OBJECTIVE To study whether minimal doses of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and lipoxin A4 (LXA4) and brain-derived neurotrophic factor (BDNF), when used in combination can protect RIN5F cells from chemical-induced cytotoxicity. As a corollary, to know whether plasma BDNF and LXA4 are altered in STZ-induced type 2 DM animals. MATERIALS AND METHODS RIN5F cells, alloxan (AL), streptozotocin (STZ), doxorubicin (DB), and benzo(a)pyrene (BP) were used in this study. Chemical-induced apoptosis and changes in antioxidants, lipid peroxides and nitric oxide (NO) and LXA4 and BDNF levels in RIN5F cells were studied. Alterations in plasma concentrations of BDNF and LXA4 in STZ-induced type 2 diabetes animals was estimated. RESULTS BDNF, LXA4 and AA, EPA and DHA protected (P < 0.001 and P < 0.01 respectively) against AL/STZ/DB/BP-induced toxicity to RIN5F cells in vitro. AL/ STZ/DB/BP inhibited BDNF and LXA4 production by RIN5F cells and were restored to normal by AA, EPA and DHA. Sub-optimal doses of BDNF, LXA4, AA and EPA when used in combination protected against cytotoxic action of AL/STZ/DB/BP on RIN5F cells in vitro by restoring LXA4/BDNF levels and altered antioxidant/lipid peroxides/NO levels (P < 0.01) to normal. STZ (65 mg/kg)-induced type 2 diabetes mellitus animals showed reduced plasma BDNF and LXA4 levels (P < 0.001). DISCUSSION AL/STZ/DB/BP-induced cytotoxicity to RIN5F cells in vitro can be prevented by BDNF, LXA4 and AA. AL/STZ/DB/BP are cytotoxic, possibly, by suppressing the production of LXA4 and BDNF in RIN5F cells. STZ-induced type 2 DM animals have decreased plasma levels of LXA4 and BDNF. CONCLUSION The results of the present study suggest that BDNF, LXA4, EPA, DHA, AA, GLA and BDNF protect pancreatic β cells from the cytotoxic action of various chemicals and prevent development of diabetes mellitus. LXA4 seems to be the mediator of these cytoprotective actions of BDNF and PUFAs suggesting a close interaction exists among these molecules (BDNF, PUFAs and LXA4). Hence, methods developed to deliver a combination of PUFAs (especially AA), LXA4 and BDNF may prevent development of diabetes mellitus (both type 1 and type 2).

中文翻译：

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PUFA，BDNF和脂蛋白A4在体外可抑制RIN5F细胞的化学诱导的细胞毒性，而在体内可抑制链脲佐菌素诱导的2型糖尿病。

目的研究联合使用最小剂量的花生四烯酸（AA），二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）和脂蛋白A4（LXA4）和脑源性神经营养因子（BDNF）是否可以保护RIN5F细胞免于化学作用诱导的细胞毒性。作为推论，要知道血浆BDNF和LXA4在STZ诱导的2型DM动物中是否发生了改变。材料与方法本研究使用RIN5F细胞，四氧嘧啶（AL），链脲佐菌素（STZ），阿霉素（DB）和苯并（a）re（BP）。研究了化学诱导的细胞凋亡以及RIN5F细胞中抗氧化剂，脂质过氧化物和一氧化氮（NO）以及LXA4和BDNF水平的变化。估计了STZ诱导的2型糖尿病动物血浆BDNF和LXA4的浓度变化。结果BDNF，LXA4和AA，EPA和DHA受保护（P <0.001和P <0。分别对抗AL / STZ / DB / BP诱导的对RIN5F细胞的毒性。AL / STZ / DB / BP抑制RIN5F细胞产生BDNF和LXA4，并通过AA，EPA和DHA恢复至正常。亚最佳剂量的BDNF，LXA4，AA和EPA联合使用可通过恢复LXA4 / BDNF水平和改变抗氧化剂/脂质过氧化物/ NO水平来保护AL / STZ / DB / BP对RIN5F细胞的体外细胞毒作用（P <0.01）正常。STZ（65 mg / kg）诱导的2型糖尿病动物显示血浆BDNF和LXA4水平降低（P <0.001）。讨论BDNF，LXA4和AA可以预防AL / STZ / DB / BP对RIN5F细胞的体外细胞毒性。AL / STZ / DB / BP可能具有细胞毒性，可能是通过抑制RIN5F细胞中LXA4和BDNF的产生来实现的。STZ诱导的2型DM动物的LXA4和BDNF血浆水平降低。结论本研究结果表明，BDNF，LXA4，EPA，DHA，AA，GLA和BDNF保护胰腺β细胞免受各种化学物质的细胞毒作用，并预防糖尿病的发展。LXA4似乎是BDNF和PUFA的这些细胞保护作用的介质，表明这些分子（BDNF，PUFA和LXA4）之间存在紧密的相互作用。因此，开发用于递送PUFA（尤其是AA），LXA4和BDNF的组合的方法可能会预防糖尿病（1型和2型）的发展。LXA4似乎是BDNF和PUFA的这些细胞保护作用的介质，表明这些分子（BDNF，PUFA和LXA4）之间存在紧密的相互作用。因此，开发用于递送PUFA（尤其是AA），LXA4和BDNF的组合的方法可能会预防糖尿病（1型和2型）的发展。LXA4似乎是BDNF和PUFA的这些细胞保护作用的介质，表明这些分子（BDNF，PUFA和LXA4）之间存在紧密的相互作用。因此，开发用于递送PUFA（尤其是AA），LXA4和BDNF的组合的方法可能会预防糖尿病（1型和2型）的发展。