Crataegus laevigata Suppresses LPS-Induced Oxidative Stress during Inflammatory Response in Human Keratinocytes by Regulating the MAPKs/AP-1, NFκB,and NFAT Signaling Pathways

Crataegus laevigata belongs to the family Rosaceae, which has been widely investigated for pharmacological effects on the circulatory and digestive systems. However, there is limited understanding about its anti-oxidative stress and anti-inflammatory effects on skin. In this study, 70% ethanol C. laevigata berry extract (CLE) was investigated on lipopolysaccharide (LPS)-stimulated keratinocytes. The LPS-induced overproduction of reactive oxygen species (ROS) was suppressed by the treatment with CLE. In response to ROS induction, the overexpression of inflammatory regulating signaling molecules including mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB), and nuclear factor of activated T-cells (NFAT) were reduced in CLE-treated human keratinocytes. Consequently, CLE significantly suppressed the mRNA levels of pro-inflammatory chemokines and interleukins in LPS-stimulated cells. Our results indicated that CLE has protective effects against LPS-induced injury in an in vitro model and is a potential alternative agent for inflammatory treatment.     

Rosmarinic Acid Prevents Cisplatin-Induced Liver and Kidney Injury by Inhibiting Inflammatory Responses and Enhancing Total Antioxidant Capacity,Thereby Activating the Nrf2 Signaling Pathway

Drug-induced liver and kidney damage is an emergent clinical issue that should be addressed. Rosmarinic acid (RA) has obvious anti-inflammatory and antioxidant effects, so we evaluated the anti-inflammatory and antioxidant effects of RA pretreatment on serum and liver and kidney tissues of cisplatin (CP)-treated mice and explored the possible mechanisms. The results showed that RA pretreatment effectively downregulated the serum, liver, and kidney levels of ALT, AST, BUN, and CRE and the inflammatory factors IL-1β, IL-6, and TNF-α, and simultaneously enhanced the total antioxidant capacity of the liver and kidney. RA pretreatment significantly reduced the levels of MPO, MDA, and NO in liver and kidney tissue, inhibited the mRNA expression of IL-1β, IL-6, and TNF-α in liver and kidney tissue, activated the Nrf2 signaling pathway, and upregulated the mRNA expression of downstream target genes. Our findings show that RA could effectively prevent and alleviate acute liver and kidney injury caused by CP.     

Fermented Oyster Extract Attenuated Dexamethasone-Induced Muscle Atrophy by Decreasing Oxidative Stress

It is well known that oxidative stress induces muscle atrophy, which decreases with the activation of Nrf2/HO-1. Fermented oyster extracts (FO), rich in γ-aminobutyric acid (GABA) and lactate, have shown antioxidative effects. We evaluated whether FO decreased oxidative stress by upregulating Nrf2/HO-1 and whether it decreased NF-κB, leading to decreased IL-6 and TNF-α. Decreased oxidative stress led to the downregulation of Cbl-b ubiquitin ligase, which increased IGF-1 and decreased FoxO3, atrogin1, and Murf1, and eventually decreased muscle atrophy in dexamethasone (Dexa)-induced muscle atrophy animal model. For four weeks, mice were orally administered with FO, GABA, lactate, or GABA+Lactate, and then Dexa was subcutaneously injected for ten days. During Dexa injection period, FO, GABA, lactate, or GABA+Lactate were also administered, and grip strength test and muscle harvesting were performed on the day of the last Dexa injection. We compared the attenuation effect of FO with GABA, lactate, and GABA+lactate treatment. Nrf2 and HO-1 expressions were increased by Dexa but decreased by FO; SOD activity and glutathione levels were decreased by Dexa but increased by FO; NADPH oxidase activity was increased by Dexa but decreased by FO; NF-κB, IL-6, and TNF-α activities were increased by Dexa were decreased by FO; Cbl-b expression was increased by Dexa but restored by FO; IGF-1 expression was decreased by Dexa but increased by FO; FoxO3, Atrogin-1, and MuRF1 expressions were increased by Dexa but decreased by FO. The gastrocnemius thickness and weight were decreased by Dexa but increased by FO. The cross-sectional area of muscle fiber and grip strength were decreased by Dexa but increased by FO. In conclusion, FO decreased Dexa-induced oxidative stress through the upregulation of Nrf2/HO-1. Decreased oxidative stress led to decreased Cbl-b, FoxO3, atrogin1, and MuRF1, which attenuated muscle atrophy.     

Oat (Avena sativa) Extract against Oxidative Stress-Induced Apoptosis in Human Keratinocytes

Oat (Avena sativa) is well known for its various health benefits. The protective effect of oat extract against oxidative stress-induced apoptosis in human keratinocytes HaCaT was determined. First, extracts of two varieties of oat, Daeyang and Choyang, were analyzed for fat-soluble antioxidants such as α-tocotrienol, γ-oryzanols, lutein and zeaxanthin using an UPLC system and for antioxidant activity using a DPPH assay. Specifically, an 80% ethanol extract of Daeyang oat (Avena sativa cv. Daeyang), which had high amounts of antioxidants and potent radical scavenging activity, was further evaluated for protective effect against oxidative stress-induced cell death, intracellular reactive oxygen species levels, the phosphorylation of DNA damage mediating genes such as H2AX, checkpoint kinase 1 and 2, and p53 and the activation of apoptotic genes such as cleaved caspase-3 and 7 and poly (ADP-ribose) polymerase in HaCaT cells. The Daeyang and Choyang oat 80% ethanol extracts had 26.9 and 24.1 mg/100 g γ-oryzanols, 7.69 and 8.38 mg/100 g α-tocotrienol, 1.25 and 0.34 mg/100 g of lutein and 1.20 and 0.17 mg/100 g of zeaxanthin, respectively. The oat 80% ethanol extract treatment (Avena sativa cv. Daeyang) had a protective effect on oxidative stress-induced cell death in HaCaT cells. In addition, the oat 80% ethanol extracts led to a significant decrease in the intracellular ROS level at a concentration of 50–200 μg/mL, the attenuation of DNA damage mediating genes and the inhibition of apoptotic caspase activities in a dose dependent manner (50–200 μg/mL). Thus, the current study indicates that an oat (Avena sativa cv. Daeyang) extract rich in antioxidants, such as polyphenols, avenanthramides, γ-oryzanols, tocotrienols and carotenoids, has a protective role against oxidative stress-induced keratinocyte injuries and that oat may a useful source for oxidative stress-associated skin damage.     

Protective Effects of Sal B on Oxidative Stress-Induced Aging by Regulating the Keap1/Nrf2 Signaling Pathway in Zebrafish

The models of oxidative damage-induced aging were established by adding ethanol (C₂H₅OH), hydrogen peroxide (H₂O₂) and 6-hydroxydopamine (6-OHDA) to zebrafish embryos in this research. To find effective protective drugs/foods, Salvianolic acid B (Sal B) was added after the embryos were treated by these oxidative reagents. After being treated with ethanol, H₂O₂ and 6-OHDA, the morphological changes were obvious and the deformities included spinal curvature, heart bleeding, liver bleeding, yolk sac deformity and pericardial edema, and the expression of oxidative stress-related genes Nrf2b, sod1 and sod2 and aging-related genes myl2a and selenbp1 were significantly up-regulated compared to the control group. While after adding 0.05 μg/mL and 0.5 μg/mL Sal B to the ethanol-treated group, death rates and MDA levels decreased, the activity of antioxidant enzyme (SOD, CAT and GSH-Px) changed and Nrf2b, sod1, sod2, myl2a, selenbp1, p53 and p21 were down-regulated compared to the ethanol-treated group. The bioinformatics analysis also showed that oxidative stress-related factors were associated with a variety of cellular functions and physiological pathways. In conclusion, Sal B can protect against aging through regulating the Keap1/Nrf2 pathway as well as antioxidative genes and enzyme activity.     

Exogenous Melatonin Activating Nuclear Factor E2-Related Factor 2 (Nrf2) Pathway via Melatonin Receptor to Reduce Oxidative Stress and Apoptosis in Antler Mesenchymal Stem Cells

Antler growth depends on the proliferation and differentiation of mesenchymal stem cells (MSCs), and this process may be adversely affected by oxidative stress. Melatonin (MLT) has antioxidant functions, but its role in Cervidae remains largely unknown. In this article, flow cytometry, reactive oxygen species (ROS) identification, qPCR, and other methods were used to investigate the protective mechanism of MLT in H₂O₂-induced oxidative stress of antler MSCs. The results showed that MLT significantly increases cell viability by relieving the oxidative stress of antler MSCs. MLT inhibits cell apoptosis by protecting mitochondrial function. We blocked the melatonin receptor with luzindole (Luz) and found that the receptor blockade significantly increases H₂O₂-induced hyperoxide levels and causes significant inhibition of mitochondrial function. MLT treatment activates the nuclear factor E2-related factor 2 (Nrf2) antioxidant signaling pathway, up-regulates the expression of NAD(P)H quinone oxidoreductase 1 (NQO1) and other genes and it could inhibit apoptosis. In contrast, the melatonin receptor blockade down-regulates the expression of Nrf2 pathway-related genes, but significantly up-regulates the expression of apoptotic genes. It was indicated that MLT activates the Nrf2 pathway through the melatonin receptor and alleviates H₂O₂-induced oxidative stress and apoptosis in antler MSCs. This study provides a theoretical basis for further studying the oxidative stress and antioxidant process of antler MSCs and, thereby, increasing antler yields.     

Recombinant Human Annexin A5 Alleviated Traumatic-Brain-Injury Induced Intestinal Injury by Regulating the Nrf2/HO-1/HMGB1 Pathway

Aims: Annexin A5 (ANXA5) exhibited potent antithrombotic, antiapoptotic, and anti-inflammatory properties in a previous study. The role of ANXA5 in traumatic brain injury (TBI)-induced intestinal injury is not fully known. Main methods: Recombinant human ANXA5 (50 µg/kg) or vehicle (PBS) was administered to mice via the tail vein 30 min after TBI. Mouse intestine tissue was gathered for hematoxylin and eosin staining 0.5 d, 1 d, 2 d, and 7 d after modeling. Intestinal Western blotting, immunofluorescence, TdT-mediated dUTP nick-end labeling staining, and enzyme-linked immunosorbent assays were performed 2 days after TBI. A series of kits were used to assess lipid peroxide indicators such as malonaldehyde, superoxide dismutase activity, and catalase activity. Key findings: ANXA5 treatment improved the TBI-induced intestinal mucosa injury at different timepoints and significantly increased the body weight. It significantly reduced apoptosis and matrix metalloproteinase-9 and inhibited the degradation of tight-junction-associated protein in the small intestine. ANXA5 treatment improved intestinal inflammation by regulating inflammation-associated factors. It also mitigated the lipid peroxidation products 4-HNE, 8-OHDG, and malonaldehyde, and enhanced the activity of the antioxidant enzymes, superoxide dismutase and catalase. Lastly, ANXA5 significantly enhanced nuclear factor E2-related factor 2 (Nrf2) and hemeoxygenase-1, and decreased high mobility group box 1 (HMGB1). Significance: Collectively, the results suggest that ANXA5 inhibits TBI-induced intestinal injury by restraining oxidative stress and inflammatory responses. The mechanisms involved sparking the Nrf2/hemeoxygenase-1-induced antioxidant system and suppressing the HMGB1 pathway. ANXA5 may be an attractive therapeutic candidate for protecting against TBI-induced intestinal injury.     

Terpenoids from the Seeds of Toona sinensis and Their Ability to Attenuate High Glucose-Induced Oxidative Stress and Inflammation in Rat Glomerular Mesangial Cells

Toona sinensis (A. Juss.) Roem is an edible medicinal plant that belongs to the genus Toona within the Meliaceae family. It has been confirmed to display a wide variety of biological activities. During our continuous search for active constituents from the seeds of T. sinensis, two new acyclic diterpenoids (1–2), together with five known limonoid-type triterpenoids (3–7), five known apotirucallane-type triterpenoids (8–12), and three known cycloartane-type triterpenoids (13–15), were isolated and characterized. Their structures were identified based on extensive spectroscopic experiments, including nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectra (HR-ESI-MS), and electronic circular dichroism (ECD), as well as the comparison with those reported in the literature. We compared these findings to those reported in the literature. Compounds 5, 8, and 13–14 were isolated from the genus Toona, and compounds 11 and 15 were obtained from T. sinensis for the first time. The antidiabetic nephropathy effects of isolated compounds against high glucose-induced oxidative stress and inflammation in rat glomerular mesangial cells (GMCs) were assessed in vitro. The results showed that new compounds 1 and 2 could significantly increase the levels of Nrf-2/HO-1 and reduce the levels of NF-κB, TNF-α, and IL-6 at concentrations of 30 μM. These results suggest that compounds 1 and 2 might prevent the occurrence and development of diabetic nephropathy (DN) and facilitate the research and development of new antioxidant and anti-inflammatory drugs suitable for the prevention and treatment of DN.     

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress,Inflammation, and Akt/GSK-3β Signaling

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO₄) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO₄-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO₄ and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR.     

Polygonatum cyrtonema Hua Polysaccharides Protect BV2 Microglia Relief Oxidative Stress and Ferroptosis by Regulating NRF2/HO-1 Pathway

Neuronal-regulated cell death (RCD) due to the accumulation of ROS within the central nervous system (CNS) is one of the crucial causes of central system diseases. Caspase-dependent apoptosis is the only form of RCD. As research progressed, several nonapoptotic cell death pathway RCDs were identified. Ferroptosis is a nonapoptotic RCD characterized by lipid peroxidation and plasma membrane damage. Polygonatum cyrtonema Hua. Polysaccharides (PCP) are an effective antioxidant. Based on this, the protective effect and mechanism of PCP against H₂O₂-induced microglial injury were investigated. Furthermore, the protective mechanism of PCP against ferroptosis in microglia was explored. Our results indicated that PCP could reduce oxidative stress-induced ROS accumulation by activating the NRF2/HO-1 signaling pathway, thus attenuating RCD in microglia. Subsequent studies have revealed that PCP alleviates ferroptosis in microglia due to protein levels of ERASTIN/RSL3 inhibitor SLC7A11/GPX4 by activating the NRF2/HO-1 signaling pathway. Therefore, we hypothesized that PCP exerts antioxidative and anti-ferroptosis effects by activating the expression of the NRF2/HO-1 pathway. This facilitates new ideas for clinically effective prevention and treatment of diseases due to accumulated reactive oxygen species in the CNS. Simultaneously, PCP has the development potential as a new drug candidate for treating CNS diseases.     

Europinidin Inhibits Rotenone-Activated Parkinson’s Disease in Rodents by Decreasing Lipid Peroxidation and Inflammatory Cytokines Pathways

Background: Europinidin is a derivative of delphinidin obtained from the plants Plumbago Europea and Ceratostigma plumbaginoides. This herb has wide medicinal applications in treating various diseases but there are very few studies available on this bioactive compound. Considering this background, the present study is designed for the evaluation of Europinidin against Parkinson’s disease. Aim: The investigation aims to assess the effect of Europinidin in the rotenone-activated Parkinson’s paradigm. Methods: To evaluate neuroprotective activity, rotenone (1.5 mg/kg s.c) and europinidin (10 mg/kg and 20 mg/kg) was administered in rats for 21 days. The behavioural parameters were performed before sacrificing the rats. On the 22nd day, all the rats were assessed for biochemical markers (SOD, GSH, MDA, Catalase), neurotransmitter levels (Dopamine, 5-HIAA, DOPAC, and HVA levels), and neuroinflammatory markers (IL-6, IL-1β and TNF-α). Results: It was found that rotenone produced significant (p < 0.001) oxidative damage, a cholinergic deficit, dopaminergic loss, and a rise in neuroinflammatory markers in rats. Conclusion: The study concludes that europinidin possesses anti-oxidant and anti-inflammatory properties. The results suggest the therapeutic role of europinidin against rotenone-activated behavioural, biochemical, and neuroinflammatory alterations in rats.     

Quercetin Prevents LPS-Induced Oxidative Stress and Inflammation by Modulating NOX2/ROS/NF-kB in Lung Epithelial Cells

Oxidative stress caused by the production of reactive oxygen species (ROS) plays a major role in inflammatory processes. We hypothesized that modulation of ROS via quercetin may protect against oxidative stress and inflammation. Thus, this study aimed to investigate the effects of quercetin on oxidative stress and inflammation in lung epithelial A549 cells. The lipopolysaccharide (LPS)-induced elevation of intracellular ROS levels was reduced after quercetin treatment, which also almost completely abolished the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) induced by LPS stimulation. In addition, quercetin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and reduced levels of inflammatory cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, which had increased significantly after LPS exposure. Our data demonstrated that quercetin decreased ROS-induced oxidative stress and inflammation by suppressing NOX2 production.     

Combination Therapy of Carnosic Acid and Methotrexate Effectively Suppressed the Inflammatory Markers and Oxidative Stress in Experimental Arthritis

Background: Combination therapy with methotrexate (MTX) is the most common therapeutic strategy used for the treatment of patients with rheumatoid arthritis (RA). In this study, we combined the natural compound carnosic acid (CA) with MTX to reduce inflammation and oxidative stress in adjuvant arthritis (AA). Methods: AA was induced in 6–8 rats per group. MTX was administrated twice a week at a dose of 0.3 mg/kg b.w., while CA was administered daily at a dose of 100 mg/kg both in monotherapy and in combination with MTX. Plasma samples were collected on the 14th, 21st, and 28th day. Body weight and hind paw volume were measured once a week. Results: We found that, mainly, the CA + MTX combination significantly reduced the hind paw swelling, the levels of IL-17A, MMP-9, and MCP-1 in plasma, and GGT activity in joint homogenates. The mRNA expression of HO-1, catalase, and IL-1β in the liver were significantly improved by CA + MTX only. Our results indicate that adding CA to MTX treatment could be a good therapeutic option for patients suffering from RA. Conclusions: The addition of CA to methotrexate treatment significantly improved its efficacy in decreasing the development of AA by inhibiting the markers of inflammation and oxidative stress.     

Protective Effects of Cinnamaldehyde on the Inflammatory Response,Oxidative Stress,and Apoptosis in Liver of Salmonella typhimurium-Challenged Mice

Salmonella typhimurium infection is associated with gastrointestinal disorder and cellular injury in the liver of both humans and animals. Cinnamaldehyde, the main component of essential oil from cinnamon, has been reported to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects. However, it remains unknown whether cinnamaldehyde can alleviate Salmonella typhimurium infection-induced liver injury in mice. In the present study, we found that cinnamaldehyde attenuated Salmonella typhimurium-induced body weight loss, the increase of organ (liver and spleen) indexes, hepatocyte apoptosis, and the mortality rate in mice. Further study showed that cinnamaldehyde significantly alleviated Salmonella typhimurium-induced liver injury as shown by activities of alanine transaminase, aspartate transaminase, and myeloperoxidase, as well as malondialdehyde. The increased mRNA level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) and chemokines (CCL2 and CCL3) induced by Salmonella typhimurium were significantly abolished by cinnamaldehyde supplementation. These alterations were associated with a regulatory effect of cinnamaldehyde on TLR2, TLR4, and MyD88. 16S rDNA sequence analysis showed that Salmonella typhimurium infection led to upregulation of the abundances of genera Akkermansia, Bacteroides, Alistipes, Muribaculum, and Prevotellaceae UCG-001, and downregulation of the abundances of genera Lactobacillus, Enterorhabdus, and Eggerthellaceae (unclassified). These alterations were reversed by cinnamaldehyde supplementation. In conclusion, cinnamaldehyde attenuated the inflammatory response, oxidative stress, and apoptosis in the liver of Salmonella typhimurium-infected mice. Supplementation of cinnamaldehyde might be a preventive strategy to alleviate liver injury caused by Salmonella typhimurium infection in humans and animals.     

Myricitrin,a Glycosyloxyflavone in Myrica esculenta Bark Ameliorates Diabetic Nephropathy via Improving Glycemic Status,Reducing Oxidative Stress,and Suppressing Inflammation

The present study evaluated the therapeutic potential of myricitrin (Myr), a glycosyloxyflavone extracted from Myrica esculenta bark, against diabetic nephropathy. Myr exhibited a significant hypoglycemic effect in high fat-fed and a single low-dose streptozotocin-induced type 2 diabetic (T2D) rats. Myr was found to improve glucose uptake by the skeletal muscle via activating IRS-1/PI3K/Akt/GLUT4 signaling in vitro and in vivo. Myr significantly attenuated high glucose (HG)-induced toxicity in NRK cells and in the kidneys of T2D rats. In this study, hyperglycemia caused nephrotoxicity via endorsing oxidative stress and inflammation resulting in the induction of apoptosis, fibrosis, and inflammatory damages. Myr was found to attenuate oxidative stress via scavenging/neutralizing oxidative radicals and improving endogenous redox defense through Nrf-2 activation in both in vitro and in vivo systems. Myr was also found to attenuate diabetes-triggered renal inflammation via suppressing NF-κB activation. Myr inhibited hyperglycemia-induced apoptosis and fibrosis in renal cells evidenced by the changes in the expressions of the apoptotic and fibrotic factors. The molecular docking predicted the interactions between Myr and different signal proteins. An in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted the drug-likeness character of Myr. Results suggested the possibility of Myr to be a potential therapeutic agent for diabetic nephropathy in the future.     

高效液相色谱法测定木奈果中的山梨醇和糖类

用高效液相色谱外标法测定了木奈果中的可溶性糖和山梨醇 ,采用 μ Spherogelcarbohydrate柱和示差折光检测器 ,以水为流动相 ,柱温 85℃。相关系数在 0 970 9以上 ,加标回收率为 75 0 0 %～ 88 37%。测定结果表明 ,可溶性糖在果肉中的累积依果肉不同的生长发育阶段有特征性的变化。     

A Novel Synthetic Precursor of Styryl Sulfone Neuroprotective Agents Inhibits Neuroinflammatory Responses and Oxidative Stress Damage through the P38 Signaling Pathway in the Cell and Animal Model of Parkinson’s Disease

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson’s disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP⁺)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.