Interleukin-33 as a Biomarker Affecting Intrathecal Synthesis of Immunoglobulin in Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

INTRODUCTION: The purpose of this study was to analyze IL-33 maybe as a biomarker especially with respect to intrathecal immunoglobulin G (IgG) synthesis which was involved in the immune-mediated process in the demyelinating disease of the central nervous system. METHODS: We aimed to determine the risk association of the serum and CSF levels of IL-33 in aquaporin-4 (AQP4)+neuromyelitis optica spectrum disorder (NMOSD) patients and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) patients compared with the control group. Levels of inflammatory (IL-2, IL-4, IL-6, and IL-10) markers and QAlb, the IgG index, and 24-h IgG synthesis rate were assessed in 28 AQP4+NMOSD patients and 11 MOGAD patients. Disease severity was assessed using the Expanded Disability Status Scale (EDSS). RESULTS: The level of IL-33 in serum decreased first but then increased gradually in AQP4+NMOSD and MOGAD. The serum level of IL-2, IL-4, and IL-10 increased more significantly and decreased more rapidly after methylprednisolone treatment. The level of IL-33 in CSF increased progressively in AQP4+NMOSD and MOGAD, especially in MOGAD. The QAlb levels were increased significantly in the CSF of MOGAD patients and AQP4+NMOSD patients on the acute stage of the disease. The IgG index and 24-h IgG synthesis rate were also increased significantly in the CSF of two groups similarly. CONCLUSIONS: Thus, we concluded that IL-33 may induce dysfunction of the blood-brain barrier and lead to intrathecal synthesis of immunoglobulin in the AQP4+NMOSD and MOGAD, especially in MOGAD. It maybe as a biomarker, at least in part, was involved in the demyelinating diseases of the central nervous system.

Calcium Involved in the Enrichment of γ-Aminobutyric Acid (GABA) in Broccoli Sprouts under Fructose Treatment.

The effect of fructose on γ-aminobutyric acid (GABA) content and its metabolic pathway in broccoli sprouts was investigated. The results demonstrated that the fructose treatment not only significantly increased the fresh weight, GABA, and glutamate contents in sprouts, but also promoted the activity of glutamic acid decarboxylase (GAD) and the expressions of BoGAD1 and BoGAD2. Meanwhile, fructose treatment inhibited the stem length of broccoli sprouts and enhanced the abscisic acid (ABA) production in comparison with the control. Ca2+, CaM contents, and BoCaM2 expression in broccoli sprouts were also stimulated after fructose treatment. Exogenous fructose increased inositol trisphosphate (IP3) content and activated the activity of phosphatidylinositol-specific phospholipase C (PI-PLC) and the expression of BoPLC2, contributing to Ca2+ influx into the cells. These results suggested that Ca2+ played an essential role in GABA enrichment under fructose treatment, which may be associated with GAD and PI-PLC.

Atg7 Knockout Alleviated the Axonal Injury of Neuro-2a Cells Induced by Tri-Ortho-Cresyl Phosphate.

Autophagy is believed to be essential for the maintenance of axonal homeostasis in neurons. However, whether autophagy is causally related to the axon degeneration in organophosphorus-induced delayed neuropathy (OPIDN) still remains unclear. This research was designed to investigate the role of autophagy in axon degeneration following tri-ortho-cresyl phosphate (TOCP) in an in vitro model. Differentiated wild-type and Atg7-/- neuro-2a (N2a) cells were treated with TOCP for 24 h. Axonal degeneration in N2a cells was quantitatively analyzed; the key molecules responsible for axon degeneration and its upstream signaling pathway were determined by Western blotting and real-time PCR. The results found that Atg7-/- cells exhibited a higher resistance to TOCP insult than wild-type cells. Further study revealed that TOCP caused a significant decrease in pro-survival factors NMNATs and SCG10 and a significant increase in pro-degenerative factor SARM1 in both cells. Notably, Atg7-/- cells presented a higher level of pro-survival factors and a lower level of pro-degenerative factors than wild-type cells in the same setting of TOCP administration. Moreover, DLK-MAPK pathway was activated following TOCP. Altogether, our results suggest that autophagy is able to affect TOCP-induced axonal injury via regulating the balance between pro-survival and pro-degenerative factors, providing a promising avenue for the potential therapy for OPIDN patients.

No-observed-adverse-effect level of hair pyrrole adducts in chronic n-hexane intoxication in rats.

n-Hexane has been reported to induce serious peripheral neuropathy in workers. Pyrrole adducts are the unique reaction products of n-hexane in organisms and have been demonstrated to be critical to n-hexane neuropathy. Our previous studies have demonstrated that pyrrole adducts could accumulate in hair and showed high correlation with neuropathy at the end of experiments in rat models. In the present study, we examined the time course of hair pyrrole adducts and behavioral changes in rats exposed to different dosages of n-hexane in both treatment (24 weeks) and recovery phases. Our results showed: 1. After treatment, 1.0, 2.0, and 4.0 g/kg dosage groups all lost weight, but the 0.5 g/kg dosage group showed no impairment; after recovery, all impaired rats regained weight. 2. After treatment, 1.0, 2.0, and 4.0 g/kg dosage groups all showed a rise in gait scores, decreased rotarod latency, and decreased motor nerve conduction velocity, whereas the 0.5 g/kg dosage group showed no impairment; after recovery, all impaired rats were completely rehabilitated. 3. After treatment, levels of pyrrole adducts in serum, urine, and hair of experimental groups increased; after recovery, serum and urine pyrrole adducts showed no difference from the control (P > 0.05), whereas hair pyrrole adducts were significantly different from the control (P < 0.01). 4. The half-lives of serum and urine pyrrole adducts were 47.8-78.0 h and 42.7-52.9 h, while the half-life of hair pyrrole adducts was 14-24 weeks. 5. During treatment and recovery, levels of serum, urine, and hair pyrrole adducts showed high correlation with gait scores (P < 0.01), and hair pyrrole adducts had the largest partial correlation coefficient. In conclusion, hair pyrrole adducts could serve as a stable and reliable biomarker for the prevention of n-hexane intoxication. Furthermore, the no-observed-adverse-effect level of hair pyrrole adducts in rats is 275.2 ±â€¯61.5 nmol/g protein. Further studies are required for the definition of the biological exposure limit in humans.

Diallyl sulfide-induced attenuation of n-hexane-induced peripheral nerve impairment is associated with metabolic inhibition of n-hexane.

Chronic exposure to n-hexane could induced serious peripheral nerve impairments. It has been well documented that the metabolic activation from n-hexane to 2,5-hexanedione (2,5-HD) is vital in the pathogenesis. Diallyl sulfide (DAS) is an extract of garlic and able to block the bioactivation of xenobiotic. The current study was designed to investigate whether DAS can attenuate n-hexane induced neuropathy. Male Wistar rats were pretreated with DAS (50 or 100 mg/kg.bw) and then n-hexane (3 g/kg.bw) for 7 weeks. Behavioral performance, biomarker measurement and toxicokinetic studies were performed. Enzymatic methods and western blotting analyses were also conducted to investigate the hepatic phase I enzymes (including cytochrome P450(CYP)2E1, CYP1A1 and CYP2B1) and phase II enzymes (including glutathione S transferase theta 1 (GSTT1) and NA(D)PH dehydrogenase quinone 1 (NQO1)). The results showed that DAS improved the behavioral performance while reducing the toxic metabolite: 2,5-HD and pyrrole adducts. Besides, DAS reduced the expression of CYP2E1 with a proportional decrease in activity, which largely decreased the bioactivation of n-hexane in vivo. The results suggested that DAS decreased the toxic metabolites of n-hexane to attenuate n-hexane-induced peripheral neuropathy.

Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation.

Mitochondrial dysfunction was considered as a critical event involved in acetaminophen (APAP)-induced acute liver injury. Mitophagy is a type of autophagy responsible for the selective removal of damaged mitochondria. However, the exact role and possible mechanism of mitophagy in APAP-induced hepatotoxicity remains largely unknown. In this study, C57/BL6 mice were used to establish a model of acute liver injury via intraperitoneal (i.p.) injection with different doses of APAP. Furthermore, autophagy intervention experiments were achieved by the administration of rapamycin (RAPA) or chloroquine (CQ) one hour prior to dosing 300 mg/kg APAP. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in mitophagy and NLRP3 inflammasome pathway were determined by electron microscopy, immunoblot, immunofluorescence and real-time PCR. The results demonstrated that APAP overdose resulted in an activation of PINK1/Parkin-mediated mitophagy in mice liver. Moreover, the expression of the critical molecules in NF-kB and NLRP3 inflammasome signaling pathway were markedly increased by APAP. Our further investigation found that pretreatment with RAPA protected against APAP-induced hepatoxicity in mice. Notably, RAPA significantly inhibited the activation of NF-kB and NLRP3 inflammasome and the production of IL-1ß in APAP-treated mice. By contrast, pretreatment with CQ further enhanced NLRP3 inflammasome signaling pathway. Taken together, these results indicated that activation of PINK1/Parkin-mediated mitophagy protects against APAP-induced acute liver injury in mice through inhibiting inflammasome activation. Therefore, mitophagy may represent a promising therapeutic target for APAP-induced liver injury.

Activation of PINK1-Parkin-dependent mitophagy in Tri-ortho-cresyl phosphate-treated Neuro2a cells.

Tri-ortho-cresyl phosphate (TOCP) is a typical organophosphorus compound that can cause organophosphate-induced delayed neuropathy (OPIDN), which is pathologically characterized by axonal degeneration. Nowadays, mitochondrial dysfunction is regarded as a potential mechanism contributing to OPIDN progress. Mitophagy, a selective type of autophagy, is required to segregate damaged mitochondria from healthy mitochondrial networks and deliver them to lysosome for degradation. This research was designed to investigate the role of mitophagy in axon degeneration following TOCP administration in an in vitro model. Differentiated neuro2a (N2a) cells were divided into four groups and treated with 0, 5, 10, and 20 µM TOCP for 24 h, respectively. The critical proteins in PINK1-Parkin-dependent mitophagy including LC3, P62, PINK1, Parkin, mitochondrial proteins, and autophagic receptors were detected by immunoblotting and immunofluorescence. After TOCP treatment, increased level of ROS in N2a cells revealed a significant mitochondria damage. Meanwhile, it was observed that much more PINK1, Parkin, and LC3-II were translocated to the mitochondria. Furthermore, immunofluorescence analysis demonstrated that the co-localization of Parkin and LC3 was significantly increased. These results suggested that PINK1-Parkin dependent mitophagy pathway in N2a cells was activated by TOCP treatment. In addition, P62, a major autophagic receptor, was markedly accumulated on the mitochondria, which indicated that P62 might play a critical role in facilitating mitophagy under TOCP-induced axonal degeneration. Taken together, our results suggest that TOCP exposure resulted in the activation of PINK1-Parkin-dependent mitophagy in N2a cells. Mitophagy may act as a positively reactive mode in eliminating dysfunctional mitochondria and therefore protect neurons against TOCP neurotoxicity.

Diallyl sulfide treatment protects against acetaminophen-/carbon tetrachloride-induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice.

The purpose of the present study was to investigate the effects and underlying mechanisms of diallyl sulfide (DAS), an organosulfur compound extracted from garlic, on drug-induced or chemical-induced liver injury caused by acetaminophen (APAP) or carbon tetrachloride (CCl4) in mice. DAS (100, 200, or 400 µmol kg-1) was orally administered 1 hour before APAP or CCl4 intraperitoneal injection, and the serum and liver tissue were collected 24 hours after APAP or CCl4 exposure. The serum aminotransferase activities and liver histopathological examination showed that DAS exhibited obvious hepatoprotective effects against acute liver injury induced by APAP or CCl4. In addition, exposure to APAP or CCl4 resulted in an increased content of malonaldehyde as well as a decreased ratio of reduced to oxidized glutathione, and a decreased level of superoxide dismutase and catalase activity in the liver (p < 0.05); however, pretreatment with DAS restored the perturbations of the antioxidant system in the liver. Beyond that, DAS pretreatment reduced the APAP-/CCl4-induced increase in phosphorylation of inhibitor of kappa B alpha (IκBα) and p65 subunit of nuclear factor kappa B (NF-κB) expression in the cytoplasm and nucleus in the liver. DAS pretreatment also decreased the excessive level of TNF-α caused by APAP or CCl4 in serum (p < 0.05). Moreover, DAS pretreatment regulated the expression of cleaved caspase 3, Bax and Bcl-2 in the liver and suppressed APAP-/CCl4-induced hepatocyte apoptosis. In conclusion, DAS exhibits hepatoprotective effects against drug-induced and chemical-induced liver injuries induced by APAP or CCl4 in mice, probably due to its ability to reduce hepatic oxidative stress and inhibit inflammatory injury and hepatocyte apoptosis.

Diallyl sulfide protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice.

The effects of diallyl sulfide (DAS) and the potential mechanisms were investigated on lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced acute liver injury in mice. DAS (50, 100, 200 µmol/kg) were orally given 1 h prior to LPS (10 µg/kg)/D-GalN (500 mg/kg) intraperitoneal injection. Serum and liver were collected at 8 h after LPS/D-GalN treatment. DAS Pretreatment reduced the activities of serum aminotransferase and attenuated histopathological damage in LPS/D-GalN-induced liver injury. Additionally, LPS/D-GalN-induced liver oxidative stress was ameliorated by DAS pretreatment, as evidenced by the decreased content of MDA and increased level of GSH, SOD, CAT in liver. Moreover, LPS/D-GalN-induced the excessive levels of TNF-α, IL-1ß and MCP-1 in serum and liver was decreased by DAS pretreatment. Furthermore, DAS pretreatment attenuated LPS/D-GalN-induced hepatocyte apoptosis, as evidenced by TUNEL staining and protein expression of cleaved caspase3, Bax and Bcl-2 in liver. DAS also up-regulated the expression of p-PI3K p85 and p-Akt in a dose-dependent manner, and Akt inhibitor MK-2206 weakened the inhibitory effect of DAS on hepatocyte apoptosis induced by LPS/D-GalN. In conclusion, the results suggest that DAS exerts the protective effect on LPS/GalN-induced acute liver injury, and this effects possibly by suppressing oxidative stress, inflammation and regulating hepatocyte apoptosis via the PI3K/Akt pathway.

Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease.

Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate-cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.

Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.

Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.

The protective effect of diallyl trisulfide on cytopenia induced by benzene through modulating benzene metabolism.

It has been known that metabolism of benzene is necessary for its toxicity. The purpose of our study is to investigate the effect of diallyl trisulfide (DATS) on attenuating cytopenia in peripheral blood introduced by benzene through regulating benzene metabolism in rats. We established benzene poisoning model with benzene (1.3 g/kg), while the DATS treatment groups were treated with DATS plus benzene (15 or 30 mg/kg) for 28 days, respectively. The results of blood parameters and concentration of metabolites of benzene (t, t-MA and SPMA) determination in urine showed that DATS could effectively attenuate the cytopenia induced by benzene through regulating benzene metabolism. Western blot and chemical method were used to detect the activities and protein expression levels of enzymes CYP2E1 and GSTT1 in liver and enzymes MPO and NQO1 in bone marrow were tested. The results suggested that the inhibition of bioactivation in liver and bone marrow catalyzed by CYP2E1 and MPO and the activation of detoxification catalyzed by GSTT1 and NQO1 might be the critical mechanism, through which DATS modulated benzene metabolism to prevent benzene-induced cytopenia.

Hair pyrrole adducts serve as biomarkers for peripheral nerve impairment induced by 2,5-hexanedione and n-hexane in rats.

Pyrrole adducts are specific reaction products of 2,5-hexadione (2,5-HD) in vivo and are considered highly relevant to the pathogenesis of peripheral nerve impairments after exposure to n-hexane, though the exact mechanism remains unclear. In this study, 40 male Wistar rats were randomly divided into three experimental groups and one control group, in which all rat's hair were shaved completely at the beginning. The rats in three experimental groups were treated with 2,5-HD by gavage at dosages of 100, 200 and 300 mg/kg per day respectively, six times per week for 8 weeks. Abnormality of gait and changes in the rota-rod latency were surveilled. Pyrrole adducts in hair, urine and serum of all rats were measured at the endpoint. Results showed that the increased pyrrole adducts in hair, urine and serum accumulated in dose-response relationship. Spearman's correlation analysis between pyrrole adducts and gait scores showed that hair pyrrole adducts were highly relevant to the gait scores. Moreover, we treated rats with n-hexane and succeed to verify the results aforesaid. Further, multiply linear regression analysis showed that hair pyrrole adducts have higher partial correlation coefficients than these in serum and urine in both 2,5-HD and n-hexane treated models. Our findings draw the conclusion that the hair pyrrole adducts might serve as a promising biomarker of n-hexane induced peripheral neuropathy.

Hepatoprotective effects of garlic against ethanol-induced liver injury: A mini-review.

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with a diverse spectrum from steatosis to hepatitis, fibrosis, and cirrhosis. Epidemiological studies reveal that alcohol is one of the major causes of advanced liver disease in Europe, United States, and China. Despite the considerable harm, progression in ALD research is slow and the current therapies for ALD have less efficient. Garlic (Allium sativum) has been used as a flavoring agent and also a folk medicine since ancient time. Along with the prosperity in the use of herbal medicines for the treatment of human diseases in recent decades, a series of studies have focused on the beneficial effects of garlic against ALD. This mini-review highlighted the protective roles of garlic against ALD and the potential mechanisms.

Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver.

Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver.

Diallyl trisulfide (DATS) suppresses benzene-induced cytopenia by modulating haematopoietic cell apoptosis.

Benzene is a well-known occupational and environmental toxicant associated with cytopenia, which is characterized by a disorder in the peripheral blood cell counts. However, no effective preventive strategy has been developed yet to tackle the exposure to benzene in daily life. The aim of this study was to evaluate the protective effects of diallyl trisulfide (DATS) on benzene-induced haematopoietic damage and to reveal its potential mechanisms of action. In our study, male Sprague-Dawley rats were divided into six groups. Rats were administered with benzene (1.3 g/kg BW by gavage) to establish the benzene poisoning model, while the DATS treatment groups were treated with benzene plus DATS (15 mg/kg, 30 mg/kg, 45 mg/kg, respectively, by gavage) for 28 days. Our results demonstrated that the counts of peripheral blood WBC and RBC decreased to 31.0% and 79.2%, respectively, in the benzene poisoning model group compared to the control. However, blood cell counts were restored by DATS treatment (30 mg/kg, 45 mg/kg). The apoptosis rates of peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs) were increased to 274% and 284%, respectively, following benzene exposure. Furthermore, expression levels of Bcl-2, PI3K and p-Akt were downregulated and those of Bax were upregulated in both cell types. Moreover, the oxidative parameters (oxygen species, malonaldehyde) were significantly increased, while the non-enzymatic GSH/GSSG ratios and the activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase and catalase) were decreased. Interestingly, DATS treatment can restore the WBC number by 267.1% and 304.8% while RBC number by 108.6% and 117.7% in 30,45 mg/k DATS treated groups. In summary, we demonstrated that benzene-induced cytopenia was related to the apoptosis of PBMCs and BMCs, and DATS treatment could prevent benzene-induced cytopenia by suppressing oxidative stress-mediated cell apoptosis via the PI3K/Akt pathway.

Diallyl trisulfide attenuated n-hexane induced neurotoxicity in rats by modulating P450 enzymes.

Chronic exposure to n-hexane can induce serious nerve system impairments without effective preventive medicines. Diallyl trisulfide (DATS) is a garlic-derived organosulfur compound, which has been demonstrated to have many beneficial effects. The current study was designed to evaluate whether DATS could restrain n-hexane induced neurotoxicity in rats and to explore the underlying mechanisms. Rats were treated with n-hexane (3 g/kg, p.o.) and different doses of DATS (10, 20 and 30 mg/kg, p.o.) for 8 weeks. Behavioral assessment showed that DATS could inhibit n-hexane induced neurotoxicity, demonstrated by the improvement of the grip strength and decline of gait scores. Toxicokinetic analysis revealed that the Cmax and AUC0-t of 2,5-hexanedione (product of n-hexane metabolic activation) and 2,5-hexanedione protein adducts in serum were significantly declined in DATS-treated rats, and the levels of pyrrole adducts in tissues were significantly reduced. Furthermore, DATS activated CYP1A1 and inhibited n-hexane induced increased expression and activity of CYP2E1 and CYP2B1. Collectively, these findings indicated that DATS protected the rats from n-hexane-induced neurotoxicity, which might be attributed to the modulation of P450 enzymes by DATS.

Cystamine attenuated behavioral deficiency via increasing the expression of BDNF and activating PI3K/Akt signaling in 2,5-hexanedione intoxicated rats.

Organic solvent-induced neurodegeneration is a severe public health problem which has no effective prevention measures yet. Cystamine stands as a promising neuroprotective agent against many degenerative diseases. In the present study, we investigated the possible protective effects of cystamine against 2,5-hexanedione (2,5-HD) induced peripheral neuropathy. Chronic exposure to 2,5-HD (300 mg kg-1, 6 times per week for 6 weeks) resulted in obvious peripheral nerve damage shown as the elevation of gait scores and the increase of latency in an accelerating rota-rod test. Cystamine (30 mg kg-1 and 60 mg kg-1) co-treatment obviously ameliorated 2,5-HD-induced impairments of the peripheral nervous system. To decipher the underlying mechanisms, we investigated the effects of cystamine on the regulation of brain-derived neurotrophic factor (BDNF) and heat shock protein-70 (Hsp70) expression and the PI3K/Akt signaling pathway. The results revealed that cystamine up-regulated the protein levels of BDNF and Hsp70, accompanied by the activation of the PI3K/Akt pathway in the spinal cord, which might account for the protection of cystamine against 2,5-HD-induced neuropathy.

Oxidative Stress Mediated Hippocampal Neuron Apoptosis Participated in Carbon Disulfide-Induced Rats Cognitive Dysfunction.

Occupational exposure to carbon disulfide (CS2) exhibits central nervous systems toxicity. But the mechanism is unclear. The present study was designed to investigate the relationship between the CNS damage and cognitive dysfunction caused by CS2, and eventually reveal the possible oxidative-related mechanism of hippocampus pathological changes in CS2 exposed rats. Male Wistar rats were administrated with CS2 at dosage of 200, 400 and 600 mg/kg for consecutive 20 days, respectively. Cognitive performances were evaluated by Morris water maze tests. Thionin and immunohistochemical analysis were used to investigate the hippocampal neuron damage, and the expression of apoptosis related proteins (cleaved-caspase 3, Bax and Bcl-2) were detected to explore the possible mechanisms of neuronal loss. Oxidative stress parameters were checked by commercial assay kits. Rats exposed to CS2 displayed cognitive dysfunction manifested as decreased spatial learning ability and memory lesion. Pathological changes and significant neuron loss were observed in hippocampus, especially in CA1 and CA3 sub-regions. Mitochondria-dependent apoptosis pathway was implicated in the CS2-induced neuronal loss which was demonstrated by the up-regulation of cleaved-caspase 3 and Bax accompanied with down-regulation of Bcl-2. Furthermore, extensive oxidative stress induced by CS2 was also revealed by the measurement of ROS, RNS, MDA, GSH&GSSG and antioxidant enzymes (CAT, T-SOD, and GSH-Px). Our study suggested that oxidative stress mediated hippocampal neuron apoptosis might play an important role in CS2 induced CNS damage and cognitive dysfunction.

Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials.

Alcoholic liver disease (ALD) encompasses a spectrum of liver injury ranging from steatosis to steatohepatitis, fibrosis, and finally cirrhosis. Accumulating evidences have demonstrated that Kupffer cells (KCs) play critical roles in the pathogenesis of both chronic and acute ALD. It has become clear that alcohol exposure can result in increased hepatic translocation of gut-sourced endotoxin/lipopolysaccharide, which is a strong M1 polarization inducer of KCs. The activated KCs then produce a large amount of reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, which finally lead to liver injury. The critical roles of KCs and related inflammatory cascade in the pathogenesis of ALD make it a promising target in pharmaceutical drug developments for ALD treatment. Several drugs (such as rifaximin, pentoxifylline, and infliximab) have been evaluated or are under evaluation for ALD treatment in randomized clinical trials. Furthermore, screening pharmacological regulators for KCs toward M2 polarization may provide additional therapeutic agents. The combination of these potentially therapeutic drugs with hepatoprotective agents (such as zinc, melatonin, and silymarin) may bring encouraging results.