-
Anticancer Research Jan 2024Pregnancy zone protein (PZP), encoded by PZP, belongs to the α-2-macroglobulin superfamily, and plays an important role in inflammatory responses and immune cell...
BACKGROUND/AIM
Pregnancy zone protein (PZP), encoded by PZP, belongs to the α-2-macroglobulin superfamily, and plays an important role in inflammatory responses and immune cell activation in cancer. However, the relationship between gastric cancer (GC) and PZP is poorly studied. This study investigated the clinical significance of PZP expression in GC tissues of patients with locally advanced GC after curative resection.
PATIENTS AND METHODS
Using quantitative polymerase chain reaction, we measured PZP expression in GC tissues and adjacent normal gastric mucosa of 253 patients with pStage II/III GC who underwent curative resection. We compared the expression levels of PZP in GC tissues and adjacent normal gastric mucosa and examined the relationship of PZP expression in GC tissues with clinicopathological factors and overall survival (OS).
RESULTS
PZP expression was significantly associated with histology, venous invasion, and pathological stage. The high PZP expression group had significantly worse OS than did the low expression group (5-year survival 48.6% vs. 68.5%, p=0.0003). Furthermore, in multivariate analysis, high PZP expression was an independent factor for poor OS (hazard ratio=1.984, 95% confidence interval=1.307-3.012, p=0.0013).
CONCLUSION
In post-curative resection patients with locally advanced GC, PZP expression in GC tissue may be a useful prognostic marker.
Topics: Humans; Clinical Relevance; Gastrectomy; Prognosis; Stomach Neoplasms; Pregnancy Proteins
PubMed: 38159976
DOI: 10.21873/anticanres.16820 -
Journal of Alzheimer's Disease Reports 2023The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer's disease (AD) has been widely studied across populations; however, the results are inconsistent.
BACKGROUND
The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer's disease (AD) has been widely studied across populations; however, the results are inconsistent.
OBJECTIVE
This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis.
METHODS
Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I metric was used to evaluate heterogeneity, and Egger's test and Funnel plot were used to assess publication bias.
RESULTS
A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47-0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12-2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38-3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26-0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results.
CONCLUSIONS
Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results.
PubMed: 38143774
DOI: 10.3233/ADR-230131 -
Free Radical Biology & Medicine Mar 2024Our study investigated the possible molecular mechanism of glucocorticoid in steroid-induced osteonecrosis of the femoral head (SINFH) through regulating serum...
Glucocorticoids promote steroid-induced osteonecrosis of the femoral head by down-regulating serum alpha-2-macroglobulin to induce oxidative stress and facilitate SIRT2-mediated BMP2 deacetylation.
Our study investigated the possible molecular mechanism of glucocorticoid in steroid-induced osteonecrosis of the femoral head (SINFH) through regulating serum alpha-2-macroglobulin and SIRT2-mediated BMP2 deacetylation. Essential genes involved in glucocorticoid-induced SINFH were screened by transcriptome sequencing and analyzed by bioinformatics, followed by identifying downstream regulatory targets. Rat bone marrow mesenchymal stem cells were isolated and treated with methylprednisolone (MP) for in vitro cell experiments. Besides, a glucocorticoid-induced rat ONFH was established using the treatment of MP and LPS. ChIP-PCR detected the enrichment of SIRT2 in the promoter region of BMP2, and the deacetylation modification of SIRT2 on BMP2 was determined. Bioinformatics analysis revealed that glucocorticoids may induce ONFH through the SIRT2/BMP2 axis. In vitro cell experiments showed that glucocorticoids up-regulated SIRT2 expression in BMSCs by inducing oxidative stress, thereby promoting cell apoptosis. The up-regulation of SIRT2 expression may be due to the decreased ability of α2 macroglobulin to inhibit oxidative stress, and the addition of NOX protein inhibitor DPI could significantly inhibit SIRT2 expression. SIRT2 could promote histone deacetylation of the BMP2 promoter and inhibit its expression. In vitro cell experiments further indicated that knocking down SIRT2 could protect BMSC from oxidative stress and cell apoptosis induced by glucocorticoids by promoting BMP2 expression. In addition, animal experiments conducted also demonstrated that the knockdown of SIRT2 could improve glucocorticoid-induced ONFH through up-regulating BMP2 expression. Glucocorticoids could induce oxidative stress by down-regulating serum α2M to promote SIRT2-mediated BMP2 deacetylation, leading to ONFH.
Topics: Female; Pregnancy; Rats; Animals; Glucocorticoids; Pregnancy-Associated alpha 2-Macroglobulins; Femur Head; Sirtuin 2; Femur Head Necrosis; Steroids; Transcription Factors; Osteogenesis
PubMed: 38142952
DOI: 10.1016/j.freeradbiomed.2023.12.026 -
Molecular Immunology Jan 2024The bispecific antibody gefurulimab (also known as ALXN1720) was developed to provide patients with a subcutaneous treatment option for chronic disorders involving...
The bispecific antibody gefurulimab (also known as ALXN1720) was developed to provide patients with a subcutaneous treatment option for chronic disorders involving activation of the terminal complement pathway. Gefurulimab blocks the enzymatic cleavage of complement component 5 (C5) into the biologically active C5a and C5b fragments, which triggers activation of the terminal complement cascade. Heavy-chain variable region antigen-binding fragment (VHH) antibodies targeting C5 and human serum albumin (HSA) were isolated from llama immune-based libraries and humanized. Gefurulimab comprises an N-terminal albumin-binding VHH connected to a C-terminal C5-binding VHH via a flexible linker. The purified bispecific VHH antibody has the expected exact size by mass spectrometry and can be formulated at greater than 100 mg/mL. Gefurulimab binds tightly to human C5 and HSA with dissociation rate constants at pH 7.4 of 54 pM and 0.9 nM, respectively, and cross-reacts with C5 and serum albumin from cynomolgus monkeys. Gefurulimab can associate with C5 and albumin simultaneously, and potently inhibits the terminal complement activity from human serum initiated by any of the three complement pathways in Wieslab assays. Electron microscopy and X-ray crystallography revealed that the isolated C5-binding VHH recognizes the macroglobulin (MG) 4 and MG5 domains of the antigen and thereby is suggested to sterically prevent C5 binding to its activating convertase. Gefurulimab also inhibits complement activity supported by the rare C5 allelic variant featuring an R885H substitution in the MG7 domain. Taken together, these data suggest that gefurulimab may be a promising candidate for the potential treatment of complement-mediated disorders.
Topics: Humans; Complement C5; Single-Domain Antibodies; Complement System Proteins; Complement Activation; Albumins
PubMed: 38142486
DOI: 10.1016/j.molimm.2023.12.004 -
Comparative Transcriptome Analysis of the Response to and Low-Salinity Stress in the Swimming Crab .Biology Dec 2023is one of the main pathogenic bacteria of and causes mass mortality of in aquaculture. In addition, low-salinity stimulation makes more susceptible to infections....
is one of the main pathogenic bacteria of and causes mass mortality of in aquaculture. In addition, low-salinity stimulation makes more susceptible to infections. In order to elucidate the molecular mechanism of resistance to in , comparative transcriptomic analysis of blood cells stimulated by low salinity and was carried out in this study. Transcriptome sequencing of low-salinity stress and pathogen infection at different time points was completed using Illumina sequencing technology. A total of 5827, 6432, 5362 and 1784 differentially expressed genes (DEGs) involved in pathways related to ion transport and immunoregulation were found under low-salinity stress at 12, 24, 48 and 72 h compared with the control at 0 h. In contrast, 4854, 4814, 5535 and 6051 DEGs, which were significantly enriched in Toll and IMD signaling pathways, were found at 12, 24, 48 and 72 h compared with the control at 0 h under infection. Among them, 952 DEGs were shared in the two treatment groups, which were mainly involved in apoptosis and Hippo signaling pathway. Cluster analysis screened 103 genes that were differentially expressed in two factors that were negatively correlated, including immunoglobulin, leukocyte receptor cluster family, scavenger receptor, macroglobulin and other innate-immune-related genes. These results provide data support for the analysis of the mechanisms of immunity to under low-salinity stress in and help to elucidate the molecular mechanisms by which environmental factors affect immunity.
PubMed: 38132344
DOI: 10.3390/biology12121518 -
Developmental and Comparative Immunology Apr 2024There is limited knowledge regarding the blockade of cysteinyl leukotriene receptors (CysLTRs) and their effects in teleost fish. The present study investigated the...
There is limited knowledge regarding the blockade of cysteinyl leukotriene receptors (CysLTRs) and their effects in teleost fish. The present study investigated the effects of Zafirlukast, antagonist of CysLTR receptor, on the foreign body inflammatory reaction in Nile tilapia (Oreochromis niloticus). Zafirlukast-treated tilapia demonstrated a decrease in the formation of multinucleated foreign body giant cells and Langhans cells on the round glass coverslips implanted in the subcutaneous tissue, along with a significant reduction in white blood cell counts and decreased production of reactive oxygen species. There was an increase in serum levels of α2-macroglobulins, as well as a decrease in ceruloplasmin and haptoglobin. Zafirlukast treatment led to a significant decrease in the area of splenic melanomacrophage centers and a reduction in the presence of lipofuscin. These findings highlight the potential anti-inflammatory effects of zafirlukast treatment in tilapia and indicate its action on CysLTR receptor, modulating the innate immune response of tilapia during the foreign body reaction. The comprehension of chronic inflammation mechanisms in fish has become increasingly relevant, especially concerning the utilization of biomaterials for vaccine and drug delivery.
Topics: Animals; Tilapia; Immunity, Innate; Inflammation; Cichlids; Foreign Bodies; Fish Diseases; Indoles; Sulfonamides; Phenylcarbamates
PubMed: 38092068
DOI: 10.1016/j.dci.2023.105112 -
Frontiers in Neurology 2023Acute ischemic stroke (AIS) is characterized by high rates of morbidity, disability, mortality, and recurrence, often leaving patients with varying degrees of sequelae....
OBJECTIVE
Acute ischemic stroke (AIS) is characterized by high rates of morbidity, disability, mortality, and recurrence, often leaving patients with varying degrees of sequelae. Symptomatic intracranial atherosclerotic stenosis (sICAS) is a significant contributor to AIS pathogenesis and recurrence. The formation and progression of sICAS are influenced by pathways such as lipid metabolism and inflammatory response. Given its high risk of clinical recurrence, timely assessment of intracranial vascular stenosis in AIS is crucial for diagnosing sICAS, treating stroke, and preventing stroke recurrence.
METHODS
Fourteen AIS patients were divided into stenosis and control groups based on the presence or absence of intracranial vessel stenosis. Initially, 4D Label-free proteome quantification technology was employed for mass spectrometry analysis to identify differential proteins between the groups. Subsequently, functional enrichment analysis, including GO classification, KEGG pathway, and Domain, revealed trends related to differential proteins. The STRING (v.11.5) protein interaction network database was used to identify differential protein interactions and target proteins. Finally, parallel reaction monitoring (PRM) validated the selected target proteins.
RESULTS
Mass spectrometry identified 1,096 proteins, with 991 being quantitatively comparable. Using a -value <0.05 and differential expression change thresholds of >1.3 for significant up-regulation and < 1/1.3 for significant down-regulation, 46 differential proteins were identified: 24 significantly up-regulated and 22 significantly down-regulated. PRM experiments validated five proteins related to lipid metabolism and inflammatory response: namely alpha-2-macroglobulin (A2M), lipopolysaccharide-binding protein (LBP), cathepsin G (CTSG), cystatin (CST)3, and fatty acid-binding protein (FABP)1.
CONCLUSION
The detection of changes in these five proteins in AIS patients can aid in the diagnosis of sICAS, inform stroke treatment, and assist in preventing stroke recurrence. Moreover, it can contribute to the development of drugs for preventing AIS recurrence by integrating traditional Chinese and Western medicine.
PubMed: 38090270
DOI: 10.3389/fneur.2023.1291929 -
Fish & Shellfish Immunology Jan 2024This study discloses the nanoscale silicate platelet-supported nZnO (ZnONSP) applied as novel feed additives in aquaculture. The preparation of the nanohybrid...
This study discloses the nanoscale silicate platelet-supported nZnO (ZnONSP) applied as novel feed additives in aquaculture. The preparation of the nanohybrid (ZnO/NSP = 15/85, w/w) was characterized by UV-visible spectroscopy, powder X-ray diffraction and transmission electron microscope. The effects of ZnONSP on growth, zinc accumulation, stress response, immunity and resistance to Vibrio alginolyticus in white shrimp (Penaeus vannamei) were \demonstrated. To evaluate the safety of ZnONSP, shrimps (2.0 ± 0.3 g) were fed with ZnONSP containing diets (200, 400 and 800 mg/kg) for 56 days. Dietary ZnONSP did not affect the weight gain, specific growth rate, feed conversion ratio, survival rate, zinc accumulation, and the expression of heat shock protein 70 in tested shrimps. To examine the immunomodulatory effect of ZnONSP, shrimps (16.6 ± 2.4 g) were fed with the same experimental diets for 28 days. Dietary ZnONSP improved the immune responses of haemocyte in tested shrimps, including phagocytic rate, phagocytic index, respiratory burst, and phenoloxidase activity, and upregulated the expression of several genes, including lipopolysaccharide, β-1,3-glucan binding protein, peroxinectin, penaeidin 2/3/4, lysozyme, crustin, anti-lipopolysaccharide factor, superoxide dismutase, glutathione peroxidase, clotting protein and α-2-macroglobulin. In the challenge experiment, shrimps (17.2 ± 1.8 g) were fed with ZnONSP containing diets (400 and 800 mg/kg) for 7 days and then infected with Vibrio alginolyticus. Notably, white shrimps that received ZnONSP (800 mg/kg) showed significantly improved Vibrio resistance, with a survival rate of 71.4 % at the end of 7-day observation. In conclusion, this study discovers that ZnONSP is a new type of immunomodulatory supplement that are effective on enhancing innate cellular and humoral immunities, and disease resistance in white shrimp.
Topics: Animals; Immunity, Innate; Dietary Supplements; Diet; Disease Resistance; Penaeidae; Vibrio alginolyticus; Zinc
PubMed: 38070587
DOI: 10.1016/j.fsi.2023.109270 -
International Journal of Molecular... Nov 2023Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood...
Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood disability, affecting adult quality of life. The role of maternal and fetus adaptation during adverse pregnancy is still not completely understood. This study aimed to investigate the disturbance in biological processes associated with isolated IUGR via blood plasma proteomics. The levels of 125 maternal plasma proteins were quantified by liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with corresponding stable isotope-labeled peptide standards (SIS). Thirteen potential markers of IUGR (Gelsolin, Alpha-2-macroglobulin, Apolipoprotein A-IV, Apolipoprotein B-100, Apolipoprotein(a), Adiponectin, Complement C5, Apolipoprotein D, Alpha-1B-glycoprotein, Serum albumin, Fibronectin, Glutathione peroxidase 3, Lipopolysaccharide-binding protein) were found to be inter-connected in a protein-protein network. These proteins are involved in plasma lipoprotein assembly, remodeling, and clearance; lipid metabolism, especially cholesterol and phospholipids; hemostasis, including platelet degranulation; and immune system regulation. Additionally, 18 proteins were specific to a particular type of IUGR (early or late). Distinct patterns in the coagulation and fibrinolysis systems were observed between isolated early- and late-onset IUGR. Our findings highlight the complex interplay of immune and coagulation factors in IUGR and the differences between early- and late-onset IUGR and other placenta-related conditions like PE. Understanding these mechanisms is crucial for developing targeted interventions and improving outcomes for pregnancies affected by IUGR.
Topics: Pregnancy; Adult; Infant, Newborn; Female; Humans; Child; Fetal Growth Retardation; Proteomics; Quality of Life; Fetus; Placenta
PubMed: 38069155
DOI: 10.3390/ijms242316832 -
Veterinary Journal (London, England :... Feb 2024Hyperinsulinemia is the key feature of equine metabolic syndrome (EMS) which leads to debilitating sequelae. Hyperinsulinemia-associated laminitis (HAL) is one of the...
Hyperinsulinemia is the key feature of equine metabolic syndrome (EMS) which leads to debilitating sequelae. Hyperinsulinemia-associated laminitis (HAL) is one of the major sequelae of EMS, although the pathophysiological mechanisms are not well elucidated. Using an equine model, we hypothesized that expression of inflammatory markers would be increased in digital lamellae and striated muscle following prolonged hyperinsulinemia. Healthy Standardbred horses (5.4 ± 1.9 years) were alternately assigned to a prolonged euglycemic-hyperinsulinemic clamp (pEHC) or control group (n = 4 per group). Following a 48 h pEHC or a 48 h infusion of a balanced electrolyte solution (controls), biopsies were collected from digital lamellar tissue, skeletal muscle and cardiac muscle were obtained. All hyperinsulinemic horses developed laminitis regardless of previous health status at enrollment. Protein expression was quantified via Western blotting. A significant (P < 0.05) upregulation of the protein expression of heat shock protein 90 (HSP90), alpha 2 macroglobulin (A2M) and fibrinogen (α, β isoforms), as well as inflammatory cytokines including interleukin-1β were detected in digital lamellae following prolonged hyperinsulinemia. In contrast, protein expression of cytokines and acute phase proteins in heart and skeletal muscle was unchanged following hyperinsulinemia. Upregulation of inflammatory cytokines and acute phase proteins in digital lamellae during prolonged hyperinsulinemia may reveal potential biomarkers and novel therapeutic targets for equine endocrinopathic laminitis. Further, the lack of increase of inflammatory proteins and acute phase proteins in striated muscle following prolonged hyperinsulinemia may highlight potential anti-inflammatory and cardioprotective mechanisms in these insulin-sensitive tissues.
Topics: Horses; Animals; Cytokines; Foot Diseases; Horse Diseases; Hoof and Claw; Hyperinsulinism; Muscle, Skeletal; Metabolic Syndrome; Acute-Phase Proteins; Inflammation
PubMed: 38043699
DOI: 10.1016/j.tvjl.2023.106053