Amygdalin Alleviates DSS-Induced Colitis by Restricting Cell Death and Inflammatory Response, Maintaining the Intestinal Barrier, and Modulating Intestinal Flora.

Inflammatory bowel disease (IBD) refers to a cluster of intractable gastrointestinal disorders with an undetermined etiology and a lack of effective therapeutic agents. Amygdalin (Amy) is a glycoside extracted from the seeds of apricot and other Rosaceae plants and it exhibits a wide range of pharmacological properties. Here, the effects and mechanisms of Amy on colitis were examined via 16S rRNA sequencing, ELISA, transmission electron microscopy, Western blot, and immunofluorescence. The results showed that Amy administration remarkably attenuated the signs of colitis (reduced body weight, increased disease activity index, and shortened colon length) and histopathological damage in dextran sodium sulfate (DSS)-challenged mice. Further studies revealed that Amy administration significantly diminished DSS-triggered gut barrier dysfunction by lowering pro-inflammatory mediator levels, inhibiting oxidative stress, and reducing intestinal epithelial apoptosis and ferroptosis. Notably, Amy administration remarkably lowered DSS-triggered TLR4 expression and the phosphorylation of proteins related to the NF-κB and MAPK pathways. Furthermore, Amy administration modulated the balance of intestinal flora, including a selective rise in the abundance of S24-7 and a decline in the abundance of Allobaculum, Oscillospira, Bacteroides, Sutterella, and Shigella. In conclusion, Amy can alleviate colitis, which provides data to support the utility of Amy in combating IBD.

Orally administered neohesperidin attenuates MPTP-induced neurodegeneration by inhibiting inflammatory responses and regulating intestinal flora in mice.

Parkinson's disease (PD), a neurodegenerative disease, is the leading cause of movement disorders. Neuroinflammation plays a critical role in PD pathogenesis. Neohesperidin (Neo), a natural flavonoid extracted from citric fruits exhibits anti-inflammatory effects. However, the effect of Neo on PD progression is unclear. This study aimed to investigate the effects of Neo on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice and its underlying mechanism. Our results indicated that Neo administration ameliorated motor impairment and neural damage in MPTP-injected mice, by inhibiting neuroinflammation and regulating gut microbial imbalance. Additionally, Neo administration reduced colonic inflammation and tissue damage. Mechanistic studies revealed that Neo suppressed the MPTP-induced inflammatory response by inhibiting excessive activation of NF-κB and MAPK pathways. In summary, the present study demonstrated that Neo administration attenuates neurodegeneration in MPTP-injected mice by inhibiting inflammatory responses and regulating the gut microbial composition. This study may provide the scientific basis for the use of Neo in the treatment of PD and other related diseases.

HMGB1-RAGE axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte autophagy and apoptosis in diabetic mice.

Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations.

Oral administration of sophoricoside (SOP) inhibits neuronal damage and neuroinflammation to curb neurodegeneration in Parkinson's disease.

Neuronal apoptosis and neuroinflammation are key factors involved in the pathological changes of Parkinson's disease (PD). Sophoricoside (SOP) has shown anti-inflammatory and anti-apoptosis effects in various diseases. However, the role of SOP in PD has not been reported. In this experiment, we found that oral administration of SOP alleviated weight loss and motor symptoms in 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-injected mice. Further studies revealed that SOP inhibited inflammatory responses and neuronal apoptosis in the midbrain region of MPTP-injected mice. In vitro mechanistic study, we found that SOP exerts neuroprotective effects through a two-sided action. On the one hand, SOP inhibits Lipopolysaccharide (LPS)-induced inflammatory responses in microglia by inhibiting the Nuclear factor kappa-B(NF-κB) pathway. On the other hand, SOP inhibits 1-methyl-4-phenylpyridinium (MPP+)-induced neuronal apoptosis by regulating the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Thus SOP is expected to be a potential therapeutic agent for PD by targeting neuroinflammation and neuronal apoptosis.

Oral administration of Limonin (LM) exerts neuroprotective effects by inhibiting neuron autophagy and microglial activation in 6-OHDA-injected rats.

Parkinson's disease (PD) is a neurodegenerative disorder that occurs most frequently in middle-aged and elderly people. It is characterized by an insidious onset and a complex etiology, and no effective treatment has been developed. The primary characteristic of PD is the degenerative death of midbrain dopaminergic neurons. The excessive autophagy of neurons and hyperactivation of microglia were shown to be involved in the apoptosis of dopaminergic neurons. Limonin (LM), a type of pure natural compound present in grapefruit or citrus fruits (e. g., lemon, orange) has been reported to inhibit apoptosis and inflammation. However, its role and mechanism of action in PD are unclear. In this study, we explored the effect and mechanism of action of LM in PD. In vivo experiments revealed that LM ameliorated 6-OHDA-induced reduced motor activity and PD-related pathological damage in rats. In vitro experiments revealed that LM inhibited the 6-OHDA-induced apoptosis of PC12 cells by inhibiting the excessive autophagy of neurons. In addition, LM inhibited microglial inflammation by activating the AKT/Nrf-2/HO-1 pathway and protected neurons against microglial inflammation-mediated neurotoxicity. In conclusion, the findings of this experiment demonstrated that LM exerted neuroprotective effects by inhibiting neuronal autophagy-mediated apoptosis and microglial activation in 6-OHDA-injected rats, thus indicating that LM can serve as a candidate for PD by targeting neuroinflammation and neuronal autophagy to inhibit neuronal apoptosis.

Notopterol inhibits LPS-induced inflammation in BV-2 cells via AKT/Nrf2/HO-1 signaling axis.

Accumulating research has indicated that inordinate activation of microglia releases inflammatory cytokines, damages neurons, and causes neuroinflammation, which eventually could lead to neurodegenerative diseases such as Parkinson's disease and Huntington's disease, etc. Notopterol (NOT) has anti-inflammatory and anti-oxidant functions in boundary tissues, but the effects of NOT on neuroinflammation have not been covered. Therefore, this study attempts to investigate the effect of NOT on neuroinflammation and the underlying mechanisms. According to the findings, NOT dramatically decreased the expression of pro-inflammatory mediators (interleukin-6 (IL-6), inducible nitric-oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and Cyclooxygenase-2 (COX-2)) in LPS-exposed BV-2 cells. Western blot analysis revealed that NOT could promote the activation of AKT/Nrf2/HO-1 signaling pathway. Further studies have shown that anti-inflammatory property of NOT was inhibited by MK2206 (an AKT inhibitor), RA (an Nrf2 inhibitor), and SnPP IX (an HO-1 inhibitor). In addition, it was also discovered that NOT could weaken the damage of LPS to BV-2 cells and improve their survival rate. As a result, our results imply that NOT inhibits the inflammatory response of BV-2 cells through the AKT/Nrf2/HO-1 signaling axis and exerts a neuroprotective effect by inhibiting the activation of BV-2 cells.

Activation of HCA2 regulates microglial responses to alleviate neurodegeneration in LPS-induced in vivo and in vitro models.

BACKGROUND: Previous studies have shown a close association between an altered immune system and Parkinson's disease (PD). Neuroinflammation inhibition may be an effective measure to prevent PD. Recently, numerous reports have highlighted the potential of hydroxy-carboxylic acid receptor 2 (HCA2) in inflammation-related diseases. Notably, the role of HCA2 in neurodegenerative diseases is also becoming more widely known. However, its role and exact mechanism in PD remain to be investigated. Nicotinic acid (NA) is one of the crucial ligands of HCA2, activating it. Based on such findings, this study aimed to examine the effect of HCA2 on neuroinflammation and the role of NA-activated HCA2 in PD and its underlying mechanisms. METHODS: For in vivo studies, 10-week-old male C57BL/6 and HCA2-/- mice were injected with LPS in the substantia nigra (SN) to construct a PD model. The motor behavior of mice was detected using open field, pole-climbing and rotor experiment. The damage to the mice's dopaminergic neurons was detected using immunohistochemical staining and western blotting methods. In vitro, inflammatory mediators (IL-6, TNF-α, iNOS and COX-2) and anti-inflammatory factors (Arg-1, Ym-1, CD206 and IL-10) were detected using RT-PCR, ELISA and immunofluorescence. Inflammatory pathways (AKT, PPARγ and NF-κB) were delineated by RT-PCR and western blotting. Neuronal damage was detected using CCK8, LDH, and flow cytometry assays. RESULTS: HCA2-/- increases mice susceptibility to dopaminergic neuronal injury, motor deficits, and inflammatory responses. Mechanistically, HCA2 activation in microglia promotes anti-inflammatory microglia and inhibits pro-inflammatory microglia by activating AKT/PPARγ and inhibiting NF-κB signaling pathways. Further, HCA2 activation in microglia attenuates microglial activation-mediated neuronal injury. Moreover, nicotinic acid (NA), a specific agonist of HCA2, alleviated dopaminergic neuronal injury and motor deficits in PD mice by activating HCA2 in microglia in vivo. CONCLUSIONS: Niacin receptor HCA2 modulates microglial phenotype to inhibit neurodegeneration in LPS-induced in vivo and in vitro models.

α-Cyperone protects dopaminergic neurons and inhibits neuroinflammation in LPS-induced Parkinson's disease rat model via activating Nrf2/HO-1 and suppressing NF-κB signaling pathway.

Our previous study showed that α-Cyperone inhibited the inflammatory response triggered by activated microglia and protected dopaminergic neuron in in vitro cell model of Parkinson's disease (PD). It is unclear the effect of α-Cyperone in animal models of PD. In this study, our results indicated that α-Cyperone ameliorated motor dysfunction, protected dopaminergic neurons, and inhibited the reduction of dopamine and its metabolites in lipopolysaccharide (LPS)-induced PD rat model. Moreover, α-Cyperone suppressed the activation of microglia and the expression of neuroinflammatory factor (TNF-α, IL-6, IL-1ß, iNOS, COX-2 and ROS). Furthermore, the molecular mechanism research revealed that α-Cyperone inhibited neuroinflammation and oxidative stress to exert protective effect in microglia by activating Nrf2/HO-1 and suppressing NF-κB signaling pathway. Moreover, α-Cyperone upregulated the expression of antioxidant enzymes (GCLC, GCLM and NQO1) in microglia. In conclusion, our study demonstrates α-Cyperone alleviates dopaminergic neurodegeneration by inhibiting neuroinflammation and oxidative stress in LPS-induced PD rat model via activating Nrf2/HO-1 and suppressing NF-κB signaling pathway.

Isoalantolactone (IAL) Regulates Neuro-Inflammation and Neuronal Apoptosis to Curb Pathology of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease in which neuronal apoptosis and associated inflammation are involved in its pathogenesis. However, there is still no specific treatment that can stop PD progression. Isoalantolactone (IAL) plays a role in many inflammation-related diseases. However, its effect and mechanism in PD remain unclear. In this study, results showed that IAL administration ameliorated 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD-related pathological impairment and decreased motor activity in mice. Results from in vitro mechanistic studies showed that IAL regulated apoptosis-related proteins by activating the AKT/Nrf2 pathway, thereby suppressing the apoptosis of SN4741 cells induced by N-methyl-4-phenylpyridinium Iodide (MPP+). On the other hand, IAL inhibited LPS-induced release of pro-inflammatory mediators in BV2 cells by activating the AKT/Nrf2/HO-1 pathway and inhibiting the NF-κB pathway. In addition, IAL protected SN4741 from microglial activation-mediated neurotoxicity. Taken together, these results highlight the beneficial role of IAL as a novel therapy and potential PD drug due to its pharmacological profile.

Hordenine inhibits neuroinflammation and exerts neuroprotective effects via inhibiting NF-κB and MAPK signaling pathways in vivo and in vitro.

Parkinson's disease (PD) is a usual disease caused by degeneration of the central nervous system, which features the denaturation and death of dopaminergic neurons in the substantia nigra compact (SNc) of the midbrain. Neuroinflammation casts a consequential role in its pathogenesis, and the excessive activation of microglia as a major part of neuroinflammation cannot be ignored. Studies have indicated that Hordenine (HOR) functioned widely as an anti-oxidant and anti-inflammatory substance, but there are no reports on neuroinflammation effects. Therefore, this study is devoted to exploring the effect of HOR on neuroinflammation and its specific mechanism. In vivo, results revealed that HOR depressed the activation of microglia in SNc and protected dopaminergic neurons in the 6-hydroxydopamine (6-OHDA)-induced PD rat model, which terminally reduced movement disorders and weight loss. In vitro, studies have shown that HOR can inhibit inflammatory responses triggered by lipopolysaccharide (LPS) in BV-2 cells. More profound studies have discovered that the specific anti-inflammatory mechanism is intimately associated with the NF-κB and MAPK signaling pathways. All in it together, HOR acts as a significant role in preserving dopaminergic neurons by restraining neuroinflammation mediated by activation of microglia. This may provide a potential drug for Parkinson's treatment.

Inhibition of HMGB1 alleviates myocardial ischemia/reperfusion injury in diabetic mice via suppressing autophagy.

BACKGROUND: Diabetes aggravates myocardial ischemia/reperfusion (I/R) injury (MI/RI). The association between high mobility group box 1 protein (HMGB1) and autophagy in diabetic MI/RI remains unknown. Therefore, we investigated whether inhibiting HMGB1 can regulate autophagy in diabetic mice (DM) after I/R injury. METHODS: I/R models of C57BL/KsJ mice and db/db mice were established. Histological changes, infarct size (IS), HMGB1 protein, and autophagy-related proteins were detected after 24h of reperfusion. In DM treatment groups, anti-HMGB1 antibody (H-Ig) was injected via tail vein after reperfusion for 15min, and the above-mentioned experimental methods were performed at the end of reperfusion. RESULTS: Compared with the I/R group, the pathological myocardial damage and IS were significantly increased in the I/R (DM) group. Additionally, the levels of HMGB1, Beclin1, and LC3II/LC3I ratio were remarkably higher in the I/R (DM) group than those in the I/R group, while p62 level was lower. In the H-Ig (DM) group, injection of H-Ig significantly reduced the IS, as well as alleviated pathological myocardial damage. Moreover, Beclin1, LC3II/LC3I ratio, and p62 levels were notably reversed after this treatment. CONCLUSIONS: I/R-induced myocardium was aggravated by diabetes, which may be related to increased release of HMGB1 and activated autophagy. Inhibition of HMGB1 alleviates diabetic MIRI which was associated with reduced autophagy.

Camptothecin Regulates Microglia Polarization and Exerts Neuroprotective Effects via Activating AKT/Nrf2/HO-1 and Inhibiting NF-κB Pathways In Vivo and In Vitro.

Microglia, the main immune cells in the brain, participate in the innate immune response in the central nervous system (CNS). Studies have shown that microglia can be polarized into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Accumulated evidence suggests that over-activated M1 microglia release pro-inflammatory mediators that damage neurons and lead to Parkinson's disease (PD). In contrast, M2 microglia release neuroprotective factors and exert the effects of neuroprotection. Camptothecin (CPT), an extract of the plant Camptotheca acuminate, has been reported to have anti-inflammation and antitumor effects. However, the effect of CPT on microglia polarization and microglia-mediated inflammation responses has not been reported. In our study we found that CPT improved motor performance of mice and reduced the loss of neurons in the substantia nigra (SN) of the midbrain in LPS-injected mice. In the mechanism study, we found that CPT inhibited M1 polarization of microglia and promotes M2 polarization via the AKT/Nrf2/HO-1 and NF-κB signals. Furthermore, CPT protected the neuroblastoma cell line SH-SY5Y and dopaminergic neuron cell line MN9D from damage mediated by microglia activation. In conclusion, our results demonstrate that CPT regulates the microglia polarization phenotype via activating AKT/Nrf2/HO-1 and inhibiting NF-κB pathways, inhibits neuro-inflammatory responses, and exerts neuroprotective effects in vivo and in vitro.

Echinocystic Acid Inhibits Inflammation and Exerts Neuroprotective Effects in MPTP-Induced Parkinson's Disease Model Mice.

Parkinson's disease (PD), the second primary neurodegenerative disease affecting human health, is mainly characterized by dopaminergic neuron damage in the midbrain and the clinical manifestation of movement disorders. Studies have shown that neuroinflammation plays an important role in the progression of PD. Excessively activated microglia produce several pro-inflammatory mediators, leading to damage to the surrounding neurons and finally inducing neurodegeneration. Echinocystic acid (EA) exhibits an anti-inflammatory effect in peripheral tissues. However, whether it inhibited neuroinflammation remains unclear. Therefore, the current study investigates the effect of EA on neuroinflammation and whether it can improve PD symptoms through inhibiting neuroinflammation. In our experiments, we discovered that EA inhibited the production of pro-inflammatory mediators in LPS-exposed BV2 cells. Further mechanism-related studies revealed that EA inhibited inflammation by activating PI3K/Akt and inhibiting NF-κB and MAPK signal pathways in LPS-induced BV2 cells. Research revealed that EA eases microglia-mediated neuron death in SN4741 and SHSY5Y cells. In in vivo studies, the results demonstrated that EA improves weight loss and behavioral impairment in MPTP-induced mice. Further studies have revealed that EA inhibited dopaminergic neuron damage and inflammation in the mice midbrain. In conclusion, our study demonstrated that EA inhibits neuroinflammation and exerts neuroprotective effects by activating PI3K/Akt and inhibiting NF-κB and MAPK signal pathways in vivo and in vitro.

Evodiamine Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in BV-2 Cells via Regulating AKT/Nrf2-HO-1/NF-κB Signaling Axis.

Neuroinflammation is caused by excessive activation of microglia and plays an essential role in neurodegenerative diseases. After activation, microglia produce several kinds of inflammatory mediators, trigger an excessive inflammatory response, and ultimately destroy the surrounding neurons. Therefore, agents that inhibit neuroinflammation may be potential drug candidates for neurodegenerative diseases. Evodiamine (EV) has anti-inflammatory functions in peripheral tissues. However, whether EV exerts the same function in neuroinflammation is not known. In the present study, the aim was to explore whether EV attenuates microglial overactivation and therefore suppresses the development of neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells. It was found that EV effectively inhibited expression of proinflammatory mediators (cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)) via AKT/Nrf2/HO-1 activation and suppressed NF-κB p65 phosphorylation. In addition, EV could suppress LPS-induced inflammatory response and loss of dopaminergic neuron in mouse mesencephalic neuron--glia cells. Hence, these findings demonstrate that EV suppresses neuroinflammation caused by overactivated microglia via regulating the AKT/Nrf2/HO-1/NF-κB signaling axis.

Beta-naphthoflavone inhibits LPS-induced inflammation in BV-2 cells via AKT/Nrf-2/HO-1-NF-κB signaling axis.

Numerous studies have shown that over-activation of microglia could cause neuroinflammation and release pro-inflammatory mediators, which could result in neurodegenerative diseases, like Parkinson's disease, Alzheimer's disease etc. Beta-naphthoflavone (BNF) has anti-oxidant and anti-inflammatory effects in borderline tissues, but BNF has not been reported the effect associated with neuroinflammation. Therefore, the purpose of this experiment is to inquiry the impact and mechanism of BNF on neuroinflammation. The results indicated that BNF significantly inhibited the production of pro-inflammatory mediators (inducible nitric-oxide synthase (iNOS), Cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) andinterleukin-6 (IL-6)) in LPS-exposed BV-2 cells. Analysis of western blot results found that BNF accelerated the activation of AKT/Nrf-2/HO-1 signaling pathway and suppressed NF-κB pathway activation. Further study showed that BNF inhibited activation of NF-κB pathway via promoting HO-1, and SnPP IX (a HO-1 inhibitor) could inhibit anti-inflammatory function of BNF. We also found that BNF reduced the apoptosis rate of Human neuroblastoma cells (SHSY5Y) and mouse hippocampal neuron cell line (HT22) by inhibiting release of inflammatory mediators in LPS-exposed BV2 cells. In a word, our results suggested that BNF could inhibit inflammatory response via AKT/Nrf-2/HO-1-NF-κB signaling axis in BV-2 cells and exerts neuroprotective impact via inhibiting the activation of BV2 cells.

Menthol protects dopaminergic neurons against inflammation-mediated damage in lipopolysaccharide (LPS)-Evoked model of Parkinson's disease.

In neurodegenerative diseases, neuronal damage caused by neuroinflammation is very important. Many studies have suggested that the activation of microglia is critical for the neuroinflammatory process. Therefore, inhibiting neuroinflammation is considered to be a hopeful target for curing neurodegenerative diseases. In this study, we aimed to explore whether menthol can protect the dopaminergic neurons by exerting anti-inflammatory effects in vivo or in vitro. The results showed that menthol had an inhibitory effect on impaired dopaminergic neurons and LPS-induced microglial activation. Further, menthol can inhibit the expression of related pro-inflammatory enzymes and pro-inflammatory factors. Both in vitro and in vivo mechanistic studies showed that menthol inhibited the neuroinflammatory response through the MAPK, NF-κB and AKT signaling pathways.

α-Cyperone Attenuates H2O2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2.

α-Cyperone, extracted from Cyperus rotundus, has been reported to inhibit microglia-mediated neuroinflammation. Oxidative stress and apoptosis play crucial roles in the course of Parkinson's disease (PD). PD is a common neurodegenerative disease characterized by selective death of dopaminergic neurons. This study was designed to investigate the neuroprotective effects of α-cyperone against hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in dopaminergic neuronal SH-SY5Y cells. Neurotoxicity was assessed by MTT assay and the measurement of lactic dehydrogenase (LDH) release. The level of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescin diacetate (DCFH-DA) staining. The apoptosis of SH-SY5Y cells was evaluated by annexin-V-FITC staining. The translocation of NF-E2-related factor 2 (Nrf2) was determined by western blot and immunofluorescence staining. Western blot analysis was conducted to determine the expression level of cleaved-caspase-3, the pro-apoptotic factor Bax, and the anti-apoptotic factor, Bcl-2. The results showed that α-cyperone substantially decreased H2O2-induced death, release of LDH, and the production of ROS in SH-SY5Y cells. In addition, we found that α-cyperone attenuated H2O2-induced cellular apoptosis. Moreover, α-cyperone remarkably reduced the expression of cleaved-caspase-3 and Bax, and upregulated Bcl-2. Furthermore, α-cyperone enhanced the nuclear translocation of Nrf2. Pretreatment with brusatol (BT, an Nrf2 inhibitor) attenuated α-cyperone-mediated suppression of ROS, cleaved-caspase-3, and Bax, as well as α-cyperone-induced Bcl-2 upregulation in H2O2-treated SH-SY5Y cells. α-cyperone neuroprotection required Nrf2 activation. In conclusion, α-cyperone attenuated H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells via the activation of Nrf2, suggesting the potential of this compound in the prevention and treatment of PD.

Corrigendum: Isovitexin-Mediated Regulation of Microglial Polarization in Lipopolysaccharide-Induced Neuroinflammation via Activation of the CaMKKß/AMPK-PGC-1α Signaling Axis.

[This corrects the article DOI: 10.3389/fimmu.2019.02650.].

Isovitexin-Mediated Regulation of Microglial Polarization in Lipopolysaccharide-Induced Neuroinflammation via Activation of the CaMKKß/AMPK-PGC-1α Signaling Axis.

Microglia are the brain's immune cells and play an important role in regulating the microenvironment in the central nervous system. Activated microglia are capable of acquiring the pro-inflammatory (M1) phenotype and anti-inflammatory (M2) phenotype. Overactivation of microglia is neurotoxic and may lead to neuroinflammatory brain disorders. Neuroinflammation in the brain plays a crucial role part in the pathophysiology of many psychiatric and neurological diseases. The inhibition of M1 microglia and promotion of M2 microglia was demonstrated to treat and prevent these diseases through reduced neuroinflammation. Isovitexin (IVX) has anti-inflammatory properties and passes through the blood-brain barrier; however, the molecular mechanism that modulates IVX-mediated microglial polarization remains unclear. In BV-2 cells and mouse primary microglia, IVX suppressed the expression of M1 microglial markers, enhanced the expression of M2 microglial markers, and enhanced the release of interleukin 10 (IL-10). IVX promoted the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) in LPS-induced microglial activation. The inhibition of PPARγ and PGC-1α attenuated the regulatory effect of IVX in LPS-induced microglial polarization. IVX increased the expression of p-CaMKKß, p-AMPK, and PGC-1α in BV-2 cells. Inhibition of CaMKKß with STO-609 or knockdown of CaMKKß with CaMKKß siRNA attenuated IVX-mediated M2 microglial polarization in LPS-treated cells. In LPS-treated mice, the inhibition of CaMKKß and PGC-1α attenuated the IVX-mediated prevention of sickness behavior and enhanction of IVX-mediated M2 microglial polarization. IVX promoted M2 microglial polarization which exerted anti-inflammatory effects on LPS-induced neuroinflammation via the activation of the CaMKKß/AMPK-PGC-1α signaling axis.