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Background: Parkinson's disease (PD) is a neurodegenerative disorder characterised by a high prevalence of sporadic cases. Various molecular mechanisms are involved in its pathogenesis. This pilot study aimed to identify potential risk and protective human leukocyte antigen (HLA) alleles in PD, discover candidate alleles for further research, and evaluate potential blood biomarkers. Methods: A total of 43 PD patients and 79 unrelated sex-matched controls were enrolled in this study. We analysed the polymorphism of HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the blood levels of biomarkers such as S100 calcium-binding protein A9 (S1000A9), kynurenic acid (KYNA), neurofilament light chain (NfL), and glutamate decarboxylase (GAD1). Results: We found that the frequencies of the HLA-DRB1*04, -DQA1*02:01, and -DQA1*03:01 alleles were significantly higher in the PD patients than in the controls, suggesting that these alleles are potential risk factors. Furthermore, the HLA-DQA1*02:01 allele was detected more frequently in the PD group when the disease onset was at 60 years or older. On the contrary, the HLA-DRB1*01 and HLA-DQA1*05:01 alleles were less common in the PD patients, indicating a possible protective effect. Regarding biomarkers, the blood levels of S100 calcium-binding protein A9 were significantly higher, and the kynurenic acid levels were significantly lower in the PD group. The NfL levels were also higher in the PD group but did not reach statistical significance, possibly due to the sensitivity limitations of the ELISA method used. The GAD1 levels showed no significant differences between the two groups. Conclusions: Our findings indicate that the HLA-DRB1*01 and -DRB1*04 alleles and the HLA-DQA1*02:01, -DQA1*03:01, and -DQA1*05:01 alleles are associated with PD. Moreover, S100 calcium-binding protein A9 and kynurenic acid can be considered potential blood biomarkers for PD. These findings contribute to the growing body of knowledge on PD and offer new directions for further research in Latvian cohorts. [ABSTRACT FROM AUTHOR]

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by a high prevalence of sporadic cases. Various molecular mechanisms are involved in its pathogenesis. This pilot study aimed to identify potential risk and protective human leukocyte antigen (HLA) alleles in PD, discover candidate alleles for further research, and evaluate potential blood biomarkers. Methods: A total of 43 PD patients and 79 unrelated sex-matched controls were enrolled in this study. We analysed the polymorphism of HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the blood levels of biomarkers such as S100 calcium-binding protein A9 (S1000A9), kynurenic acid (KYNA), neurofilament light chain (NfL), and glutamate decarboxylase (GAD1). Results: We found that the frequencies of the HLA-DRB1*04, -DQA1*02:01, and -DQA1*03:01 alleles were significantly higher in the PD patients than in the controls, suggesting that these alleles are potential risk factors. Furthermore, the HLA-DQA1*02:01 allele was detected more frequently in the PD group when the disease onset was at 60 years or older. On the contrary, the HLA-DRB1*01 and HLA-DQA1*05:01 alleles were less common in the PD patients, indicating a possible protective effect. Regarding biomarkers, the blood levels of S100 calcium-binding protein A9 were significantly higher, and the kynurenic acid levels were significantly lower in the PD group. The NfL levels were also higher in the PD group but did not reach statistical significance, possibly due to the sensitivity limitations of the ELISA method used. The GAD1 levels showed no significant differences between the two groups. Conclusions: Our findings indicate that the HLA-DRB1*01 and -DRB1*04 alleles and the HLA-DQA1*02:01, -DQA1*03:01, and -DQA1*05:01 alleles are associated with PD. Moreover, S100 calcium-binding protein A9 and kynurenic acid can be considered potential blood biomarkers for PD. These findings contribute to the growing body of knowledge on PD and offer new directions for further research in Latvian cohorts.

Objective To research the expression level of heat shock protein 70 (HSP70) and S100 calcium-binding protein A9 (S100A9) in glioma tissue and their differential diagnostic value in low-level brain glioma and dysembryoplastic neuroepithelial tumor (DNT) .Methods All pathological specimens were taken from 160 newly diagnosed patients with gliomas in Guangdong Clifford Hospital and Chinese People′s Liberation Army Southern Theater Command Gneral Hospital from January 2015 to December 2020,including 40 patients with World Health Organization (WHO) grade Ⅰ,Ⅱ,Ⅲ and Ⅳ gliomas.Immunohistochemical method was used to detect the expression levels of HSP70 and S100A9 in 160 cases of glioma and normal brain tissue adjacent to tumor, and 20 cases of DNT.Results The detectable rates of HSP70 and S100A9 were 85.0% (136/160) and 7.5% (12/160),respectively.The expression of HSP70 in gliomas with differences WHO grades was statistically significant (P＜0.05),and the expression level increased with the improvement of who grade of gliomas, which could also be used for the differential diagnosis of low-grade gliomas and DNT.S100A9 had no statistical difference in different WHO grades (P＞0.05),and it could not be used for the differential diagnosis of DNT and low-grade glioma.There was no correlation between HSP70 and S100A9 expression in glioma tissues.Conclusion HSP70 can be used in the diagnosis of brain glioma.The expression level increases with the improvement of WHO grade of glioma, and can be used in the differential diagnosis of low-level glioma and DNT.S100A9 has no such value. [ABSTRACT FROM AUTHOR]

AIM: To investigate the differential gene expression changes in the heart of aging rat model induced by D-galactose （D-Gal）, and to verify the expression of S100 calcium-binding protein A8/A9 （S100A8/A9） and its downstream p38 mitogen-activated protein kinase （MAPK）/nuclear factor-κB （NF-κB） signaling pathway key factors. METHODS: （1） SD rats aged 8~10 weeks were randomly divided into normal control group （control group） and D-Gal group, with 6 rats in each group. The rats in D-Gal group were subcutaneously injected with D-Gal （150 mg/kg） on the back of the neck every day, while the rats in control group were injected with the same volume of normal saline. Morris water maze was used to test the learning and memory ability, and the levels of serum superoxide dismutase （SOD）, catalase （CAT） and malondialdehyde （MDA） were measured. Echocardiography was used to measure the cardiac function, HE, Masson, senescence-associated β-galactosidase （SA-β-Gal） and dihydroethidium staining was performed, and the mitochondrial ultrastructure was observed by transmission electron microscopy. Transcriptome sequencing was used to analyse the gene expression differences in rat heart. qRT-PCR and Western blot were used to detect the mRNA and protein expression of aging maker genes, S100A8/A9, and p38 MAPK/NF-κB pathway-related factors in rat myocardial tissues. （2） DGal （10 g/L） was used to induce the aging model of H9C2 cardiomyocytes, and the S100A8/A9 inhibitor paquinimod was used to intervene. The expression levels of aging-related indicators and S100A8/A9 downstream inflammatory pathway-related factors were detected. RESULTS: Compared with control group, the rats in D-Gal group had learning and memory impairment, and the serum SOD and CAT levels were significantly reduced （P<0. 01）. The ejection fraction and fraction shortening of the rats in D-Gal group were significantly decreased（ P<0. 01）, the arrangement of cardiomyocytes was disordered, fiber breakage and inflammatory cell infiltration were observed, the area of fibrosis and the levels of SA-β-Gal and reactive oxygen species were significantly increased, the mitochondrial structure was changed, and the mRNA expression levels of cyclin-dependent kinase inhibitor 1A （CDKN1A）, CDKN2A and P53 were significantly up-regulated compared with control group （P<0. 01）. Transcriptome sequencing analysis showed that the mRNA and protein levels of S100A8 and S100A9 were significantly up-regulated in aging rat hearts, and phosphorylated p38 MAPK and NF-κB protein levels and the mRNA expression of inflammatory factors such as interleukin-1β （IL-1β）, IL-6 and tumor necrosis factor-α were significantly increased （P<0. 05 or P<0. 01）. D-Gal continuous stimulation induced H9C2 cell senescence, accompanied by increased expression of S100A8/A9, while paquinimod significantly reduced D-Gal-induced cardiomyocyte SA-β-Gal positive rate and the expression of senescence marker genes, and inhibited p38 MAPK/NF-κB phosphorylation activation and expression of downstream inflammatory factors （P<0. 05 or P<0. 01）. CONCLUSION: S100A8 and S100A9 may participate in D-Gal-induced rat cardiac aging process by inducing activation of the p38 MAPK/NF-κB inflammatory pathway and increasing cardiomyocyte inflammation. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) and idiopathic pulmonary fibrosis (IPF) frequently coexist. Elevated levels of Krebs von den Lungen-6 (KL-6), endothelin-1 (ET-1) and S100 calcium-binding protein A9 (S100A9) have been observed in patients with IPF, suggesting their potential role as biomarkers for lung fibrosis. The aim of the present study was to measure the levels of KL-6, ET-1 and S100A9 in patients with IPF-OSA and to test the potential of these biomarkers as a characteristic OSA signature with diagnostic and prognostic potential for IPF. A total of 55 subjects with newly-diagnosed IPF participated in the present cross-sectional study. In addition to performing overnight attended polysomnography and pulmonary function tests, serum and bronchoalveolar lavage (BAL) levels of KL-6, along with serum levels of ET-1 and S100A9, were also assessed. A total of 15 patients with IPF and 40 patients with IPF-OSA were included. Age, sex, comorbidities and pulmonary function tests did not differ between the groups. Although there was no significant difference between groups in the levels of KL-6, ET-1 and S100A9 (P>0.05), the serum ET-1 levels tended to be elevated in patients with OSA-IPF compared with patients with IPF (1.78 vs. 1.07 pg/ml; P=0.06). Additionally, a significant association was observed between serum KL-6 levels and the severity of IPF, and also between BAL KL-6 levels and nocturnal mean SaO2 levels, even after taking into account factors such as obesity and smoking. S100A9 levels were associated with the oxygen desaturation index, even after adjustments for obesity, smoking and the gender-age-physiology index, only in the IPF-OSA group. Conclusively, the present findings suggested significant associations between serum ET-1, S100A9 and BAL KL-6 levels and specific OSA severity parameters in the IPF-OSA group. This evidence suggested that these molecules could serve as biomarkers for the identification of patients with IPF-OSA, offering a distinct OSA signature that has diagnostic and potential treatment value. Larger studies are crucial to substantiate the present findings and reinforce this hypothesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer's disease, by targeting both neuroinflammation and neurodegeneration. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent disorder that causes considerable disability in social functioning and is a risk factor for physical diseases. Recent clinical reports have demonstrated a marked association between MDD and physiological dyshomeostasis induced by metabolic disorders, including diabetes, hormone abnormalities and autoimmune diseases. The authors of the present study have previously analyzed comparative gene expression profiles in the prefrontal cortex (PFC) of a chronic mild stress (CMS) animal model of MDD. Hepatocyte nuclear factor 4a (Hnf4a) was identified as a central regulator that exerted significant influence on genes associated with physiological homeostasis. The aim of the present study was to investigate: i) the molecular mechanism of the depressive state in the PFC, and ii) the involvement of genes extracted from the comparative gene expression profiles, particularly those applicable to MDD in clinical practice. Core analysis of the previous PFC microarray results was performed using Ingenuity Pathway Analysis (IPA). Subsequently, IPA was used to search for molecules that are regulated by Hnf4a, and exist in the PFC and serum. From the core analysis, 5 genes that are associated with cell death and are expressed in the cortex were selected. Four of the extracted genes, insulin-like growth factor 1, transthyretin, serpin family A member 3 and plasminogen, were markedly affected by Hnf4a. S100 calcium-binding protein A9 (S100a9) and a2-HS-glycoprotein (Ahsg) were also chosen as they exist in serum and are also affected by Hnf4a. A significant group difference in the expression of these two genes was detected in the PFC, thalamus and hippocampus. The protein levels of AHSG and S100A9 in the PFC and hippocampus of the CMS group increased significantly when compared with the control group. These findings support the close association of Hnf4a (through genes such as S100a9 and Ahsg) with the development of various diseases induced by deregulation of physiological homeostasis during the progression of MDD. [ABSTRACT FROM AUTHOR]

Wet keratin is a hallmark of adamantinomatous craniopharyngioma (ACP), which is frequently infiltrated by inflammatory cells. S100 calcium-binding protein A9 (S100A9) has been confirmed to play a decisive role in the development of inflammation. However, the relationship between wet keratin (keratin nodules) and S100A9 in ACP is poorly understood. The objective of the present study was to explore the expression of S100A9 in ACP and its association with wet keratin formation. Immunohistochemistry and immunofluorescence were used to detect the expression of S100A9, β-catenin and Ki67 in 46 cases of ACP. A total of three online databases were used to analyze S100A9 gene expression and protein data. The results revealed that S100A9 was primarily expressed in wet keratin and some intratumoral and peritumoral cells, and its expression in wet keratin was upregulated in the high inflammation group (P=1.800x10-3). In addition, S100A9 was correlated with the degree of inflammation (r=0.6; P=7.412x10-3) and the percentage of Ki67-positive cells (r=0.37; P=1.000x10-2). In addition, a significant correlation was noted between the area of wet keratin and the degree of inflammation (r=0.51; P=2.500x10-4). In conclusion, the present study showed that S100A9 was upregulated in ACP and may be closely associated with wet keratin formation and the infiltration of inflammatory cells in ACP. [ABSTRACT FROM AUTHOR]

S100 calcium-binding protein A9 (S100A9) is highly expressed in the serum exosomes of patients with burn injuries. The present study aimed to investigate the underlying mechanisms of burn injury-associated exosomes in the regulation of myocardial cell pyroptosis. Reverse transcription-quantitative PCR and western blotting were used to examine relative mRNA and protein levels. The morphology of exosomes was visualized using transmission electron microscopy. The expression levels of IL-1β and IL-18 in cells were examined using ELISA kits. Finally, cell pyroptosis was examined using flow cytometry. When AC16 cells were treated with the serum exosomes obtained from patients with burn injuries, pyroptosis was significantly promoted and the expression levels of IL-1β and IL-18 were increased. NLR family pyrin domain containing 3 (NLRP3), S100A9, caspase-1 and Gasdermin D (GSDMD)-N expression levels were also upregulated. However, these were significantly reversed by anti-S100A9 antibodies. Thereafter, CY-09, an NLRP3 inhibitor, was revealed to restore the increase in pyroptosis and IL-18, IL-1β, caspase-1, NLRP3 and GSDMD-N expression levels caused by recombinant S100A9 to be similar to the control. These findings suggested that burn injury-associated exosomes containing S100A9 can affect AC16 cell pyroptosis through NLRP3. [ABSTRACT FROM AUTHOR]

Oral Diseases (2011) , 370-378 Porphyromonas gingivalis was recently shown to cause intimal hyperplasia in a mouse model by a novel cholesterol-independent mechanism, suggesting to be a pathogen-specific feature of cardiovascular diseases. The aim of this study was to characterize the clinical and histopathological features of aortic aneurysms in cardiovascular disease patients harboring oral P. gingivalis. Aortic aneurysm specimens were collected from 76 Japanese patients who underwent surgery, of whom dental plaque specimens were also collected from 31 patients. Bacterial DNA was extracted from each specimen to detect P. gingivalis by polymerase chain reaction. Histopathological analyses of the aortic aneurysm specimens, including immunohistochemical staining for embryonic myosin heavy chain isoform (SMemb) and S100 calcium-binding protein A9 (S100A9), were also performed. The number of aneurysms occurring in the distal aorta was significantly higher in subjects positive for P. gingivalis in dental plaque compared with those who were negative. The expressions of S100A9 and SMemb were also significantly greater in the subjects positive for P. gingivalis in dental plaque. On the other hand, there were no significant differences in adipocellular accumulation between the groups. These results suggest that aortic aneurysms in patients harboring oral P. gingivalis have greater expression of S100A9 and proliferative smooth muscle cells, which was different from the present patients without oral P. gingivalis. [ABSTRACT FROM AUTHOR]

Abstract: S100 calcium-binding protein A8 (S100A8) and S100 calcium-binding protein A9 (S100A9) are pivotal mediators of inflammatory and protective anti-infection responses for the mammalian host. In this study, we present the molecular cloning of porcine S100A8 (pS100A8) and porcine S100A9 (pS100A9). Both genes comprise 3 exons and 2 introns and are located on pig chromosome 4q21–q23 (closely linked to SW512). Homology comparison to other mammalian species affirmed that critical functional amino acids for post-transcriptional modification, inflammatory regulation, and formation of heterodimeric complexes exist in pS100A8 and pS100A9. Under normal conditions, both genes are preferentially expressed in porcine immune or immune-related organs, e.g., bone marrow, spleen, lymph nodes, and lung. Upon stimulation in porcine whole blood cultures with LPS or Poly(I:C), they are dramatically induced. Interestingly, the maximum increase of mRNA levels in blood cultures of Meishan pigs is significantly greater than that in Duroc pigs. We previously showed that pS100A8 and pS100A9 mRNA were up-regulated following Haemophilus parasuis (HPS) infection. We herein further confirm their up-regulation at the protein level in multiple HPS infected tissues (spleen, lung and liver). Functional cluster and network analysis based on our previous microarray data discovered that CEBPB may be one of the key transcription factors. A pS100A8/pS100A9-CASP3-SLC1A2 pathway regulating lipid metabolism was found. Both of their pro- and anti-inflammatory functions in response to HPS infection are highlighted. [Copyright &y& Elsevier]