Alpha 1-acid Glycoprotein Levels Research Articles

Serum alpha 1-acid glycoprotein and interleukin-8 elevations in felines with localized and metastatic tumors.

This study aimed to investigate the expression of acute phase proteins and plasma cytokines in cats with various tumor types and varying metastatic statuses. 5 clinically healthy cats and 22 cats with neoplastic disease that underwent CT imaging before treatment were enrolled. Patients were grouped based on their tumor types and metastatic status. Blood samples were collected from all cats for general blood analyses before they underwent CT imaging. The remaining plasma sample was frozen for subsequent alpha 1-acid glycoprotein (AGP), serum amyloid A (SAA), and feline cytokine panel measurements. These results were compared with those of healthy cats as well as between metastatic status and tumor types. Only 4 cats (18%) exhibited elevated SAA levels, whereas 16 (73%) showed elevated AGP levels. AGP was significantly increased in cats with tumors (P = .016), while SAA was not. Only IL-8 showed a significant difference (P = .002) between cats with primary tumors and those with radiologically suspected tumor metastasis. While AGP is a more prominent biomarker than SAA in cats with tumors, a significant elevation of AGP and SAA levels in association with metastasis and specific tumor types could not be identified. Alternatively, further investigation is warranted to evaluate the potential significance of IL-8 in tumor progression and metastasis.

Changes in plasma alpha-1 acid glycoprotein following hemorrhagic trauma: Possible role in dose differences of ALM drug therapy in rat and pig resuscitation.

The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3-times higher for pigs than rats. Since lidocaine strongly binds to serum alpha-1-acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs. Healthy adult male Sprague-Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post-surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post-surgery, and at 60 min and 6 h. Plasma AGP was measured with rat- and pig-specific enzyme-linked immunosorbent assay kits. Baseline AGP levels in rats were 3.91 μg/mL and significantly 83-fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10-fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28-29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM- or Saline-treated pigs over the monitoring period. We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.

Lung Protection After Severe Thermal Burns With Adenosine, Lidocaine, and Magnesium (ALM) Resuscitation and Importance of Shams in a Rat Model.

The management of severe burns remains a complex challenge. Adenosine, lidocaine, and magnesium (ALM) resuscitation therapy has been shown to protect against hemorrhagic shock and traumatic injury. The aim of the present study was to investigate the early protective effects of small-volume ALM fluid resuscitation in a rat model of 30% total body surface area (TBSA) thermal injury. Male Sprague-Dawley rats (320-340 g; n = 25) were randomly assigned to: 1) Sham (surgical instrumentation and saline infusion, without burn, n = 5), 2) Saline resuscitation group (n = 10), or 3) ALM resuscitation group (n = 10). Treatments were initiated 15-min after burn trauma, including 0.7 mL/kg 3% NaCl ± ALM bolus and 0.25-0.5 mL/kg/h 0.9% NaCl ± ALM drip, with animals monitored to 8.25-hr post-burn. Hemodynamics, cardiac function, blood chemistry, hematology, endothelial injury markers and histopathology were assessed. Survival was 100% for Shams and 90% for both ALM and Saline groups. Shams underwent significant physiological, immune and hematological changes over time as a result of surgical traums. ALM significantly reduced malondialdehyde levels in the lungs compared to Saline (P = .023), and showed minimal alveolar destruction and inflammatory cell infiltration (P < .001). ALM also improved cardiac function and oxygen delivery (21%, P = .418 vs Saline), reduced gut injury (P < .001 vs Saline), and increased plasma adiponectin (P < .001 vs baseline). Circulating levels of the acute phase protein alpha 1-acid glycoprotein (AGP) increased 1.6-times (P < .001), which may have impacted ALM's therapeutic efficacy. We conclude that small-volume ALM therapy significantly reduced lung oxidative stress and preserved alveolar integrity following severe burn trauma. Further studies are required to assess higher ALM doses with longer monitoring periods.

Molecular and hematological investigation of Trypanosoma evansi infection in Iranian one-humped camels (Camelus dromedarius).

Trypanosoma species cause animal trypanosomiasis that infects many animals. Trypanosoma evansi is an organism that infects camels. There are many economic problems associated with this disease, including lower milk and meat yields and abortions. The purpose of the current survey was molecular study of the presence of Trypanosoma in dromedary camel blood in the south of Iran, and its effects on the hematologic, and some acute-phase protein changes. Blood samples were aseptically collected from the jugular vein of dromedary camels (n = 100; aged from 1 to 6years) originating from Fars Province in EDTA-coated vacutainers. Genomic DNA from 100 µL of the whole blood was extracted and amplified using a PCR assay based on ITS1, 5.8S, and ITS2 ribosomal regions. Also, the PCR products obtained were sequenced. Moreover, the changes in hematological parameters and serum acute-phase proteins (serum amyloid A, alpha-1 acid glycoprotein, and haptoglobin) were measured. Among 100 tested blood, nine samples (9%, 95% CI: 4.2-16.4%) were found positive by the PCR assay. The phylogenetic tree and blast analysis showed four different genotypes closely related to the strains (accession numbers: JN896754 and JN896755) previously reported from dromedary camels in Yazd Province, center Iran. Based on hematological analysis, normocytic and normochromic anemia and lymphocytosis were detected in the PCR-positive cases compared with the negative group. Furthermore, alpha-1 acid glycoprotein was significantly increased in the positive cases. There was a substantial and positive relation between the number of lymphocytes, and the levels of alpha-1 acid glycoprotein and serum amyloid A in the blood (p = 0.045, r = 0.223 and p = 0.036, r = 0.234, respectively). A noticeable frequency of T. evansi infection was reported in dromedary camels in south Iran. This is the first report on the genetic diversity of T. evansi in this region. There was a significant association among Trypanosoma infection, lymphocytosis, and alpha-1 acid glycoprotein. Trypanosoma-positive camels had a significant decrease in hematocrit (HCT), hemoglobin (Hb), and red blood cell (RBC) values compared to the non-infected group. Further experimental studies are needed to elucidate the hematological and acute-phase protein alteration during a different phase of Trypanosoma spp. infection.

The prognostic capability of inflammatory proteins in predicting peripheral artery disease related adverse events.

Levels of inflammatory proteins and their prognostic potential have been inadequately studied in patients with peripheral artery disease (PAD). In this study, we quantified and assessed the ability of inflammatory proteins in predicting PAD-related adverse events. In this prospective case-control study, blood samples were collected from patients without PAD (n = 202) and patients with PAD (n = 275). The PAD cohort was stratified by disease severity based on ankle brachial index (ABI): mild (n = 49), moderate (n = 164), and severe (n = 62). Patients were followed for 2 years. Plasma concentrations of 5 inflammatory proteins were measured: Alpha-2-Macroglobulin (A2M), Fetuin A, Alpha-1-Acid Glycoprotein (AGP), Serum Amyloid P component (SAP), and Adipsin. The primary outcome of our study was major adverse limb event (MALE), defined as the need for vascular intervention (open or endovascular revascularization) or major amputation. The secondary outcome was worsening PAD status, defined as a drop in ABI greater than or equal to 0.15 over the study period. Multivariable logistic regression was performed to assess the prognostic value of inflammatory proteins in predicting MALE, adjusting for confounding variables. Compared to patients without PAD, three inflammatory proteins were differentially expressed in patients with PAD (AGP, Fetuin A, and SAP). The primary outcome (MALE) and secondary outcome (worsening PAD) status were noted in 69 (25%) and 60 (22%) patients, respectively. PAD-related adverse events occurred more frequently in severe PAD patients. Based on our data, the inflammatory protein AGP was the most reliable predictor of primary and secondary outcomes. On multivariable analysis, there was a significant association between AGP and MALE in all PAD disease states [mild: adjusted HR 1.13 (95% CI 1.05-1.47), moderate: adjusted HR 1.23 (95% CI 1.16-1.73), severe: adjusted HR 1.37 (95% CI 1.25-1.85)]. High levels of AGP were associated with lower 2-year MALE-free survival in all PAD disease states [mild (64% vs. 100%, p = 0.02), moderate (64% vs. 85%, p = 0.02), severe (55% vs. 88%, p = 0.02), all PAD (62% vs. 88%, p = 0.01)]. Levels of inflammatory protein AGP may help in risk stratifying PAD patients at high risk of MALE and worsening PAD status and subsequently facilitate further vascular evaluation and initiation of aggressive medical/surgical management.

Physiological and Proteomic Responses of Dairy Buffalo to Heat Stress Induced by Different Altitudes.

Buffalo are mainly distributed in low-altitude (LA), medium-altitude (MA), and high-altitude (HA) regions characterised by different thermal and oxygen environments in Yunnan province, China. Due to black skin, sparse hair, and the low density of skin sweat glands, buffalo are more sensitive to heat stress. Here, we used data-independent acquisition (DIA) proteomics to reveal a broad spectrum of proteins that play roles in adaptation to the heat stress of buffalo raised at low altitude or hypoxia at high altitude. LA buffalo showed higher body temperatures than MA- and HA buffalo, and HA buffalo had higher levels of GSH and SOD and lower levels of ROS compared to LA and MA buffalo. In 33 samples, 8476 peptides corresponding to 666 high-confidence proteins were detected. The levels of circulating complement proteins in the immune pathways were lower in LA and MA buffalo than in HA buffalo. There were higher levels of alpha-1 acid glycoprotein in LA buffalo than in MA and HA buffalo. Relative to MA buffalo, levels of blood oxygen delivery proteins were higher in LA and HA buffalo. A higher abundance of apolipoproteins was detected in LA and MA buffalo than in HA buffalo. In summary, buffalo adopted similar adaptation strategies to oxidative stress induced by heat stress or hypoxia, including immunological enhancement, high efficiency of blood oxygen delivery, and the inhibition of lipid oxidation.

The Role of Uremic Retention Solutes in the MIA Syndrome in Hemodialysis Subjects

Introduction: In chronic kidney disease (CKD), the high morbidity and mortality risk for cardiovascular disease (CVD) are not easily explained only on the basis of traditional factors. Among nontraditional ones involved in CKD, malnutrition, inflammation, and atherosclerosis/calcification have been described as the “MIA syndrome.” Methods: In this pilot study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in a population of dialysis patients. Results: As expected, we found a direct correlation between serum albumin and both phosphate and total cholesterol (r = 0.54 and 0.37, respectively; p < 0.05). Moreover, total cholesterol and phosphate directly correlate (r = 0.40, p < 0.05). The relationship between malnutrition and inflammation is highlighted by the correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = −0.56, r = −0.39, respectively; p < 0.05). Moreover, the relation between inflammation and atherosclerosis/calcification is supported by the correlation of IL-6 with VEGF levels and vascular smooth muscle cell high-Pi in vitro calcification (r = 0.81, r = 0.66, respectively; p < 0.01). Conclusion: We found significant correlations between several uremic retention solutes and malnutrition, inflammation, and atherosclerosis/calcification. Our findings support the hypothesis of a central role of the uremic milieu in the MIA syndrome and ultimately in the pathogenesis of CKD-specific CVD risk factors.

MO736: The Role of Uremic Retention Solutes in the MIA Syndrome in Haemodialysis Subjects

Abstract BACKGROUND AND AIMS In end-stage renal disease (ESRD), the high morbidity and mortality risk for cardiovascular disease (CVD) is not easily explained only on the basis of traditional factors. Among non-traditional ones, malnutrition, inflammation and atherosclerosis/calcification have been described as the ‘MIA syndrome’. METHOD In this study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in dialysis patients. Uremic retention solute levels were detected by the ELISA or using an ultra-performance liquid chromatography—tandem mass spectrometry method. The pro-calcifying, pro-apoptotic and pro-necrotic effects of uremic serum were evaluated in an in vitro model of high-Pi induced calcification in vascular smooth muscle cells (VSMC). RESULTS As expected, we found reciprocal correlations between serum albumin, total cholesterol and phosphate, linking a better nutritional status with higher phosphate levels (r = 0.37, r = 0.40, r = 0.54, respectively; P &amp;lt; 0.05). The relationship between malnutrition and inflammation is highlighted by the negative correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = –0.56, r = –0.39, respectively; P &amp;lt; 0.05). These results suggest that the increase in inflammatory mediators is probably higher in malnourished patients, and a better nutritional state seems to correlate with lower inflammatory marker levels. Moreover, we found a significant direct correlation between alpha-1 acid glycoprotein and IL-6 with a correlation coefficient of 0.54 and P &amp;lt; 0.01, indicating that both these uremic toxins might participate in the maintenance of the inflammation. The relation between inflammation and atherosclerosis/calcification is supported by the correlations between IL-6 variations that significantly correlate with both PTX3 and VEGF (r = 0.36 and r = 0.81; P &amp;lt; 0.05) and with VSMC in vitro high-Pi induced calcification (r = 0.66; P &amp;lt; 0.01). Thus, IL-6, a regulator of acute phase protein synthesis, seems to be related to CVD markers (PTX3 and VEGF) and in vitro calcification, two robust indexes of increased cardiovascular risk. In addition, the Kyn/Try ratio directly correlates with serum FGF23 levels with a correlation coefficient r of 0.60 and P &amp;lt; 0.01. Regarding atherosclerosis/calcification, we found that PTX3, TMAO, IS, myoglobin and FGF23 correlate with each other in several combinations, reflecting the elevated cardiovascular risk present in ESRD. PTX3 shows a trend towards a direct correlation with TMAO (r = 0.37 and P &amp;lt; 0.05), and IS shows a trend towards a direct correlation both with TMAO, FGF23 and myoglobin (r = 0.46, r = 0.45 and r = 0.42; P &amp;lt; 0.05). Moreover, IS and TMAO correlate also with two processes strictly related to VSMC calcification, such as apoptosis and necrosis (IS: apoptosis r = 0.69 and necrosis r = 0.47; P &amp;lt; 0.05; TMAO: apoptosis r = 0.42 and necrosis r = 0.40 with P &amp;lt; 0.05). Finally, VEGF shows a robust correlation with in vitro calcification (r = 0.74; P &amp;lt; 0.01). CONCLUSION Among all the correlations found between uremic toxin variations in dialysis patients, IL-6 seems to have a central role correlating with malnutrition and several CV markers together with vascular calcification (VC). This might be explained by the characteristics of IL-6 being contemporary an inflammatory and a CVD marker in ESRD. On the other hand, IS has a potential role in VC, suggesting a central role of the uremic milieu in MIA syndrome development. Therefore, there is an urgent need to find a more efficient dialysis treatment to improve the clearance of uremic retention solutes in order to try to ameliorate CV outcomes in ESRD patients.

Alpha-1 Acid Glycoprotein Reduction Differentiated Recovery from Remission in a Small Cohort of Cats Treated for Feline Infectious Peritonitis.

Feline infectious peritonitis (FIP) is a systemic immune-mediated inflammatory perivasculitis that occurs in a minority of cats infected with feline coronavirus (FCoV). Various therapies have been employed to treat this condition, which was previously usually fatal, though no parameters for differentiating FIP recovery from remission have been defined to enable clinicians to decide when it is safe to discontinue treatment. This retrospective observational study shows that a consistent reduction of the acute phase protein alpha-1 acid glycoprotein (AGP) to within normal limits (WNL, i.e., 500 μg/mL or below), as opposed to duration of survival, distinguishes recovery from remission. Forty-two cats were diagnosed with FIP: 75% (12/16) of effusive and 54% (14/26) of non-effusive FIP cases recovered. Presenting with the effusive or non-effusive form did not affect whether or not a cat fully recovered (p = 0.2). AGP consistently reduced to WNL in 26 recovered cats but remained elevated in 16 cats in remission, dipping to normal once in two of the latter. Anaemia was present in 77% (23/30) of the cats and resolved more quickly than AGP in six recovered cats. The presence of anaemia did not affect the cat’s chances of recovery (p = 0.1). Lymphopenia was observed in 43% (16/37) of the cats and reversed in nine recovered cats but did not reverse in seven lymphopenic cats in the remission group. Fewer recovered cats (9/24: 37%) than remission cats (7/13: 54%) were lymphopenic, but the difference was not statistically different (p = 0.5). Hyperglobulinaemia was slower than AGP to return to WNL in the recovered cats. FCoV antibody titre was high in all 42 cats at the outset. It decreased significantly in 7 recovered cats but too slowly to be a useful parameter to determine discontinuation of antiviral treatments. Conclusion: a sustained return to normal levels of AGP was the most rapid and consistent indicator for differentiating recovery from remission following treatment for FIP. This study provides a useful model for differentiating recovery from chronic coronavirus disease using acute phase protein monitoring.

The modulatory effect of carvacrol on viral shedding titer and acute phase response in broiler chickens experimentally infected with infectious bronchitis virus

Infectious bronchitis virus (IBV) is one of the major respiratory diseases of broiler causing huge economic losses. The inability to control IBV using different vaccination programs owing to the high mutation rate and recombination ability of the RNA genome generates IBV variants. This study was designed to give a specific perspective of carvacrol effect on early immune response, viral shedding titer, oxidative stress, serum biochemical parameters and clinical consequences in broilers experimentally infected by IBV. One hundred and twenty-one-day old commercial broiler chicks were equally divided into 4 groups. First group was considered as control. Second group was given carvacrol, third group was infected with IBV and fourth group was given carvacrol and infected with IBV. Infection with variant IBV induced significant upregulation of chicken interferon-inducible transmembrane protein 3 (chIFITM3) gene in trachea, elevations in serum levels of Alpha-1 acid glycoprotein (α1-AGP) and Interleukin 6 (IL-6), total leucocytic count (TLC), heterophil/lymphocyte (H/L) ratio and oxidative stress in lung and kidney tissues. Beside, histopathological changes in trachea, lung and kidney induced by IBV, elevation of kidney function tests was detected. The pretreatment with carvacrol significantly reduced viral shedding titer, chIFITM3 gene expression, IL-6 and α1-AGP levels, leucocytic response and H/L ratio with minimization of clinical signs intensity. Also, carvacrol relieved oxidative stress, ameliorated the increased uric acid level and histopathological alterations in kidney and lung caused by viral infection.

Association of plasma low-density lipoprotein receptor-related protein-1 (LRP1) with undernutrition: a case-control study in Bangladeshi adults

Purpose Studies revealed that silencing of low-density lipoprotein receptor-related protein-1 (LRP1) expression can cause inhibition of adipogenesis in animal model and contribute to reduced body size. But there is no study that has explored the association of LRP1 with body mass index (BMI) of human adults. Therefore, the aim of this study was to investigate the relationship of LRP1 with undernutrition. Methods A total of 270 Bangladeshi slum-dwelling adults were enrolled as case control design. Their socio-economic, demographic, anthropometric and biomedical data were collected. Plasma LRP1, C-reactive protein (CRP), alpha-1 acid glycoprotein (AGP) and ferritin levels were measured by ELISA, haemoglobin by HemoCue and zinc by atomic absorption spectrometry. Results The median (IQR) values of plasma LRP1 were 1673.1 (1382.5–1886.2) ng/mL in healthy participants and 707.7 (588.6–839.9) ng/mL in undernourished participants, respectively. A strong positive correlation (r = 0.70, p < 0.05) between LRP1 and BMI was found. Multivariable logistic regression analysis revealed a positive association between low plasma LRP1 (Adj. OR = 0.98, CI = 0.98, 0.99 and p < 0.05) and undernutrition. Conclusions The study found that increased level of LRP1 is associated with increased BMI, whereas lower level is associated with low BMI.

Comparison of biochemical and immunological biomarker levels of patients with COVID-19 with healthy individuals

Abstract Objectives It was aimed to compare Alpha-1 antitrypsin (AAT), Alpha-1 acid glycoprotein (AGP), Total Immunoglobulin M (Total IgM), Total Immunoglobulin G (Total IgG), Galectin-3 (Gal3), and severe acute respiratory syndrome coronavirus 2 IgG (SARS-CoV-2 IgG) levels in patients with COVID-19 and healthy individuals. Methods The study included a total of 86 participants, 44 patients diagnosed with COVID-19 by real-time reverse transcription-polymerase chain reaction (rRT-PCR) test and 42 as the control group. AAT, AGP, Total IgM, and Total IgG levels were measured using the immunoturbidimetric method. Gal3 and SARS-CoV-2 IgG levels were measured using the chemiluminescent microparticle immunoassay method. Results AAT, AGP, Total IgG, Gal3, and SARS-CoV-2 IgG levels were found to be significantly higher in the patient group compared to the control group (p&lt;0.001 for all tests). In the patient group, there was a moderate correlation between AAT-AGP and SARS-CoV-2 IgG-AAT (r=0.692; r=0.561, respectively). Conclusions High levels of AAT, AGP, Total IgG, Gal3, and SARS-CoV-2 IgG in the patient group and correlations between variables suggest that these parameters may be involved in the pathogenesis of the disease and provide an idea about the prognosis of the disease. However, new studies on this subject are needed in order to clearly reveal the laboratory tests related to the clinical course of the disease.

The connection of alpha-1 acid glycoprotein inflammatory marker with anthropometric, hormonal, and metabolic characteristic of women with polycystic ovary syndrome.

To investigate the connection of alpha-1 acid glycoprotein inflammatory biomarker with clinical, hormonal, and metabolic characteristics in women with polycystic ovary syndrome (PCOS) and normal cycling controls. A cross-sectional study was conducted on 235 women with PCOS and 92 normal cycling controls attended between 2008 and 2018. Alpha-1 acid glycoprotein levels were correlated with clinical, anthropometric, anthropometric-metabolic indexes, and hormones of women with PCOS and controls. Simple and multivariate stepwise linear regression, matched for age and body mass index confounding variables, was performed. Alpha-1 acid glycoprotein levels were higher in women with PCOS (p=0.0016). In controls, it was positively correlated with waist circumference, fat mass, body adiposity index, and lipid accumulation product, and negatively correlated with sex hormone-binding globulin (p < 0.005 for all comparisons). In PCOS, it was positively correlated with testosterone, most biomarkers of central adiposity, homeostatic model assessment of insulin-resistant, erythrocyte sedimentation rate, and negatively correlated with sex hormone-binding globulin, high-density lipoprotein cholesterol, glucose/insulin ratio, and lymphocytes (p < 0.055 for all comparisons). After multivariate regression in women with PCOS, alpha-1 acid glycoprotein retained a significant positive correlation with erythrocyte sedimentation rate and C-reactive protein. In PCOS, alpha-1 acid glycoprotein is correlated with biomarkers of adiposity, carbohydrate metabolism, and total testosterone. This inflammatory marker is also correlated with erythrocyte sedimentation rate, neutrophils, and lymphocytes, frequent markers of an inflammation state.

Impact of HIV status on systemic inflammation during pregnancy.

There are limited studies on the association of HIV infection with systemic inflammation during pregnancy. A cohort study (N = 220) of pregnant women with HIV (N = 70) (all on antiretroviral therapy) and without HIV (N = 150) were enrolled from an antenatal clinic in Pune, India. The following systemic inflammatory markers were measured in plasma samples using immunoassays: soluble CD163 (sCD163), soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), interferon-β (IFNβ), interferon-γ (IFNγ), interleukin (IL)-1β, IL-6, IL-13, IL-17A, and tumor necrosis factor α (TNFα). Generalized estimating equation (GEE) and linear regression models were used to assess the association of HIV status with each inflammatory marker during pregnancy and by trimester, respectively. Pregnant women with HIV had higher levels of markers for gut barrier dysfunction (I-FABP), monocyte activation (sCD14) and markers of systemic inflammation (IL-6 and TNFα), but surprisingly lower levels of AGP, an acute phase protein, compared with pregnant women without HIV, with some trimester-specific differences. Our data show that women with HIV had higher levels of markers of gut barrier dysfunction, monocyte activation and systemic inflammation. These markers, some of which are associated with preterm birth, might help explain the increase in adverse birth outcomes in women with HIV and could suggest targets for potential interventions.

ABCG2 Single Nucleotide Polymorphism Affects Imatinib Pharmacokinetics in Lower Alpha-1-Acid Glycoprotein Levels in Humans.

Imatinib is transported extracellularly by ABCB1 and ABCG2 efflux transporters and bound to alpha-1-acid glycoprotein (AGP) in the bloodstream. However, the clinical and pharmacokinetic effects of ABCB1 and ABCG2 on imatinib were inconsistent in the previous literature and have not been confirmed. Therefore, in the present study, we explored the effects of the ABCG2 and ABCB1 genetic polymorphisms on imatinib pharmacokinetics in association with plasma AGP levels in healthy subjects. Twenty-seven healthy individuals were recruited, genotyped for ABCG2 and ABCB1, and given a single oral dose of 400 mg imatinib. Plasma imatinib concentrations were measured and its pharmacokinetics was assessed with respect to ABCG2 (c.421C>A and c.34G>A) and ABCB1 (c.1236C>T, c.2677C>T/A, and c.3435C>T) genotypes, and plasma AGP levels. AGP levels showed a strong positive correlation with imatinib pharmacokinetics. ABCG2 c.421C>A single nucleotide polymorphism showed a statistically significant effect on imatinib pharmacokinetics in low plasma AGP levels groups (<80 mg/dl); subjects with high plasma AGP levels (n = 5, ≥80 mg/dl) were excluded. The results indicate that plasma AGP levels and ABCG2 polymorphisms modulated imatinib pharmacokinetics; however, the effects of the ABCG2 transporter was masked at high plasma AGP levels.

Alpha-1 Acid Glycoprotein as a Biomarker for Subclinical Illness and Altered Drug Binding in Rats.

Alpha-1 acid glycoprotein (AGP) is a significant drug binding acute phase protein that is present in rats. AGP levels are known to increase during tissue injury, cancer and infection. Accordingly, when determining effective drug ranges and toxicity limits, consideration of drug binding to AGP is essential. However, AGP levels have not been well established during subclinical infections. The goal of this study was to establish a subclinical infection model in rats using AGP as a biomarker. This information could enhance health surveillance, aid in outlier identification, and provide more informed characterization of drug candidates. An initial study (n = 57) was conducted to evaluate AGP in response to various concentrations of Staphylococcus aureus (S. aureus) in Sprague-Dawley rats with or without implants of catheter material. A model validation study (n = 16) was then conducted using propranolol. Rats received vehicle control or S. aureus and when indicated, received oral propranolol (10 mg/kg). Health assessment and blood collection for measurement of plasma AGP or propranolol were performed over time (days). A dose response study showed that plasma AGP was elevated on day 2 in rats inoculated with S. aureus at 106, 107 or, 108 CFU regardless of implant status. Furthermore, AGP levels remained elevated on day 4 in rats inoculated with 107 or 108 CFUs of S. aureus. In contrast, significant increases in AGP were not detected in rats treated with vehicle or 10³ CFU S. aureus. In the validation study, robust elevations in plasma AGP were detected on days 2 and 4 in S. aureus infected rats with or without propranolol. The AUC levels for propranolol on days 2 and 4 were 493 ± 44 h × ng/mL and 334 ± 54 h × ng/mL, respectively), whereas in noninfected rats that received only propranolol, levels were 38 ± 11 h × ng/mL and 76 ± 16. h × ng/mL, respectively. The high correlation between plasma propranolol and AGP demonstrated a direct impact of AGP on drug pharmacokinetics and pharmacodynamics. The results indicate that AGP is a reliable biomarker in this model of subclinical infection and should be considered for accurate data interpretation.

Hepcidin and other indicators of iron status, by alpha-1 acid glycoprotein levels, in a cohort of Mexican infants.

The purpose of this study was to describe the changes in iron status indicators at 6 and 12months of age, controlling by inflammation by measuring alpha-1 acid glycoprotein (AGP). This longitudinal study included 48 healthy-term singleton infants with birth weight ≥ 2500g, born in hospitals of the Mexican Institute for Social Security. Complete blood count, ferritin, soluble transferrin receptor (sTfR), hepcidin, and AGP were measured in blood at 6 and 12months of age. sTfR/ferritin ratio and total body iron (TBI) stores were calculated. Hemoglobin and sTfR/ferritin ratio increased with age, while ferritin and TBI decreased. In infants without inflammation, hepcidin, sTfR, and MVC did not show significant changes from 6 to 12months of age, while ferritin and TBI decreased. In infants with inflammation, hepcidin, TBI, and ferritin levels increased, while hemoglobin and sTfR/ferritin ratio decreased. MVC and sTfR did not change significantly in the presence or absence of inflammation. Hepcidin concentration correlated positively and significantly with ferritin and TBI stores and showed significant negative correlation with sTfR/ferritin ratio. Our study showed that, in absence of inflammation and ID, during the first year of life, physiological changes occur in hemoglobin and ferritin levels as well as in indicators derived from ferritin and sTfR; in contrast, hepcidin and sTfR did not show significant change. However, hepcidin concentration was lower in infants with ID and was higher when inflammation was present, supporting that infants have a functional hepcidin response to changes in iron stores.

A pilot study to evaluate the serum Alpha-1 acid glycoprotein response in cats suffering from feline chronic gingivostomatitis

BackgroundFeline chronic gingivostomatitis (FCGS) is a multifactorial immune-mediated disease that can lead to chronic pain, anorexia, and weight loss and has substantial health and welfare effects. Currently, the recommended treatment includes dental extractions to decrease the inflammatory stimulation associated with dental plaque. However, complete remission is observed in less than half of the cases, and the majority need comprehensive medical management. This study aimed to evaluate the serum levels of the acute phase protein alpha-1 acid glycoprotein (AGP) in cats with FCGS and to examine whether dental extractions contribute to a significant decrease in the systemic inflammatory response at two postoperative time points.ResultsAGP serum concentrations in the cats with FCGS were significantly higher at all time points than that in the control groups and were significantly correlated with the global caudal stomatitis score at day 0 but not at day 30 or 60. A significant improvement of some clinical scores, such as perceived comfort and global caudal stomatitis, was observed 60 days after the dental extraction. However, the levels of AGP did not significantly change over time.ConclusionsCats with FCGS were more likely to have a systemic inflammatory response compared with age- and dental disease-matched controls. Dental extractions, in most cases, did not contribute to a significant decrease of AGP both at 30 and 60 days. Therefore, this study reinforces the need to pursue comprehensive medical management after dental extractions to attenuate the systemic inflammatory response as a result of this disease.

FengLiao affects gut microbiota and the expression levels of Na+/H+ exchangers, aquaporins and acute phase proteinsin mice with castor oil-induced diarrhea.

The severe side effects of chemosynthetic anti-diarrhea drugs have created an interest in low-toxic alternative plant-derived compounds. FengLiao consists of Polygonum hydropiper Linn. and Daphniphyllum calycinum Bench., and is widely used in China to treat diarrhea due to low levels of toxicity. In this study, the effects of FengLiao were analyzed in a castor oil-induced diarrhea model, using the anti-diarrhea drug, loperamide, as the positive control. The effects were evaluated using stool characteristics and the expression levels of various diarrhea-related factors in the jejunum and liver, as well as changes in the microbiota of the jejunum. The symptoms of diarrhea and stool consistency were improved through FengLiao and loperamide treatment. Furthermore, FengLiao down-regulated alpha 1-acid glycoprotein (AGP) and C-reactive protein (CRP) levels, and up-regulated transferrin (TRF) mRNA levels in the liver, and down-regulated Aquaporin 3 (AQP3) and Na+/H+ exchanger isoform 8 (NHE8) expression in the epithelial cells of the jejunum. It also increased the relative abundance of Bifidobacterium, Aerococcus, Corynebacterium_1 and Pseudomonas, and lowered the Firmicutes/Bacteroidetes (F/B) ratio, which maintained the balance between immunity and intestinal health. Taken together, FengLiao alleviated castor oil-induced diarrhea by altering gut microbiota, and levels of jejunum epithelial transport proteins and acute phase proteins.

Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations.

Background and objectivesProtease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naïve patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations.MethodsSparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated.ResultsOur model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure were CYP3A5*3 and SLCO3A1 rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC50 in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients.ConclusionsThese results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT03101644, date of registration: 5 April, 2017.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00920-z) contains supplementary material, which is available to authorized users.