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Harpagophytum procumbens (Hp) is often used in the supportive treatment of inflammatory and degenerative diseases of the skeletal system. Although the clinical efficacy in osteoarthritis has been demonstrated in clinical trials, the molecular target(s) of Hp are unclear. This study quantified the effects of the ethanol Hp extract (60% v/v ethanol, sole active ingredient of Pascoe(R)-Agil), on the expression and release of the major pro-inflammatory mediators in LPS-stimulated human monocytes and the intracellular signalling pathways involved in inflammation. The Hp extract dose-dependently inhibited the release of TNF[alpha] as well as that of interleukin (IL)-6, IL-1[beta] and prostaglandin E(2) (PGE(2) ). The Hp prevented TNF[alpha] and IL-6 mRNA expression in human monocytes and cyclooxygenase-2 (COX-2) in RAW 264.7 cells. Furthermore, the Hp extract inhibited LPS-stimulated AP-1-mediated gene transcription activity and binding to the AP-1 response elements. The extract had no effect on the LPS-induced binding of nuclear factor-[kappa]B in RAW 264.7 cells, on LPS-induced degradation of I[kappa]B[alpha] or on LPS-induced activation of mitogen-activated protein kinases (MAPK), p38MAPK and JNK in human monocytes. The data indicate that a standardized ethanol Hp extract inhibits induction of pro-inflammatory gene expression, possibly by blocking the AP-1 pathway. This is novel evidence of a possible mechanism of action of this antiinflammatory drug. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia.Results: Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE2 production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by beta-adrenoreceptors, since beta-, but not alpha-adrenoreceptor agonists produced similar results. Furthermore, beta-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and beta-adrenoreceptor agonists.Conclusions: Considering that PGE2 displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Resveratrol, a polyphenol present in grapes and red wine, has been studied due to its vast pharmacological activity. It has been demonstrated that resveratrol inhibits production of inflammatory mediators in different in vitro and in vivo models. Our group recently demonstrated that resveratrol reduced the production of prostaglandin (PG) E2 and 8-isoprostane in rat activated microglia. In a microglial-neuronal coculture, resveratrol reduced neuronal death induced by activated microglia. However, less is known about its direct roles in neurons. In the present study, we investigated the effects of resveratrol on interleukin (IL)-1beta stimulated SK-N-SH cells. Resveratrol (0.1-5 microM) did not reduce the expression of cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1 (mPGES-1), although it drastically reduced PGE2 and PGD2 content in IL-1beta-stimulated SK-N-SH cells. This effect was due, in part, to a reduction in COX enzymatic activity, mainly COX-2, at lower doses of resveratrol. The production of 8-iso-PGF2alpha, a marker of cellular free radical generation, was significantly reduced by resveratrol. The present work provides evidence that resveratrol reduces the formation of prostaglandins in neuroblastoma cells by reducing the enzymatic activity of inducible enzymes, such as COX-2, and not the transcription of the PG synthases, as demonstrated elsewhere. [ABSTRACT FROM AUTHOR]

Background: Recent in vitro evidence indicates that blockade of 5-hydroxytryptamine (5-HT) receptor 3 (5-HT3) is able to confer protection in different models of neuronal injury. The purpose of the present study was to investigate the effect of tropisetron, a 5-HT3 receptor antagonist, on infarct size and neurological score in a model of ischemic stroke induced by permanent middle cerebral artery occlusion (pMCAO) in the rat.Methods: Two different doses of tropisetron (5 and 10 mg/kg) or vehicle were administered intraperitoneally 30 min before pMCAO. Neurological deficit scores, mortality rate and infarct volume were determined 24 h after permanent focal cerebral ischemia.Results: Tropisetron failed to reduce cerebral infarction. Animals receiving tropisetron showed a significant increase (p < 0.05) in neurological deficits and mortality rate.Conclusion: Data from this study indicate that blockade of 5-HT3 receptors with tropisetron worsens ischemic brain injury induced by pMCAO. These findings could have important clinical implications. Patients taking tropisetron, and possibly other 5-HT3 antagonists, could potentially have a worse outcome following a brain infarct. [ABSTRACT FROM AUTHOR]

Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Inflammatory processes in the brain can exert important neuroprotective functions. However, in neurological and psychiatric disorders, it is often detrimental due to chronic microglial over-activation and the dysregulation of cytokines and chemokines. Growing evidence indicates the emerging yet prominent pathophysiological role of neuroinflammation in the development and progression of these disorders. Despite recent advances, there is still a pressing need for effective therapies, and targeting neuroinflammation is a promising approach. Therefore, in this study, we investigated the anti-neuroinflammatory potential of a marketed and quantified proprietary herbal extract of Ginkgo biloba leaves called EGb 761 (10-500 µg/mL) in BV2 microglial cells stimulated by LPS (10 ng/mL). Our results demonstrate significant inhibition of LPS-induced expression and release of cytokines tumor necrosis factor-α (TNF-α) and Interleukin 6 (IL-6) and chemokines C-X-C motif chemokine ligand 2 (CXCL2), CXCL10, c-c motif chemokine ligand 2 (CCL2) and CCL3 in BV2 microglial cells. The observed effects are possibly mediated by the mitogen-activated protein kinases (MAPK), p38 MAPK and ERK1/2, as well as the protein kinase C (PKC) and the nuclear factor (NF)-κB signaling cascades. The findings of this in vitro study highlight the anti-inflammatory properties of EGb 761 and its therapeutic potential, making it an emerging candidate for the treatment of neuroinflammatory diseases and warranting further research in pre-clinical and clinical settings.

Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.

Microglia are essential contributors to synaptic transmission and stability and communicate with neurons via the fractalkine pathway. Transcranial direct current stimulation [(t)DCS], a form of non-invasive electrical brain stimulation, modulates cortical excitability and promotes neuroplasticity, which has been extensively demonstrated in the motor cortex and for motor learning. The role of microglia and their fractalkine receptor CX3CR1 in motor cortical neuroplasticity mediated by DCS or motor learning requires further elucidation. We demonstrate the effects of pharmacological microglial depletion and genetic Cx3cr1 deficiency on the induction of DCS-induced long-term potentiation (DCS-LTP) ex vivo. The relevance of microglia-neuron communication for DCS response and structural neuroplasticity underlying motor learning are assessed via 2-photon in vivo imaging. The behavioural consequences of impaired CX3CR1 signalling are investigated for both gross and fine motor learning. We show that DCS-mediated neuroplasticity in the motor cortex depends on the presence of microglia and is driven in part by CX3CR1 signalling ex vivo and provide the first evidence of microglia interacting with neurons during DCS in vivo. Furthermore, CX3CR1 signalling is required for motor learning and underlying structural neuroplasticity in concert with microglia interaction. Although we have recently demonstrated the microglial response to DCS in vivo, we now provide a link between microglial integrity and neuronal activity for the expression of DCS-dependent neuroplasticity. In addition, we extend the knowledge on the relevance of CX3CR1 signalling for motor learning and structural neuroplasticity. The underlying molecular mechanisms and the potential impact of DCS in rescuing CX3CR1 deficits remain to be addressed in the future., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Punicalagin (PU), the major ellagitannin found in pomegranates, is characterized by multiple antioxidant activities. The aim of this study is to assess the protective effects of PU against isoproterenol (ISO)-induced acute myocardial damage and to investigate its underlying vascular mechanisms using rat model. METHODS: Rats were randomly divided into five groups and were treated orally (p.o.) with PU (25 and 50 mg/kg) for 14 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 15th and 16th days to induce Myocardial infarction. Cardiac markers, oxidative stress markers, and inflammatory cytokines levels were determined in the heart tissue. Immunohistochemistry analysis was performed to determine the protein expression pathways of inflammation, apoptosis and oxidative stress (Nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (HO-1) in all the groups. In silico study was carried out to evaluate the molecular interaction of PU with some molecular targets. RESULTS: Our results showed that ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), associated with several histopathological changes. ISO also induced an increase of MDA, PCO, NO, and 8-hydroxy-2-deoxyguanosine (8-OHdG), along with a decrease of antioxidant enzyme activities in the myocardial tissues. In addition, an increase of TNF-α, NF-κB, IL-6, IL-1β, iNOS, Nrf2 and (HO-1) was observed. Pre-treatment with PU reduced myocardial infract area, ameliorated histopathological alterations in myocardium, and decreased activities of myocardial injury marker enzymes in ISO-induced rats. In addition, PU remarkably restored ISO-induced elevation of lipid peroxidation and decrease of antioxidants, significantly reduced myocardial pro-inflammatory cytokines concentrations in this animal model. Molecular docking analysis of PU with protein targets showed potent interactions with negative binding energies. In conclusion, PU can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Schizophrenia spectrum disorders (SSD) can be associated with neurodegenerative processes causing disruption of neuronal, synaptic, or axonal integrity. Some previous studies have reported alterations of neurodegenerative markers (such as amyloid beta [Aβ], tau, or neurofilaments) in patients with SSD. However, the current state of research remains inconclusive. Therefore, the rationale of this study was to investigate established neurodegenerative markers in the cerebrospinal fluid (CSF) of a large group of patients with SSD., Study Design: Measurements of Aβ1-40, Aß1-42, phospho- and total-tau in addition to neurofilament light (NFL), medium (NFM), and heavy (NFH) chains were performed in the CSF of 100 patients with SSD (60 F, 40 M; age 33.7 ± 12.0) and 39 controls with idiopathic intracranial hypertension (33 F, 6 M; age 34.6 ± 12.0) using enzyme-linked immunoassays., Study Results: The NFM levels were significantly increased in SSD patients (P = .009), whereas phospho-tau levels were lower in comparison to the control group (P = .018). No other significant differences in total-tau, beta-amyloid-quotient (Aβ1-42/Aβ1-40), NFL, and NFH were identified., Conclusions: The findings argue against a general tauopathy or amyloid pathology in patients with SSD. However, high levels of NFM, which has been linked to regulatory functions in dopaminergic neurotransmission, were associated with SSD. Therefore, NFM could be a promising candidate for further research on SSD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neuroinflammation and oxidative stress are conditions leading to neurological and neuropsychiatric disorders. Natural compounds exerting anti-inflammatory and anti-oxidative effects, such as Licochalcone A, a bioactive flavonoid present in a traditional Chinese herb (licorice), might be beneficial for the treatment of those disorders. Therefore, this study aimed to investigate the anti-inflammatory and anti-oxidative effects of Licochalcone A in LPS-activated primary rat microglia. Licochalcone A dose-dependently prevented LPS-induced PGE 2 release by inhibiting the arachidonic acid (AA)/cylcooxygenase (COX) pathway decreasing phospholipase A2, COX-1, and COX-2 protein levels. Furthermore, LPS-induced levels of the cytokines IL-6 and TNFα were reduced by Licochalcone A, which also inhibited the phosphorylation and, thus, activation of the mitogen-activated protein kinases (MAPK) p38 MAPK and Erk 1/2. With the reduction of 8-iso-PGF 2α , a sensitive marker for oxidative stress, anti-oxidative effects of Licochalcone A were demonstrated. Our data demonstrate that Licochalcone A can affect microglial activation by interfering in important inflammatory pathways. These in vitro findings further demonstrate the potential value of Licochalcone A as a therapeutic option for the prevention of microglial dysfunction related to neuroinflammatory diseases. Future research should continue to investigate the effects of Licochalcone A in different disease models with a focus on its anti-oxidative and anti-neuroinflammatory properties.

Background: Despite intensive research, the etiological causes of autism spectrum disorder (ASD) remain elusive. Immunological mechanisms have recently been studied more frequently in the context of maternal autoantibodies and infections, as well as altered cytokine profiles. For the detection of immunological processes in the central nervous system, analyses of cerebrospinal fluid (CSF) are advantageous due to its proximity to the brain. However, cytokine studies in the CSF of ASD patients are sparse., Methods: CSF was collected from a patient sample of 24 adults (m = 16, f = 8, age: 30.3 ± 11.6 years) with ASD and compared to a previously published mentally healthy control sample of 39 neurological patients with idiopathic intracranial hypertension. A magnetic bead multiplexing immunoassay was used to measure multiple cytokines in CSF., Results: Significantly decreased interferon-γ-induced protein-10 (p = 0.001) and monocyte chemoattractant protein-1 (p = 0.041) levels as well as significantly higher interleukin-8 levels (p = 0.041) were detected in patients with ASD compared with the control group., Conclusion: The main finding of this study is an altered cytokine profile in adult patients with ASD compared to the control group. This may indicate immune dysregulation in a subgroup of adult ASD patients. Further studies in larger cohorts that examine a broader spectrum of chemokines and cytokines in general are needed to detect possible specific immune signatures in ASD., Competing Interests: Declaration of competing interest KR: None. BLF: None. HK: None. JR: None. KN: None. SJM: None. RD: Lecture fees from Roche and travel grants from Biogen. KD: Steering Committee Neurosciences, Janssen. LTvE: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen and Cyberonics. DE: None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools., Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST., Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events., Competing Interests: Conflict of Interest Authors Dr. Rajeev K. Singla and Shailja Singla have an honorary-based associations with the iGlobal Research and Publishing Foundation (iGRPF), New Delhi, India. Dr. Bernd Fiebich is associated with VivaCell Biotechnology GmbH. RKS, SS and BF along with the remaining authors, declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Given their role as Editor/Associate Editor/ Editorial board members, “Prof. Thomas Efferth”, “Ilkay Erdogan Orhan”, “Milen Georgiev”, “Davide Barreca”, “Maurizio Battino”, “Anupam Bishayee”, “Michael Heinrich”,and“Jianbo Xiao”had no involvement in the peer-review of this article and has no access to information regarding its peer-review., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Cannabidiol (CBD) has been suggested as a potential therapy for inflammatory and fibrotic diseases. Cannabidiol was demonstrated to reduce alcohol-induced liver inflammation and steatosis but its specific activity on the fibrotic process was not investigated. Herein, the antifibrotic effects of cannabidiol in the skin were analysed in vitro using NIH-3T3 fibroblasts and human dermal fibroblasts and in vivo using the bleomycin-induced model of skin fibrosis. In a second model, non-alcoholic liver fibrosis was induced in mice by CCl 4 exposure. Cannabidiol was administered daily, intraperitoneally in mice challenged with bleomycin and orally in CCl 4 mice, and skin and liver fibrosis and inflammation were assessed by immunochemistry. Cannabidiol inhibited collagen gene transcription and synthesis and prevented TGFβ-and IL-4 induced fibroblast migration. In the bleomycin model, cannabidiol prevented skin fibrosis and collagen accumulation around skin blood vessels, and in the CCl 4 model cannabidiol significantly attenuated liver fibrosis measured by picrosirius red and Tenascin C staining and reduced T cell and macrophage infiltration. Altogether, our data further support the rationale of the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the management of fibrotic diseases including Systemic Sclerosis and Non-Alcoholic Fatty Liver Disease., Competing Interests: Authors FR-P and MP are employed by VivaCell Biotechnology España. BF is employed by VivaCell Biotechnology GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 del Río, Ruiz-Pino, Prados, Fiebich, Tena-Sempere and Muñoz.)

Introduction: Infectious and immunological theories of schizophrenia have been discussed for over a century. Contradictory results for infectious agents in association with schizophrenia spectrum disorders (SSDs) were reported. The rationale of this study was to investigate intrathecal antibody synthesis of the most frequently discussed neurotropic pathogens using a pathogen-specific antibody index (AI) in patients with SSD in comparison to controls., Methods: In 100 patients with SSD and 39 mentally healthy controls with idiopathic intracranial hypertension (IIH), antibodies against the herpesviruses EBV, CMV, and HSV 1/2 as well as the protozoan Toxoplasma gondii, were measured in paired cerebrospinal fluid (CSF) and serum samples with ELISA-kits. From these antibody concentrations the pathogen-specific AIs were determined with the assumption of intrathecal antibody synthesis at values > 1.5., Results: No significant difference was detected in the number of SSD patients with elevated pathogen-specific AI compared to the control group. In a subgroup analysis, a significantly higher EBV AI was observed in the group of patients with chronic SSD compared to patients with first-time SSD diagnosis (p = 0.003). In addition, two identified outlier EBV patients showed evidence for polyspecific immune reactions (with more than one increased AI)., Conclusions: Evidence for the role of intrathecal EBV antibody synthesis was found in patients with chronic SSD compared to those first diagnosed. Apart from a possible infectious factor in SSD pathophysiology, the evidence for polyspecific immune response in outlier patients may also suggest the involvement of further immunological processes in a small subgroup of SSD patients., (© 2022. The Author(s).)

Introduction: In the current study, we evaluated the effectiveness of two well-defined probiotic strains, Lactobacillus paracasei LPc-G110 (CCTCC M 2013691) and Lactobacillus plantarum GOS42 (DSM 32131), during an experimental gingivitis challenge. The primary objective was to evaluate clinically the effectiveness of lozenges containing one of the two oral probiotic strains, compared with placebo lozenges, on the gingival bleeding (bleeding on marginal probing; BOMP change) after a two-week experimental gingivitis period. The secondary objectives were to assess the effects of the test products on gingival health (Modified Gingival Index; MGI), dental plaque accumulation and fluorescence, and the dynamics of immunological and microbiological aspects after the wash-in phase, followed by a two-week period refraining from oral hygiene and a two-week wash-out phase., Methods: This single-center challenge intervention study was a triple-blind randomized placebo-controlled clinical trial with three parallel groups. The full study population consisted of 117 healthy 18-55 years old human volunteers. Subjects were instructed to use one lozenge, 3 times daily after each meal, containing either L. plantarum, L. paracasei , or lozenges without probiotics (placebo group). After a 2-week wash-in period, the subjects were requested to refrain from any form of oral hygiene for 2 weeks., Results: There were no differences in the primary outcome (BOMP change) among the groups. However, gingival health (MGI) in individuals from the groups exposed to the test products recovered better from experimental gingivitis than the individuals in the placebo group ( p = 0.021, one-way ANOVA). The two test products inhibited pro-inflammatory cytokine IL-1ß production, measured in saliva, during the experimental gingivitis period. Both test strains significantly reduced bacterial DNA in tongue samples and L. paracasei strain showed stronger microbiome-modulating potential than the L. plantarum strain., Conclusions: The two tested lozenges with the L. paracasei or L. plantarum strains did show potential for beneficial effects for the oral health of the host during experimental gingivitis to the oral ecosystem., Competing Interests: TR and BF are employed by VivaCell Biotechnology GmbH. TS is employed by Symrise AG. MG is a former employee of Symrise AG and is currently employed by Spindiag GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from Symrise. The funder (represented by TS and MG) had the following involvement with the study: interpretation of findings and writing of the article. These authors had no involvement in the final evaluation of the data or the discussion of the article., (Copyright © 2022 Volgenant, van der Waal, Brandt, Buijs, van der Veen, Rosema, Fiebich, Rose, Schmitter, Gajfulin, Crielaard and Zaura.)

Background: Cannabis sativa L. extracts (CSE) are used for treating inflammatory conditions, but little is known about their immunomodulatory effects. We investigated a novel CSE with high (14%) CBD and low (0.2%) THC concentration in comparison with pure CBD on primary human lymphocytes., Methods: Proliferation, cell cycle distribution, apoptosis/necrosis and viability were analysed with standard methods. Genotoxicity was evaluated with the comet-assay. The effect on T lymphocyte activation was evaluated via CD25/CD69 marker expression, degranulation assays and the production of cytokines. The influence on the transcription factors was analysed using Jurkat reporter cell lines. Specific CB2 receptor antagonist SR144528 and TRPV1 receptor antagonist A78416B were used to study the involvement of CB2 or TRPV1 receptors., Results: CSE inhibited the proliferation of activated T lymphocytes in a dose-dependent manner without inducing apoptosis, necrosis, or affecting cell viability and DNA integrity. The inhibitory effect was mediated via the suppression of T lymphocytes activation, particularly by the suppression of CD25 surface marker expression. Furthermore, CSE interferes with the functionality of the T lymphocytes, as indicated by inhibition of degranulation, IL-2, and IFN-γ production. AP-1-and-NFAT-reporter activation was reduced implicating an AP-1-and-NFAT-mediated mode of action. The effects were in part reversed by SR144528 and A78416B, showing that the effects were mainly mediated by CB2 and TRPV1 receptors., Conclusion: CSE and CBD have immunomodulatory effects and interfere with the activation and functionality of T lymphocytes. A comparison between CSE and CBD suggests that the immunosuppressive effect of CSE is mostly due to the effect of CBD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Plant-derived products have been used since the beginnings of human history to treat various pathological conditions. Practical experience as well as a growing body of research suggests the benefits of the use of turmeric ( Curcuma longa ) and some of its active components in the reduction of oxidative stress, a mechanism leading to neurodegeneration. In this current study, we investigated the effects of a preparation of Curcuma longa , and its constituents curcumin, tetrahydrocurcumin, and curcumenol, in one of the molecular pathways leading to oxidative stress, which is the release of NO, a free radical involved in stress conditions, using the BV2 microglial cell line. The concentration-dependent reduction of NO is linked to reduced amounts of iNOS protein- and mRNA-synthesis and is possibly mediated by the phosphorylation of mitogen-activated protein kinases (MAPK) such as p42/44 or p38 MAPK. Therefore, the use of turmeric extract is a promising therapeutic option for diseases linked to the dysregulation of oxidative stress, with fewer side-effects in comparison to the currently used pharmacotherapeutics.

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson's disease, and Alzheimer's disease. Clinical studies demonstrate a reduction of the mentioned diseases' symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE 2 -concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE 2 -levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

Microglia play a major role in certain neuropathological conditions. In a recent paper, Reusch et al. demonstrated how signaling pathways downstream of cannabinoid type 2 (CB 2 ) and toll-like receptors (TLRs) converge in these cells. The findings suggest that CB 2 receptors play a permissive role in microglia activation mediated by TLRs., Competing Interests: Declaration of interests The authors declare no other competing interests in relation to this work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An emerging number of studies address the involvement of neuroinflammation and oxidative stress in the pathophysiology of central nervous system (CNS) disorders such as depression, schizophrenia, anxiety, and neurodegenerative diseases. Different cytokines and molecules, such as prostaglandin (PG) E 2 , are associated with neuroinflammatory processes. The active acetaminophen metabolite AM404 has been shown to prevent inflammation and neuroinflammation in primary microglia and organotypic hippocampal slice cultures. However, its effects on pathophysiological conditions in the CNS and especially on neurons are still poorly understood. In this study, we therefore evaluated the effects of AM404 and acetaminophen on the arachidonic acid cascade and oxidative stress induced by interleukin (IL)-1β in human SK-N-SH neuronal cells. We observed that AM404 and acetaminophen significantly and concentration-dependent inhibited IL-1β-induced release of PGE 2 , independent of cyclooxygenases (COX)-1 and COX-2 enzymatic activity as well as COX-2 mRNA and protein levels in SK-N-SH-cells. The reduction of IL-1β-induced PGE 2 -release by AM404 and acetaminophen treatment might be mediated by the 8-iso-PGF 2α pathway since IL-1β-induced synthesis of this free radical marker is dose-dependently reduced by both compounds, respectively. Therefore, understanding of the potential therapeutic properties of AM404 in neuroinflammation and oxidative stress might lead to future treatment options of different neurological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Apweiler, Streyczek, Saliba, Ditrich, Muñoz and Fiebich.)

Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E 2 . However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases.

An important mediator of inflammation is prostaglandin E 2 (PGE 2 ), whose levels are determined by the activity of the enzyme cyclooxygenase (COX). Of the two isoforms of the enzyme, COX-2 has been shown to be induced in macrophages during inflammation. Although general COX inhibitors, belonging to the class of nonsteroidal anti-inflammatory drugs, or specific COX-2 inhibitors, called coxibs, are useful in the control of acute inflammation, adverse reactions were seen when used chronically in the treatment of rheumatoid arthritis or neurodegenerative diseases. Extracellular ATP (eATP) has been reported as a damage-associated molecular pattern signal. In this report, we show that eATP synergistically increases the levels of COX-2 enzyme and PGE 2 in LPS-activated RAW264.7 macrophages and human monocytes. Activation of macrophages also occurred when cultured in media obtained from dying neurons that contained higher levels of ATP. We show that eATP increases the levels of COX-2 protein, which is sustained up to 36 h poststimulation. This is in turn due to sustained levels of phosphorylated, or activated, cyclin-dependent kinase 9 and p38 MAPK in ATP-treated cells compared to LPS-stimulated cells. The eATP-dependent increase in COX-2/PGE 2 levels in LPS-activated RAW264.7 cells could be abolished using antagonists for purinergic P2X7 -and P2Y6 receptors. Similarly, the increase in COX-2/PGE 2 levels in the peritoneum of LPS-treated mice could be significantly abolished in mice that were preinjected with the nonspecific P2 receptor antagonist, suramin. P2 receptor antagonists, therefore, should be explored in our search for an ideal anti-inflammatory candidate., (©2021 Society for Leukocyte Biology.)

Increasing environmental exposure to silica nanoparticles (SiNPs) and limited neurotoxicity studies pose a challenge for safety evaluation and management of these materials. This study aimed to explore the adverse effects and underlying mechanisms of subacute exposure to SiNPs by the intraperitoneal route on hippocampus function in rats. Data showed that SiNPs induced a significant increase in oxidative/nitrosative stress markers including reactive oxygen species (ROS), malondialdehyde (MDA), protein oxidation (PCO) and nitrite (NO) production accompanied by reduced antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) and decreased glutathione (GSH). Phenotypically, SiNPs exhibited spatial learning and memory impairment in the Morris water maze (MWM) test, a decrease of the discrimination index in the novel object recognition test (NORT) and higher anxiety-like behavior. SiNPs affected the cholinergic system as reflected by reduced acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. In addition, SiNPs significantly increased mRNA expression level of genes related to inflammation (TNF-α, IL-1β, IL-6, and COX-2) and decreased mRNA expression level of genes related to cholinergic system including choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), AChE, muscarinic acetylcholine receptor M1 (m1AChR) and nicotinic acetylcholine receptors (nAChR). Histopathological results further showed an alteration in the hippocampus of treated animals associated with marked vacuolation in different hippocampus areas. These findings provide new insights into the molecular mechanism of SiNPs-induced hippocampal alterations leading to impairment of cognitive and behavioral functions, and implicating oxidative stress and inflammation in the hippocampus, as well as disruption of cholinergic system., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Transcranial direct current stimulation [(t)DCS], modulates cortical excitability and promotes neuroplasticity. Microglia has been identified to respond to electrical currents as well as neuronal activity, but its response to DCS is mostly unknown., Objective: This study addresses effects of DCS applied in vivo to the sensorimotor cortex on physiological microglia properties and neuron-microglia communication., Methods: Time lapse in vivo 2-photon microscopy in anaesthetized mice was timely coupled with DCS of the sensorimotor cortex to observe microglia dynamics on a population-based and single cell level. Neuron-microglia communication during DCS was investigated in mice with a functional knock out of the fractalkine receptor CX3CR1. Moreover, the role of voltage gated microglial channels and DCS effects on phagocytosis were studied., Results: DCS promoted several physiological microglia properties, depending on the glial activation state and stimulation intensity. On a single cell level, process motility was predominantly enhanced in ramified cells whereas horizontal soma movement and galvanotaxis was pronounced in reactive microglia. Blockage of voltage sensitive microglial channels suppressed DCS effects in vivo and in vitro. Microglial motility changes were partially driven by the fractalkine signaling pathway. Moreover, phagocytosis increased after DCS in vitro., Conclusion: Microglia dynamics are rapidly influenced by DCS. This is the first in vivo demonstration of a direct effect of electrical currents on microglia and indirect effects potentially driven by neuronal activity via the fractalkine pathway., Competing Interests: Declaration of competing interest None. Materials & Correspondence. All requests should be sent to the senior author. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)