Growth differentiation factor 11 (GDF11), belonging to the transforming factor-β superfamily, regulates anterior-posterior patterning and inhibits neurogenesis during embryonic development. However, recent studies recognized GDF11 as a rejuvenating (or anti-ageing) factor to reverse age-related cardiac hypertrophy, repair injured skeletal muscle, promote cognitive function, etc. The effects of GDF11 are contradictory and the mechanism of action is still not well clarified. The objective of the present study was to investigate effects of GDF11 on PC12 neural stem cells in vitro and to reveal the underlying mechanism. We systematically assessed the effects of GDF11 on the life activities of PC12 cells. GDF11 significantly suppressed cell proliferation and migration, promoted differentiation and apoptosis, and arrested cell cycle at G2/M phase. Both TMT-based proteomic analysis and phospho-antibody microarray revealed PI3K-Akt pathway was enriched when treated with GDF11. Inhibition of ALK5 or PI3K obviously attenuated the effects of GDF11 on PC12 neural stem cells, which exerted that GDF11 regulated neural stem cells through ALK5-dependent PI3K-Akt signaling pathway. In summary, these results demonstrated GDF11 could be a negative regulator for neurogenesis via ALK5 activating PI3K-Akt pathway when it directly acted on neural stem cells.

Intravenous immunoglobulin (IVIG) is a first-line drug prepared from human plasma for the treatment of autoimmune diseases (AIDs), especially immune thrombocytopenia (ITP). Significant differences exist in protein types and expression levels between male and female plasma, and the prevalence of autoimmune diseases varies between sexes. The present study seeks to explore potential variations in IVIG sourced from distinct sex-specific plasma (DSP-IVIG), including IVIG sourced from female plasma (F-IVIG), IVIG sourced from male plasma (M-IVIG), and IVIG sourced from a blend of male and female plasma (Mix-IVIG). To address this question, we used an ITP mouse model and a monocyte–macrophage inflammation model treated with DSP IVIG. The analysis of proteomics in mice suggested that the pathogenesis and treatment of ITP may involve FcγRs mediated phagocytosis, apoptosis, Th17, cytokines, chemokines, and more. Key indicators, including the mouse spleen index, CD16⁺ macrophages, M1, M2, IL-6, IL-27, and IL-13, all indicated that the efficacy in improving ITP was highest for M-IVIG. Subsequent cell experiments revealed that M-IVIG exhibited a more potent ability to inhibit monocyte phagocytosis. It induced more necrotic M2 cells and fewer viable M2, resulting in weaker M2 phagocytosis. M-IVIG also demonstrated superiority in the downregulation of surface makers CD36, CD68, and CD16 on M1 macrophages, a weaker capacity to activate complement, and a stronger binding ability to FcγRs on the THP-1 surface. In summary, DSP-IVIG effectively mitigated inflammation in ITP mice and monocytes and macrophages. However, M-IVIG exhibited advantages in improving the spleen index, regulating the number and typing of M1 and M2 macrophages, and inhibiting macrophage-mediated inflammation compared to F-IVIG and Mix-IVIG.

Alzheimer’s disease (AD) is a common neurodegenerative disease that currently has no known cure. Intravenous immunoglobulin (IVIG), which contains AD-related antibodies and has anti-inflammatory properties, has shown potential as a treatment for AD. However, the efficacy of clinical trials involving AD patients treated with IVIG has been inconsistent. Our previous study found that different IVIGs had significantly varied therapeutic effects on 3xTg-AD mice. In order to investigate the relationship between the composition and function of IVIG and its efficacy in treating AD, we selected three IVIGs that showed notable differences in therapeutic effects. Then, the concentrations of specific antibodies against β-amyloid (Aβ)₄₂, tau, and hyperphosphorylated tau (p-tau) in three IVIGs, as well as their effects on systemic inflammation induced by lipopolysaccharide (LPS) in Balb/c mice, were analyzed and compared in this study. The results indicated that these IVIGs differed greatly in anti-Aβ₄₂/tau antibody concentration and anti-p-tau ratio, and improved LPS-stimulated peripheral inflammation, liver and kidney injury, and neuroinflammation in Balb/c mice to varying degrees. Combined with our previous results, the efficacy of IVIG against AD may be positively correlated with its level of AD-related antibodies and anti-inflammatory ability. AD-related antibody analysis and functional evaluation of IVIG should be given sufficient attention before clinical trials, as this may greatly affect the therapeutic effect of AD treatment.

Background: Mechanism of action of intravenous immunoglobulin (IVIG) is complex, and involves the immunoglobulin G (IgG) Fc fragment binding to Fc receptors on immune cells as activators and inhibitors. Antibody-dependent cell-mediated cytotoxicity (ADCC) is a mechanism that mainly depends on FcγRIIIA. However, the IVIG Fc fragment-binding activity to FcγRIIIA is unknown, and the IVIG-mediated ADCC remains to be clarified. This study attempts to explore the IVIG-mediated ADCC and provide correlative evidence. Methods: This study evaluated the IVIG-mediated ADCC using a time-resolved fluorescence (TRF) cell cytotoxicity assay in vitro, and Jurkat-NFAT-Luc-CD16 cells were used to detect the IVIG Fc fragment-binding activity to FcγRIIIA. Quantitative real-time polymerase chain reaction (PCR) analyses were conducted to detect mRNA synthesis when IVIG incubated with effector cells, and the final expression of FcγRIIIA on the cell membranes were detected by flow cytometry. Results: The results showed that IVIG had optimal binding activity to FcγRIIIA fitted with a four-parameter curve equation regression model with R²=0.99 and caused specific ADCC of about 40%. Meanwhile, IVIG upregulated the expression of FCGR3A by two-fold, and the FcγRIIIA level was markedly increased from 33.7% up to 66.7%. Conclusions: This study investigated the IVIG-mediated ADCC, including measurement of the IVIG Fc fragment-binding activity to FcγRIIIA and the regulation of FcγRIIIA expression by IVIG. The results indicate that ADCC that can kill tumor cells and IVIG can also promote FCGR3A synthesis, increasing FcγRIIIA expression on immune cells membranes. The findings provide further evidence for the IVIG-mediated ADCC and understanding of the biological activity of IVIG.