N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model.

Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1ß, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.

The Role and Mechanisms of Action of Natural Compounds in the Prevention and Treatment of Cancer and Cancer Metastasis.

Cancer has emerged as one of the world's most concerning health problems. The progression and metastasis mechanisms of cancer are complex, including metabolic disorders, oxidative stress, inflammation, apoptosis, and intestinal microflora disorders. These pose significant challenges to our efforts to prevent and treat cancer and its metastasis. Natural drugs have a long history of use in the prevention and treatment of cancer. Many effective anti-tumor drugs, such as Paclitaxel, Vincristine, and Camptothecin, have been widely prescribed for the prevention and treatment of cancer. In recent years, a trend in the field of antitumor drug development has been to screen the active antitumor ingredients from natural drugs and conduct in-depth studies on the mechanisms of their antitumor activity. In this review, high-frequency keywords included in the literature of several common Chinese and English databases were analyzed. The results showed that five Chinese herbal medicines (Radix Salviae, Panax Ginseng C. A. Mey, Hedysarum Multijugum Maxim, Ganoderma, and Curcumaelongae Rhizoma) and three natural compounds (quercetin, luteolin, and kaempferol) were most commonly used for the prevention and treatment of cancer and cancer metastasis. The main mechanisms of action of these active compounds in tumor-related research were summarized. Finally, we found that four natural compounds (dihydrotanshinone, sclareol, isoimperatorin, and girinimbin) have recently attracted the most attention in the field of anti-cancer research. Our findings provide some inspiration for future research on natural compounds against tumors and new insights into the role and mechanisms of natural compounds in the prevention and treatment of cancer and cancer metastasis.

Rapid decrease of GAD 67 content before the convulsion induced by hyperbaric oxygen exposure.

Exposure to hyperbaric oxygen (HBO) can lead to seizures, the etiology of which is not completely understood. Glutamic acid decarboxylase (GAD) plays a very important role in maintaining excitatory-inhibitory balance of the central nervous system (CNS). In the present study we investigated the effects of HBO on the activity and content of GAD in vivo and in primarily cultured neurons to probe in detail its effect on the formation of convulsion induced by HBO exposure. The results obtained from in vivo and in vitro experiments were identical. In the latent period before the onset of seizure, the GAD activity followed a rise-and-fall pattern with the prolongation of HBO exposure. At the time of the onset of seizure, GAD activity descended to the normal level. Besides, in the latent period, GAD content also reduced. Such reduction came from a GAD subtype, GAD67, while the content of another GAD subtype, GAD65, remained almost unchanged. Our investigations indicated that GAD is indeed an enzyme highly sensitive to the effect of HBO exposure. The rapid reduction in GAD67 content may be very closely related to seizures induced by HBO exposure.

Neuroprotection of nicotiflorin in permanent focal cerebral ischemia and in neuronal cultures.

Nicotiflorin is a single component extracted from traditional Chinese medicine Flos Carthami. In this study, we investigated its neuroprotection in permanent focal cerebral ischemia model in rats, and in an in vitro model of ischemia. At doses of 2.5, 5 and 10 mg/kg, nicotiflorin administered immediately after the onset of ischemia markedly reduced brain infarct volume and neurological deficits. For primarily cultured neurons suffered 2 h hypoxia followed by 24 h reoxygenation, nicotiflorin significantly attenuated cell death and reduced LDH release. Morphological observation also directly confirmed its protective effect on neuron. These results provided strong pharmacological basis for its potential therapeutic role in cerebral ischemic illness.

Nicotiflorin reduces cerebral ischemic damage and upregulates endothelial nitric oxide synthase in primarily cultured rat cerebral blood vessel endothelial cells.

Nicotiflorin is a flavonoid glycoside extracted from a traditional Chinese medicine Flos Carthami. In the current study, we investigated the neuroprotective effect of nicotiflorin on a transient focal cerebral ischemia-reperfusion model in rats. Nicotiflorin (2.5-10 mg/kg) administered after onset of ischemia markedly reduced brain infarct volume by 24.5-63.2% and neurological deficits. Also the effect of nicotiflorin on endothelial nitric oxide synthase (eNOS) activity, mRNA and protein expression after hypoxia-reoxygenation (H-R) treatment was investigated in an in vitro model mimic cerebrum ischemia-reperfusion in vivo. After total 4 h hypoxia and 12 h reoxygenation, eNOS activity, mRNA and protein levels in the primarily cultured rat cerebral blood vessel endothelial cells treated with nicotiflorin (25-100 microg/ml) 2 h after onset of hypoxia were significantly higher than eNOS activity, mRNA and protein levels in the pure H-R cells and also higher than eNOS activity, mRNA and protein levels in cells cultured under normoxic conditions. The results demonstrated that nicotiflorin had a protective effect against cerebral ischemic damage. The results also gave an important elucidation for the mechanism underlying the protective effect at the cellular level.

[Experimental studies of Panax notoginseng saponins and Ginkgo biloba extracts on preventing acute oxygen toxicity].

AIM: To investigate the preventive effects of Panax notoginseng saponins (PNS) and Ginkgo biloba extracts (GbE) on acute oxygen toxicity and the possible mechanisms. METHODS: Mice were injected intraperitoneally with PNS and GbE for 5 days, then were exposed to 500 kPa hyperbaric oxygen (HBO) for 60 min, the convulsion latency, times and interval were observed. Moreover, reactive oxygen (RO) unit, MDA, NO, GSH levels and GSH-Px, CAT, MAO activities of mice brain were determined after they were exposed to HBO for 15 min. RESULTS: PNS and GbE could markedly prolong the convulsion latency and interval, reduce convulsion times, decrease contents of MDA and NO in mice brain, keep RO unit, GSH and GSH-Px at higher levels, but had no effects on CAT and MAO activities. CONCLUSION: PNS and GbE could effectively prevent acute oxygen toxicity, which were related to their antioxidant activities.