Bioaccumulation and toxicity of perfluorooctanoic acid and perfluorooctane sulfonate in marine algae Chlorella sp.

The ocean is an important sink for perfluorinated alkyl acids (PFAAs), but the toxic mechanisms of PFAAs to marine organisms have not been clearly studied. In this study, the growth rate, photosynthetic activity, oxidative stress and bioaccumulation were investigated using marine algae Chlorella sp. after the exposure of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate acid (PFOS). The results showed that PFOA of <40 mg/L and PFOS of <20 mg/L stimulated algal reproduction, and high doses inhibited the algal growth. The absorbed PFOA and PFOS by algal cells damaged cell membrane and caused metabolic disorder. The photosynthesis activity was inhibited, which was revealed by the significantly reduced maximal quantum yield (Fv/Fm), relative electron transfer rate (rETR) and carbohydrate synthesis. However, the chlorophyll a content increased along with the up-regulation of its encoding genes (psbB and chlB), probably due to an overcompensation effect. The increase of ROS and antioxidant substances (SOD, CAT and GSH) indicated that PFOA and PFOS caused oxidative stress. The BCF of marine algae Chlorella sp. to PFOA and PFOS was calculated to be between 82 and 200, confirming the bioaccumulation of PFOA and PFOS in marine algae. In summary, PFOA and PFOS can accumulate in Chlorella sp. cells, disrupt photosynthesis, trigger oxidative stress and inhibit algal growth. PFOS shows higher toxicity and bioaccumulation than PFOA. The information is important to evaluate the environmental risks of PFAAs.

Blockade of Kv1.3 potassium channel inhibits CD8+ T cell-mediated neuroinflammation via PD-1/Blimp-1 signaling.

Kv1.3 potassium channel is considered as a target for the treatment of autoimmune diseases such as multiple sclerosis (MS), since Kv1.3 blockade suppresses memory T cell activation including cytotoxic CD8+ T cells. However, the underlying signaling pathway related to autoimmune CD8+ T cell inhibition by Kv1.3 channel in neuroinflammatory diseases remains unclear. We found that ImK, a selective Kv1.3 blocker, reduced auto-reactive CD8+ T cell infiltration in the spinal cords of experimental autoimmune encephalomyelitis (EAE) rats, an animal model of MS. ImK suppressed transcriptional factor Blimp-1 expression and reduced the cytotoxicity of CD8+ T cells on neuronal cells. Furthermore, ImK upregulated co-inhibitory molecule PD-1 to inhibit B lymphocyte-induced maturation protein (Blimp-1) in an IL-2 independent way. In addition, PD-1 inhibitor impaired the suppression of ImK on CD8+ T cells and accelerated EAE progression. Our study demonstrated a novel regulatory mechanism of Kv1.3 blockade on modulating CD8+ T cell differentiation through PD-1/Blimp-1 signaling. This work expands the understanding of Kv1.3 channel for modulating neuroinflammation.

A Kv1.3 channel-specific blocker alleviates neurological impairment through inhibiting T-cell activation in experimental autoimmune encephalomyelitis.

AIM: Multiple sclerosis (MS) is a neurological autoimmune disorder characterized by mistaken attacks of inflammatory cells against the central nervous system (CNS), resulting in demyelination and axonal damage. Kv1.3 channel blockers can inhibit T-cell activation and have been designed for MS therapy. However, little is known about the effects of Kv1.3 blockers on protecting myelin sheaths/axons in MS. This study aimed at investigating the neuroprotection efficacy of a selective Kv1.3 channel blocker ImKTx88 (ImK) in MS animal model. METHODS: Experimental autoimmune encephalomyelitis (EAE) rat model was established. The neuroprotective effect of ImK was assessed by immunohistochemistry and transmission electron microscopy (TEM). In addition, the antiinflammatory effect of ImK by suppressing T-cell activation was assessed by flow cytometry and ELISA in vitro. RESULTS: Our results demonstrated that ImK administration ameliorated EAE clinical severity. Moreover, ImK increased oligodendrocytes survival, preserved axons, and myelin integrity and reduced the infiltration of activated T cells into the CNS. This protective effect of the peptide may be related to its suppression of autoantigen-specific T-cell activation via calcium influx inhibition. CONCLUSION: ImK prevents neurological damage by suppressing T-cell activation, suggesting the applicability of this peptide in MS therapy.

Kv1.3 channel blocker (ImKTx88) maintains blood-brain barrier in experimental autoimmune encephalomyelitis.

BACKGROUND: Disruption of blood-brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model. RESULTS: In this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over-expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production. CONCLUSIONS: ImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB.

[Anti-hepatofibrosis effect of fasudil hydrochloride on Schistosoma japonicum-infected mice].

OBJECTIVE: To investigate the anti-fibrotic effect of fasudil hydrochloride on Schistosoma japonicum-infected mice, and the effect of fasudil hydrochloride on hepatic stellate cells (HSCs). METHODS: Thirty female BALB/c mice were randomly divided into 3 groups viz, normal control group (NC group), infection group, and experiment group. Mice in both infection group and experiment group were infected with (14:2) cercariae of S japonicum. At 6 weeks post infection, mice in experiment group were intraperitoneally injected with fasudil hydrochloride (10 mg/kg) twice a day for 7 d, while mice in NC group and infection group received the same volume of physiological saline. All mice were sacrificed 12 h after the last injection. Livers from NC group and infection group were used to prepare tissue sections for hematoxylin and eosin (HE) staining, or sirius red staining, and observed under light microscope. Livers from all three groups were used to detect content of hydroxyproline (Hyp) and the mRNA expressions of alpha-smooth muscle actin (alpha-SMA), type I collagen alpha1 (Col1alpha1) and epithelial cell transforming sequence 2 (Ect2). HSCs from mice in all three groups were isolated to detect the mRNA levels of alpha-SMA, Col1alpha1, and Ect2, respectively. RESULTS: Pathological sections showed that in livers from mice in infection group, inflammatory cells infiltrated and collagenous fibre proliferated around portal areas and egg granulomas. The content of Hyp in liver from mice of NC group, infection group, and experiment group was (279.7 +/- 21.2) microg, (528.0 +/- 15.0) microg, and (355.4 +/- 22.6) microg, respectively. The content of Hyp in livers from mice of experiment group was significantly reduced compared to infection group (P < 0.01). The mRNA expression of alpha-SMA, Col1alpha1 and Ect2 in livers and HSCs from mice in experiment group were significantly down-regulated compared to infection group (P < 0.05). CONCLUSION: Fasudil hydrochloride can depress hepatofibrosis in Schistosoma japonicum-infected mice.