Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system

Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60 % even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects.     

The antioxidant gallic acid induces anxiolytic-, but not antidepressant-like effect,in streptozotocin-induced diabetes

The physiopathology of anxiety or depression related to diabetes is still poorly understood. The treatment with antidepressant drugs is a huge challenge due to theirs adherence low rate and many adverse effects. Thus, the seeking for a better treatment for these associated diseases is of utmost importance. Given that the oxidative stress in different tissues occurs in diabetes and anxiety or depression as well, the antioxidant gallic acid becomes an interesting compound to be investigated. Thus, the effects of long-term treatment with gallic acid (0, 10, 20 and 40 mg/kg; gavage) were evaluated in diabetic (DBT) animals submitted to the elevated plus-maze (EPM), the light-dark transition (LDT) tests and modified forced swim test (mFST). Also, indirect parameters of oxidative stress, lipid peroxidation (LPO) and reduced glutathione (GSH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC). The results showed that DBT animals presented a decrease in the spent time in the open arms, in the end arm exploration and head dips when evaluated in the EPM test; moreover, a decrease in the spent time in the lit compartment of LDT test was observed, suggesting an anxiogenic-like behavior. During the mFST, an increase in the mean counts of immobility and a decrease in the mean counts of swimming and climbing were observed, indicating a depressive-like behavior. These aversive behaviors were more pronounced when compared to normoglycemic (NGL) animals and streptozotocin-treated animals that not become DBT. In addition, DBT rats showed an increase in the oxidative stress parameters in the HIP and PFC that was reversed by the gallic acid treatment (lowest dose - 10 mg/kg), i.e., the treatment decreased the elevated LPO levels and increased the reduced GSH in the HIP and PFC. Also, gallic acid treatment was able to produce an anxiolytic-like effect in the EPM and LDT tests, but not antidepressant–like effect in the FST. Taken together, the results suggest that the antioxidant/neuroprotective effect of gallic acid treatment in HIP and PFC of DBT animals may be essential to the anxiolytic-like effect.     

尼美舒利和5-氟尿嘧啶联用对胃癌细胞的协同抑制作用及机制

目的 体外研究选择性环氧合酶-2（COX-2）抑制剂尼美舒利和5-氯尿嘧啶（5-FU）对胃癌细胞的抑制作用及机制。方法 以胃癌细胞株MKN45、MKN28为研究对象．观察尼美舒利和5-FU单独或联合应用对细胞增殖、凋亡和细胞周期的影响。应用MTT法检测细胞增殖，流式细胞仪检测细胞凋亡（FITC-Annexin-V/PI双标记）和细胞剧期，RT-PCR观察朋药前后COX-2 mRNA在两株细胞中的表达，Western免疫印迹法观察经两种药物单独和联合作用48h后细胞内凋亡相关蛋白Bax和Bcl-2的表达。结果 在MKN45和MKN28细胞中均可观察到不同水平的COX-2 mRNA表达，尼美舒利和5FU联合应用可明显抑制COX-2 mRNA表达。尼美舒利可抑制两株细胞的增殖并诱导凋亡。尼美舒利和5-FU具有协同抑制细胞增殖及诱导凋亡的作用，该作用与两种药物作用顺序无关，但在联用时作用最强。两药协同抑制增殖的作用主要通过协同杀伤和诱导凋亡而实现。5-FU增强了凋亡诱导蛋白Bax的表达，而尼美舒利则减少凋亡抑制蛋白Bcl-2的表达。两药联用可明显抑制胃癌细胞株生长。结论 选择性环氧合酶-2抑制剂尼美舒利和5-FU通过抑制COX-2 mRNA的表达硬增强Bax／Bcl-2的表达比率诱导胃癌细胞凋亡．从而对胃癌细胞起到协同抑制增殖的作用。     

An unusual central nervous system involvement in rheumatoid arthritis: combination of pachymeningitis and cerebral vasculitis

Severe primary central nervous system (CNS) involvement such as vasculitis and pachymeningitis can rarely occur in rheumatoid arthritis (RA) even in the absence of systemic disease activation. The authors illustrate a female patient with well-controlled RA who presented with headaches, encephalopathy, seizures and relapsing focal neurological deficits. Primary rheumatoid cerebral vasculitis and pachymeningitis were diagnosed based on suggestive brain magnetic resonance (MR) imaging, MR angiography, cerebrospinal fluid analysis and cerebral angiography. MR showed abnormal leptomeningeal enhancement and hyperintense FLAIR signal in the cortical subarachnoid spaces consistent with pachymeningitis. Cerebral angiography findings were consistent with vasculitis. Aggressive treatment resulted in significant clinicoradiological resolution. Cerebral vasculitis is a rare but certain manifestation of RA. This complication can be diagnosed in the presence of suggestive angiographic and CSF findings. The condition may be steroid resistant, and needs to be treated more aggressively.     

The effect of hydroxyethylrutoside and its combination with acetylsalicylic acid in patients with obliterative atherosclerosis

The effect of 7-mono-hydroxyethylrutoside and its combination with acetylsalicylic acid was evaluated in a controlled clinical trial, performed in 105 patients with obliterative atherosclerosis of the lower limbs, and using non-invasive measurement of peripheral haemodynamic parameters--blood flow during reactive hyperaemia and ankle systolic blood pressure. Patients, randomized into three groups, received either placebo or 7-mono-hydroxyethylrutoside alone or in combination with acetylsalicylic acid for 12 months. The placebo group showed a decrease in maximum calf blood flow and a decrease in ankle systolic pressure. Administration of 7-mono-hydroxyethylrutoside did not lead to any significant changes in systolic pressure but there was a decrease in the maximum calf blood flow. There were no statistically significant changes in patients receiving the 7-mono-hydroxyethylrutoside and acetylsalicylic acid combination who, by contrast, showed a tendency to increased values of the parameters measured.     

Synergistic effects of interferon-alpha in combination with chemoradiation on human pancreatic adenocarcinoma

AIM: To determine whether IFN-α is the agent that turns a slightly effective treatment (radiochemotherapy) into a potent therapy, we tested IFN-α for its synergistic properties. METHODS: Eight pancreatic carcinoma cell lines were treated with the single agents and combinations of these. The role of IFN-α regarding a) direct inhibitory effects; b) radio and chemosensitizing effects; c) anti-angiogenic properties and d) enhancement of immunogenicity was investigated. RESULTS: Our results show that IFN-α has direct inhibitory properties and some synergistic influence as determined by AnnexinV/PI stain and cell count. IFN-α is also able to prevent the increase in proliferation rate and VEGF secretion of CDDP resistant cells. Having taken the results from immunogenicity experiments together, we found cells that can be influenced by IFN-α but were less susceptible against T cells. Furthermore, high expression of MHC molecules, CD118, EGF-R and Fas was predictive for a good response. CONCLUSION: In conclusion, IFN-α has direct cytotoxic effects, acts as a radiosensitizer and circumvents tumor cell-regrowth after CDDP treatment. These mechanisms may be responsible for the good clinical outcome of CapRI.     

NDV联合负载胃癌细胞抗原DC-CIK对胃癌细胞的杀伤效果及机制

目的探讨新城疫病毒（NDV）联合负载胃癌细胞抗原（Ag）的树突状细胞（DC）及细胞因子诱导的杀伤细胞（CIK）对胃癌细胞的杀伤效果及机制。方法用人外周血单个核细胞诱导培养DC及CIK,体外培养人胃癌细胞SGC-7901,反复冻融法制备胃癌细胞Ag悬液冲击致敏DC,CIK与负载胃癌细胞Ag的DC共培养。建立胃癌裸鼠模型,将其随机分为四组各6只。PBS组瘤内注射PBS100μl／只;NDV组瘤内注射NDV0．25ml／只;Ag-DC-CIK组瘤内注射负载抗原的DC诱导的CIK细胞0．2ml／只;NDV＋Ag-DC-CIK组先瘤内注射NDV0．25ml／只,1d后再注射负载抗原的DC诱导的CIK细胞0．2ml／只;各组均隔日注射1次,共3次。14d后测量肿瘤体积,计算抑瘤率。观察肿瘤坏死情况并评分。结果NDV＋AS—DC-CIK组肿瘤平均体积小于NDV组和Ag—DC-CIK组,抑瘤率、肿瘤坏死面积评分高于NDV组和Ag-DC—CIK组;P均〈0．05。结论NDV和负载胃癌细胞Ag的DC-CIK能协同杀伤胃癌细胞,杀伤效果强于二者单用效果;其机制为NDV可增加胃癌细胞的抗原性,为CIK细胞提供更多靶点。     

Synergistic antitumor effect of CXCL10 with hyperthermia

Purpose IFN–inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) has been described as an antiangiogenic chemokine and displays a potent antitumor activity in vivo. In the present study, we try to investigate whether the combination therapy of hyperthermia, a physical antiangiogenic modality, with CXCL10 would completely eradicate the established solid tumors. Methods Immunocompetent BALB/c mice bearing Meth A fibrosarcoma were established. Mice were treated with either CXCL10 at 25 μg/kg once a day for 20 days, hyperthermia was given twice (at 42°C for 1 h, on day 6 and 12 after the initiation of CXCL10), or together. Tumor volume and survival time were observed. The microvessel density was determined by CD31 immunofluorescence. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues. Results The results showed that CXCL10 and hyperthermia inhibited the growth of Meth A fibrosarcoma and interestingly, the combination therapy enhanced the antiangiogenic effects and completely eradicated the established solid tumors. Histological examination revealed that CXCL10 + hyperthermia led to increased induction of apoptosis, tumor necrosis, and elevated lymphocyte infiltration compared with the controls. Moreover, the tumor eradicated animals developed a protective T-cell-dependent antitumor memory response against Meth A tumor cells rechallenge. Conclusions Our finding is that the combination therapy can achieve a synergistic antitumor efficacy, supporting the idea that the combination of two antiangiogenic agents may lead to improved clinical outcome. These findings could open new perspectives in clinical antitumor therapy. Ping Chen, Ling-lin Yang, Huo-zhen Hu, and Yu-quan Wei contributed equally to this work.     

Synergistic effect of carbapenem–teicoplanin combination during severe Rhodococcus equi pneumonia in a kidney transplant recipient

Abstract: Rhodococcus equi is a bacterial pathogen of domestic animals that can infect immunocompromised patients, especially those with impaired cellular immunity, such as transplant recipients. No standard treatment has been established, but therapy must be prolonged, as relapses are common and can occur at the initial site or distant locations. Here we report a case of R. equi -associated pulmonary abscess in a renal transplant recipient successfully treated with a combination of carbapenem and teicoplanin. This combination was shown to be synergistic. It has minimal side effects in transplant recipients and appears to be an effective initial treatment for this severe infection.     

Synergistic antiviral effect in vitro of azidothymidine and amphotericin B methyl ester in combination on HIV infection.

The nucleoside analogue azidothymidine (AZT) and the methyl ester of amphotericin B (AME) were assayed for antiviral effect on HIV infection singly and in combination. Both compounds were effective in inhibiting HIV infection of MT-4 cells. At concentrations where either compound alone had no significant effect on infection, the compounds in combination were potent inhibitors of HIV as evaluated by reduction in HIV antigen production and HIV induced cytopathic effect. These results indicate that a combination therapy employing compounds with different modes of action like AZT and AME may have synergistic antiviral properties. Amphotericin B itself significantly reduced HIV infectivity in vitro and should not be used as an antifungal agent in cultures intended to propagate HIV.     

Synergistic cell killing by combination therapy of retinoic acid and hyperthermia in human epidermoid laryngeal carcinoma cells in culture

In vitro monolayer culture and clonogenic assay were used to investigate the individual and combined effect of temperature and retinoic acid (RA) on cellular morphology and colony forming ability of human epidermoid laryngeal carcinoma (HEp-2) cells. 20 micromol. RA alone inhibited multilayer formation and induced cell flattening. Hyperthermia (42 degrees C) individually caused formation of cytoplasmic processes and irregularities in cellular shape and size. Combined effect of hyperthermia (42 degrees C) and 20 micromol. RA treatment caused bleb formation on cell surfaces and lysis of cytoplasmic and nuclear membrane. RA treatment also caused dose-dependent reduction of colony growth. Heat-induced cell killing was only observed at lethal temperatures of 43 degrees C and above. RA in combination with heat synergistically inhibited colony formation even at non lethal temperatures of 41 and 42 degrees C. These results indicate that RA in combination with hyperthermia may facilitate the therapy of human epidermoid larynx carcinoma.     

Synergistic effect of bile acid,endotoxin, and ammonia on brain edema

The effects of cytotoxic substances such as ammonia, bile acids and endotoxin, all of which increase in the circulating blood during fulminant hepatic failure (FHF), on the blood-brain barrier (BBB) permeability and development of brain edema were examined in the rats. Direct intracarotid injection of various bile acids resulted in the staining of the cerebral hemisphere with Evans blue as well as the increase of brain water contents. Elevation of ammonia was also observed in the cerebral hemisphere where the reversible opening of the BBB was induced by deoxycholate under hyperammonemic conditions. To see the synergistic significance of cytotoxic substances (ammonia, bile acid and endotoxin) under the more physiological condition as FHF, they were simultaneously injected into a peripheral vein. Brain uptake index of 14C-inulin and brain water content increased, and electron micrographs showed the swollen astrocytic foot processes surrounded brain capillary, but not opening of tight junction, the same as an animal model of fulminant hepatic failure. The results suggest that ammonia, bile acids and endotoxin might have a possible synergistic role in the pathogenesis of the brain edema, mainly cytotoxic, and vasogenic due to acceleration of vesicular transport, in FHF.