Basic & Clinical Pharmacology & Toxicology最新文献

Along with the hallmark of α-synuclein deposition, neuroinflammation and iron accumulation have emerged as essential pathological features for dopaminergic neuron degeneration in PD patients and animal models. Preclinical studies have highlighted gentiopicroside's anti-inflammatory activities in treating arthritis, colitis and pancreatitis, and its neuroprotective effects on neurological diseases such as AD, chronic neuropathic pain and ischemia. However, the effects and mechanisms of gentiopicroside on PD-related conditions remain uncertain. Here, we evaluated the potential benefits of gentiopicroside using a unilateral 6-OHDA rat model and a MPP⁺-induced cell model. Our findings indicated that gentiopicroside improved motor deficits and restored nigral TH-positive neurons in vivo. Mechanistically, gentiopicroside ameliorated inflammatory responses of 6-OHDA-induced rats, decreased NF-κB and pro-inflammatory cytokines levels and reduced Iba-1-positive microglia in the substantia nigra. Furthermore, gentiopicroside regulated the levels of DMT1 and FPN1, thereby inhibiting iron accumulation in PD rats. In vitro, gentiopicroside preserved the viability of MPP⁺-treated SH-SY5Y cells and suppressed NF-κB activity and its downstream factors' levels. Meanwhile, gentiopicroside inhibited lipid peroxidation and ROS production, while it upregulated the expression of GPX4 in MPP⁺-treated cells. And these antiferroptosis effects were also linked to iron transporters regulation. Conclusively, gentiopicroside exhibits neuroprotective effects via alleviating neuroinflammation and iron-dependent ferroptosis, offering promise for PD treatment.

Tobacco smoking during pregnancy has been associated with an increased risk of adverse outcomes like low birth weight. This study determined changes in the circulating metabolome linked to maternal smoking in the first trimester and correlated these changes to the growth of the foetus. The circulating metabolome was examined from first trimester plasma samples by non-targeted (global) liquid chromatography mass spectrometry-based metabolite profiling of 227 pregnant women (99 smokers and 117 non-smokers) from the Kuopio Birth Cohort Study. Tobacco smoking was self-reported through a questionnaire and verified with cotinine measurements from plasma samples. In summary, 64 significant differences were observed between the groups after correction for multiple testing e.g. in metabolites indicating endocrine disruption (e.g. dehydroepiandrosterone sulphate [DHEA-S], VIP = 2.70, d = 0.68, p < 0.0001), metabolites associated with oxidative stress (e.g. bilirubin, VIP = 2.00, d = 0.50, p < 0.0001) and lipid metabolism (e.g. LysoPC 16:1, VIP = 2.07, d = 0.51, p < 0.0001). Some of these metabolites, e.g. DHEA-S and bilirubin, correlated with low birth weight, and some, e.g. LysoPC 16:1, correlated with small head circumference at birth. In conclusion, maternal smoking during the first trimester of pregnancy was associated with an altered metabolite profile linked to endocrine disruption and increased oxidative stress.

The renal system is a significant organ system vulnerable to stress due to its physiological function of toxin elimination. Exposure to a wide array of xenobiotics in humans causes deleterious effects in the kidneys. In the present study, we observed the toxic effect of a coexposure of bisphenol A and acetaminophen on the renal function and renal mitochondria of Wistar rats and its amelioration by melatonin. The animals were grouped and treated for 4 weeks as follows: (I) control; (II) melatonin; (III) bisphenol A; (IV) acetaminophen; (V) bisphenol A and acetaminophen; and (VI) bisphenol A, acetaminophen and melatonin. Coadministration of bisphenol A and acetaminophen exposure significantly impaired renal function, elevating creatinine (2.28 mg/dL), BUN (65.42 mg/dL) and uric acid (6.11 mg/dL), while increasing oxidative stress and inflammatory markers (CAT: 3.85-μmol H₂O₂/min/mg protein, GPx: 189.57-nmol NADPH/min/mg protein, GR: 96.62-nmol NADPH/min/mg protein, MnSOD: 107.24-nmol (−) epinephrine/min/mg protein, IL-6: 1750 pg/mL, TNFα: 1677 pg/mL). Melatonin coadministration improved renal markers (creatinine: 1.60 mg/dL, BUN: 45.59 mg/dL, uric acid: 4.61 mg/dL) and partially restored antioxidant defences and inflammatory markers (CAT: 5.74-μmol H₂O₂/min/mg protein, GPx: 422.74-nmol NADPH/min/mg protein, GR: 136.91-nmol NADPH/min/mg protein, MnSOD: nmol (−) epinephrine prevented from oxidation/min/mg protein, IL-6: 1677 pg/mL, TNFα: 900 pg/mL). These findings suggest that melatonin mitigates bisphenol A and acetaminophen-induced renal damage by enhancing antioxidant defences and reducing inflammation.