Background: Circulating complement C3 fragments released during septic shock might contribute to the development of complications such as profound hypotension and disseminated intravascular coagulation. The role of C3 in the course of septic shock varies in the literature, possibly because circulating C3 exists in different forms indistinguishable via traditional ELISA-based methods. We sought to test the relationship between C3 forms, measured by Western blotting with its associated protein size differentiation feature, and clinical outcomes. Methods: Secondary analysis of two prospective cohorts of patients with septic shock: a discovery cohort of 24 patents and a validation cohort of 181 patients. C3 levels were measured by Western blotting in both cohorts using blood obtained at enrollment. Differences between survivors and non-survivors were compared, and the independent prognostic values of C3 forms were assessed. Results: In both cohorts there were significantly lower levels of the C3-alpha chain in non-survivors than in survivors, and persisted after controlling for sequential organ failure assessment score. Area under the receiver operating characteristics to predict survival was 0.65 (95% confidence interval: 0.56–0.75). At a best cutoff value (Youden) of 970.6 μg/mL, the test demonstrated a sensitivity of 68.5% and specificity of 61.5%. At this cutoff point, Kaplan–Meier survival analysis showed that patients with lower levels of C3-alpha chain had significantly lower survival than those with higher levels (P < 0.001). Conclusion: Circulating C3-alpha chain levels is a significant independent predictor of survival in septic shock patients.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays critical roles in the physiological process of oocyte mature and IVF outcomes of patients with infertility. However, the regulation of BDNF expression in the microenvironment surrounding the oocyte is still unknown. We initially predicted some microRNA (miRNA) candidates targeting bdnf with a series of bioinformatics analysis tools to determine the underlying regulatory mechanisms of BDNF, particularly the effect of miRNAs on BDNF expression. Then, we assessed whether the expression of these 14 selected miRNAs was negatively associated with BDNF expression in follicular fluid (FF) samples obtained from mature (>18 mm) or immature (<15 mm) follicles. Finally, we used the candidate miRNAs, miR-103a-3p and miR-10a-5p, to further investigate the relationship between their expression in FF and the outcomes of infertile patients undergoing IVF–ET treatment. The results of the bioinformatics analysis revealed 14 miRNAs that might directly regulate BDNF expression and might have a close relationship with oocyte development. BDNF was expressed at significantly lower levels in FF from immature follicles than in FF from mature follicles, and only the expression of miR-103a-3p and miR-10a-5p was negatively correlated with BDNF expression in FF. Moreover, in another cohort of 106 infertile women undergoing IVF-ET treatment, miR-103a-3p or miR-10a-5p expression predicted the developmental status of the corresponding oocytes in which high expression of miR-103a-3p or miR-10a-5p resulted in a poor quality of embryo on days 3 and 5 during the IVF-ET treatment. In conclusion, our study is the first to show that miR-103a-3p or miR-10a-5p negatively affects the maturation of oocytes by regulating the expression of BDNF in human FF. Additionally, the expression levels of miR-103a-3p or miR-10a-5p in FF may predict the outcomes of IVF, which are helpful for improving embryo selection and consequently the IVF success rate in the clinic.
Hypoxia takes places in pathogenic conditions, such as heart ischemia. Complements factors have been reported to play an important role in ischemia-reperfusion injury in various animal models. We studied the cellular response to complement under hypoxia condition using a human cardiomyocyte cell line AC16. Under hypoxia condition without serum (thus no exogenous complements provided), these cardiomyocytes underwent apoptosis. However, when pure human C3 was supplemented after hypoxia, these cells had less apoptosis and maintained a reasonable survival rate. The results indicate that complement C3 can increase the cardiomyocytes resistance to apoptosis under the hypoxia condition.
Myocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Previous animal studies showed that circulation complement C3 was deposited in the ischemic myocardium flooded with oxygenated blood upon reperfusion. Recently, we reported that myocardial necrosis was decreased in C3-/- mice after heart I/R. The current study used in the same heart model to test the effect of C3 on myocardial apoptosis. Our results showed that myocardial apoptosis was increased in C3-/- mice after heart I/R. Further, comparative proteomics analyses found that cytochrome c was present in the myocardial C3-complex following I/R. These results indicate that C3 can interact with cytochrome c in the cytosol of cardiomyocytes during myocardial I/R, which may sequester cytochrome c and thus reduce the number of cells undergoing apoptosis. In summary, our findings raise the possibility of a new mechanism affecting cell death relevant to pathologic conditions such as ischemia: a circulating innate immune factor, i.e. complement, can interact with intracellular factor(s), and influence the types of cell death that occur.
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