Safinamide prevents lipopolysaccharide (LPS)-induced inflammation in macrophages by suppressing TLR4/NF-κB signaling.

Inflammation is a basal host defense response that eliminates the causes and consequences of infection and tissue injury. Macrophages are the primary immune cells involved in the inflammatory response. When activated by LPS, macrophages release various pro-inflammatory cytokines, chemokines, inflammatory mediators, and MMPs. However, unbridled inflammation causes further damage to tissues. Safinamide is a selective and reversible monoamine oxidase B (MAOB) inhibitor that has been used for the treatment of Parkinson's disease. In this study, we aimed to investigate whether safinamide has effects on LPS-treated macrophages. Our results show that safinamide inhibited the expression of pro-inflammatory cytokines such as IL-1α, TNF-α, and IL-6. Furthermore, safinamide suppressed the production of CXCL1 and CCL2, thereby preventing leukocyte migration. In addition, safinamide reduced iNOS-derived NO, COX-2-derived PGE2, MMP-2, and MMP-9. Importantly, the functions of safinamide mentioned above were found to be dependent on its inhibitory effect on the TLR4/NF-κB signaling pathway. Our data indicates that safinamide may exert a protective effect against inflammatory response.

Recombinant human soluble thrombomodulin protects against brain injury in a CVST rat model, via downregulation of the HMGB1-RAGE axis.

Cerebral venous sinus thrombosis (CVST) is a distinct cerebrovascular disorder, and ~50% of CVST patients progress to cerebral venous infarction, resulting in elevation of cerebral venous pressure. Anticoagulation is the standard initial treatment and is associated with a reduced relative risk of mortality and dependency. Recombinant human soluble thrombomodulin (rhs­TM) is a promising therapeutic natural anticoagulant comparable to antithrombin, tissue factor pathway inhibitor, and activated protein C. The present study aimed to investigate the protective effects of rhs­TM in a CVST rat model, and identify any underlying mechanisms. Rats were treated with rhs­TM intravenously prior to CVST. Following neurological function evaluation, animals were sacrificed and brain water content and infarct volume were assessed. Brain tissue was collected from the infarcted segments and mRNA and protein expression levels of high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­6, caspase­3, B­cell lymphoma­2 and Bcl­2 associated X were analyzed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. rhs­TM significantly prevented neurological deficits in locomotor function and reduced infarct volume. The expression levels of HMGB1­RAGE were upregulated in the infarcted segments of rat brains following CVST. Pretreatment with rhs­TM inhibited the HMGB1­RAGE axis, alleviating the expression levels of the proinflammatory cytokines, TNF­α, IL­1ß and IL­6; however, expression levels of the apoptosis-associated genes and proteins remained unaffected. The results of the present study indicated that rhs­TM protects against CVST in the rat model via inhibition of the HMGB1­RAGE axis and inflammation, but not via apoptosis.

[Effect of capsule of Shenshuai Yangzhen on malnutrition rats with chronic renal failure by 5/6 nephrectomy].

OBJECTIVE: To investigate the effects of capsule of Shenshuai Yangzhen, a preparation of traditional Chinese medicine, on malnutrition rats with chronic renal failure (CRF). METHODS: SD rats received 5/6 nephrectomy for preparation of CRF models, and fed 4% casein at the same time. Observed when malnutrition began. Those consistents with malnutrition of CRF condition were randomized into model control group, Ketosteril group, Shenshuai Yangzhen group, and normal control group. After 4-weeks treatment as indicated, The blood parameters, like blood serum albumin (ALB), type-1 insulin like growth factor (IGF-1), total cholesterol (TC), triglyeride (TG), urea nitrogen (BUN), serum creatinine (Scr), haemoglobin (Hb), 24 hour urineprotein (24hUpr) and weight were determined. Nephrotic tissue was observed by microscope (included HE and PAS). RESULTS: Malnutrition situation in CRF rats began at the end of 10-weeks. After 4-weeks treatment, weight in Shenshuai Yangzhen group were higher significantly (P < 0.05). Compared with model control group, blood serum BUN (P < 0.05), SCr (P < 0. 05) and 24h Upr (P < 0.001) in Shenshuai Yangzhen group were significantly lower with substantially elevated blood serum ALB, Hb, IGF-1 (P < 0.01; P < 0.001; P < 0.001, respectively). Pathology of Shenshuai Yangzhen group was a meliorated significantly after treated. CONCLUSION: Capsule of Shenshuai Yangzhen has a possible therapic effect on improving malnutrition in rats with renal insufficiency.

[Anti-apoptosis effect of astragaloside on adriamycin induced rat's cardiotoxicity].

OBJECTIVE: To study the possible mechanism of anti-myocardial cell apoptosis of astragaloside induced by adriamycin (ADR). METHODS: Fifty SD rats were randomized into five groups: the normal control group,the model group, the astragaloside low dose (A-L) group, the astragaloside medium dose (A-M) group and the astragaloside high dose (A-H) group, 10 in each group. The normal control group was given normal saline by intraperitoneal injection, while the other four groups were given ADR by intraperitoneal injection once every other day for six times with the total dosage of 15 mg/kg. At the same time, different dosage of astragaloside was administrated by gavage to the three treated groups, and sodium carboxymethycellulose (SCMC) was given to the normal control and the model group. Myocardial cell apoptosis was examined by in situ end-labeled DNA (TUNEL), protein and mRNA expressions of bax, bcl-2 were detected respectively with immunohistochemistry assay and RT-PCR. RESULTS: Compared with those in the normal control, apoptosis index was significantly higher, the protein and mRNA expressions of bcl-2 were lower and those of bax were higher, in the model group, resulted in lower ratio of bcl-2/bax (P < 0.05 or P < 0.01). However, in the A-H group, apoptosis index decreased significantly, the expressions of bcl-2 were higher, those of bax were lower, and ratio of the bcl-2/bax increased (all P < 0.05). CONCLUSION: High dose of astragaloside could suppress the myocardial cell apoptosis induced by ADR with the possible mechanism related to regulating the expressions of bcl-2 and bax.

[Inhibitory effect of CVB3-VP1 siRNA on CVB3 replication].

AIM: To inhibit the expression of CVB3 VP1 protein and the replication of CVB3 with synthesized siRNAs. METHODS: According to the sequence and secondary structure of CVB3 VP1 protein, four pieces of siRNAs were designed following the requirement from Journal of Nature Cell Biology were synthesized in Shanghai GeneChem Company. Then they were transfected into HeLa cells by liposome (Lipofectamine 2000), but the non-transfected cells and non-specific siRNAs were taken as control. 48 hours later, the patho-morphous changes were observed, virus titer changes were examined by TCID50, CVB3-VP1 protein expression were detected by immunofluorescence with FITC dyeing, and CVB3-RNA level was tested by semi-quantitative RT-PCR. RESULTS: Two pieces of the four specific synthesized siRNAs (VP1-1 and VP1-2) were found to have obvious inhibitory effect on CVB3 replication and VP1 protein expression were reduced greatly. Besides, the changes of pathological cells were obviously mitigated. CONCLUSION: Specific siRNAs can effectively inhibit the expression of CVB3 VP1 protein and the replication of CVB3 in HeLa cells.