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.

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.

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.

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.

Peiminine Protects Dopaminergic Neurons from Inflammation-Induced Cell Death by Inhibiting the ERK1/2 and NF-κB Signalling Pathways.

Neuroinflammation, characterized marked by microglial activation, plays a very important role in the pathogenesis of Parkinson's disease (PD). Upon activation, pro-inflammatory mediators are produced by microglia, triggering excessive inflammatory responses and ultimately damaging dopaminergic neurons. Therefore, the identification of agents that inhibit neuroinflammation may be an effective approach for developing novel treatments for PD. In this study, we sought to investigate whether peiminine protects dopaminergic neurons by inhibiting neuroinflammation. We evaluated the effects of peiminine on behavioural dysfunction, microglial activation and the loss of dopaminergic neurons in a rat model of lipopolysaccharide (LPS)-induced PD. BV-2 cells were pretreated with peiminine for 1 h and then stimulated with LPS for different times. Then, inflammatory responses and the related signalling pathways were analysed. Peiminine markedly attenuated behavioural dysfunction and inhibited the loss of dopaminergic neurons and microglial activation in the LPS-induced PD rat model. In BV-2 cells, peiminine significantly decreased LPS-induced expression of the pro-inflammatory mediators TNF-α, IL-6 and IL-1ß, COX-2 and iNOS by inhibiting the phosphorylation of ERK1/2, AKT and NF-κB p65. Based on these results demonstrated that peiminine has a role in protecting dopaminergic neurons in the LPS-induced PD rat model by inhibiting neuroinflammation.

Farrerol Ameliorates TNBS-Induced Colonic Inflammation by Inhibiting ERK1/2, JNK1/2, and NF-κB Signaling Pathway.

Farrerol, a type of 2, 3-dihydro-flavonoid, is obtained from Rhododendron. Previous studies have shown that Farrerol performs multiple biological activities, such as anti-inflammatory, antibacterial, and antioxidant activity. In this study, we aim to investigate the effect of Farrerol on colonic inflammation and explore its potential mechanisms. We found that the effect of Farrerol was evaluated via the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in mice and found that Farrerol has a protective effect on TNBS-induced colitis. Farrerol administration significantly improved the weight change, clinical scores, colon length, and intestinal epithelium barrier damage and markedly decreased the inflammatory cytokines production in TNBS-induced mice. The protective effect of Farrerol was also observed in LPS-induced RAW264.7 cells. We found that Farrerol observably reduced the production of inflammatory mediators including IL-1ß, IL-6, TNF-α, COX-2, and iNOS in LPS-induced RAW264.7 cells via suppressing AKT, ERK1/2, JNK1/2, and NF-κB p65 phosphorylation. In conclusion, the study found that Farrerol has a beneficial effect on TNBS-induced colitis and might be a natural therapeutic agent for IBD treatment.

Tubeimoside I Protects Dopaminergic Neurons Against Inflammation-Mediated Damage in Lipopolysaccharide (LPS)-Evoked Model of Parkinson's Disease in Rats.

Parkinson's disease (PD), a frequent degenerative disease in the elderly, is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc). Neuroinflammation caused by over-activated microglia plays a crucial role in the pathogenesis of PD. Tubeimoside I (TBMS1) has a broad anti-inflammatory effect in peripheral tissues, but the effect on neuroinflammation has not been reported. Therefore, we explored whether TBMS1 could protect dopaminergic neurons by inhibiting the activation of microglia in lipopolysaccharide (LPS)-induced PD rat model. In addition, then, the effect and mechanism of TBMS1 on neuroinflammation were assessed in LPS-exposed murine microglial BV-2 cells. The results in vivo showed that TBMS1 suppressed microglial activation and dopaminergic neurons' reduction in LPS-injected PD rat model. In vitro study found that TBMS1 could inhibit LPS-induced inflammatory responses in BV-2 cells, and this effect was mediated by suppressing the phosphorylation of protein kinase B (AKT), nuclear factor-kappa B (NF-κB p65), p38 and extracellular regulated protein kinases (ERK1/2). Taken together, these results demonstrated for the first time that TBMS1 played a role in protecting dopaminergic neurons by inhibiting neuroinflammation mediated by microglia.

Galangin Reduces the Loss of Dopaminergic Neurons in an LPS-Evoked Model of Parkinson's Disease in Rats.

Parkinson's disease (PD) is caused by the loss of dopaminergic (DA) neurons in the midbrain substantia nigra (SN). Neuroinflammation, which is marked by microglial activation, plays a very important role in the pathogenesis of PD. Pro-inflammatory mediators produced by activated microglia could damage DA neurons. Hence, the inhibition of microglial activation may provide a new approach for treating PD. Galangin has been shown to inhibit inflammation in a variety of diseases, but not PD. In this study, we aimed to investigate the anti-inflammatory effect of galangin and the underlying mechanisms in Lipopolysaccharide (LPS) induced PD models. We first examined the protective effect of galangin in the LPS-induced PD rat model. Specifically, we investigated the effects on motor dysfunction, microglial activation, and the loss of DA neurons. Then, galangin was used to detect the impact on the inflammatory responses and inflammatory signaling pathways in LPS-induced BV-2 cells. The in vivo results showed that galangin dose-dependently attenuates the activation of microglia, the loss of DA neurons, and motor dysfunction. In vitro, galangin markedly inhibited LPS-induced expression of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), cyclooxygenase 2 (COX-2), and induced nitric oxide synthase (iNOS) via associating with the phosphorylation of c-JUN N-terminal Kinase (JNK), p38, protein kinase B (AKT), and nuclear factor κB (NF-κB) p65. Collectively, the results indicated that galangin has a role in protecting DA neurons by inhibiting microglial activation.

Hordenine Alleviates Lipopolysaccharide-Induced Mastitis by Suppressing Inflammation and Oxidative Stress, Modulating Intestinal Microbiota, and Preserving the Blood-Milk Barrier.

Mastitis is a common mammalian disease occurring in the mammary tissue and poses a major threat to agriculture and the dairy industry. Hordenine (HOR), a phenylethylamine alkaloid naturally extracted from malt, has various pharmacological effects, but its role in mastitis is unknown. The aim of this study was to investigate the role of HOR and its underlying mechanism in a lipopolysaccharide (LPS)-induced inflammatory response model of mouse mammary epithelial cells (EpH4-Ev) and mouse mastitis model. The experimental results showed that HOR attenuated LPS-induced mammary tissue damage (from 3.75 ± 0.25 to 1.75 ± 0.25) and restored the integrity of the blood-milk barrier. Further mechanistic studies revealed that HOR inhibited LPS-induced overactivation of the TLR4-MAPK/NF-κB signaling pathway and activated the AMPK/Nrf2/HO-1 signaling pathway. Additionally, HOR altered the composition of the intestinal microbiota in mice, ultimately reducing the extent of inflammatory injury (from 3.33 ± 0.33 to 0.67 ± 0.33) and upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-3). The findings of this study provide a theoretical basis in the rational use of HOR for the prevention and treatment of mastitis and the maintenance of mammalian mammary gland health.

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.

Allantoin ameliorates dopaminergic neuronal damage in MPTP-induced Parkinson's disease mice via regulating oxidative damage, inflammation, and gut microbiota disorder.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that often occurs in older people. Neuroinflammation and oxidative stress are important factors in the development of PD. Gastrointestinal dysfunction is the most common non-motor symptom, and inflammation of the gut, which activates the gut-brain axis, maybe a pathogenic factor. Previous studies have attributed anti-inflammatory and antioxidant effects to Allantoin, but its function and mechanism of action in PD are unclear. This study aimed to investigate the effect and mechanism of Allantoin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Our results showed that Allantoin administration ameliorated motor dysfunction and neuronal damage in mice injected with MPTP by inhibiting neuroinflammation and oxidative damage. Mechanistic studies showed that Allantoin suppresses inflammatory responses by inhibiting the overactivation of the NF-κB and MAPK signaling pathways, as well as oxidative stress by regulating the AKT/Nrf2/HO-1 signaling pathway. Notably, Allantoin also restored intestinal barrier function by modulating the gut microbiota and improving antioxidant and anti-inflammatory capacities to alleviate MPTP-induced motor deficits. In conclusion, the present study shows that the administration of Allantoin attenuated neurodegeneration in mice injected with MPTP by inhibiting neuroinflammation and oxidative stress and modulating the composition of the gut microbiome.

Narirutin mitigates dextrose sodium sulfate-induced colitis in mice by modulating intestinal flora.

BACKGROUND: Ulcerative colitis (UC) is a prolonged inflammatory disease of the gastrointestinal tract. Current therapeutic options remain limited, underscoring the imperative to explore novel therapeutic strategies. Narirutin (NR), a flavonoid naturally present in citrus fruits, exhibits excellent anti-inflammatory effects in vitro, yet its in vivo efficacy, especially in UC, remains underexplored. OBJECTIVE: This work examined the effect of NR on dextrose sodium sulfate (DSS)-induced UC in mice in vivo, with a specific focus on the role of gut flora in it. METHODS: The effects of NR (10, 20, and 40 mg/kg) on DSS-induced UC in mice were investigated by monitoring changes in body weight, disease activity index (DAI) scores, colon length, and histological damage. Colonic levels of pro-inflammatory mediators, tight junction (TJ) proteins, and inflammation-related signaling pathway proteins were analyzed via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. The role of gut microbiota in NR against colitis was analyzed through 16S rRNA sequencing, flora clearance assays, and fecal microbiota transplantation (FMT) assays. RESULTS: NR administration suppressed DSS-induced colitis as reflected in a decrease in body weight loss, DAI score, colon length shortening, and histological score. Furthermore, NR administration preserved the integrity of the DSS-induced intestinal barrier by inhibiting the reduction of TJ proteins (claudin3, occludin, and zonula occludens-1). Moreover, NR administration markedly repressed the activation of the toll-like receptor 4-mitogen-activated protein kinase/nuclear factor-κB pathway and reduced the amount of pro-inflammatory mediators in the colon. Importantly, the results of 16S rRNA sequencing showed that the intestinal flora of mice with colitis exhibited richer microbial diversity following NR administration, with elevated abundance of Lactobacillaceae (Lactobacillus) and decreased abundance of Bacteroidaceae (Bacteroides) and Shigella. In addition, the anti-colitis effect of NR almost disappeared after gut flora clearance. Further FMT assay also validated this gut flora-dependent protective mechanism of NR. CONCLUSION: Our findings suggest that NR is a prospective natural compound for the management of UC by modulating intestinal flora.

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.

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.

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.

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.

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.

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.