Serum stromal cell-derived factor-1 concentrations are increased and associated with nonalcoholic fatty liver disease in children with obesity.

INTRODUCTION: Stromal cell-derived factor-1 (SDF-1) is a newly discovered small molecule adipocytokine, and research has shown that it is closely related to the occurrence and development of obesity. However, there are currently few research reports on SDF-1 in childhood obesity and nonalcoholic fatty liver disease (NAFLD), and this study aims to explore the relationship between SDF-1 and obesity related indicators in obese children. METHODS: Serum SDF-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and biochemical data were collected, such as body mass index (BMI), waist and hip circumference, blood pressure, liver enzymes, cholesterol, and fasting insulin. Children with NAFLD or not were evaluated through Color Doppler Ultrasound. RESULTS: Serum SDF-1 concentrations were significantly higher in obese subjects than in non-obese subjects (P < 0.05), and were elevated in the NAFLD obese subjects than in the non-NAFLD obese subjects (P < 0.05). SDF-1 was positively correlated with BMI, waist-to-hip ratio, systolic blood pressure, body fat percentage (BFP), basal metabolic rate (BMR), alanine transaminase (ALT), aspartate transaminase (AST), glutyltranspeptidase (GT), and homoeostasis model of HOMA-IR, independent of their uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), gender and age. BFP and BMR were associated with the serum SDF-1 concentrations in multivariable linear regression analysis. CONCLUSION: These results suggest that SDF-1 levels are elevated in obese children and are associated with NAFLD, indicating that SDF-1 may play a role in the development of childhood obesity and metabolic disorders.

CXCL12 and CXCL13 Cytokine Serum Levels Are Associated with the Magnitude and the Quality of SARS-CoV-2 Humoral Responses.

A better understanding of the immunological markers associated with long-lasting immune responses to SARS-CoV-2 infection is of paramount importance. In the present study, we characterized SARS-CoV-2-specific humoral responses in hospitalized (ICU and non-ICU) and non-hospitalized individuals at six months post-onset of symptoms (POS) (N = 95). We showed that the proportion of individuals with detectable anti-SARS-CoV-2 IgG or neutralizing (NAb) responses and the titers of antibodies were significantly reduced in non-hospitalized individuals, compared to ICU- or non-ICU-hospitalized individuals at 6 months POS. Interestingly, SARS-CoV-2-specific memory B cells persist at 6 months POS in both ICU and non-ICU patients and were enriched in cells harboring an activated and/or exhausted phenotype. The frequency/phenotype of SARS-CoV-2-specific memory B cells and the magnitude of IgG or NAb responses at 6 months POS correlated with the serum immune signature detected at patient admission. In particular, the serum levels of CXCL13, IL-1RA, and G-CSF directly correlated with the frequency of Spike-specific B cells and the magnitude of Spike-specific IgG or NAb, while the serum levels of CXCL12 showed an antagonizing effect. Our results indicate that the balance between CXCL12 and CXCL13 is an early marker associated with the magnitude and the quality of the SARS-CoV-2 humoral memory.

Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice.

OBJECTIVE: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe-/- (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe-/- background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1-derived peritoneal macrophages. CONCLUSIONS: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.

A combination of circulating microRNA-375-3p and chemokines CCL11, CXCL12, and G-CSF differentiate Crohn's disease and intestinal tuberculosis.

Differentiation of Crohn's disease (CD) from intestinal tuberculosis (ITB) is a big challenge to gastroenterologists because of their indistinguishable features and insensitive diagnostic tools. A non-invasive biomarker is urgently required to distinguish ITB/CD patients particularly in India, a TB endemic region, where CD frequency is increasing rapidly due to urbanization. Among the three differentially expressed miRNAs obtained from small RNA transcriptomic profiling of ileocaecal/terminal ileal tissue of ITB/CD patients (n = 3), only two down-regulated miRNAs, miR-31-5p, and miR-215-5p showed comparable data in qRT-PCR. Out of which, only miR-215-5p was detectable in the patient's plasma, but there was no significant difference in expression between ITB/CD. On the other hand, miR-375-3p, the pulmonary TB specific marker was found in higher amount in the plasma of ITB patients than CD while reverse expression was observed in the ileocaecal/terminal ileal tissues of the same patients. Next, using Bioplex pro-human cytokine 48-plex screening panel, only three chemokines, Eotaxin-1/CCL11, SDF-1α/CXCL12, and G-CSF have noted significantly different levels in the serum of ITB/CD patients. ROC analysis has revealed that compared to a single molecule, a combination of miR-375-3p + Eotaxin-1/CCL11 + SDF-1α /CXCL12 + G-CSF showed a better AUC of 0.83, 95% CI (0.69-0.96) with 100% specificity and positive predictive value while sensitivity, negative predictive value, and accuracy were 56%, 69%, and 78% respectively in distinguishing ITB from CD. This study suggests that a combination of plasma markers shows better potential in differentiating ITB from CD than a single marker and this panel of markers may be used for clinical management of ITB/CD patients.

CXCL1, CXCL10 and CXCL12 Chemokines are Variously Expressed in Acute Myeloid Leukemia Patients Prior and Post Bone Marrow Transplantation.

AIM: The chemokine-receptor axes play parts in development of leukemia, CXCL1, CXCL10 and CXCL12 are involved in immune responses. Thus, we have examined the serum levels of these chemokines in parallel with their related cognate receptors (CXCR1, CXCR3 and CXCR4) in AML (acute myeloid leukemia) patients prior and post BMT (bone marrow transplantation) therapy. MAIN METHODS: Clinical specimens were collected from 46 AML patients (23 M1 and 23 M3 subtypes) before/after BMT. CXCL1, CXCL10 and CXCL12 concentrations were determined by ELISA. The mRNA levels of the related receptors were detected by QRT_PCR. Data were analyzed by T-test, χ2 and ANOVA statistical methods in SPSS software version 18. A difference was regarded significant if P value < 0.05. KEY FINDINGS: Our results indicated that the elevated levels of CXCL12 in AML patients were remained unchanged after transplantation.  The CXCL10 concentration was decreased in patients. All studied chemokines were elevated in BMT patients with history of 9 times PLT transfusion. In patients who received BMT from siblings CXCL1 and CXCL10 have been elevated, whereby they were compared to patients who received BMT from parents while CXCL12 sustained unchanged in groups. Serum measures of CXCL1 and CXCL10 were induced in acute and chronic GVHD patients in compare to these without GVHD. SIGNIFICANCE: According to the results, it can be concluded that these chemokines play fundamental parts in pathogenesis of both AML and BMT. It is worthy to note that chemokines could be used as diagnostic markers alongside with possible promising therapeutic targets.

Frequency of CCR5-Δ32, CCR2-64I and SDF1-3'A alleles in HIV-infected and uninfected patients in Istanbul, Turkey.

INTRODUCTION: Co-receptors involved in cell entry of the human immunodeficiency virus (HIV) and mutations in genes encoding their ligands may play a role in the susceptibility to infection and resistance to the progression of the infection. The best studied mutations that can exist in these genes are the CCR5-Δ32, CCR2-64I and SDF1-3'A mutations. The frequency of these mutations vary from continent to continent and even from region to region. However, there is limited information on their distribution throughout the Turkish population. Istanbul is the city with the highest number of documented HIV-infected patients in Turkey, which can be attributed to the population size. The aim of this study was to determine the distribution of three AIDS-related gene variants among HIV-infected and uninfected population in Istanbul, Turkey and to estimate the contribution of these variants to susceptibility or resistance to HIV. METHODOLOGY: A total of 242 healthy individuals and 200 HIV-positive patients were included in the study. CCR5 polymorphisms were genotyped by polymerase chain reaction. CCR2 and SDF1 polymorphisms were genotyped using PCR restriction fragment length polymorphism (PCR-RFLP). RESULTS: The allelic frequencies for CCR5-Δ32, CCR2-64I and SDF1-3'A were 4.07%, 19.8% and 28.7%, respectively. No individual was found to carry the homozygous CCR5-Δ32 mutation in either cohort. No polymorphism was found to be significantly elevated in the HIV-infected cohort compared to the healthy group. CONCLUSIONS: The distribution of CCR5-Δ32, CCR2-64I, and SDF1-3'A variants does not differ between HIV-infected and uninfected patients. CCR2-64I and SDF1-3'A frequencies are relatively high where as the frequency of CCR5-Δ32 is low.

Inflammatory markers in acute myocardial infarction and the correlation with the severity of coronary heart disease.

INTRODUCTION: The inflammatory hypothesis of atherosclerosis is appealing in acute coronary syndromes, but the dynamics and precise role are not established. OBJECTIVES: The study investigates the levels of C reactive protein (CRP), interleukin 1ß (IL-1ß) and stromal-derived factor 1α (SDF-1α) at the time of acute myocardial infarction (AMI) and at 1 and 6 months afterwards, compared with a control group. RESULTS: In the acute phase of AMI, CRP and SDF-1α were significantly higher, while IL-1ß showed lower levels compared with controls. CRP positively correlated with coronary stenosis severity (rho = 0.3, p=.05) and negatively related with left ventricle ejection fraction (LVEF) at 1 month (rho= -0.43, p=.05). IL-1ß weakly correlated with the severity of coronary lesions (rho =0.29, p=.02) and strongly with LVEF (rho= -0.8, p=.05). SDF-1α, slightly correlated with LVEF at 1 month (rho = 0.22, p=.01) and with the severity of coronary atherosclerosis (rho= -0.41, p=.003). CONCLUSIONS: CRP, IL-1ß and SDF-1α have important dynamic in the first 6 months after AMI and CRP and SDF-1α levels correlated with the severity of coronary lesions and LVEF at 1 month after the acute ischaemic event.

The role of BAFF and G-CSF for rituximab-induced late-onset neutropenia (LON) in lymphomas.

Mechanisms for late-onset neutropenia (LON) after rituximab treatment are poorly defined both for non-Hodgkin lymphoma (NHL) and for autoimmune disorders. We performed a case-control analysis of a prospective cohort of 169 evaluable consecutive rituximab-treated NHL patients to assess cytokines involved in neutro- and lymphopoiesis (G-CSF, SDF1, BAFF, APRIL) and inflammation (CRP) as possible LON mechanisms. Fifteen patients (9%) developed LON (peripheral blood /PB/ absolute neutrophil counts /ANC/ < 0.5 G/L, all with marked depletion of CD20+ B-lymphocytes in bone marrows); they were compared with 20 matched NHL controls without LON. At start of LON, significantly higher PB G-CSF and BAFF levels (P = 0.0004 and 0.006, respectively), as well as CRP rises were noted compared to controls; these G-CSF and BAFF and most CRP values returned to levels of the controls in post-LON samples. G-CSF (but not BAFF) changes correlated to CRP rises (but not to ANC levels). BAFF levels correlated significantly to absolute monocyte counts and PB large granular lymphocyte counts (but not to ANC, C-CSF or CRP values). No changes of SDF1 or APRIL levels were noted. Neither LON cases nor controls displayed anti-neutrophil autoantibodies. Collectively, LON in NHL patients was timewise related to transient bursts of blood G-CSF and BAFF concentrations, suggesting that these neutro- and lymphopoiesis growth factors play a role in emergence of rituximab-induced LON, and that inflammation may be a trigger for G-CSF production during LON.

Serum stromal cell-derived factor-1 levels are associated with diabetic kidney disease in type 2 diabetic patients.

The present study was designed to explore whether serum stromal cell-derived factor-1 (SDF-1) levels were associated with diabetic kidney disease (DKD). Serum SDF-1 levels were measured by sandwich ELISA. Patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g for 3 months were identified as having DKD. Among the recruited type 2 diabetic patients, 18.71% (n = 32) were found to have DKD, and the serum SDF-1 levels of these patients were higher than those of patients without DKD (p < 0.05). Serum SDF-1 levels were positively correlated with cystatin C levels, the UACR and DKD incidence (r = 0.330, 0.183 and 0.186, respectively, p < 0.05) and inversely related to eGFR (r = -0.368, p < 0.001). After adjusting for other clinical covariates by multivariate logistic regression analyses, serum SDF-1 levels were found to be an independent contributor to DKD, and the odds ratio (95% confidence interval) was 1.438 (1.041-1.986). Furthermore, receiver operating characteristic analysis revealed that the optimal SDF-1 cutoff value for indicating DKD was 5.609 ng/mL (its corresponding sensitivity was 82.00%, and specificity was 46.90%). Our results demonstrated that serum SDF-1 levels were closely associated with DKD and could be considered a potent indicator for DKD in patients with T2D.

The increased intrathecal expression of the monocyte-attracting chemokines CCL7 and CXCL12 in tick-borne encephalitis.

Tick-borne encephalitis (TBE) is a relatively severe and clinically variable central nervous system (CNS) disease with a significant contribution of a secondary immunopathology. Monocytes/macrophages play an important role in the CNS inflammation, but their pathogenetic role and migration mechanisms in flavivirus encephalitis in humans are not well known. We have retrospectively analyzed blood and cerebrospinal fluid (CSF) monocyte counts in 240 patients with TBE presenting as meningitis (n = 110), meningoencephalitis (n = 114), or meningoencephalomyelitis (n = 16), searching for associations with other laboratory parameters, clinical presentation, and severity. We have measured concentrations of selected monocytes-attracting chemokines (CCL7, CXCL12, CCL20) in serum and CSF of the prospectively recruited patients with TBE (n = 15), with non-TBE aseptic meningitis (n = 6) and in non-infected controls (n = 8). The data were analyzed with non-parametric tests, p < 0.05 considered significant. Monocyte CSF count correlated with other CSF inflammatory parameters, but not with the peripheral monocytosis, consistent with an active recruitment into CNS. The monocyte count did not correlate with a clinical presentation. The median CSF concentration of CCL7 and CXCL12 was increased in TBE, and that of CCL7 was higher in TBE than in non-TBE meningitis. The comparison of serum and CSF concentrations pointed to the intrathecal synthesis of CCL7 and CXCL12, but with no evident concentration gradients toward CSF. In conclusion, the monocytes are recruited into the intrathecal compartment in concert with other leukocyte populations in TBE. CCL7 and CXCL12 have been found upregulated intrathecally but are not likely to be the main monocyte chemoattractants.

Peripheral Blood Biomarkers CXCL12 and TNFRSF13C Associate with Cerebrospinal Fluid Biomarkers and Infiltrating Immune Cells in Alzheimer Disease.

Neuroinflammation-induced neurodegeneration and immune cell infiltration are two features of Alzheimer disease (AD). This study aimed to identify potential peripheral biomarkers that interact with cerebrospinal fluid (CSF) and infiltrating immune cells in AD. Blood and CSF data were downloaded from the Alzheimer's disease Neuroimaging Initiative database. We identified differentially expressed genes (DEGs) in AD and assessed infiltrating immune cells using the Immune Cell Abundance Identifier (ImmuCellAI) algorithm. Blood-brain barrier (BBB) and immune-related genes were identified from medical databases, and common genes were used to construct a protein-protein interaction network (PPI). Potential biomarkers reflecting the clinical features of AD were screened using Pearson correlations and logistic regression analysis. We identified 210 DEGs in the AD group. ImmuCellAI indicated that blood samples from patients with AD had a higher abundance of exhausted T (Tex; 0.196 vs. 0.132) and induced regulatory T (iTreg; 0.180 vs. 0.137) cells than controls. Thirty-two genes overlapped between the BBB and immune-related genes, and 27 genes in the PPI network were associated with eight pathways, including the cytokine-cytokine receptor interaction pathway (hsa04060) and the chemokine signaling pathway (hsa04062). Pearson correlations showed that five genes were associated with the CSF biomarkers, Aß, total, and phosphorylated tau. Logistics analysis showed that the B cell-associated genes, CXCL12 and TNFRSF13C, were independent risk factors for AD diagnosis. Peripheral CXCL12 and TNFRSF13C genes that correlated with immune cell infiltration in AD might serve as easily accessible biomarkers for the early diagnosis of AD.

Prolonged oxygen exposure causes the mobilization and functional damage of stem or progenitor cells and exacerbates cardiac ischemia or reperfusion injury in healthy mice.

Oxygen is often administered to patients and occasionally to healthy individuals as well; however, the cellular toxicity of oxygen, especially following prolonged exposure, is widely known. To evaluate the potential effect of oxygen exposure on circulating stem/progenitor cells and cardiac ischemia/reperfusion (I/R) injury, we exposed healthy adult mice to 100% oxygen for 20 or 60 min. We then examined the c-kit-positive stem/progenitor cells and colony-forming cells and measured the cytokine/chemokine levels in peripheral blood. We also induced cardiac I/R injury in mice at 3 h after 60 min of oxygen exposure and examined the recruitment of inflammatory cells and the fibrotic area in the heart. The proportion of c-kit-positive stem/progenitor cells significantly increased in peripheral blood at 3 and 24 h after oxygen exposure for either 20 or 60 min (p < .01 vs. control). However, the abundance of colony-forming cells in peripheral blood conversely decreased at 3 and 24 h after oxygen exposure for only 60 min (p < .05 vs. control). Oxygen exposure for either 20 or 60 min resulted in significantly decreased plasma vascular endothelial growth factor levels at 3 h, whereas oxygen exposure for only 60 min reduced plasma insulin-like growth factor 1 levels at 24 h (p < .05 vs. control). Protein array indicated the increase in the levels of some cytokines/chemokines, such as CXCL6 (GCP-2) at 24 h after 60 min of oxygen exposure. Moreover, oxygen exposure for 60 min enhanced the recruitment of Ly6g- and CD11c-positive inflammatory cells at 3 days (p < .05 vs. control) and increased the fibrotic area at 14 days in the heart after I/R injury (p < .05 vs. control). Prolonged oxygen exposure induced the mobilization and functional impairment of stem/progenitor cells and likely enhanced inflammatory responses to exacerbate cardiac I/R injury in healthy mice.

The Diagnostic and prognostic value of CXCL12 (SDF-1α) level in Mycobacterium tuberculosis infection and disease.

INTRODUCTION: New diagnostic tools are being investigated for rapid and accurate TB detection. We aimed to find out the diagnostic yield and accuracy of chemokine CXCL12 (SDF-1a) levels in diagnosing active TB (aTB) and making a differential diagnosis from other several infectious/non-infectious pulmonary conditions. METHODOLOGY: We collected demographic, clinic features and studied plasma CXCL12 levels using ELISA kit of the participants, classified into five categories: aTB (n = 30); cured TB (cTB, n = 15); close contacts of aTB (CC, n = 15); chronic obstructive pulmonary disease (COPD) with active nonspecific pulmonary infection (infCOPD, n = 15); and healthy controls (HC, n = 15). RESULTS: CXCL12 levels were highest in aTB, but no significant difference was seen between other groups. When a cut-off level for CXCL12 was determined as 2835 pg/mL, the increased CXCL12 rate was significantly more in aTB than CC and HC (p = 0.02, p = 0.05). Also, participants with an active infection (aTB and infCOPD) had significantly higher increased CXCL12 rates (p = 0.01). The sensitivity and specificity of CXCL12 for diagnosing aTB were found to be 0.56 and 0.63, respectively. We found that bacterial load, the radiological severity and the extent of chest x-ray involvement were independent factors for increased CXCL12 levels. CONCLUSIONS: Our study demonstrates that CXCL12 may be a representative of active pulmonary infection regardless of the cause but correlated with the severity of the disease; enabling this test to be used as a prognostic factor rather than a diagnostic test for aTB.

Measurement of 45 cytokine, chemokine and growth factors in established cell culture supernatants and autologous serum from advanced melanoma patients.

Melanoma is one of the most aggressive forms of human cancer and its incidence has significantly increased worldwide over the last decades. This neoplasia has been characterized by the release of a wide variety of soluble factors, which could stimulate tumor cell proliferation and survival in an autocrine and paracrine manner. Consequently, we sought to evaluate the pattern of soluble factors produced by pre-metastatic and metastatic melanoma established cultures, and to determine whether these factors can be detected in the autologous serum of malignant melanoma patients. Our results showed that both melanoma cultures had a common profile of 27 soluble factors mainly characterized by the high expression of VEGF-A, IL-6, MCP-1, IL-8, and SDF-1. In addition, when we compared supernatants, we observed significant differences in VEGF-A, BDNF, FGF-2, and NGF-ß concentrations. As we found in melanoma cultures, serum samples also had their specific production pattern composed by 21 soluble factors. Surprisingly, PDGF-BB and EGF were only found in serum, whereas IL-2, IL-4, IL-8, IL31, FGF2, and GRO-α were only expressed in the supernatant. Significant differences in PDGF-BB, MIP-1ß, HGF, PIGF-1, BDNF, EGF, Eotaxin, and IP-10 were also found after comparing autologous serum with healthy controls. According to this, no correlation was found between culture supernatants and autologous serum samples, which suggests that some factors may act locally, and others systemically. Nonetheless, after validation of our results in an independent cohort of patients, we concluded that PDGF-BB, VEGF-A, and IP-10 serum levels could be used to monitor different melanoma stages.

A Multipurpose First-in-Human Study With the Novel CXCR7 Antagonist ACT-1004-1239 Using CXCL12 Plasma Concentrations as Target Engagement Biomarker.

The C-X-C chemokine receptor 7 (CXCR7) has evolved as a promising, druggable target mainly in the immunology and oncology fields modulating plasma concentrations of its ligands CXCL11 and CXCL12 through receptor-mediated internalization. This "scavenging" activity creates concentration gradients of these ligands between blood vessels and tissues that drive directional cell migration. This randomized, double-blind, placebo-controlled first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a first-in-class drug candidate small-molecule CXCR7 antagonist. Food effect and absolute bioavailability assessments were also integrated in this multipurpose study. Healthy male subjects received single ascending oral doses of ACT-1004-1239 (n = 36) or placebo (n = 12). At each of six dose levels (1-200 mg), repeated blood sampling was done over 144 hours for pharmacokinetic/pharmacodynamic assessments using CXCL11 and CXCL12 as biomarkers of target engagement. ACT-1004-1239 was safe and well tolerated up to the highest tested dose of 200 mg. CXCL12 plasma concentrations dose-dependently increased and more than doubled compared with baseline, indicating target engagement, whereas CXCL11 concentrations remained unchanged. An indirect-response pharmacokinetic/pharmacodynamic model well described the relationship between ACT-1004-1239 and CXCL12 concentrations across the full dose range, supporting once-daily dosing for future clinical studies. At doses ≥ 10 mg, time to reach maximum plasma concentration ranged from 1.3 to 3.0 hours and terminal elimination half-life from 17.8 to 23.6 hours. The exposure increase across the dose range was essentially dose-proportional and no relevant food effect on pharmacokinetics was determined. The absolute bioavailability was 53.0% based on radioactivity data after oral vs. intravenous 14 C-radiolabeled microtracer administration of ACT-1004-1239. Overall, these comprehensive data support further clinical development of ACT-1004-1239.

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes. STUDY DESIGN: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers. SETTING & PARTICIPANTS: Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline. OUTCOMES: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models. RESULTS: Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. LIMITATIONS: The observational study design precludes causal inference. CONCLUSIONS: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.

Association of serum CXCL12 levels with arthropathy in patients with systemic sclerosis.

AIM: Systemic sclerosis (SSc) is an autoimmune connective tissue disease, in which extensive fibrotic change and vasculopathy affect the skin and various internal organs. It also involves the joints, causing stiffness, arthralgia, and arthritis. Although arthropathy is commonly observed in SSc, its underlying mechanism remains unknown. CXCL12, also known as stromal cell derived factor 1, is associated with inflammation, mesenchymal cell recruitment, angiogenesis, and collagen production, and is implicated in the development of various joint diseases. To assess the potential contribution of CXCL12 to SSc development, we investigated the clinical association of serum CXCL12 levels in patients with SSc. METHOD: We conducted a cross-sectional analysis of 68 patients with SSc and 20 healthy controls recruited in a single center over 9 years. Serum CXCL12 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum CXCL12 levels were significantly higher in patients with SSc than in healthy controls (median 1554.0 pg/mL, 25th-75th centiles 1313.0-1914.0 pg/mL vs 967.4 pg/mL, 608.8-1271.0 pg/mL, P < 0.001). Patients with SSc with elevated CXCL12 levels had significantly more cases of arthropathy than those with normal CXCL12 levels (85.7% vs 25.0%, P = 0.01). Furthermore, patients with SSc with elevated CXCL12 levels showed an increased trend in the prevalence of limited range of motion of the finger joints compared with those with normal CXCL12 levels (60.0% vs 18.6%, P =0 .07). Moreover, serum CXCL12 levels were significantly correlated with the titers of rheumatoid factor in patients with SSc (r = .41, P = 0.001). CONCLUSION: Elevated serum CXCL12 levels may be related to the development of SSc arthropathy.

Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239.

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.

Dipeptidyl Peptidase-4 deficiency effectively protects the brain and neurological function in rodent after acute Hemorrhagic Stroke.

This study tested the hypothesis that abrogated dipeptidyl peptidase-4 (DPP4) activity played a crucial role on reducing stroke volume and preserving neurological function in rodent after acute hemorrhagic stroke (AHS). Animals (n=6/each group) were categorized into group 1 (sham-control of F344 rat), group 2 (sham-control of DPP4-deficiency rat), group 3 [AHS by right cerebral injection of autologous blood (100 µL) in F344 rat], group 4 (AHS + sitagliptin/600 mg/kg 3 h prior to and at 3 h then once per day after AHS) and group 5 (AHS in DPP4-deficiency rat). The results of corner test showed the neurological function was significantly improved from days 3, 7, and 14 in groups 4 and 5 than in group 3 (all p<0.001). By days 1 and 14 after AHS procedure, the circulating levels of SDF-1α and GLP-1 were significantly increased from groups 1/2 to group 5 (all p<0.001), whereas circulating DPP4 activity was significantly increased in group 3 than other groups (all p<0.001). The brain ischemic area (BIA) was highest in group 3, lowest in groups 1/2 and significantly lower in group 5 than in group 4 (all p<0.0001). The protein expressions of oxidative-stress/inflammatory/apoptotic/cell-proliferation signaling, and the cellular expressions of inflammatory/DNA-damaged biomarkers exhibited a similar pattern to BIA among the groups (all p<0.01). In conclusion, deprivation of DPP4 activity protected the brain from AHS damage and preserved neurological function.

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients.

BACKGROUND: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+T-cell turnover. METHODS: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-ß/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery. FINDINGS: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response. INTERPRETATION: SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance. FUNDING: This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII).