Browsing by Subject "COMPLEMENT"

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  • Viiklepp, Kristina; Nissinen, Liisa; Ojalill, Marjaana; Riihilä, Pilvi; Kallajoki, Markku; Meri, Seppo; Heino, Jyrki; Kähäri, Veli-Matti (2022)
    Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, with increasing incidence worldwide. Previous studies have shown the role of the complement system in cSCC progression. In this study, we have investigated the mechanistic role of serine proteinase C1r, a component of the classical pathway of the complement system, in cSCC. Knockout of C1r in cSCC cells using CRISPR/Cas9 resulted in a significant decrease in their proliferation, migration, and invasion through collagen type I compared with that of wild-type cSCC cells. Knockout of C1r suppressed the growth and vascularization of cSCC xenograft tumors and promoted apoptosis of tumor cells in vivo. mRNA-sequencing analysis after C1r knockdown revealed significantly regulated Gene Ontology terms cell-matrix adhesion, extracellular matrix component, basement membrane, and metalloendopeptidase activity and Kyoto Encyclopedia of Genes and Genomes pathway extracellular matrix-receptor interaction. Among the significantly regulated genes were invasion-associated matrix metalloproteinases (MMPs) MMP1, MMP13, MMP10, and MMP12. Knockout of C1r resulted in decreased production of MMP-1, MMP-13, MMP-10, and MMP-12 by cSCC cells in culture. Knockout of C1r inhibited the expression of MMP-13 by tumor cells, suppressed invasion, and reduced the amount of degraded collagen in vivo in xenografts. These results provide evidence for the role of C1r in promoting the invasion of cSCC cells by increasing MMP production.
  • Ilmakunnas, M.; Turunen, A. J.; Lindgren, L.; Salmela, K. T.; Kyllönen, L. E.; Andersson, S.; Petäjä, J.; Pesonen, E. J. (2019)
    Background. Inflammation, coagulation, and fibrinolysis are tightly linked together. Reperfusion after transient ischemia activates both neutrophils, coagulation, and fibrinolysis. Experimental data suggest that tissue plasminogen activator (tPA) regulates renal neutrophil influx in kidney ischemia and reperfusion injury. Methods. In 30 patients undergoing kidney transplantation, we measured renal neutrophil sequestration and tPA release from blood samples drawn from the supplying artery and renal vein early after reperfusion. tPA antigen levels were measured using a commercial enzyme-linked immunosorbent assay kit. For each parameter, transrenal difference (Delta) was calculated by subtracting the value of the arterial sample (ingoing blood) from the value of the venous sample (outgoing blood). Results. Positive transrenal gradients of tPA antigen occurred at 1 minute [Delta = 14 (3-46) ng/mL, P <.01] and 5 minutes [Delta = 5 (-3 to 27) ng/mL, P <.01] after reperfusion. At 5 minutes after reperfusion, a negative transrenal gradient of neutrophils was observed [Delta = -0.17 (-1.45 to 0.24) x 10E9 cells/L, P <.001]. At 1 minute after reperfusion, neutrophil sequestration into the kidney (ie, negative transrenal neutrophil count) correlated significantly with tPA release from the kidney (ie, positive transrenal tPA concentration), (R = -0.513 and P = .006). Conclusions. The findings suggest a proinflammatory role for tPA in ischemia and reperfusion injury in human kidney transplantation.
  • Becker, Noémie S.; Rollins, Robert E.; Nosenko, Kateryna; Paulus, Alexander; Martin, Samantha; Krebs, Stefan; Takano, Ai; Sato, Kozue; Kovalev, Sergey Y.; Kawabata, Hiroki; Fingerle, Volker; Margos, Gabriele (2020)
    BackgroundBorrelia bavariensis is one of the agents of Lyme Borreliosis (or Lyme disease) in Eurasia. The genome of the Borrelia burgdorferi sensu lato species complex, that includes B. bavariensis, is known to be very complex and fragmented making the assembly of whole genomes with next-generation sequencing data a challenge.ResultsWe present a genome reconstruction for 33 B. bavariensis isolates from Eurasia based on long-read (Pacific Bioscience, for three isolates) and short-read (Illumina) data. We show that the combination of both sequencing techniques allows proper genome reconstruction of all plasmids in most cases but use of a very close reference is necessary when only short-read sequencing data is available. B. bavariensis genomes combine a high degree of genetic conservation with high plasticity: all isolates share the main chromosome and five plasmids, but the repertoire of other plasmids is highly variable. In addition to plasmid losses and gains through horizontal transfer, we also observe several fusions between plasmids. Although European isolates of B. bavariensis have little diversity in genome content, there is some geographic structure to this variation. In contrast, each Asian isolate has a unique plasmid repertoire and we observe no geographically based differences between Japanese and Russian isolates. Comparing the genomes of Asian and European populations of B. bavariensis suggests that some genes which are markedly different between the two populations may be good candidates for adaptation to the tick vector, (Ixodes ricinus in Europe and I. persulcatus in Asia).ConclusionsWe present the characterization of genomes of a large sample of B. bavariensis isolates and show that their plasmid content is highly variable. This study opens the way for genomic studies seeking to understand host and vector adaptation as well as human pathogenicity in Eurasian Lyme Borreliosis agents.
  • Asgharzadeh, Fereshteh; Barneh, Farnaz; Fakhraie, Maryam; Barkhordar, Seyede Leili Adel; Shabani, Mohammad; Soleimani, Atena; Rahmani, Farzad; Ariakia, Fatemeh; Mehraban, Saeedeh; Avan, Amir; Hashemzehi, Milad; Arjmand, Mohammad-Hassan; Behnam-Rassouli, Reyhaneh; Jaberi, Najmeh; Sayyed-Hosseinian, Sayyed-Hadi; Ferns, Gordon A.; Ryzhikov, Mikhail; Jafari, Mohieddin; Khazaei, Majid; Hassanian, Seyed Mahdi (2021)
    Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic shortand systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/ anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.
  • Holm, Matilda; Joenväärä, Sakari; Saraswat, Mayank; Tohmola, Tiialotta; Ristimäki, Ari; Renkonen, Risto; Haglund, Caj (2020)
    Colorectal cancer (CRC) includes tumors in the right colon, left colon, and rectum, although they differ significantly from each other in aspects such as prognosis and treatment. Few previous mass spectrometry-based studies have analyzed differences in protein expression depending on the tumor location. In this study, we have used mass spectrometry-based proteomics to analyze plasma samples from 83 CRC patients to study if differences in plasma protein expression can be seen depending on primary tumor location (right colon, left colon, or rectum). Differences were studied between the groups both regardless of and according to tumor stage (II or III). Large differences in plasma protein expression were seen, and we found that plasma samples from patients with rectal cancer separated from samples from patients with colon cancer when analyzed by principal component analysis and hierarchical clustering. Samples from patients with cancer in the right and left colon also tended to separate from each other. Pathway analysis discovered canonical pathways involved in lipid metabolism and inflammation to be enriched. This study will help to further define CRC as distinct entities depending on tumor location, as shown by the widespread differences in plasma protein profile and dysregulated pathways.
  • Sober, Siim; Rull, Kristiina; Reiman, Mario; Ilisson, Piret; Mattila, Pirkko; Laan, Maris (2016)
    Recurrent pregnancy loss (RPL) concerns similar to 3% of couples aiming at childbirth. In the current study, transcriptomes and miRNomes of 1st trimester placental chorionic villi were analysed for 2 RPL cases (>= 6 miscarriages) and normal, but electively terminated pregnancies (ETP; n = 8). Sequencing was performed on Illumina HiSeq 2000 platform. Differential expression analyses detected 51 (27%) transcripts with increased and 138 (73%) with decreased expression in RPL compared to ETP (DESeq: FDR P <0.1 and DESeq2: <0.05). RPL samples had substantially decreased transcript levels of histones, regulatory RNAs and genes involved in telomere, spliceosome, ribosomal, mitochondrial and intra-cellular signalling functions. Downregulated expression of HIST1H1B and HIST1H4A (Wilcoxon test, fc
  • Syed, Shahan; Hakala, Pipsa; Singh, Anirudh K.; Lapatto, Helena A. K.; King, Samantha J.; Meri, Seppo; Jokiranta, T. Sakari; Haapasalo, Karita (2019)
    The most frequent form of hemolytic-uremic syndrome (HUS) is associated with infections caused by Shiga-like toxin-producing Enterohaemorrhagic Escherichia coli (STEC). In rarer cases HUS can be triggered by Streptococcus pneumoniae. While production of Shiga-like toxins explains STEC-HUS, the mechanisms of pneumococcal HUS are less well known. S. pneumoniae produces neuraminidases with activity against cell surface sialic acids that are critical for factor H-mediated complement regulation on cells and platelets. The aim of this study was to find out whether S. pneumoniae neuraminidase NanA could trigger complement activation and hemolysis in whole blood. We studied clinical S. pneumoniae isolates and two laboratory strains, a wild-type strain expressing NanA, and a NanA deletion mutant for their ability to remove sialic acids from various human cells and platelets. Red blood cell lysis and activation of complement was measured ex vivo by incubating whole blood with bacterial culture supernatants. We show here that NanA expressing S. pneumoniae strains and isolates are able to remove sialic acids from cells, and platelets. Removal of sialic acids by NanA increased complement activity in whole blood, while absence of NanA blocked complement triggering and hemolytic activity indicating that removal of sialic acids by NanA could potentially trigger pHUS.
  • Ostergaard, Jakob Appel; Jansson Sigfrids, Fanny; Forsblom, Carol; Dahlström, Emma H.; Thorn, Lena M.; Harjutsalo, Valma; Flyvbjerg, Allan; Thiel, Steffen; Krarup Hansen, Troels; Groop, Per-Henrik (2021)
    H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA(1c), systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.
  • Kasperkiewicz, Katarzyna; Swierzko, Anna S.; Przybyla, Marta; Szemraj, Janusz; Barski, Jaroslaw; Skurnik, Mikael; Kaluzynski, Andrzej; Cedzynski, Maciej (2020)
    Yersinia enterocolitica O:3 is mentioned among the most common arthritogenic pathogens. Bacterial components (including lipopolysaccharide (LPS)) may persist in the joint after eradication of infection. Having an adjuvant activity, LPS may enhance production of anticollagen antibodies, involved in the pathogenesis of rheumatoid arthritis. Furthermore, its ability to activate complement contributes to the inflammation. The aim of this work was to investigate whether Yersinia LPS (coinjected with collagen) is associated with arthritis progression or other pathological effects and to elucidate the mechanism of this association. It was demonstrated that murine mannose-binding lectin C (MBL-C) recognizes the inner core heptoses of the Rd1 chemotype LPS of Yersinia. In addition, the Rd1 LPS activates the MBL-associated serine protease 1 (MASP-1) stronger than the S and Ra chemotype LPS and comparable to Klebsiella pneumoniae O:3 LPS. However, in contrast to the latter, Yersinia Rd1 LPS was associated neither with the adjuvancity nor with the enhancement of pathological changes in animal paws/impairment of motility. On the other hand, it seemed to be more hepatotoxic when compared with the other tested endotoxins, while the enlargement of inguinal lymph nodes and drop in hepatic MBL-C expression (at the mRNA level) were independent of LPS chemotype. Our data did not suggest no greater impact Y. enterocolitica O:3 on the development or severity of arthropathy related to anticollagen antibody-induced arthritis in mice, although its interaction with MBL-C and subsequent complement activation may contribute to some adverse effects.
  • Reichhardt, Martin Parnov; Jarva, Hanna; Lokki, Anna Inkeri; Laivuori, Hannele; Vuorela, Piia; Loimaranta, Vuokko; Glasner, Andreas; Siwetz, Monika; Huppertz, Berthold; Meri, Seppo; FINNPEC Study Grp (2016)
    Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality worldwide. The etiology is not clear, but an immune attack towards components of placenta or fetus has been indicated. This involves activation of the complement system in the placenta. We have previously described the presence of the complement-regulating protein salivary scavenger and agglutinin (SALSA) in amniotic fluid. In this study we investigated the potential role of SALSA in pregnancy by analyzing its presence in amniotic fluid and placental tissue during healthy and complicated pregnancies. SALSA levels in amniotic fluid increased during pregnancy. Before 20 weeks of gestation the levels were slightly higher in patients who later developed pre-eclampsia than in gestation age-matched controls. In the placenta of pre-eclamptic patients syncytial damage is often followed by the formation of fibrinoid structures. SALSA was found clustered into these fibrinoid structures in partial co-localization with complement C1q and fibronectin. In vitro analysis showed direct protein binding of SALSA to fibronectin. SALSA binds also to fibrin/fibrinogen but did not interfere with the blood clotting process in vitro. Thus, in addition to antimicrobial defense and epithelial differentiation, the data presented here suggest that SALSA, together with fibronectin and C1q, may be involved in the containment of injured placental structures into fibrinoids.