Artemisinin protects dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in a mouse model of Parkinson's disease.

Artemisinin is an antimalarial drug that has been used for almost half a century. However, the anti-Parkinson's disease (PD) effects of artemisinin with respect to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress have not yet been investigated while focusing on NF-E2-related factor 2 (Nrf2) signaling. Thus, we sought to assess the behavioral and oxidative mechanistic effects of artemisinin on MPTP-induced toxicity via the Nrf2 signaling pathway. We explored this through immunohistochemical assays, ELISA, in differentiated PC12 cells treated with siRNA, and with a PD mouse model. Artemisinin increased Nrf2 DNA-binding activity and HO-1 and NQO1 expression. Artemisinin treatment protected cells against MPP+ -induced neuronal death signaling, including NADH dehydrogenase activity, reactive oxygen species, mitochondrial membrane potential, and cleaved caspase-3. Moreover, it protected cells against MPTP-induced behavioral impairments and significantly reduced dopaminergic neuronal loss. Additionally, Nrf2 pre-inhibition using ML385 neutralized the inhibitory effects of artemisinin on dopaminergic neuronal damage and behavioral impairments induced by MPTP. Our results suggest that artemisinin inhibits MPTP-induced behavioral and neurotoxic effects in mice. This provides a foundation for further research to evaluate artemisinin as a potential therapeutic agent for PD.

Changes in RBM47 expression based on the timing of melatonin administration and its effects on Nrf2 activity in the hippocampus.

Melatonin is an endogenous indoleamine that plays a significant role in various physiological processes, including the sleep-wake cycle, anxiety, immunity, and circadian rhythms. However, it is important to clarify that melatonin does not directly control circadian rhythms. Circadian rhythms are primarily synchronized by light, which acts on the suprachiasmatic nucleus (SCN) and subsequently regulates melatonin production. This light-mediated synchronization of circadian rhythms is essential for maintaining the alignment of the body with the light-dark cycle. In this study, we investigated the efficacy of melatonin administration during different times of the day or night and explored its neuroprotective effects. Furthermore, we aimed to apply these findings to rodent models of dementia, aging, and neuro-inflammation for potential therapeutic applications. Our study uncovered novel evidence suggesting the involvement of RNA-binding motif protein (RBM)-47 and Nrf2 in the signaling pathways associated with melatonin administration during both day and night. We examined the role of RBM47 in Nrf2 activity through siRNA or CRISPR-mediated knockdown experiments using hippocampal neuronal cells and lentivirus injections in mice. In 5xFAD/aging/neuroinflammatory mouse models, antioxidant effects were enhanced when melatonin was administered during the day compared to nighttime administration. Furthermore, mRNA analysis and molecular biology experiments revealed the differential expression of RBM47 depending on the timing of melatonin administration. These findings suggest that a decrease in RBM47 expression may improve the antioxidant defense system in the hippocampus. Consequently, administering melatonin during the day rather than at night may present a plausible therapeutic strategy as an antioxidant.

Effects of 20-hydroxyecdysone on UVB-induced photoaging in hairless mice.

We recently reported that exposure of skin to ultraviolet B (UVB) irradiation for 2 weeks induces stress and accelerates skin aging. Interestingly, aldosterone synthase is known to be crucial in generating UVB-induced stress-related responses, suggesting that drugs that regulate its activity can be used as skin antiaging agents. Through extensive drug screening, we have identified 20-hydroxyecdysone (20E), a steroidal prohormone secreted by the prothoracic glands of insects, as a potent inhibitor of UVB-induced aging. Although 20E has been shown to exert antistress and anti-collagenase effects in vitro, its effects in vivo remain unexplored. Furthermore, the pharmacological and physiological effects of 20E on UVB-mediated photoaging are poorly understood. Therefore, in this study, we investigated the effects of 20E on aldosterone synthase and UVB-induced photoaging and skin lesions in hairless mice, focusing on the stress-related hypothalamic-pituitary-adrenal axis. We confirmed that 20E inhibited aldosterone synthase and reduced corticosterone levels. When applied to a UV-induced skin aging animal model, it ameliorated UV-induced stress and protected against the decrease in collagen levels. Importantly, when the aldosterone synthase inhibitor osilodrostat, an FDA-approved drug, was applied to the UV-induced skin aging model, the stress-reducing and antiaging effects of 20E were not observed. Thus, we conclude that 20E inhibits UVB-induced skin aging by blocking aldosterone synthase and is a potential candidate to prevent skin aging.

Effectiveness of Sopoongsan for chronic upper body pruritus in patients with atopic or seborrheic dermatitis: A pilot study protocol for a randomized, double-blind, placebo-controlled, parallel trial.

INTRODUCTION: Chronic pruritus persists for > 6 weeks and is known to decrease patients' quality of life. Due to the complex pathological mechanism of chronic pruritus, there is still a lack of satisfactory therapeutic agents; therefore, complementary therapies are required to improve itching symptoms. In the Republic of Korea, Sopoongsan, an herbal formula, has been used to treat itching, dizziness, and skin paralysis. To our knowledge, this is the first study to evaluate whether Sopoongsan improves chronic pruritus and to identify Sopoongsan-related changes in the immune response in patients with chronic upper body pruritus. METHODS: A randomized, double-blind, placebo-controlled parallel trial will be conducted to assess 20 patients with chronic upper body pruritus for 3 months who have been diagnosed with allergic atopic dermatitis or seborrheic dermatitis. The patients will be randomly allocated to either the placebo-control (n = 10) or treatment (n = 10) group. The total study period will be 8 weeks (i.e., administration of Sopoongsan or placebo drugs for 4 wk and follow-up for 4 wk). Participants will be allowed to receive external treatment, except for antipruritic medications administered orally, throughout the study period. The primary outcome measure will be the numeric rating scale results for itching, whereas the secondary outcome measures will be questionnaire survey (Dermatological Life Quality Index and Epworth Sleepiness Scale) findings and the immune response index, including interferon gamma, interleukin-4, immunoglobulin E, thymic stromal lymphopoietic protein, and histamine, to investigate the biological mechanisms underlying chronic pruritus. DISCUSSION AND CONCLUSIONS: We expect that the results of this study will provide important clinical evidence regarding the effectiveness of Sopoongsan on itching symptoms, quality of life, sleep disturbance, and changes in the immune response. The findings will help elucidate the mechanism underlying the therapeutic effect of Sopoongsan for chronic pruritus and lay the foundation for further studies in this area.

Early stage ultraviolet irradiation damage to skin collagen can be suppressed by HPA axis control via controlled CYP11B.

UV rays constitute an extremely important environmental factor known to operate adaptative mechanisms that maintain biological homeostasis in the skin, adrenal glands, and the brain. The skin is extremely vulnerable to UV rays. UV rays deform collagen, the main component of elastic fibers, decreasing its normal function, and ultimately reducing skin's elasticity. We confirmed that psychological stress occurring during the early stages of UVB-irradiation degraded collagen function by inhibiting production rather than the decomposition of collagen, thereby promoting skin aging. UV irradiation for 0-2 weeks increased the level of a stress factor, corticosterone (CORT). High-performance liquid chromatography and western blot analysis confirmed that the increase was caused by enhanced CYP11B1/2 levels during steroid synthesis in the adrenal gland. Precursor levels decreased significantly during the two weeks of UV irradiation. Skin collagen and collagen fibers reduced drastically during this time. Furthermore, the administration of osilodrostat, a USFDA-approved drug that selectively inhibits CYP11B1/2, preserved skin collagen. The mechanism underlying the reduction of CORT by osilodrostat confirmed that the amount of skin collagen could be preserved with treatment. In addition, upon suppression of the CORT receptor, the amount of collagen was controlled, and skin aging was suppressed by the hypothalamic-pituitary-adrenal axis. Therefore, this study confirmed an inverse relationship between adrenal CYP11B1/2 levels and collagen during the initial stages of UV irradiation of the skin. The findings of this study may be useful for developing new detection mechanisms for aging, following their further verification.

Resilin, an insect-derived elastomeric protein, protects dopaminergic neurons in Parkinson disease models.

Parkinson disease (PD) is a prevalent neurodegenerative disorder that is characterized by motor and behavioral disturbances, including resting tremors, rigidity, bradykinesia, and postural instability. The primary cause of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region that subsequently reduces the dopamine content in the striatum (ST); this is a promising therapeutic target for PD. Resilin is an elastomeric protein with high strain, low stiffness, and high resilience that is found in insect cuticles. However, scant evidence supports the application of resilin in neurodegenerative diseases, including PD. Herein, we investigated the protective effects of resilin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mouse models and explored the mechanisms underlying its action. Resilin significantly and concentration-dependently reduced 1-methyl-4-phenylpyridinium+ (MPP+)-induced apoptotic neurotoxicity in differentiated PC12 and SH-SY5Y cells. Moreover, resilin prevented dopamine depletion in ST, and immunohistochemical findings indicated that resilin protects against dopaminergic neuronal loss induced by MPTP in the SNpc and ST. Behavioral studies using pole and rotarod tests showed significantly improved PD-related motor impairment in mice treated with resilin. We then explored the molecular mechanisms underlying the apoptosis of dopaminergic neurons using protein arrays and discovered that resilin inhibits dopaminergic neuronal death through the apoptosis signaling factors cytochrome c and caspases-9 and -3 in the SNpc. Thus, resilin has potential in treating PD by controlling apoptosis signals.

Effects of the Higenamine, a Potent Compound from Aconitum, on UVB-Induced Photoaging in Hairless Mice.

Aim: Higenamine [1-[(4-hydroxyphenyl) methyl]-1, 2, 3, 4-tetrahydroisoquinoline-6, 7-diol], a potent cardiotonic compound from Aconitum, contributes to vascular relaxation and bronchodilation. However, the effects and mechanisms of action of higenamine on skin aging remain poorly understood. In this study, the effects of higenamine on UVB-induced photoaging were examined in the hairless mouse model. Methods: The dorsal skin of hairless mice (CrlOri : SKH1) was exposed to chronic UVB irradiation (100-300 mJ/cm2 for 6 weeks), with subsequent administration of higenamine (1-20 mg/kg, p.o.) for 2 weeks. TGF-ß, Smad3 DNA-binding phosphorylation, and COL1A1 levels were analyzed by immunohistochemistry, and histological analysis of the skin was performed via H&E and MT staining. Results: Higenamine increased TGF-ß, Smad3 DNA-binding phosphorylation, and COL1A1 expression in primary human fibroblast cells and mouse skin. Higenamine suppressed UVB-induced photoaging via skin recovery, improved epidermal thickness, and prevented Smad3, DNA-binding phosphorylation, and COL1A1 depletion via TGF-ß signaling. Conclusion: Higenamine enhances collagen production in the skin through TGF-ß/Smad3 signaling and potentially suppresses UVB-induced skin aging.

Cera Flava Alleviates Atopic Dermatitis by Activating Skin Barrier Function via Immune Regulation.

Cera Flava (CF), a natural extract obtained from beehives, is widely used in dermatological products owing to its wound healing, wrinkle reduction, UV-protective, and skin cell turnover stimulation effects. However, its effect on AD-like skin lesions is unknown. In this study, we used a mouse model of AD to evaluate the effects of CP at the molecular and phenotypic levels. Topical house dust mite (HDM) sensitization and challenge were performed on the dorsal skin of NC/Nga mice to induce AD-like cutaneous lesions, phenotypes, and immunologic responses. The topical application of CF for 6 weeks relieved HDM-induced AD-like phenotypes, as quantified by the dermatitis severity score, scratching frequency, and skin moisture. CP decreased immunoglobulin E, histamine, and thymic stromal lymphopoietin levels. Histopathological analysis showed that CF decreased epidermal thickening and the number of mast cells. CF attenuated HDM-induced changes in the expression of skin barrier-related proteins. Furthermore, CF decreased the mRNA levels of inflammatory factors, including interleukin (IL)-1ß, IL-4, IL-13, IL-8, TARC, MDC, and RANTES, in dorsal skin tissue via the TLR2/MyD88/TRAF6/ERK pathway. CF influences skin barrier function and immune regulation to alleviate AD symptoms. It may therefore be an effective alternative to topical steroids for the treatment of AD.

Chronic Ultraviolet Irradiation to the Skin Dysregulates Adrenal Medulla and Dopamine Metabolism In Vivo.

Ultraviolet (UV) radiation has a strong biological effect on skin biology, and it switches on adaptive mechanisms to maintain homeostasis in organs such as the skin, adrenal glands, and brain. In this study, we examined the adaptation of the body to repeated bouts of UVB radiation, especially with respect to the catecholamine synthesis pathway of the adrenal glands. The effects of UVB on catecholamine-related enzymes were determined by neurochemical and histological analyses. To evaluate catecholamine changes after chronic excessive UVB irradiation of mouse skin, we examined dopamine and norepinephrine levels in the adrenal glands and blood from UV-irradiated and sham-irradiated mice. We found that chronic excessive UVB exposure significantly reduced dopamine levels in both tissues but did not affect norepinephrine levels. In addition, UVB irradiation significantly increased the levels of related enzymes tyrosine hydroxylase and dopamine-ß-hydroxylase. Furthermore, we also found that apoptosis-associated markers were increased and that oxidative defense proteins were decreased, which might have contributed to the marked structural abnormalities in the adrenal medullas of the chronically UVB-irradiated mice. This is the first evidence of the damage to the adrenal gland and subsequent dysregulation of catecholamine metabolism induced by chronic exposure to UVB.

Epigenetic mechanisms involved in the neuroprotective effect of scorpion extract in a Parkinson's disease murine model based on multi-omics approach.

OBJECTIVE: To investigate whether scorpion extract elicits a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice models, and the genes associated with the therapeutic effects using RNA sequencing (seq) analysis. METHODS: This study investigated the changes in interaction between messenger ribonucleic acid (mRNA) expression and deoxyribonucleic acid (DNA) methylation related to the protective effects of scorpion extracts, in the substantia nigra (SN) region of a MPTP-induced Parkinson's disease (PD) model. RESULTS: In this model, scorpion extracts attenuated the motor impairment as demonstrated by the rotarod and open field tests. Scorpion extracts consistently attenuated the decrease of tyrosine hydroxylase (TH) positive neural cells in the SN and striatum of mice. We profiled genome- wide DNA methylation using Methyl-Seq and measured the transcriptome using RNA-Seq in murine SN in the following groups: vehicle-treated MPTP-induced PD mice and scorpion extract- treated MPTP-induced PD mice. In total, 13 479 differentially expressed genes were identified in association with the anti-PD effect of the scorpion extract, mainly in the promoter and coding regions. Among them, 47 were negatively correlated down- regulated genes. Nineteen genes out of 47 down- regulated genes were negatively correlated with the expression of the other 28 genes. Among these genes, SGSM1 was related to dopaminergic neu- rons including dopamine transporters, TH, dihy- droxyphenylalanine decarboxylase, and dopamine D2 receptor. CONCLUSION: This study provides insights into the anti-parkinsonian effects of scorpion extract and reveals the epigenetic targets in its therapeutic mechanism.

Simultaneous Quantification of Four Marker Compounds in Bauhinia coccinea Extract and Their Potential Inhibitory Effects on Alzheimer's Disease Biomarkers.

Bauhinia coccinea is a tropical woody plant widely distributed in Vietnam and Unnan in southern China. Although many studies have shown the biological activities of extracts from various other species in the genus, no studies have investigated the effects of B. coccinea extracts on biological systems. In the present study, a quantitative analysis of four marker compounds of ethanol extracts of B. coccinea branches (EEBC) was performed using the high performance liquid chromatography (HPLC)-photodiode array (PDA) method. Among gallic acid, (+)-catechin, ellagic acid, and quercitrin contained in EEBC, the most abundant compound was (+)-catechin (18.736 mg/g). In addition, we investigated the EEBC on neuroprotection, antioxidation, and Alzheimer's disease (AD) marker molecules, acetylcholinesterase (AChE), and amyloid-ß (Aß). EEBC significantly inhibited hydrogen peroxide (H2O2)-induced cell death in a HT22 neuronal cell line and increased 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl scavenging activity markedly. EEBC also inhibited AChE and Aß aggregation. Among the four compounds, gallic acid exhibited strong inhibitory effects against AChE activation. In the Aß aggregation assay, the four marker compounds exhibited inhibitory effects lower than 30%. According to the results, EEBC could exert anti-AChE activation and Aß aggregation activities based on the interactive effects of the marker compounds. Our findings suggest that EEBC are sources of therapeutic candidates for application in the development of AD medication based on AChE and Aß dual targeting.

Cicadidae Periostracum Attenuates Atopic Dermatitis Symptoms and Pathology via the Regulation of NLRP3 Inflammasome Activation.

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease of complex etiology. Despite its increasing prevalence, treatment for AD is still limited. Crude drugs, including herbal extracts or natural resources, are being used to treat AD symptoms, with minimum side effects. Cicadidae Periostracum (CP), derived from the slough of insects belonging to the family Cicadidae, is a commonly used crude drug in traditional Asian medicine to treat/control epilepsy, shock, and edema. However, the effect of CP on AD-like skin lesions is unknown. In this study, we examined the effect of a CP water extract on AD disease development in vivo, using a house dust mite-induced AD mouse model, and in vitro, using HaCaT keratinocytes and a 3D human skin equivalent system. Importantly, CP administration alleviated house dust mite-induced AD-like symptoms, suggested by the quantified dermatitis scores, animal scratching behaviors, skin moisture retention capacity, and skin lesion and ear thickness. Furthermore, histopathological analysis demonstrated that CP decreased intralesional mast cell infiltration. In addition, CP treatments decreased the systemic levels of immunoglobulin E, histamine, and thymic stromal lymphopoietin (TSLP) and the local mRNA expression of TSLP and several Th1/Th2 cytokines. Our data suggest that these effects were mediated by the inhibition of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation. In vivo and in vitro CP treatments resulted in the downregulation of inflammasome components, such as ASC and cleaved caspase-1, as well as related mediators such as IL-1ß and reactive oxygen species. Collectively, our results suggest that CP is a potential therapeutic agent for AD, controlling inflammatory responses through the suppression of NLRP3 inflammasome activation.

The insect molting hormone 20-hydroxyecdysone protects dopaminergic neurons against MPTP-induced neurotoxicity in a mouse model of Parkinson's disease.

20-hydroxyecdysone (20E), a steroidal prohormone, is secreted from the prothoracic glands. While 20E has been shown to have neuroprotective effects in Parkinson's disease (PD) models in vitro, its effects have not yet been examined in vivo. We sought to assess the behavioral and mechanistic effects of 20E on MPTP-induced toxicity in mice. To this end, we used behavioral tests, stereological analyses of dopaminergic neurons by tyrosine hydroxylase immunohistochemistry, and assessments of apoptotic mechanisms, focusing on Nrf2 signaling through Western blotting and ELISA assays. A 20E treatment protected against MPTP-induced motor incoordination, postural imbalance, and bradykinesia, and significantly reduced dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) and the striatum (ST). It also attenuated dopamine deficiency in the ST, modulated levels of antioxidative enzymes superoxide dismutase, catalase, and glutathione in the SNpc, increased the Bcl-2/Bax ratio, and inhibited cytosolic cytochrome c release and caspase-9, -7, and -3 activity in the SNpc. These results indicated that 20E inhibited the apoptotic cascade. Furthermore, the attenuation of MPTP neurotoxicity was associated with inhibited cleaved-caspase signaling pathways, along with upregulated Nrf2 pathways in the SNpc, suggesting that 20E mitigates MPTP-induced neurotoxicity via mitochondria-mediated apoptosis by modulating anti-oxidative activities. Our results suggest that 20E can inhibit MPTP-induced behavioral and neurotoxic effects in mice. This lays the foundation for further research on 20E as a potential target for therapeutic use.

Similarity of therapeutic networks induced by a multi-component herbal remedy, Ukgansan, in neurovascular unit cells.

The neurovascular unit, which includes neurons, glial cells, and vascular cells, plays crucial roles in the onset and progression of Alzheimer's disease (AD). Therefore, effective drugs against AD should be able to target the multi-cellular neurovascular unit and the therapeutic relationships among neurovascular cells should be defined. Here, we examined the therapeutic effects of Ukgansan (UGS), an herbal remedy with multi-targeting capabilities, using in vitro neurovascular unit models and an in vivo model of AD. In addition, we compared the therapeutic networks induced by UGS and its components in different neurovascular cell types. We found that UGS and its components protected neurovascular cells against diverse damaging agents and improved the behavioral patterns of AD model mice. A comparison of UGS- or its components-induced therapeutic networks, constructed from high-throughput data on gene expression, pathway activity, and protein phosphorylation, revealed similarities among neurovascular cell types, especially between BV-2 microglia and HBVP (human brain vascular pericytes). These findings, together with the functional connections between neurovascular cells, can explain the therapeutic effects of UGS. Furthermore, they suggest underlying similarities in the therapeutic mechanisms in different neurovascular cell types.

Protective Effects of Scolopendra Water Extract on Trimethyltin-Induced Hippocampal Neurodegeneration and Seizures in Mice.

Trimethyltin (TMT) is an organotin compound with potent neurotoxic action characterized by neuronal degeneration in the hippocampus. This study evaluated the protective effects of a Scolopendra water extract (SWE) against TMT intoxication in hippocampal neurons, using both in vitro and in vivo model systems. Specifically, we examined the actions of SWE on TMT- (5 mM) induced cytotoxicity in primary cultures of mouse hippocampal neurons (7 days in vitro) and the effects of SWE on hippocampal degeneration in adult TMT- (2.6 mg/kg, intraperitoneal) treated C57BL/6 mice. We found that SWE pretreatment (0-100 µg/mL) significantly reduced TMT-induced cytotoxicity in cultured hippocampal neurons in a dose-dependent manner, as determined by lactate dehydrogenase and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. Additionally, this study showed that perioral administration of SWE (5 mg/kg), from -6 to 0 days before TMT injection, significantly attenuated hippocampal cell degeneration and seizures in adult mice. Furthermore, quantitative analysis of Iba-1 (Allograft inflammatory factor 1)- and GFAP (Glial fibrillary acidic protein)-immunostained cells revealed a significant reduction in the levels of Iba-1- and GFAP-positive cell bodies in the dentate gyrus (DG) of mice treated with SWE prior to TMT injection. These data indicated that SWE pretreatment significantly protected the hippocampus against the massive activation of microglia and astrocytes elicited by TMT. In addition, our data showed that the SWE-induced reduction of immune cell activation was linked to a significant reduction in cell death and a significant improvement in TMT-induced seizure behavior. Thus, we conclude that SWE ameliorated the detrimental effects of TMT toxicity on hippocampal neurons, both in vivo and in vitro. Altogether, our findings hint at a promising pharmacotherapeutic use of SWE in hippocampal degeneration and dysfunction.

Cicadidae Periostracum, the Cast-Off Skin of Cicada, Protects Dopaminergic Neurons in a Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta (SNPC) and the striatum. Nuclear receptor-related 1 protein (Nurr1) is a nuclear hormone receptor implicated in limiting mitochondrial dysfunction, apoptosis, and inflammation in the central nervous system and protecting dopaminergic neurons and a promising therapeutic target for PD. Cicadidae Periostracum (CP), the cast-off skin of Cryptotympana pustulata Fabricius, has been used in traditional medicine for its many clinical pharmacological effects, including the treatment of psychological symptoms in PD. However, scientific evidence for the use of CP in neurodegenerative diseases, including PD, is lacking. Here, we investigated the protective effects of CP on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced PD in mice and explored the underlying mechanisms of action, focusing on Nurr1. CP increased the expression levels of Nurr1, tyrosine hydroxylase, DOPA decarboxylase, dopamine transporter, and vesicular monoamine transporter 2 via extracellular signal-regulated kinase phosphorylation in differentiated PC12 cells and the mouse SNPC. In MPTP-induced PD, CP promoted recovery from movement impairments. CP prevented dopamine depletion and protected against dopaminergic neuronal degradation via mitochondria-mediated apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X, cytochrome c, and cleaved caspase-9 and caspase-3 by inhibiting MPTP-induced neuroinflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase 2, and glial/microglial activation. Moreover, CP inhibited lipopolysaccharide-induced neuroinflammatory cytokines and response levels and glial/microglial activation in BV2 microglia and the mouse brain. Our findings suggest that CP might contribute to neuroprotective signaling by regulating neurotrophic factors primarily via Nurr1 signaling, neuroinflammation, and mitochondria-mediated apoptosis.

Batryticatus Bombyx Protects Dopaminergic Neurons Against MPTP-Induced Neurotoxicity by Inhibiting Oxidative Damage.

Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Altered redox homeostasis in neurons interferes with several biological processes, ultimately leading to neuronal death. Oxidative damage has been identified as one of the principal mechanisms underlying the progression of PD. Several studies highlight the key role of superoxide radicals in inducing neuronal toxicity. Batryticatus Bombyx (BB), the dried larva of Bombyx mori L. infected by Beauveria bassiana (Bals.) Vuill., has been used in traditional medicine for its various pharmacological effects. In the present study, BB showed a beneficial effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity by directly targeting dopaminergic neurons. Treatment with BB improved behavioral impairments, protected dopaminergic neurons, and maintained dopamine levels in PD mouse models. Here, we investigated the protective effects of BB on MPTP-induced PD in mice and explored the underlying mechanisms of action, focusing on oxidative signaling. In MPTP-induced PD, BB promoted recovery from impaired movement, prevented dopamine depletion, and protected against dopaminergic neuronal degradation in the substantia nigra pars compacta (SNpc) or the striatum (ST). Moreover, BB upregulated mediators of antioxidative response such as superoxidase dismutase (SOD), catalase (CAT), glutathione (GSH), Heme oxygenase 1 (HO-1), and NAD(P)H (nicotinamide adenine dinucleotide phosphate) dehydrogenase (NQO1). Thus, treatment with BB reduced the oxidative stress, improved behavioral impairments, and protected against dopamine depletion in MPTP-induced toxicity.

Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway.

The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription-polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases.

Annona atemoya Leaf Extract Improves Scopolamine-Induced Memory Impairment by Preventing Hippocampal Cholinergic Dysfunction and Neuronal Cell Death.

We explored the preventative effect of Annona atemoya leaf (AAL) extract on memory impairment in a scopolamine (SCO)-induced cognitive deficit mouse model. Fifty-eight mice were randomly divided into six groups and orally treated with AAL extract at (50, 100, or 200 mg/kg) or tacrine (TAC) for 21 days. Memory deficits were induced by a single injection of 1 mg/kg SCO (i.p.) and memory improvement was evaluated by using behavioral tests such as the passive avoidance task and Y-maze test. The levels of cholinergic functions, neuronal cell death, reactive oxygen species, and protein expression related to hippocampal neurogenesis were examined by immunohistochemical staining and western blotting. The administration of AAL extract improved memory impairment according to increased spontaneous alternation in the Y-maze and step-through latency in passive avoidance test. AAL extract treatment increased the acetylcholine content, choline acetyltransferase, and acetylcholinesterase activity in the hippocampus of SCO-stimulated mice. In addition, AAL extract attenuated oxidative stress-induced neuronal cell death of hippocampal tissue. In terms of the regulatory mechanisms, AAL extract treatment reversed the SCO-induced decreases in the expression of Akt, phosphorylation of cAMP response element binding protein, and brain-derived neurotrophic factor. Our findings demonstrate that AAL extract has the ability to alleviate memory impairment through preventative effect on cholinergic system dysfunction and oxidative stress-related neuronal cell death in a SCO-induced memory deficit animal model. Overall, AAL may be a promising plant resource for the managing memory dysfunction due to neurodegenerative diseases, such as Alzheimer's disease (AD).