Search

Venom-induced thrombocytopenia (VIT) is one of the most important hemotoxic effects of a snakebite, which is often associated with venom-induced consumptive coagulopathy (VICC). Refractory thrombocytopenia without significant coagulation abnormalities has also been reported after envenomation by some viperid snakes; however, the mechanisms are not well understood and therapeutic strategies are lacking. Here, we found that patients injured by Daboia siamensis or Agkistrodon halys snakes, who were resistant to standard antivenom treatment, had developed coagulopathy-independent thrombocytopenia. Venoms from these viperid snakes, rather than from the elapid snake (Bungarus multicinctus), induced platelet surface expression of neuraminidase-1 (NEU-1), and significantly increased the desialylation of the glycoproteins on human platelets. The desialylated platelets caused by viperid snake venoms were further internalized by macrophages, which resulted in reduced platelet numbers in peripheral blood. Importantly, neuraminidase inhibitor significantly decreased viper venom-induced platelet desialylation, therefore inhibiting platelet phagocytosis by macrophages, and alleviating venom-induced thrombocytopenia. Collectively, these findings support an important role for desialylated platelet clearance in the progression of viper envenomation-induced, coagulopathy-independent thrombocytopenia. Our study demonstrates that the neuraminidase inhibitor may be a potential therapy or adjuvant therapy to treat snakebite-induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Objective: This study aims to elucidate the role of T follicular helper (Tfh) cells and their subsets in idiopathic membranous nephropathy (IMN). Methods: The frequencies of Tfh cell subsets and B cell subsets in peripheral blood (PB) were detected in both IMN patients and healthy controls (HCs). The involvement of Tfh cells in the disease pathogenesis was examined by coculturing human Tfh cells with B cells. The dynamic changes of Tfh cells in PB or spleen were monitored in passive Heymann nephritis (PHN) rats. Results: The frequencies of circulating Tfh (cTfh) cells, cTfh2 cells, and plasmablasts were enriched in the PB of patients with IMN. cTfh cells expressed higher ICOS, and lower BTLA than healthy counterparts. The frequency of ICOS + cTfh2 was associated with the severity of IMN, including 24h urine protein, IgG4 concentration and the IgG4: IgG ratio. Positive correlations were also observed between the frequency of cTfh2 cells with plasmablasts, serum IL-21 and IL-4 levels. Importantly, cTfh cells isolated from IMN patients were able to induce the differentiation of B cells to memory B cells (MBC) and plasmablasts, this process could be substantially attenuated by blocking the IL-21. Similar increases of ICOS + cTfh cells were also detected in spleen of PHN rats, concomitant with elevated urine protein levels. Conclusions: Collectively, our results demonstrate that the imbalance of cTfh cell subsets play a crucial pathogenic role in IMN by inducing the differentiation of B cells through IL-21, and cTfh2 cells might serve as useful markers to evaluate the progression of IMN. [ABSTRACT FROM AUTHOR]

• Circulating CD19+CD24hiCD38hi B cells are expanded in IMN patients. • The frequency of CD19+CD24hiCD38hi B cells are associated with disease severity in IMN patients. • The percentage of CD19+CD24hiCD38hi B cells was positively associated with Th17 cell frequency in IMN patients. • CD19+CD24hiCD38hi B cells in IMN patients displayed a skewed pro-inflammatory cytokine profile. CD19+CD24hiCD38hi regulatory B cells exert immunosuppressive functions by producing IL-10, but their role in idiopathic membranous nephropathy (IMN) remains elusive. Here, we investigated the frequency and functional changes of circulating CD19+CD24hiCD38hi B cells and evaluated the correlation of CD19+CD24hiCD38hi B cells with clinical features and T helper cell subsets in IMN patients. Compared with healthy controls (HCs), IMN patients showed an increased frequency of CD19+CD24hiCD38hi B cells, but a significant reduction in the percentage of CD19+CD24hiCD38hi B cells was observed 4 weeks after cyclophosphamide treatment. The frequency of CD19+CD24hiCD38hi B cells was positively correlated with the levels of 24h urinary protein, but negatively correlated with serum total protein and serum albumin, respectively. CD19+CD24hiCD38hi B cells in IMN patients displayed a skewed pro-inflammatory cytokine profile with a higher level of IL-6 and IL-12, but a lower concentration of IL-10 than their healthy counterparts. Accompanied by upregulation of Th2 and Th17 cells in IMN patients, the percentage of CD19+CD24hiCD38hi B cell subset was positively associated with Th17 cell frequency. In conclusion, CD19+CD24hiCD38hi B cells were expanded but functionally impaired in IMN patients. Their altered pro-inflammatory cytokine profile may contribute to the pathogenesis of IMN. [ABSTRACT FROM AUTHOR]

• Inflammatory MDSCs are expanded in RA patients and arthritic mice. • The frequencies of MDSCs correlated strongly with disease severity and Th17 response in RA patients. • TPT inhibited the expression of arginase-1 in MDSCs. • TPT reduces the severity of arthritis and the frequency of MDSCs effectively. • MDSCs may function as a novel and effective therapeutic target for TPT in RA. Triptolide (TPT) is widely used in the treatment of rheumatoid arthritis (RA). However, its regulatory mechanisms are not fully understood. This study demonstrated that Myeloid-derived suppressor cells (MDSCs) were expanded in both RA patients and arthritic mice. The frequency of MDSCs was correlated with RA disease severity and T helper 17 (Th17) responses. MDSCs from RA patients promoted the polarization of Th17 cells in vitro , which could be substantially attenuated by blocking arginase-1 (Arg-1). TPT inhibited the differentiation of MDSCs, particularly the monocytic MDSCs (M-MDSCs) subsets, as well as the expression of Arg-1 in a dose dependent manner. Alongside, TPT treatment reduced the potential of MDSCs to promote the polarization of IL-17+ T cell in vitro. Consistently, TPT immunotherapy alleviated adjuvant-induced arthritis (AIA) in a mice model, and reduced the frequency of MDSCs, M-MDSCs and IL-17+ T cells simultaneously. The presented data suggest a pathogenic role of MDSCs in RA and may function as a novel and effective therapeutic target for TPT in RA. [ABSTRACT FROM AUTHOR]

• Natural Halloysite nanotubes (HNTs) exhibit tubular morphology with empty lumen. • The fast and high water-absorption makes HNTs blood components concentrator. • Rich negative charges of HNTs acutely trigger the intrinsic coagulation cascade. • Nanosized HNTs activate platelets via GPIIb/IIIa receptor pathway. • The better hemostasis performance of PET fibers arises from well-dispersion of HNTs. Halloysite nanotubes (HNTs), a traditional mineral Chinese medicine, have been used to stop bleeding for thousands of years. However, the coagulation mechanisms of HNTs and their practical application potential have not been fully elucidated. In this study, HNTs were found to accelerate hemostasis via multiple dependent approaches: (i) absorbing water and concentrating blood due to their super-hydrophilicity and unique tubular nanostructure; (ii) triggering an intrinsic coagulation cascade by negatively charged surface interaction; and (iii) accelerating clot formation by activating and linking with platelets. To solve the difficulty in the application of powder, a HNT-coated polyester fiber dressing was designed by an impregnation method. The HNT coating enables the dressing to resist massive hemorrhaging of the liver and vessels, as well as epidermal bleeding. Moreover, the HNT-coated fiber dressings are not accompanied by burning or adhesion at the wound sites. In summary, this work provides profound insight into HNT hemostasis through the physical and biological interactions between HNTs and blood, which represents a promising strategy for effective prehospital treatment and civilian needs. [ABSTRACT FROM AUTHOR]

Natural products are a large source of clinically effective antitumor drugs. Millepachine, a natural product derived from leguminous plants, was reported to display antitumor activity. In this study, the novel compound, (1H-indol-5-yl) (5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone (MIL-1), was designed and synthesized by fusing millepachine and indole rings. MIL-1 exerted much better antitumor activity than millepachine, manifesting as a 24- to 201-fold increase in vitro cytotoxicity and a 2.4-fold increase in in vivo antitumor activity in hepatocellular cell lines-derived models. The immunofluorescence and HPLC detection revealed that MIL-1 was a potent microtubule targeting agent by interfering with the equilibrium of tubulin-microtubule dynamics and irreversibly binding to tubulin. MIL-1 displayed remarkable antitumor activity with an IC 50 of 31–207 nM towards various human cancer cell lines derived from various organs and tissues, and it exerted no evidence of toxicity against normal cells. Mechanistic studies showed that MIL-1 arrested the cell cycle at G2/M phase and induced apoptosis by activating caspase-3 activity and reactive oxygen species (ROS) accumulation. Moreover, the superior antitumor effect of MIL-1 is worthy of further detailed study for the treatment of hepatocellular carcinoma (HCC). • MIL-1 derived from natural product millepachine were designed and synthesized. • MIL-1 exerted a 24–201 folds increase in cytotoxicity than millepachine. • MIL-1 exerted a 2.36-fold increase in vivo antitumor activity. • MIL-1 targeted tubulin system through binding irreversibly to β-tubulin. • MIL-1 arrested cell cycle at G2/M phase and induced HepG2 cell apoptosis. [ABSTRACT FROM AUTHOR]