CPCGI confers neuroprotection by enhancing blood circulation and neurological function in cerebral ischemia/reperfusion rats.

The current study used a rat middle cerebral artery occlusion (MCAO) model with the aim to explore the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain ischemia/reperfusion injury in rats. Improvement in the infarct­side microcirculation and the overall recovery of neurological function were detected by triphenyltetrazolium chloride staining, laser speckle blood flow monitoring, latex perfusion, immunofluorescence and immunoblotting. The results revealed that administration of CPCGI for 7 consecutive days following ischemic stroke contributed to the recovery of neurological function and the reduction of cerebral infarct volume in rats. Blood flow monitoring results demonstrated that the administration of CPCGI effectively promoted cerebral blood flow following stroke, and contributed to the protection of the ischemic side blood vessels. In addition, CPCGI treatment increased the numbers of new blood vessels in the peripheral ischemic region, and upregulated the expression levels of vascular endothelial growth factor, angiopoietin 1 and its receptor TEK receptor tyrosine kinase, fibroblast growth factor and Wnt signaling pathway­associated proteins. Taken together, the present results indicated that CPCGI improved the blood circulation and neurological function following cerebral ischemia/reperfusion in rats.

Effects of compound porcine cerebroside and ganglioside on neurotoxicity caused by oxaliplatin chemotherapy: preliminary results.

OBJECTIVE: Oxaliplatin has shown good anti-tumour activity in the treatment of tumours involving the digestive system. However, its application is limited because of severe neurotoxicity in some patients. The purpose of this study was to evaluate whether compound porcine cerebroside and ganglioside (CPCG) can reduce or prevent oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS: Patients with digestive system tumour who received oxaliplatin-based chemotherapy were retrospectively divided into experimental and control groups according to the receipt of CPCG during chemotherapy. Adverse events at the end of each chemotherapy cycle were recorded. We compared the incidence of neurotoxicity between the two groups and graded the neurotoxicity symptoms using the Common Terminology Criteria for Adverse Events v5.0. RESULTS: The study included 115 patients (experimental group, 57; control group, 58). The number of chemotherapy cycles (6.65 vs. 6.41, p=0.540) and oxaliplatin dose (775.92 mg/m2 vs. 724.20 mg/m2, p=0.250) were comparable between the two groups. All patients developed grade 1 to 3 neurotoxicity; grade 4-5 neurotoxicity was not observed. The incidence of neurotoxicity and the probability of advanced neurotoxicity were significantly lower in the experimental group than in the control group (p<0.05). After a 6 to 18 months follow-up, the two groups showed no significant differences in the chemotherapy response and recurrence rate (p=0.846). CONCLUSIONS: CPCG reduces oxaliplatin-induced neurotoxicity without reducing the efficacy of oxaliplatin-based regimens; thus, it can be used for preventing oxaliplatin-induced neurotoxicity in patients with cancer.

Cerebrosides from Sea Cucumber Improved Aß1-42 -Induced Cognitive Deficiency in a Rat Model of Alzheimer's Disease.

SCOPE: Cerebrosides are a class of neutral glycosphingolipids, which are widely found to be present in brain tissue. In this study, the protective effect of sea cucumber cerebrosides (Cer) against ß-amyloid (Aß)-induced cognitive impairment is investigated. METHODS AND RESULTS: Male SD rats receive a ventricle injection Aß1-42 peptide to establish an Alzheimer's disease model. Then, the protective effects of Cer against Aß1-42 -induced cognitive impairment by gavage and feed addition are evaluated. The Morris water maze test results show that oral administration of Cer can significantly ameliorate Aß1-42 -induced cognitive deficiency at both high dose (200 mg per kg·per day) and low dose (40 mg per kg·per day) for 27 days. Dietary supplement of Cer by feed addition also exhibits the amelioration on the impaired cognitive function. Further findings indicate that Cer ameliorates Aß1-42 -induced neuronal damage and suppresses the induced apoptosis by decreasing the level of Bax/Bcl-2. Additionally, Cer enhances the expressions of PSD-95 and synaptophysin by activating BDNF/TrkB/CREB signaling pathway, thereby ameliorating Aß1-42 -induced synaptic dysfunction. Furthermore, Cer attenuates Aß1-42 -induced tau hyperphosphorylation by activating the PI3K/Akt/GSK3ß signaling pathway. CONCLUSION: Sea cucumber cerebrosides possess neuroprotective effects against Aß1-42 -triggered cognitive deficits, which may be a potential nutritional preventive strategy for neurodegenerative diseases.

The Protective Activities of Dietary Sea Cucumber Cerebrosides against Atherosclerosis through Regulating Inflammation and Cholesterol Metabolism in Male Mice.

SCOPE: Cerebroside is an active component extracted from sea cucumber (SCC), which is a traditional tonic food in China. In this study, the protective effect of SCC on atherogenesis is investigated and the possible underlying mechanism is determined. METHOD AND RESULTS: Male C57BL/6J obese mice were first used to explore the impact of SCC at different doses on alleviating lipid disorders and insulin sensitivity. Then ApoE-/- mice were used to evaluate the protective activities of SCC on atherosclerosis. The results demonstrated that dietary SCC increased the insulin sensitivity and reduced serum and hepatic lipid profiles in a dose-dependent manner in C57BL/6J mice. In ApoE-/- mice, SCC treatment significantly decreased the atherosclerotic lesion formation and attenuated inflammation by decreasing the levels of inflammatory cytokines, such as CRP, TNF-α, IL-6. Compared to the model group, the SCC group showed lower cholesterol levels in serum and liver by mediating the expression of genes related to hepatic LDL uptake and cholesterol excretion. CONCLUSION: Dietary SCC has the potential to eliminate atherosclerosis through regulating inflammation and cholesterol metabolism, and may be beneficial for the health of patients with cardiovascular disease.

Immunohistochemical expression of cereblon and MUM1 as potential predictive markers of response to lenalidomide in extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma).

Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014. In total, 28% (13/46) of biopsy specimens derived from gastric tissues, while 72% (33/46) originated from extragastric MALT lymphoma. In terms of CRBN, 54% showed high expression (CRBN+, ≥50% positive cells); the remaining 46% were classified as low expression (CRBN-). In contrast to other reports, there was a non-significant trend towards worse response rates in CRBN+ (68% versus 86%, P = 0.161). Relapse rates (P = 0.592) and PFS (P = 0.306) did not differ between CRBN+/CRBN-, but all 3 patients progressing on lenalidomide were CRBN+ and both patients completely lacking CRBN expression responded to treatment. Concerning MUM1, 62% were MUM1-negative (MUM1-) and 38% positive (MUM1+). There was no difference in response to lenalidomide by MUM1-status (MUM1+ 71% versus MUM1- 79%, P = 0.546) and also relapse rates (P = 0.828) and PFS (P = 0.681) did not differ. Interestingly, a subgroup analysis of gastric lymphoma revealed a significantly better PFS for CRBN- and MUM1- patients, respectively (both P < 0.05). To conclude, there was no significant difference in response to lenalidomide between patients with low or high expression of CRBN/MUM1 in a general population of MALT lymphoma, and immunohistochemical CRBN/MUM1 assessment cannot be recommended in the clinical routine.

Cerebroside D, a glycoceramide compound, improves experimental colitis in mice with multiple targets against activated T lymphocytes.

In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1ß in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation.

Dietary sea cucumber cerebroside alleviates orotic acid-induced excess hepatic adipopexis in rats.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease in industrialized countries. The present study was undertaken to explore the preventive effect of dietary sea cucumber cerebroside (SCC) extracted from Acaudina molpadioides in fatty liver rats. METHODS: Male Wistar rats were randomly divided into four groups including normal control group, NAFLD model group, and two SCC-treated groups with SCC at 0.006% and 0.03% respectively. The fatty liver model was established by administration of 1% orotic acid (OA) to the rats. After 10d, serum and hepatic lipid levels were detected. And the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were also determined. Besides, to gain the potential mechanism, the changes of key enzymes and gene expressions related to the hepatic lipid metabolism were measured. RESULTS: Dietary SCC at the level of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats. SCC administration elevated the serum triglyceride (TG) level and the ALT, AST activities in OA-fed rats. The activities of hepatic lipogenic enzymes including fatty acid synthase (FAS), malic enzyme (ME) and glucose-6-phosphatedehydrogenase (G6PDH) were inhibited by SCC treatment. And the gene expressions of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c) were also reduced in rats fed SCC. However, dietary SCC didn't affect the activity and mRNA expression of carnitine palmitoyltransferase (CPT) in liver. Besides, suppression of microsomal triglyceride transfer protein (MTP) activity was observed in SCC-feeding rats. CONCLUSIONS: These results suggested that dietary SCC could attenuate hepatic steatosis due to its inhibition of hepatic lipogenic gene expression and enzyme activity and the enhancement of TG secretion from liver.

[Effect of sea cucumber cerebroside on lipid metabolism in fatty liver rats].

OBJECTIVE: To investigate the effect of sea cucumber cerebroside (SCC) on the lipid metabolism in rats with orotic acid-induced fatty liver. METHODS: The non-alcoholic fatty liver disease (NAFLD) model was established by adding orotic acid to the diets in rats. The rats were randomly assigned to four groups:control group, NAFLD group, NAFLD + low SCC group and NAFLD + high SCC group. After 10 days of feeding, the serum and hepatic lipid concentrations and the aminopherase activities were measured; the composition of hepatic fatty acids was also analyzed. RESULT: The serum TC and TG levels reduced significantly in the NAFLD group as compared with the controls (P<0.05), while the sea cucumber cereborside feeding raised the serum lipid concentrations (P<0.05). The hepatic TC and TG levels dramatically increased in the NAFLD group in comparison with the controls (P<0.05, P<0.01), while the hepatic lipid accumulations decreased in both SCC groups (P<0.05, P<0.01). The ALT and AST activities in the NAFLD group increased markedly when compared with the controls (P<0.05, P <0.01), while the sea cucumber cerebroside feeding attenuated the hepatic injury levels (P<0.05, P<0.01). Compared with the control group, the stearoyl-CoA desaturase (SCD) activity increased significantly in the NAFLD group (P<0.05), but decreased in SCC groups (P<0.05). CONCLUSION: Sea cucumber cerebroside can attenuate the rat fatty liver induced by orotic acid.

Effect of liposomes containing cerebroside and cerebroside sulfate on cytoskeleton of cultured oligodendrocytes.

Oligodendrocytes (OLs) and the myelin produced by them are enriched in two glycosphingolipids, galactosylceramide (GalC) and its sulfated form, cerebroside sulfate (CBS). We showed earlier that these two glycolipids in opposed liposomal membranes or in methanol solution can adhere to each other. Here we have examined the potential effect of an interaction between GalC/CBS in apposed membranes of oligodendrocytes (OLs) by incubating cultured OLs with GalC/CBS-containing liposomes and observing the effect on the membrane sheets produced by OLs and on the distribution of OL constituents using fluorescent antibodies and confocal microscopy. The GalC/CBS-containing liposomes caused redistribution or a decrease in the density of anti-GalC and anti-MBP staining but had no effect on the density or distribution of staining by anti-PI(4,5)P(2) that remained uniformly distributed in the membrane sheets. There was no apparent change in the area of the membrane sheets nor in the amount of MBP in OL membranes, as determined by slot blots. In addition, the GalC/CBS-containing liposomes caused depolymerization of microtubules and actin filaments suggesting that the interaction of GSL-containing liposomes with the extracellular surface of the OL caused transmission of a signal across the membrane. Because these two glycolipids can adhere to each other across apposed membranes, the liposomal glycolipids may be interacting with a GalC/CBS-enriched signaling domain in the OL plasma membrane.

Oleamide potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor activity but does not alter minimum alveolar anesthetic concentration.

UNLABELLED: A naturally occurring brain lipid, cis-9,10-octadeceamide--oleamide (OA), is found in increased concentrations in the cerebrospinal fluid of sleep-deprived cats, which suggests that it may be an endogenous sleep-inducing substance. We studied the effects of this fatty-acid derivative on the function of cloned gamma-aminobutyric acid (GABA(A)) receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA synthesized in vitro to express simple GABA(A) receptors (alpha1beta1, alpha3beta1, alpha5beta1, and alpha1beta2 subunit combinations) and receptors in which the GABA-induced chloride currents were potentiated in the presence of benzodiazepines (alpha1beta1gamma2s and alpha1beta2gamma2s subunit combinations). OA only produced significant potentiation of the peak Cl- current when applied with GABA to benzodiazepine-sensitive GABA(A) receptors. The peak currents of the simple GABA(A) receptors in the presence of OA were either unaffected or slightly inhibited by OA, but the overall mean currents were not significantly altered. Oleic acid was also capable of potentiating benzodiazepine-sensitive GABA(A) receptor function. The function of other ligand-gated ion channels, such as the N-methyl-D-aspartate receptor (NR1 + NR2A or 2C) and the 5-HT3 receptor expressed in Xenopus oocytes, were unaffected by OA. Sprague-Dawley rats receiving intraperitoneal injections of oleamide (10, 20, or 100 mg/kg) showed no change in the minimum alveolar anesthetic concentration (MAC) of desflurane required to abolish movement in response to noxious (tail clamp) stimulation (control MAC 6.48% +/- 1.28% atm; 100 mg/kg OA MAC 7.05% +/- 0.42% atm). These results reinforce the view that oleyl compounds may be natural modulators of inhibitory ion channel function, but that these effects contribute little to the central nervous system depression produced by volatile anesthetics as measured by MAC. IMPLICATIONS: The putative sleep-inducing substance, oleamide, potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor function but does not alter desflurane minimum alveolar anesthetic concentration in rats.

Effect of a hexosylceramide fraction of the hemodialysate Solcoseryl on wound-healing angiogenesis.

Rabbit ear chambers were used to investigate the effects of a locally applied hexosylceramide fraction (Hex-Cer) of the hemodialysate Solcoseryl on wound-healing angiogenesis. The transparent methacrylate ear chambers were inserted under full aseptic precautions. Immediately after implantation the chambers in control rabbits were filled with physiological saline while the chambers in experimental rabbits were injected with a solution containing either 0.3 or 2.5 micrograms/ml of Hex-Cer, respectively. On the second postoperative day the chambers were reinjected with the corresponding solutions. Thereafter the chambers were examined three times weekly. The onset and rate of the neovascular response were measured by using a standard dissecting microscope equipped with a camera. Vessel growth in ear chambers treated with Hex-Cer at the lower concentration showed very little difference from that seen in control chambers; in both groups the first appearance of new capillaries occurred on an average of 18 days after implantation, and the chambers became fully filled with vessels by the 30th day. However, in chambers treated with Hex-Cer at the higher concentration, the first invasion of capillaries was detected 3 days earlier than in controls (P less than 0.05). Correspondingly, in the chambers treated with Hex-Cer complete vascularization was achieved 7 days earlier than in the control chambers (P less than 0.01). It is concluded that locally applied Hex-Cer exerted an accelerating effect on wound-healing angiogenesis.

Experimental allergic neuritis: demyelination induced by P2 alone and non-specific enhancement by cerebroside.

Experimental allergic neuritis was induced in male inbred Lewis rats immunized with myelin, P2 alone, P2 mixed with galactocerebroside and P2 mixed with glucocerebroside. Neurological deficit started significantly earlier in myelin-immunized rats than in P2-immunized rats. Although myelin-immunized rats appeared most severely affected, differences between the groups in maximum neurological deficit were not significant. The course of the disease of the P2-galactocerebroside-immunized animals did not differ from that of the P2-glucocerebroside-immunized group. Histologically, cellular infiltration and demyelination were more conspicuous 12 days after immunization in the group immunized with myelin than in the other rats. After 21 days, primary demyelination was prominent in all groups: its frequency and severity were similar in the myelin-immunized and P2-immunized animals. The P2-galactocerebroside-immunized group had significantly more frequent demyelination than the P2-immunized group. Wallerian degeneration was prominent in all groups at this stage. We conclude that P2 alone does induce demyelination and that galactocerebroside added to the immunizing emulsion enhances the response but no more than the non-myelin lipid glucocerebroside.