Isochlorogenic acid A ameliorated lead-induced anxiety-like behaviors in mice by inhibiting ferroptosis-mediated neuroinflammation via the BDNF/Nrf2/GPX4 pathways.

Lead (Pb) is a common environmental neurotoxicant that causes behavioral impairments in both rodents and humans. Isochlorogenic acid A (ICAA), a phenolic acid found in a variety of natural sources such as tea, fruits, vegetables, coffee, plant-based food products, and various medicinal plants, exerts multiple effects, including protective effects on the lungs, livers, and intestines. The objective of this study was to investigate the potential neuroprotective effects of ICAA against Pb-induced neurotoxicity in ICR mice. The results indicate that ICAA attenuates Pb-induced anxiety-like behaviors. ICAA reduced neuroinflammation, ferroptosis, and oxidative stress caused by Pb. ICAA successfully mitigated the Pb-induced deficits in the cholinergic system in the brain through the reduction of ACH levels and the enhancement of AChE and BChE activities. ICAA significantly reduced the levels of ferrous iron and MDA in the brain and prevented decreases in GSH, SOD, and GPx activity. Immunofluorescence analysis demonstrated that ICAA attenuated ferroptosis and upregulated GPx4 expression in the context of Pb-induced nerve damage. Additionally, ICAA downregulated TNF-α and IL-6 expression while concurrently enhancing the activations of Nrf2, HO-1, NQO1, BDNF, and CREB in the brains of mice. The inhibition of BDNF, Nrf2 and GPx4 reversed the protective effects of ICAA on Pb-induced ferroptosis in nerve cells. In general, ICAA ameliorates Pb-induced neuroinflammation, ferroptosis, oxidative stress, and anxiety-like behaviors through the activation of the BDNF/Nrf2/GPx4 pathways.

Lead-induced liver fibrosis and inflammation in mice by the AMPK/MAPKs/NF-κB and STAT3/TGF-ß1/Smad2/3 pathways: the role of Isochlorogenic acid a.

Lead (Pb) is a nonessential heavy metal, which can cause many health problems. Isochlorogenic acid A (ICAA), a phenolic acid present in tea, fruits, vegetables, coffee, plant-based food products, and various medicinal plants, exerts multiple effects, including anti-oxidant, antiviral, anti-inflammatory and antifibrotic functions. Thus, the purpose of our study was to determine if ICAA could prevent Pb-induced hepatotoxicity in ICR mice. An evaluation was performed on oxidative stress, inflammation and fibrosis, and related signaling. The results indicate that ICAA attenuates Pb-induced abnormal liver function. ICAA reduced liver fibrosis, inflammation and oxidative stress caused by Pb. ICAA abated Pb-induced fibrosis and decreased inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α). ICAA abrogated reductions in activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Masson staining revealed that ICAA reduced collagen fiber deposition in Pb-induced fibrotic livers. Western blot and immunohistochemistry analyses showed ICAA increased phosphorylated AMP-activated protein kinase (p-AMPK) expression. ICAA also reduced the expression of collagen I, α-smooth muscle actin (α-SMA), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c-jun N-terminal kinase (p-JNK), p-p38, phosphorylated signal transducer and phosphorylated activator of transcription 3 (p-STAT3), transforming growth factor ß1 (TGF-ß1), and p-Smad2/3 in livers of mice. Overall, ICAA ameliorates Pb-induced hepatitis and fibrosis by inhibiting the AMPK/MAPKs/NF-κB and STAT3/TGF-ß1/Smad2/3 pathways.

Hepatoprotective effect of avicularin on lead-induced steatosis, oxidative stress, and inflammation in mice associated with the MAPK/HSP60/NLRP3 and SREBP1c pathway.

Lead (Pb), an environmental hazard, causes severe diseases in the liver, kidney, cardiovascular system, hematopoietic system, reproductive system, and nervous system. Avicularin (AVI), the main dietary flavonoid found in many citrus fruits, exhibited potential protective properties on organs. However, the molecular mechanisms of these protective actions are currently not clear. In our study, the effects of AVI on Pb-induced hepatotoxicity were evaluated using ICR mice. Changes in oxidative stress, inflammation, lipid metabolism, and related signaling were evaluated. We found for the first time that treatment with AVI significantly reduced hepatic steatosis, inflammation, and oxidative stress induced by Pb. AVI attenuated Pb-induced liver dysfunction and lipid metabolism disorder in mice. AVI decreased the serum biochemical indicators of lipid metabolism. AVI decreased the expression levels of lipid metabolism-related protein SREBP-1c, acetyl-CoA carboxylase (ACC), and FAS. AVI suppressed Pb-induced inflammation in livers, as indicated by decreasing the TNF-α and IL-1ß levels. AVI suppressed oxidative stress by increasing the activation of SOD, CAT, and GPx. Furthermore, AVI inhibited the activities of JNK, ERK, p38, and NF-κB. AVI further decreased the levels of HSP60, NLRP3, p-IκBα, and p-p65 in the livers of mice. Collectively, this study indicated that AVI mitigated Pb-induced hepatic steatosis, oxidative stress, and inflammation by regulating the SREBP-1c and MAPK/HSP60/NLRP3 signaling pathways.

Isochlorogenic acid B alleviates lead-induced anxiety, depression and neuroinflammation in mice by the BDNF pathway.

Lead (Pb) can cause neurobehavioral abnormalities. Isochlorogenic acid B (ICAB), a dietary flavonoid found in tea, sweet potato, artichoke, propolis and several plants, exhibited potential neuroprotective properties. In this study, we aimed to investigate the mechanisms of Pb-induced anxiety, depression and neuroinflammation, and the neuroprotective effect of ICAB in mouse brains. We found that ICAB supplementation significantly improved behavioral abnormalities, neuroinflammation and oxidative stress induced by Pb. ICAB attenuated Pb-induced anxiety and depression behavior in mice, as indicated by decreasing the duration of immobility in tail suspension test and increasing the crossing number, rearing number and time in center in open field test. Accordingly, ICAB inhibited oxidative stress by decreasing malondialdehyde (MDA) level and increasing the antioxidant enzyme activity. ICAB also inhibited Pb-induced inflammation in brain, as indicated by decreasing the tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels. ICAB increased the expression levels of brain derived neurotrophic factor (BDNF) and the phosphorylation of cAMP-responsive element binding protein (CREB), phosphoinositide 3-kinases-protein kinase B (PI3K/AKT). Furthermore, ICAB decreased the levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), glycogen synthase kinase-3 beta (GSK-3ß) and p38. Collectively, this study demonstrated that ICAB improved Pb-induced anxiety, depression, neuroinflammation and oxidative stress by regulating the BDNF signaling pathway.

Avicularin Attenuates Lead-Induced Impairment of Hepatic Glucose Metabolism by Inhibiting the ER Stress-Mediated Inflammatory Pathway.

Lead (Pb), an environmental hazard, causes several human diseases. Avicularin (Avi), a main dietary flavonoid found in several plants and fruits, exhibits potential protective properties on organs. However, the molecular mechanisms of Avi's protective effects against Pb-induced damage are not clear. In our study, the effects of Avi on Pb-induced hepatotoxicity were evaluated using ICR mice. We have revealed for the first time that treatment with Avi significantly reduced hepatic inflammation, endoplasmic reticulum stress (ERS) and glucose metabolism disorder induced by Pb. Avi decreased the serum biochemical indicators of glucose metabolism. Avi increased the activities of glycogenolysis rate-limiting enzyme hexokinase (HK), pyruvate kinase (PK), glucokinase (GK) and glycogen phosphorylase (PYG) and inhibited the activities of gluconeogenesis rate-limiting enzyme phosphoenolpyruvate carboxy kinase (PEPCK) and glucose-6-phosphate dehydrogenase (G6PD). Avi decreased the protein expression levels of glucose-regulated protein 78 (GRP78), phosphorylated inositol requiring enzyme 1 (p-IRE1), phosphorylated RNA-dependent protein kinase-like ER kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α). The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were decreased in the liver as a result of Avi suppression Pb-induced inflammation. These results indicated that Avi attenuated Pb-induced impairment of hepatic glucose metabolism by the ERS and inflammation pathway.