glycoside Hydrolases (GH), and Glycosyl Transferases (GT) were noted in metabolic pathway analysis.

    Conclusions: CDD improves the structure of the intestinal flora and metabolic function in depressed patients.

  • Article
    Hong-Bao HUANG, Xiao-Qin WU, Dong-Lin LU, Xiao-Qiong LUO, Li QIN, Qiu-Yan HUANG, Jing-Xi WEI, Fa-Qin CHEN
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2013-2023. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.209
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    Background: Alpha-crystallin B chain (CRYAB) is a small-molecule heat-shock protein whose function primarily binds misfolded proteins to prevent protein aggregation and contribute to the intracellular architecture. This study aimed to investigate the role of CRYAB in cervical cancer (CC).

    Methods: The expression of CRYAB in CC was analyzed using GEPIA2 online tool and detected in CC cell lines HeLa and SiHa using quantitative polymerase chain reaction. The CRYAB overexpression virus vector was constructed, packaged and infected HeLa and SiHa cells. After the induction of CRYAB overexpression, cell viability, apoptosis, cell cycle, cell migration, and invasion capabilities were examined. Then, RNA sequencing for cells overexpressing CRYAB and subsequent bioinformatic analysis were performed, to screen for key pathways and genes that are associated with the function of CRYAB.

    Results: CRYAB expression was significantly decreased in CC tissues and cell lines. After CRYAB overexpression was induced, the viability of HeLa and SiHa cells decreased, apoptosis increased, and S-phase cells decreased significantly. Moreover, CRYAB overexpression significantly weakened the migration and invasion abilities of cells. Sequencing results showed that after CRYAB was overexpressed, 1858 genes demonstrated high expression and 1837 genes showed low expression. Results of the bioinformatic analysis showed that the differential expression genes were mainly enriched in the FoxO signaling pathway, endocytosis, cell cycle, and other pathways.

    Conclusions: CRYAB affects cell viability, apoptosis, cell cycle, cell migration and invasion, and may participate in CC development.

  • Article
    Jia Gao, Yanbo Wang, Haixia Xie, Airong Wu, Zhuoqiong Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2025-2035. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.210
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    Objectives: Patients with spinal cord injury (SCI) often have different degrees of psychological distress, which is related to the injury’s suddenness and the associated high level of disability. The Pictorial Representation of Illness and Self Measure-Revised 2 (PRISM-R2) has been developed as a visual measure for assessing patients suffering from SCI. This study aimed to validate the effectiveness of PRISM-R2 in assessing the suffering of patients with SCI in Mainland China.

    Setting: Data were collected from hospitalized individuals with SCI at the Shanghai Yangzhi Rehabilitation Hospital (School of Medicine, Tongji University).

    Methods: The evaluation tools include: (1) The Pictorial Representation of Illness and Self Measure-Revised 2 (PRISM-R2), (2) the World Health Organization Quality of Life Short Form Survey (WHOQOL-BREF), (3) the Multidimensional Body-Self Relations Questionnaire (MBSRQ), (4) the Patient Health Questionnaire-9 (PHQ-9), (5) the Social Support Rating Scale (SSRS), (6) the Numerical Rating Scale (NRS) and (7) the Modified Barthel Index (MBI). The validity of the PRISM-R2 content was also tested by content analysis.

    Results: The Self Illness Separation (SIS) and the Illness Perception Measure (IPM) showed a strong correlation (r = –0.54; p < 0.05). Qualitative data indicated that the interpretation of the PRISM-R2 task is not only consistent among patients, but it is consistent with that expected from existing literature on suffering. As expected, PRISM-R2 showed strong correlations with psychological variables (notably depression and social support, and appearance orientation) and also correlated with WHOQOL-BREF subscale scores.

    Conclusions: PRISM-R2 effectively reflects the perception of psychological variables and suffering in SCI patients and it may be beneficial in evaluating or guiding the intervention for people with SCI.

  • Article
    Hai-rong Li, Guan-liang Chen, Xiao-li Fang, Xing-jiu Cai, Rong-li Xu, Dong-dong Li, Zhi-wei Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2037-2046. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.211
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    Background: miRNAs can control the hypernomic proliferation of pulmonary artery smooth muscles (PASMCs), which is implicated in the pulmonary arterial hypertension (PAH) development. However, the mechanism of miRNAs is unknown, so this study was expected to explore it.

    Methods: Up-regulated miRNAs were analyzed in data sets GSE21284 and GSE67597 associated with PAH, and sera from PAH patients and healthy volunteers were collected and human PASMCs (hPASMCs) were cultured under hypoxic and normoxic conditions, to check for up-regulated miRNAs expressions via quantitative real-time polymerase chain reaction (qRT-PCR). Following screening miR-486-5p out, the target relationship of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and miR-486-5p was predicted and validated, using bioinformatics website and dual-luciferase reporter assay. Next, miR-486-5p or PTEN expression was interfered, then cell migration ability, proliferation level, and apoptosis level were observed, using CCK-8 (Cell Counting Kit-8), flow cytometry and scratch assays; Besides, the PI3K/Akt (phosphatidylinositol4,5-bisphosphate 3-kinase/protein kinase B) signaling pathway-related protein expression of cells was checked, using Western blot.

    Results: PTEN expression was significantly down-regulated while miR-486-5p was greatly mounted in hypoxia-cultured hPASMCs and in the serum of PAH patients. Knocked down of miR-486-5p caused a significant reduction in PI3K/Akt axis activity, inhibition of hPASMC migration and proliferation under normoxic and hypoxic circumstances, and increase in apoptosis. Importantly, a target relationship was detected between PTEN and miR-486-5p, and the function of this RNA was significantly restored by knocking what down.

    Conclusions: miR-486-5p can activate PI3K/Akt signaling to regulate the function of hypoxia-induced hPASMCs, through targeting PTEN.

  • Article
    Li Lei, Yunrong Li, Xiaofang Zhao, Shoushan Chen, Bo Huang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2047-2058. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.212
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    Background: Pertussis is an acute respiratory infectious disease caused by Bordetella pertussis. Over the past decade, the rising incidence of pertussis in many countries, including China, has attracted great attention globally.

    Methods: Current research focuses on the underlying immune mechanisms of cells in response to pertussis infection and to perform a further analysis and interpretation. A sequencing dataset of human airway epithelium cells infected with B. pertussis was collected from the GEO (Gene Expression Omnibus) database, and transcriptome analysis was subsequently performed.

    Results: After analysis of differentially expressed genes (DEGs), a total of 149 DEGs were obtained, including 109 down-regulated genes and 40 up-regulated genes. Most were enriched in antigen processing and presentation, endocytosis, toxoplasmosis, and natural killer cell mediated cytotoxicity. WGCNA (weighted correlation network analysis) was also performed and the genes were grouped into different modules as per the corresponding expression trends, among which the yellow, purple and royalblue gene modules indicated a positive correlation with the grouping. Further enrichment analysis and PPI (protein-protein interaction) analysis of the DEGs in the yellow module indicated that CD74, CD274, PDCD1LG2, integrin subunit alpha M (ITGAM) and PTPN22 played a role in the infected cells by B. pertussis.

    Conclusions: This study collected pertussis sequencing datasets using the GEO database, and analyzed the underlying immune mechanism of pertussis-infected cells, and provided a theoretical basis for mining potential regulatory factors and improving the immune efficacy of vaccines.

  • Article
    Yu Jiang, Biao-jie Qin, Jin-ying Hu, Nan Wang, Li-li Gao
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2059-2067. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.213
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    Aim: To create a mice model to better evaluate the relationship between α1,6-fucosyltransferase (Fut8) with lung diseases like pulmonary fibrosis and lung inflammation. We created a mice model with Fut8 gene conditional knockout in the alveolar epithelial cell.

    Method: Alveolar epithelial cell specific Fut8 conditional knockout (CKO) mouse model was established based on the Cre/Loxp (cyclization recombination enzyme/locus of X (cross)-overinP1) system. Mice genotypes were identified by polymerase chain reaction (PCR). Fut8 protein and messenger ribonucleic acid (mRNA) expression in lung tissues or alveolar epithelial cells were examined using RT-PCR (reverse transcription-polymerase chain reaction), western blot and immunofluorescence (IF). Lectin blots and IF were used to assess the core fucosylation in lung tissues and primary alveolar epithelial cells. Fut8 enzyme activity was tested by high performance liquid chromatography (HPLC). Changes of lung tissue morphology were evaluated by histological examination.

    Result: Fut8 protein and mRNA expression in lung tissue of CKO mice was down-regulated compared to wild type (WT) mice (p < 0.05). The primary alveolar epithelial cells did not express Fut8 protein in CKO mice. CKO mice protein core fucosylation in lung tissues and primary alveolar epithelial cells decreased compared to WT mice. Fut8 enzyme activity in lung tissues of CKO mice was weakener than that one in WT mice (p < 0.05). There is no obvious pathological damage in CKO mice lung tissues.

    Conclusions: The alveolar epithelial cell-specific Fut8 conditional knockout mouse model was successfully created, which may be helpful to study the role of Fut8 and lung disease.

  • Article
    Hui-jing Gao, Liang Teng, Jun Zhao, Jian-hua Wang, Xin Ran, Nan Xu, Yue-hong Gong, Li-mei Wen, Bao-juan Wang, Bei Chen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2069-2084. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.214
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    Objective: Harmine (HM) is the main alkaloid of Peganum harmala L., which has antitumor, insecticide, and anti-inflammatory effects. However, it has limited use in clinical practice, due to potential high neurotoxicity. Therefore, the structure of HM was modified, to obtain H-2-104, which is a derivative with low neurotoxicity and reported benefit in the treatment of cystic echinococcosis (CE). This study explored the pharmacokinetic profile and tissue distribution of H-2-104.

    Methods: Plasma was collected from healthy rats at various time points following oral (20, 40, 80 mg/kg) and intravenous (i.v.; 1, 2, 4 mg/kg) administration of H-2-104. After the oral administration, tissues were collected at different time points and treated with acetonitrile precipitation. Using tinidazole as an internal standard, the concentration of H-2-104 in plasma and the distribution concentration in tissues were determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Then, multiple methods were used to evaluate the linear kinetics of H-2-104. Pharmacokinetic parameters were obtained using the 3P97 pharmacokinetic software.

    Results: The pharmacokinetics of H-2-104 in rats after oral and i.v. administration demonstrated linear kinetic characteristics, consistent with the two-compartment model. H-2-104 was rapidly absorbed but slowly metabolized after oral administration. After i.v. administration, H-2-104 rapidly spread and was quickly metabolized. The absolute oral bioavailability was 52.20%.

    Conclusions: The UPLC-MS/MS method established in this study was sensitive, efficient and reliable and could be used for the pharmacokinetics and tissue distribution study of H-2-104. This study provided a scientific basis for evaluating the druggability of HM derivatives and could be used as a reference for structural modification and dosage form design.

  • Article
    Peng Guo, Xiaojiao Zhang, Zhanxiu Zhang, Bo Luan
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2085-2091. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.215
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    Objective: To examine the expression of plasma chymase and angiotensin-2 (Ang-2) in patients with acute ST-elevation myocardial infarction (STEMI) and to observe the influence of percutaneous coronary intervention (PCI) and reperfusion on the levels of these factors. Furthermore, we aim to evaluate the correlation of chymase and Ang-2 with cardiac ventricular remodeling after ischemia/reperfusion.

    Methods: We retrospectively analyzed the data of 120 STEMI patients who underwent primary PCI within 2 h after admission, and were categorized into three groups according to the target vessel. Plasma expressions of chymase, angiotensin-converting enzyme 2 (ACE2), and Ang-1/2 were detected at different time points through enzyme-linked immunosorbent assay (ELISA). Left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) were subsequently determined through echocardiography, as indices of cardiac ventricular remodeling. Lastly, statistical analyses were conducted to differentiate the correlations.

    Results: Plasma chymase, ACE2, Ang-1, and Ang-2 levels in the left anterior descending artery (LAD) group were significantly higher than those in the left circumflex and right coronary artery groups before PCI (p < 0.01). The plasma expression levels of chymase, ACE2, and Ang-1/2 were reduced immediately with PCI. However, the levels in the LAD group were still the highest among all three groups. The four plasma neuroendocrine factors continued to be elevated on day 7 after PCI. Furthermore, logistic regression analysis confirmed that plasma chymase and Ang-2 were highly correlated with decreasing LVEF and enlarging LVEDV on day 7 after PCI.

    Conclusions: The present study showed that plasma chymase, ACE2, and Ang-2 levels were elevated in patients with STEMI, especially in the LAD group. Primary PCI led to rapid decreases in plasma chymase, ACE2, Ang-1, and Ang-2 levels.

  • Article
    Xiao-Bing Zhou, Ling-Feng Lai, Xiao-Fei Huang, Fei-Xiang Gong, Cong Ding, Tao Hong
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2093-2104. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.216
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    Objective: To investigate the role of phosphatidylethanolamine binding protein 1/15-Lipoxygenase 2/Glutathione Peroxidase 4 (PEBP1/15-lox2/GPX4) signaling pathway in cerebral ischemia reperfusion (I/R)-induced ferroptosis.

    Methods: The expression of PEBP1, 15-lox2, GPX4 and SLC7A11 in the peripheral serum samples of stroke patients and healthy controls was detected with quantitative polymerase chain reaction (qPCR). HT22 was selected to establish the hypoxia reoxygenation model. Enzyme linked immunosorbent assay (ELISA) was applied to detect the levels of superoxide dismutase (SOD) and malondialdehyde (MDA), transmission electron microscope to observe the microstructure of mitochondria, and western blotting to detect the expression levels of SLC7A11, 15-lox2, GPX4 and PEBP1, co-immunoprecipitation (CO-IP) to verify the interaction of PEBP1 with 15-lox2. Additionally, the function of PEBP1/15-lox2/GPX4 signaling pathway was further investigated in cerebral I/R-induced injury.

    Results: The expression of PEBP1 and 15-lox2 was significantly higher, while the expression of GPX4 and SLC7A11 was significantly lower in stroke patients, than that in healthy controls (p < 0.05). In HT22 cells, hypoxia reoxygenation significantly promoted MDA level and significantly reduced SOD level, compared with control. Additionally, hypoxia reoxygenation significantly increased PEBP1, 15-lox2 expression and p-PEBP1 level, and significantly reduced GPX4 and SLC7A11 expression (p < 0.05). These changes were significantly relieved by PEBP1 knockdown and significantly aggravated by PEBP1 overexpression. Morphological results also showed that PEBP1 knockdown also prevented hypoxia reoxygenation-induced cell injury. Co-Immunoprecipitation (CO-IP) also indicated a direct interaction between PEBP1 and 15-lox2. In vivo data showed that cerebral I/R significantly increased the infarct size, MDA level, PEBP1 and 15-lox2 expression, p-PEBP level, and significantly reduced SOD, GPX4 and SLC7A1 expression, compared with sham group. PEBP1 knockdown significantly attenuated those changes (p < 0.05). Morphological results further indicated that PEBP1 knockdown prevented cerebral I/R-induced injury.

    Conclusions: PEBP1/15-lox2/GPX4 signaling pathway participates in cerebral ischemia reperfusion-induced ferroptosis.

  • Article
    Ying Wang, Wang Lu, Hu Chen, Qian Yang, Yang Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2105-2112. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.217
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    Aim: In order to clarify the efficacy and mechanism of Huatan Tongluo Formula (HTTLF) combined with western medicine in the treatment of chronic heart failure complicated with depression.

    Methods: This study selected 120 patients with chronic heart failure and depression who were treated in our hospital from June 2019 to December 2021. The patients were randomly divided into 2 groups. Among them, 60 patients in the control group received conventional western medicine treatment, and 60 patients in the observation group were treated with HTTLF on the basis of conventional western medicine treatment. The clinical efficacy, quality of life, depression, biochemical indicators, and safety indicators of the two groups were compared, and the drug targets of the HTTLF were analyzed and verified by molecular docking and co-precipitation techniques.

    Results: The results showed that the combination of HTTLF and western medicine could significantly improve the symptoms and signs of disease model animals. Molecular docking and co-precipitation experiments showed that isorhamnetin, as the main component of HTTLF, targets the expression of MMP-9. After treatment, the depression self-rating scale score in the observation group was significantly lower than that in the control group, and the quality-of-life score was higher than that in the control group.

    Conclusions: HTTLF can target MMP-9 through monomer isorhamnetin, and combined with western medicine can significantly improve the therapeutic effect of chronic heart failure complicated with depression.

  • Article
    Qingqi Feng, Ang Li, Wei Wang, Weiping Wang, Zhengda Zhang, Jiufu Gu, Chaochun Yu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2113-2122. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.218
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    Aim: This study aimed to explore the effect and related mechanisms of paeonol (PAE) in intracerebral hemorrhage (ICH) in rats.

    Methods: The severity of neurological deficits in rats were assessed using Neurological deficits scores (NDA), righting reflex test, and foot stepping fault test, followed by measurements of water content and cell apoptosis level in rat brain tissues. Next, enzyme linked immunosorbent assay (ELISA) was used to evaluate the inflammatory cytokines and brain-specific biomarkers in the rat brain tissues. Oxidative stress levels in serum and phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/Akt) pathway-associated protein expression in rat brain tissues were assessed using different biochemical detection kit and Western blot analysis, respectively.

    Results: Rats with ICH presented severer brain injury, brain edema and neurological deficits than those only receiving sham operation (p < 0.01). In addition, the inflammation, oxidative stress and apoptosis levels were significantly up-regulated in ICH rats (p < 0.01). However, PAE treatment not only alleviated ICH-caused brain injury, neurological deficits and brain edema, but also inhibited inflammatory (down-regulation of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-18 levels, p < 0.01) and oxidative stress responses (SOD (superoxide dismutase) and GSH (glutathione) levels increased, and MDA (malondialdehyde) levels were down-regulated, p < 0.01). Moreover, both Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining and Western blot analysis indicated that PAE inhibited ICH induced apoptosis (p < 0.01). Additionally, PAE was able to activate the PI3K/Akt signaling pathway.

    Conclusions: Overall, PAE mitigates neurological deficits, brain edema and brain injury via ICH induced apoptosis, oxidative stress and inflammation suppression. This effect might be related to the PI3K/Akt signaling pathway activation. In a sentence, PAE is likely to be an effective therapeutic agent for ICH.

  • Article
    De-fu Yu, Run-ze Yu, Biao Zhang, Tao Chen, Zheng Shen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2123-2130. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.219
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    Objective: To investigate the biological function of the miR-140-5p/Nrf2 (nuclear factor erythroid 2-Related factor 2) axis in the development and progression of osteoarthritis.

    Methods: The optimal concentration of Interleukin-1β (IL-1β)-induced mouse chondrocytes ATDC-5 cells was selected by CCK-8 (cell counting kit-8), subsequent to the construction of an in vitro osteoarthritis model. Quantitative real-time polymerase chain reaction (RT-qPCR) was applied to test the transfection efficiency of ATDC-5 cells and miR-140-5p mimics. Additionally, cell apoptosis and cycle were determined by flow cytometry, cell viability was observed through CCK-8 assay, and Heme Oxygenase-1 (HO-1), Nrf2, B-cell lymphoma-2-Associated X (BAX), and B-cell lymphoma-2 (Bcl-2) protein expression levels were analyzed via western blotting. IL-6, TNF (tumor necrosis factor)-α and MDA (malonyldialdehyde) were studied by conducting ELISA (enzyme-linked immunosorbent assay); And the targeting association of Nrf2 and miR-140-5p, was by dual-luciferase reporter assay analysis.

    Results: The outcomes suggested that IL-1β (10 ng/mL) notably inhibited ATDC-5 cell viability. Relative to controls, Nrf2 protein expression markedly rose and miR-140-5p levels remarkably declined in ATDC-5 cells following IL-1β treatment. Dual-luciferase reporter test indicated that Nrf2 served as a miR-140-5p target gene. In addition, miR-140-5p overexpression greatly promoted IL-1β-induced ATDC-5 cell viability and inhibited ATDC-5 cell cycle arrest and apoptosis. Moreover, miR-140-5p overexpression significantly decreased Nrf2, BAX and HO-1 levels while increased Bcl-2 in IL-1β-induced ATDC-5 cells. Moreover, miR-140-5p overexpressed in ATDC-5 cells down-regulated intracellular inflammatory cytokines—MDA, IL-6 and TNF-α levels.

    Conclusions: Altogether, miR-140-5p may alleviate osteoarthritis by inhibiting inflammatory response, chondrocyte apoptosis, cell cycle arrest, and oxidative stress.

  • Article
    Xin-Hua Liang, Hui-Ling Li, Xiu-Chun Zhou, Miao Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2131-2138. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.220
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    Objectives: To explore the effects of cancer-associated fibroblasts (CAFs) on the proliferation, migration, invasion and ferroptosis of endometrial cells.

    Methods: The fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA) and glutathione peroxidase 4 (GPX4) levels in endometrial tissues of patients with endometrial carcinoma (EC), endometrial hyperplasia (EH) and proliferative endometrium (PE) were detected by immunohistochemistry. CAFs and Ishikawa cells were co-cultured using a Transwell®. The cell proliferation rate, invasion ability and migration ability were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay and Transwell® assay were used for determining. Biochemical assays were employed to measure Fe2+ levels in cells. Western blotting was performed to observe the GPX4 protein expression level in the cells.

    Results: Compared with patients suffering from EH, patients with EC exhibited higher α-SMA, FAP and GPX4 levels in endometrial tissue. The α-SMA, FAP and GPX4 levels in both EC and EH patients were higher than that in PE patients. Compared with the normal endometrial fibroblasts (NEFs) group, the proliferation rate, migration ability, invasion ability and GPX4 protein expression levels of Ishikawa cells in the CAFs group were obviously raised, while the Fe2+ level was notably lowered.

    Conclusions: EC-derived CAFs promote EC cells to proliferate, migrate and invade, as well as inhibit ferroptosis.

  • Article
    Shu-lan Chen, Jun Li, Jin-gao Li, Xiao-ting Pan, Hong-wen Wu, Fei Xu
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2139-2147. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.221
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    Background: Pre-treatment lactate dehydrogenase to albumin ratio (LAR) is a significant biomarker of prognosis in cancer patients. This retrospective cohort study assessed whether pre-treatment LAR is correlated with prognosis in patients with nasopharyngeal carcinoma (NPC).

    Methods: A total of 790 non-metastatic NPC patients were enrolled in this study. Utilizing the X-tile software, the appropriate cutoff values for pre-treatment LAR were determined. Survival probabilities and differences in survival curves for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS) were generated and assessed by the Kaplan–Meier method and log-rank test. Multivariate analysis (MVA) was used to explore LAR pre-treatment predictive value in DMFS, OS, and PFS.

    Results: The median follow-up period of this study was 84 months. LAR optimal cutoff value was 5.6. Patients with a high LAR level had inferior 5-year DMFS (57.5% vs 84.1%, p < 0.001), OS (63.5% vs 79.7%, p < 0.001) and PFS (52.9% vs 74.8%, p < 0.001) than those with a low LAR level. MVA showed that the high LAR level was an adverse independent factor for DMFS (hazard ratio (HR) = 2.620; 95% confidence interval (CI): 1.738–3.950; p < 0.001), OS (HR = 1.742; 95% CI: 1.195–2.540; p = 0.004), and PFS (HR = 1.924; 95% CI: 1.325–2.794; p < 0.001), while lactate dehydrogenase and albumin were dependent predictive of DMFS, OS and PFS. A subgroup survival analysis revealed significant correlations between LAR and clinical outcomes in both Epstein-Barr virus (EBV) DNA negative and positive populations and a trend toward statistically significant differences in DMFS in the EBV-DNA negative subgroup.

    Conclusions: Pre-treatment high LAR level was an independent adverse predictive factor for NPC patients and can serve as a predictive biomarker of prognosis, especially for DMFS.

  • Article
    Shao-Hong Zhang, Ling Lin, Xian-Hua Ye, Xue-Bin Shen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2149-2154. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.222
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    Objective: To evaluate the relationship between the apolipoprotein B (ApoB)/ apolipoprotein A1 (ApoAI) ratio and apolipoprotein F (ApoF) with myocardial infarction (MI) in patients with coronary heart disease (CHD).

    Methods: 231 patients with CHD were screened for inclusion. Among them, 178 patients with MI were included in the MI group, and 53 patients without MI were included in the non-MI (n-MI) group. The laboratory indexes such as ApoB/ApoAI and ApoF of coronary heart disease patients were recorded, and the laboratory indexes and basic data of MI group and n-MI group were compared and analyzed. The relationship between the value ApoB/ApoAI and ApoF with MI in CHD patients was assessed using multivariate logistic regression analysis. Receiver operating characteristic (ROC) curve was used to find best cut-off values of parameters related with the occurrence of MI.

    Results: Sex, age, body mass index (BMI), smoking, drinking, hypertension or diabetes was similar between groups (p > 0.05). ApoF level was lower, and ApoB, ApoB/ApoAI, uric acid (UA), low density liptein (LDL) levels and Gensini score were higher (p < 0.05) in the MI group compared to the n-MI group. ApoAI, blood urea nitrogen (BUN), creatinine (Cr), triglyceride (TG), total cholesterol (TC) or high density liptein (HDL) was similar between groups (p > 0.05). Logistic regression analysis showed that ApoF levels acted as a protective factor for MI, and the ApoB/ApoAI was a risk factor for MI (p < 0.05). However, ApoB, UA, and LDL levels did not significantly correlate with MI (p > 0.05). ROC analysis showed that the area under the curve (AUC) of ApoF to determine MI was 0.732, and the best cut-off value was ≤56.19 µg/mL. The AUC of ApoB/ApoAI to determine MI was 0.701, and the best cut-off value was >1.03. Finally, the AUC of the two combined to determine MI was 0.816 (p < 0.05).

    Conclusions: Elevated ApoB/ApoAI and decreased ApoF are independent factors impacting the occurrence of MI in patients with coronary artery disease, among which elevated ApoB/ApoAI acts as a risk factor, and elevated ApoF acts as a protective factor. The risk of MI is higher when ApoB/ApoAI is ≤56.19 µg/mL and when ApoF is >1.03.

  • Article
    Xiaofei Lan, Yan Chen, Qihua Bi, Azhong Li, Rong Xiang, Tao Chen
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2155-2165. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.223
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    Background: Aged packed red blood cells (pRBCs) cause pulmonary thrombosis, during which P-Selectin and peroxisome proliferator-activated receptor-gamma (PPARγ) are abnormally expressed. This study explored the effect and mechanism of action of aged pRBC on pulmonary microthrombus formation.

    Methods: Microparticles were collected from murine pRBCs and cultured with murine lung microvascular endothelial cells (MLECs), which had been pretreated with pioglitazone (a PPARγ agonist) or not. P-selection and PPARγ levels in MLECs were determined using ELISA (enzyme linked immunosorbent assay), qRT-PCR (quantitative reverse transcription polymerase chain reaction) or western blot. MLEC viability and apoptosis were assessed using CCK-8 (cell counting kit-8) assay and flow cytometry. Male C57BL/6 mice were injected with pRBC-derived microparticles labeled by 5(6)-Carboxyfluorescein diacetate N-succinimidyl ester (CFSE). Pulmonary micro-thrombosis was checked for with hematoxylin-eosin staining and immunohistochemistry, and the microparticles distribution was checked for with a fluorescence microscope.

    Results: pRBC-derived microparticle-processed MLECs showed significantly upregulated P-selection expression and significantly downregulated PPARγ, with significantly increased viability and significantly inhibited apoptosis. Pioglitazone reversed the effect of pRBC-derived microparticle on the PPARγ and P-selection expressions, viability and apoptosis in MLECs. Injection of pRBC-derived microparticles significantly increased the number of microthrombi in each high-powered field and significantly promoted the aggregation of platelets and the microparticles in murine lung, but injection of pioglitazone significantly alleviated pRBC-derived microparticle-delivered effects on murine lung.

    Conclusions: Aged pRBC-derived microparticles significantly promoted pulmonary micro-thrombosis through PPARγ inhibition-requiring P-selectin upregulation.

  • Article
    Qin Zhou, Shutao Zheng, Zi kelia Mu Lager, Zhiwen Zhao, Wukui Huang, Xinsheng Lv, Lili Liu, Wei Cheng
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2167-2176. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.224
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    Background: Despite the overall decline in the incidence rate of esophageal squamous cell carcinoma (ESCC), it remains a high rate of mortality. As a deubiquitinating enzyme, the antitumor effect of ubiquitin-specific peptidase 53 (USP53) has been demonstrated on a few malignancies, but its role and mechanism in ESCC have not been clarified. Therefore, this study aims to explore the role and mechanism of USP53 in ESCC.

    Methods: The effects of USP53 combined with and without axis inhibition protein (Axin1) on cell functions were explored using the CCK-8 (Cell Counting Kit-8 assay) and Flow cytometry assay. The corresponding molecular mechanisms were further detected using Western blot assays. The combination of USP53 and Axin1 was verified by the immunoprecipitation assay. The influence of USP53 on the growth of implanted tumors was tested in vivo and the mechanism was further confirmed by western blot.

    Results: USP53 overexpression inhibited ESCC cell viability, cell cycle progression and glutamine metabolism in vitro, but inhibition of USP53 had the opposite effect. Similar results were also obtained in vivo showing that overexpression of USP53 suppressed tumor growth. In addition, we found that USP53 interacted with and induced deubiquitination of Axin1. Mechanistically, USP53 silencing promoted ESCC cell viability and cell cycle progression through the deubiquitination of Axin1.

    Conclusions: USP53 inhibits the development of ESCC by regulating the deubiquitination of Axin1. USP53 may be used as a molecular target for ESCC therapy.

  • Article
    Shuai Huang, Qiang Yu, Zheng Li
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2177-2182. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.225
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    Objectives: To analyze the application of different doses of rosuvastatin combined with ticagrelor in acute ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI).

    Methods: The clinical data of 72 patients with acute STEMI treated with PCI at People’s Hospital in Yuncheng County (from July 2018 to July 2019) were retrospectively analyzed and 64 patients who met the research conditions were selected as the study subjects. Then, they were assigned to a low-dose group (LDG, n = 34, 10 mg of rosuvastatin + ticagrelor) and a high-dose group (HDG, n = 30, 20 mg of rosuvastatin + ticagrelor) according to different treatment methods. The indexes such as cardiac troponin I (cTnI) and renal function in the first examination and reexamination after surgery of both groups were detected to evaluate the clinical value of different medication schemes.

    Results: At 48 h after PCI (T2), the cTnI and creatine kinase isoenzyme (CK-MB) levels were notably lower in HDG than in LDG (p < 0.001). No obvious differences were found in the renal function indexes between HDG and LDG at different time points (p > 0.05). After treatment, the Myocardial Infarction Dimensional Assessment Scale (MIDAS) score in HDG was markedly lower than that in LDG (p < 0.001).

    Conclusions: Rosuvastatin can effectively improve the cTnI level and quality of life of patients with acute STEMI after PCI, and high-dose rosuvastatin has a better treatment effect. Further research is helping to provide an accurate solution for such patients.

  • Article
    Shuai Huang, Xiaoying Song, Xi Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2183-2191. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.226
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    Purpose: This study investigated the action and mechanism of Ligustrazine (TMP) on myocardial infarction (MI).

    Methods: A MI model was established, using adult male Sprague-Dawley (SD) rats. Heart function indicators were measured, using echocardiography. Real-time reverse transcription polymerase chain reaction (qRT-PCR) assay was used, to measure the micro ribonucleic acid-181a-5p (miR-181a-5p) expression. The therapeutic effect of (miR-181a-5p) on MI mice was investigated, using western blot. Hematoxylin-eosin (HE) staining was used, to determine the cross-section area (CSA) of myocardial cells. The expression of inflammatory cytokines was determined, using ELISA (enzyme-linked immunosorbent assay) kits.

    Results: The left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) significantly declined while the left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) obviously increased 14 days after MI was established. TMP treatment significantly promoted cardiac function of MI rats. The CSA was significantly elevated in MI rats and TMP treatment significantly abated CSA expression. TMP treatment significantly inhibited the inflammatory cytokines and significantly up-regulated apoptosis-related protein of cardiac tissues in MI rats. In addition, miR-181a-5p significantly increased in MI rats, significantly reversing the therapeutic effect of TMP on MI rats. Signal transducer and activator of transcription 3 (STAT3) was predicted to combine with miR-181a-5p.

    Conclusions: TMP treatment significantly promoted cardiac function and inhibited the levels of inflammatory cytokines to alleviate MI, by regulating the miR-181a-5p/STAT3 axis.

  • Article
    Shiyuan Xie, Zaihong Lin, Guangping Zhang, Shu Du, Yan Jiang, Jing Liu, Tuantuan Chen, Zenghui Fu, Huili Yu, Yulei Yang, Yan Jin
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2193-2202. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.227
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    Background: This study aimed to explore the correlation of micro RNA-122 (miR-122) levels with blood lipid and the mechanism of action, and to verify the correlation of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) levels with sterol concentration, cerebral infarct (CI) and hyperlipidemia. The study tried to provide a new therapeutic target for the prevention and treatment of brain nerve cell injury and even CI caused by hyperlipidemia.

    Methods: Clinical cases of hyperlipidemia were retrospectively collected to analyze the correlation of hyperlipidemia with CI using a cohort study. Mice were grouped to construct a mouse model of hyperlipidemia. All mice were injected intraperitoneally with 25 µg/kg saline, miR-122 antagomiR daily. Area with CI in the brain was measured by after 14 days, and the infected tissues were collected. Serum lipid parameters were measured with automatic biochemical analyzer. Grouped culture was conducted with liver cell lines. miR-122 expression in liver tissues and liver cells cultured in vitro was checked for with qRT-PCR. Luciferase reporter gene demonstrated the interaction between miR-122 with HMGCR. HMGCR expression in liver cells cultured in vitro, and caspase3, cleaved caspase3, Bcl-2 and Bax expression in brain tissues were analyzed by Western blot.

    Results: Hyperlipidemia was a risk factor for CI. Blood lipid detection showed significantly increased blood lipid in mice with hyperlipidemia after modogenesis, and decreased blood lipid after inhibiting miR-122. CI in mice with hyperlipidemia significantly improved after inhibiting miR-122. Luciferase reports and Western blot results showed that miR-122 regulated blood lipid by targeting HMGCR and subsequently improved CI.

    Conclusions: miR-122 targeting HMGCR plays an important role in the regulation of blood lipids. Inhibition of miR-122 can reduces the expression of HMGCR and then reduce blood lipids and reduce neuronal apoptosis in cerebral infarction.

  • Article
    Bingling Zhang, Ting Fang, Sheng Li, Lan Xiang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2203-2209. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.228
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    Background: Colon cancer is an aggressive digestive system cancer. Increasing research suggests that the bacteria Salmonella is associated with human cancers and could restrain tumor growth. However, the effect of Salmonella in colon cancer has been puzzling.

    Methods: Salmonella enterica serovar choleraesuis vaccine strain was used for this research to estimate the function of Salmonella in colon cancer. Function experiments were utilized for analyzing cell apoptosis and proliferation. Proteins levels in cells were assessed by western blot.

    Results: It was observed that enhanced Salmonella concentration was negatively correlated with the viability of colon cancer cells. Cell cycle was arrested following treatment with Salmonella in G0/G1 phase. Moreover, it was verified that at cellular level Salmonella could restrain tumor cell proliferation and restrain phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling activity.

    Conclusions: Salmonella exhibits anti-cancer properties via restraint of the PI3K/AKT/mTOR pathway in colon cancer. This work brings new insights for colon cancer treatment.

  • Article
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2211-2218. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.229
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    Background: Tauroursodeoxycholic acid (TUDCA) treatment significantly decreases the blood sugar content and exerts renoprotective effects in db/db mice. These changes are likely related to endoplasmic reticulum (ER) stress and apoptosis inhibition.

    Purpose: To elucidate the mechanism underlying the association between the renoprotective effect of TUDCA and ER stress inhibition.

    Methods: Renal proximal tubular cells (HK-2 (Human Kidney-2) cells) were cultured with or without TUDCA (0.1, 0.2, and 0.4 mmol/L) in normal or high-concentration glucose (HG) media. After 48 h, we determined the HK-2 apoptosis and proliferation rates by flow cytometry and methyl thiazol tetrazolium (MTT) assay, respectively. Furthermore, we detected intracellular reactive oxygen species (ROS) levels and the mitochondrial membrane potential per group. Finally, we analyzed the expression of ER stress-related markers using western blotting and real-time polymerase chain reaction.

    Results: TUDCA treatment protected HK-2 cells from HG damage, reduced apoptosis, and restored cell proliferation inhibited by HG through the ER stress pathway. The protective effect on HK-2 cells corresponded with ROS inhibition and mitochondrial membrane potential stabilization. Additionally, TUDCA treatment downregulated CCAAT enhancer binding protein (C/EBP) homologous protein (i.e., CHOP) and glucose-regulated protein: 78 kDa (i.e., GRP78) expression, which were upregulated in the HG group.

    Conclusions: Our results suggest that TUDCA protected renal proximal tubular cells against HG-induced apoptosis by suppressing ER stress.

  • Article
    Feng Du, Yanli Guo, Taochun Ye, Wei Zhang
    Journal of Biological Regulators and Homeostatic Agents. 2022, 36(6): 2219-2228. https://doi.org/10.23812/j.biol.regul.homeost.agents.20223606.230
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    Background: Myocardial ischemia-reperfusion (I/R) injury is a difficult clinical presentation in patients with ischemic heart after re-establishing blood flow. It can induce arrhythmia, ventricular systolic dysfunction, and enlarge the infarct size. Acupuncture (Acu), as a part of traditional Chinese medicine (TCM) therapy, has acceptable effectiveness and minimal side effects. This attracted increasing interest in managing myocardial I/R injury. However, its mechanism of action is in not fully understood. This study evaluated acupuncture approach for myocardial I/R injury and explored its mechanism of action in rats, using coronary artery ligation to simulate myocardial I/R injury.

    Methods: Before modeling, rats were pinpricked at Gongsun (SP 4), Neiguan (PC 4), Guanyuan (CV 4), Juque (CV 14), Tiantu (CV 22), Xinshu (BL 15), Li Dui (ST 45) points. After modeling, rats were immediately injected with recombinant adenovirus of sphingosine kinases type 1 (SPHK1) pDC316 overexpression (pDC-SPHK1). The protective effects of acupuncture on myocardial I/R injury were shown to be mediated through histomorphology, cardiomyocyte apoptosis, myocardial enzymes, and anti-inflammatory response.

    Results: Multiple-point acupuncture inhibited the activation of SPHK1/tissue inhibitor of metalloproteinase-1 (TIMP1) signaling pathway in myocardial tissue. Acupuncture intervention reduced left ventricular dysfunction, myocardial infarction area, cardiomyocyte apoptosis, and excessive inflammation caused by I/R. SPHK1 overexpression significantly reversed these protective effects of acupuncture intervention on myocardial I/R injury.

    Conclusions: Taken together, multi-point acupuncture may be an effective alternative therapy to prevent myocardial I/R injury.