Anti-neuroinflammatory Activity Research Articles

Activity-guided isolation and identification of antiherpesvirus and antineuroinflammatory active terpenoids from Artemisia vulgaris L. based on the LC-MS/MS molecular network

Seven undescribed terpenoids, comprising two guaiane-type sesquiterpene lactones (1−2), one eucalyptol-type sesquiterpene (3), one monolactone (4), and three triterpenoids (5−7), along with 35 known analogues, were isolated from the leaves of Artemisia vulgaris L. Their structures and configurations were analysed by extensive spectroscopy. Compounds 1, 2, 8−10, 13, 17, 19, and 28 showed antineuroinflammatory activity, and compounds 1 and 2 revealed remarkable antineuroinflammatory effects, with an IC50 value of 2.2 ± 0.1 and 1.6 ± 0.1 μM, more potent than the positive control drug dexamethasone. Furthermore, compounds 1 and 2 could inhibit the expression of BV-2 inflammatory genes (IL-6, TNF-α, IL-1β) induced by LPS, downregulate the critical inflammatory protein production of iNOS and COX-2. The anti-HSV-1 activity screening revealed that compounds 28, 29 and 38 exhibited inhibitory activity against HSV-1 proliferation. Particularly, compound 28 exhibited a significant anti-HSV-1 effect, inhibiting the proliferation of HSV-1 and acyclovir-resistant strains of HSV-1/153 and HSV-1/Blue. Our research identified compounds 1, 2, and 28 from A. vulgaris., which could potentially serve as lead compounds for antineuroinflammatory and anti-HSV-1 activities.

Ilexchinene, a new seco-ursane triterpenoid from the leaves of Ilex chinensis with therapeutic effect on neuroinflammation by attenuating the MAPK/NF-κB signaling pathway

BackgroundNeuroinflammation is a vital factor participating in the whole pathogenetic process of diverse neurodegenerative disorders, but accessible clinical drugs are still insufficient due to their inefficacy and side effects. Triterpenoids are reported to possess potential anti-neuroinflammatory activities, and the leaves of Ilex chinensis are a commonly used herbal medicine containing many ursane-type and oleanane-type triterpenoids. However, the novel triterpenoids from I. chinensis and their underlying mechanisms are still elusive. PurposeTo isolate novel seco-ursane triterpenoids with anti-neuroinflammatory effects from the leaves of I. chinensis and reveal their underlying mechanisms. Study design and methodsThe novel compound was purified by column chromatography and identified by comprehensive spectroscopic experiments. The LPS-induced BV-2 cell model and LPS-induced acute murine brain inflammation model were used to assess the anti-neuroinflammatory effect of the structure and further understand its underlying mechanisms by cell viability, ELISA, Western blot analysis, qRT‒PCR analysis, behavior analysis, H&E staining, and immunofluorescence staining experiments. ResultsIlexchinene is a novel ursane-type triterpenoid with a rare 18,19-seco-ring skeleton that was first isolated and identified from I. chinensis. Ilexchinene evidently reduced the overexpression of inflammatory substances in vitro. A mechanistic study suggested that ilexchinene could decrease NF-κB activation to prevent the formation of the NLRP3 inflammasome in the early neuroinflammatory response; in addition, it could prevent the phosphorylation of ERK and JNK. In vivo, ilexchinene remarkably improved LPS-induced mouse behavioral deficits and diminished the number of overactivated microglial cells. Furthermore, ilexchinene evidently diminished the overexpression of inflammatory substances in mouse brains. A mechanistic study confirmed that ilexchinene markedly suppressed the MAPK/NF-κB pathway to relieve the neuroinflammatory response. ConclusionWe identified a novel 18,19-seco-ursane triterpenoid from the leaves of I. chinensis and revealed its underlying mechanism of neuroinflammation for the first time. These findings suggest that ilexchinene might possess promising therapeutic effects in neuroinflammation.

ACETYLCHOLINESTERASE INHIBITION, NOOTROPIC AND ANTIOXIDANT EFFECT OF EXTRACTS FROM AGAVE SPECIES

Background: The systemic administration of Lipopolysaccharide (LPS) is a pharmacological model to evaluate different processes associated with neurodegeneration; it is capable of causing an increase in the oxidative state in the brain and increasing the activity of the enzyme acetylcholinesterase (ACh-E), involved in the degradation of acetylcholine (ACh). This cholinergic transmission system participates in memory processes, a crucial symptom in neurodegenerative disorders, and its modulation with scopolamine turns out to be an essential tool in the evaluation of plants. Species of the genus Agave are considered a natural resource of economic and cultural importance in Mexico. They possess compounds with anti-inflammatory, antioxidant, and anti-neuroinflammatory activities. Methods: Extracts of A. tequilana (At-A), A. angustifolia (Aan-A), A. americana (Aam-A) at 125 mg/kg were administered to male ICR mice with LPS to evaluate the ACh-E inhibition, the concentration of the antioxidant enzyme Gluthatione Reductase (GR) and the prooxidant enzyme NADPH Oxidase (NOX). Also, the nootropic effect of these extracts on scopolamine-induced cognitive impairment was evaluated. Results: The three Agave species studied decreased the ACh-E enzyme activity, Vmax value, and KM. These products increased the GR concentration from 0.173±0.003 (vehicle) to 0.642±0.002 µMol/mg in At-A, which was the highest one. Regarding NOX, only the A. tequilana extract decreased it (0.513±0.002µMol/mg)compared with Vehicle (0.621±0.008µMol/mg). A. tequilana and A. americana species significantly improved the retention latency parameter (260 seconds) during the passive avoidance test. Conclusion: Agave species showed promising results in developing novel drugs for neurodegenerative disease therapy. Peer Review History: Received: 17 June 2023; Revised: 22 July; Accepted: 27 August, Available online: 15 September 2023 Academic Editor: Dr. Asia Selman Abdullah, Pharmacy institute, University of Basrah, Iraq, asia_abdullah65@yahoo.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Sangeetha Arullappan, Universiti Tunku Abdul Rahman, Malaysia, sangeetha@utar.edu.my Prof. Ali Gamal Ahmed Al-kaf, Sana'a university, Yemen, alialkaf21@gmail.com

Rutin hydrate relieves neuroinflammation in zebrafish models: Involvement of NF-κB pathway as a central network

Neuroinflammation is prevalent in multiple brain diseases and may also lead to dementia, cognitive impairment, and impaired spatial memory function associated with neurodegenerative diseases. A neuroprotective and antioxidant flavonoid, rutin hydrate (RH), was evaluated for the anti-neuroinflammatory activity mediated by copper sulfate (CuSO4) solution and lipopolysaccharide (LPS) in zebrafish. The results showed that 100 mg/L RH significantly reduced the ratio of neutrophil mobility in caudal hematopoietic tissue (CHT) region caused by CuSO4 and the number of neutrophils co-localized with facial peripheral nerves. In the LPS model, RH co-injection significantly diminished neutrophil and macrophage migration. Therefore, RH exhibited a significant rescue effect on both models. In addition, RH treatment remarkably reduced the effects of neuroinflammation on the locomotor ability, expression levels of genes associated with behavioral disorders, and acetylcholinesterase (AChE) activity. Furthermore, network pharmacology techniques were employed to investigate the potential mechanisms, and the associated genes and enzyme activities were validated in order to elucidate the underlying mechanisms. Network pharmacological analysis and zebrafish model indicated that RH regulated the expressions of NF-κB pathway-related targets (Toll-like receptor 9 (tlr9), nuclear factor kappa B subunit 1 (nfkb1), RELA proto-oncogene (RelA), nitric oxide synthase 2a, inducible (nos2a), tumour necrosis factor alpha-like (tnfα), interleukin 6 (il6), interleukin 1β (il1β), chemokine 8 (cxcl8), and macrophage migration inhibitory factor (mif)) as well as six key factors (arachidonic acid 4 alpha-lipoxygenase (alox4a), arachidonate 5-lipoxygenase a (alox5), prion protein a (prnpa), integrin, beta 2 (itgb2), catalase (CAT), and alkaline phosphatase (ALP) enzymes). Through this study, a thorough understanding of the mechanism underlying the therapeutic effects of RH in neuroinflammation has been achieved, thereby establishing a solid foundation for further research on the potential therapeutic applications of RH in neuroinflammatory disorders.

Potential natural product 3,4-seco-schitriterpenoids from Kadsura japonica L. as anti-neuroinflammatory agents

In the present study, the undescribed schitriterpenoids, kadsujanonols A−I (1–9), and eleven reported compounds (10–20) were isolated from K. japonica L. vines. Their structures of 3,4-seco-schitriterpenoids were elucidated mainly by spectroscopic analyses including 1H-, 13C-, and 2D-NMR, IR, HRESIMS spectra. The spatial configurations were determined by the single-crystal X-ray diffraction analysis of kadsujapnonol A (1), 15, 17, and 18, CD data and computational analysis. Furthermore, all isolates were evaluated for the anti-neuroinflammatory activity on LPS-stimulated NO production in BV2 microglial cells and compounds 2, 4, 5, 7, 9, 11, 13–16, and 18 exposed better or comparable suppression abilities than PDTC. Among them, kadlongilactone B (14) showed the best significant inhibiting ability (IC50 = 0.87 μg/mL) and the effect is through the attenuation of the inflammatory transcription factor p65NF-κB. Preliminary structure–activity relationship revealed that δ-lactone at the side chain and 7-member lactone at C-3/C-4, and 3,4:9,10 ring opening are important.

Unprecedented Neoverrucosane and Cyathane Diterpenoids with Anti-Neuroinflammatory Activity from Cultures of the Culinary-Medicinal Mushroom Hericium erinaceus.

The culinary medicinal mushroom Hericium erinaceus holds significant global esteem and has garnered heightened interest within increasingly ageing societies due to its pronounced neuroprotective and anti-neuroinflammatory properties. Within this study, two novel diterpenes, 16-carboxy-13-epi-neoverrucosane (1) and Erinacine L (2); three known xylosyl cyathane diterpenoids, Erinacine A (3), Erinacine C (4), and Erinacine F (5); and four lanostane-type triterpenoids, and three cyclic dipeptides (10-12), in addition to orcinol (13), were isolated from the rice-based cultivation medium of H. erinaceus. Their structures were determined by NMR, HR-ESI-MS, ECD, and calculated NMR. Compound 1 marks a pioneering discovery as the first verrucosane diterpene originating from basidiomycetes, amplifying the scope of fungal natural product chemistry, and the intricate stereochemistry of Compound 5 has been comprehensively assessed for the first time. Compounds 2-5 not only showed encouraging neurotrophic activity in rat adrenal pheochromocytoma PC-12 cells, but also significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 microglia cell cultures with IC50 values as low as 5.82 ± 0.18 μM. To elucidate the mechanistic underpinnings of these bioactivities, molecular docking simulation was used to analyze and support the interaction of 1 and 2 with inducible NO synthase (iNOS), respectively. In particular, compound 2, a cyathane-xyloside containing an unconventional hemiacetal moiety, is a compelling candidate for the prevention of neurodegenerative diseases. In summation, this investigation contributes substantively to the panorama of fungal diterpene structural diversity, concurrently furnishing additional empirical substantiation for the role of cyathane diterpenes in the amelioration of neurodegenerative afflictions.

Eudesmane sesquiterpenoid glycosides from the leaves of Pittosporum lenticellatum with anti-neuroinflammatory activity

Chemical investigation of the EtOAc extract of the leaves of Pittosporum lenticellatum led to the isolation of twenty-five previously undescribed eudesmane sesquiterpenoid glycosides, pitlencosides A－Y (1–25); their structures were elucidated by extensive spectroscopic analysis, including 1D and 2D NMR, HR-ESI-MS, ECD spectra, and X-ray crystallographic analysis. Among them, compounds 4, 5, 7, 8, 15 and 16 exhibited significant inhibitory effects on the production of nitric oxide in lipopolysaccharide-induced BV-2 microglial cells by suppressing the expression of inducible nitric oxide synthase and cyclooxygenase-2, with IC50 values ranging from 7.95 to 25.88 μM, which showed stereo-chemical and substituent dependents. Western blot analysis and molecular docking simulation confirmed the anti-inflammatory activity of compounds 4, 5, 7, 8, 15 and 16.

A new anti-neuroinflammation labdane diterpenoid from Salvia tricuspis.

One new labdane diterpenoid, tricuspion A (1), as well as five known triterpenoids (2-6) were isolated from Salvia tricuspis Franch (family Labiatae). The structure of tricuspion A was identified by extensive spectroscopic analysis and by comparison with previously reported data. Compounds 1-6 were evaluated for their inhibitory effects on the NO production in LPS-stimulated BV-2 microglia cells, and 1 exhibited potent inhibitory activity with IC50 value of 14.92 ± 0.51 μM. Compound 1 might exert anti-neuroinflammatory activity through inhibiting the excessive production of NO and down-regulating the protein expression of iNOS and COX-2. As such, labdane diterpenoid (tricuspion A) could provide promising anti-neuroinflammatory lead compound for further structural modification.

Discovery of acylated isoquercitrin derivatives as potent anti-neuroinflammatory agents in vitro and in vivo

Neuroinflammation is considered as an important pathological mechanism in neurodegenerative diseases. The natural isoquercitrin (IQ) was reported to have potential anti-neuroinflammatory activity. The acylation of glycoside in IQ enhanced its hydrophobicity, which was expected to enhance the protective effect against inflammation. In this study, three carboxylic acids with anti-neuroinflammatory effects including cinnamic acid, ibuprofen (IBU) and acetylsalicylic acid were introduced into the 6''-OH of IQ through the corresponding vinyl esters intermediates (8a-8c). Ultimately, the acylated IQ derivatives (Compound 9a-9c) were obtained with 35–42% yields using immobilized lipase Novozym 435 as catalyst. Subsequently, their anti-neuroinflammatory activities were evaluated in lipopolysaccharide (LPS)-induced BV2 cells. Compound 9b improved cell viability in the range of ≤50 μM and significantly decreased NO, PGE2 production and TNF-α, IL-1β release and oxidative stress level with a concentration-dependent manner. Also, it could downregulate iNOS, COX-2, TNF-α and IL-1β expression levels, approximately 40% reduction were achieved when 15μM compound 9b was employed. In addition, compound 9b resisted phosphorylation and degradation of IkBαs, suppressing the activation of NF-κB signaling pathway, exhibiting excellent neuroinflammatory inhibition. Moreover, the administration of compound 9b (30, 60 mg/kg) alleviated behavioral disorders and neuronal damages in LPS-induced neuroinflammatory mice. Meanwhile, the decreased TNF-α, IL-1β release, expression and the inhibited glial cells activation were obtained in compound 9b-treated group, which was superior to that of IQ or IBU. Overall, these findings demonstrated that compound 9b, formed by the introduction of ibuprofen into IQ, can serve as a novel promising therapeutic agent for anti-neuroinflammation.

Repositioning the existing drugs for neuroinflammation: a fusion of computational approach and biological validation to counter the Parkinson's disease progression.

Parkinson's disease is caused by the deficiency of striatal dopamine and the accumulation of aggregated α-synuclein in the substantia nigra pars compacta (SNpc). Neuroinflammation associated with oxidative stress is a key factor contributing to the death of dopaminergic neurons in SNpc and advancement of Parkinson's disease. Two molecular targets, i.e., nuclear factor kappa-light-chain-enhancer (NF-kB) and α-synuclein play a substantial role in neuroinflammation progression. Therefore, the compounds targeting these neuroinflammatory targets hold a great potential to combat Parkinson's disease. Thereby, in this study, molecular docking and Connectivity Map (CMap) based gene expression profiling was utilized to reposition the approved drugs as neuroprotective agents for Parkinson's disease. With in silico screening, two drugs namely theophylline and propylthiouracil were selected for anti-neuroinflammatory activity evaluation in in vivo models of chronic neuroinflammation. The neuroinflammatory effect of the identified compounds was confirmed by quantifying the expression of three important neuroinflammatory mediators, i.e. IL-6, TNF-alpha, and IL-1 beta on brain tissue using ELISA assay. The ELISA experiment demonstrated that both compounds significantly decreased the expression of neuroinflammatory mediators, highlighting the compounds' potential in neuroinflammation management. Furthermore, the drug and disease interaction network of the two identified drugs and diseases (neuroinflammation and Parkinson's disease) suggested that the two drugs might interact with various targets namely adenosine receptors, Poly [ADP-ribose] polymerase-1, myeloperoxidase (MPO) and thyroid peroxidase through multiple pathways associated with neuroinflammation and Parkinson's disease. Computational studies suggest that a particular drug may be effective in managing Parkinson's disease associated with neuroinflammation. However, further research is needed to confirm this in biological experiments.

SIRT1 activation by 2,3,5,6-tetramethylpyrazine alleviates neuroinflammation via inhibiting M1 microglia polarization.

Neuroinflammation has been reported as a potential contributing factor to brain diseases, and is characterized by activated microglia with release of multiple inflammatory mediators. 2,3,5,6-Tetramethylpyrazine (TMP) is an active alkaloid in Ligusticum chuanxiong Hort. and has various biological activities, including anti-inflammatory and neuroprotection properties. However, the anti-neuroinflammatory activity of TMP has been less studied and its potential molecular mechanisms in this field remain unclear. This study aimed to investigate the effects of TMP and its underlying mechanisms in neuroinflammation. In vitro, lipopolysaccharide (LPS)-stimulated BV2 microglia were used to assess the effects of TMP on inflammatory cytokines as well as the components of the SIRT1/NF-κB signaling pathway, which were measured by using ELISA, western blotting, qRT-qPCR and immunofluorescence. Moreover, LPS-induced acute neuroinflammation model in mice was performed to detect whether TMP could exert anti-neuroinflammatory effects in vivo, and the EX527, a SIRT1 inhibitor, were given intraperitoneally every two days prior to TMP treatment. Serums and spinal trigeminal nucleus (Sp5) tissues were collected for ELISA assay, and the Sp5 tissues were used for HE staining, Nissl staining, immunofluorescence, qRT-PCR and western blotting. In vitro, TMP treatment significantly reduced the secretion of pro-inflammatory cytokines, including TNF-α and IL-6, promoted SIRT1 protein expression and inactivated NF-κB signaling pathway in LPS-induced neuroinflammation. Interestingly, pretreatment with EX527 blocked the therapeutic effects of TMP on neuroinflammation in vitro. Furthermore, TMP reduced the levels of pro-inflammatory cytokines and chemokines, and prevented microglia from polarizing towards a pro-inflammatory state through activating SIRT1 and inhibiting NF-κB activation in LPS-induced neuroinflammation in mice. And EX527 reversed the beneficial effects of TMP against LPS exposure in mice. In summary, this study unravels that TMP could mitigate LPS-induced neuroinflammation via SIRT1/NF-κB signaling pathway.

Hyperelatolides A-D, Antineuroinflammatory Constituents with Unusual Carbon Skeletons from Hypericum elatoides.

Four new δ- and γ-lactone derivatives, hyperelatolides A-D (1-4, respectively), were discovered from the aerial portions of Hypericum elatoides R. Keller. Their structures were elucidated by analysis of NMR spectra, HRESIMS, quantum chemical calculations of NMR and ECD spectra, and X-ray crystallographic data. Hyperelatolides A (1) and B (2) represent the first examples of δ-lactone derivatives characterized by a (Z)-(5,5-dimethyl-2-(2-oxopropyl)cyclohexylidene)methyl moiety and a benzoyloxy group attached to the β- and γ-positions of the δ-lactone core, respectively, while hyperelatolides C (3) and D (4) are unprecedented γ-lactone derivatives featuring substituents similar to those of 1 and 2. All compounds were tested for their inhibitory effects on NO production in LPS-activated BV-2 cells. Lactones 1 and 2 exhibited considerable antineuroinflammatory activity, with IC50 values of 5.74 ± 0.27 and 7.35 ± 0.26 μM, respectively. Moreover, the mechanistic study revealed that lactone 1 significantly suppressed nuclear factor kappa B signaling and downregulated the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-induced cells, which may contribute to its antineuroinflammatory activity.

Cannabidiol Analogue CIAC001 for the Treatment of Morphine-Induced Addiction by Targeting PKM2.

Opioid addiction is a chronically relapsing disorder that causes critical public health problems. Currently, there is a lack of effective drug treatment. Herein, one cannabidiol derivative, CIAC001, was discovered as an effective agent for treating morphine-induced addiction. In vitro, CIAC001 exhibited significantly improved anti-neuroinflammatory activity with lower toxicity. In vivo, CIAC001 ameliorated the morphine-induced withdrawal reaction, behavioral sensitization, and conditional position preference by inhibiting morphine-induced microglia activation and neuroinflammation. Target fishing for CIAC001 by activity-based protein profiling led to the identification of pyruvate kinase M2 (PKM2) as the target protein. CIAC001 bound to the protein-protein interface of the PKM2 dimer and promoted the tetramerization of PKM2. Moreover, CIAC001 exhibited an anti-neuroinflammatory effect by reversing the decrease of the PKM2 tetramer and inhibiting the nuclear translocation of PKM2. In summary, this study identified CIAC001 as a lead compound in targeting PKM2 to treat morphine-induced addiction.

Exploring the Therapeutic Effects of Multifunctional N-Salicylic Acid Tryptamine Derivative against Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Neuroinflammation and oxidative stress play an important role in the whole course of PD, which have been the focus of PD drug development. In our previous research, a series of N-salicylic acid tryptamine derivatives were synthesized, and the biological evaluation showed that the compound LZWL02003 has good anti-neuroinflammatory activity and displayed great therapeutic potency for neurodegenerative disease models. In this work, the neuroprotective efficiency of LZWL02003 against PD in vitro and in vivo has been explored. It was found that LZWL02003 could protect human neuron cells SH-SY5Y from MPP+-induced neuronal damage by inhibiting ROS generation, mitochondrial dysfunction, and cellular apoptosis. Moreover, LZWL02003 could improve cognition, memory, learning, and athletic ability in a rotenone-induced PD rat model. In general, our study has demonstrated that LZWL02003 has good activity against PD in in vitro and in vivo experiments, which can potentially be developed into a therapeutic candidate for PD.

Discovery of anti-neuroinflammatory agents from 1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidin-2-amine derivatives by regulating microglia polarization

Neuroinflammation mediated by microglia activation leads to various neurodegenerative and neurological disorders. In order to develop more and better options for this disorders, a series of 3,4-dihydrobenzo[b]oxepin-5(2H)-one derivatives (BZPs, 6–19) and novel 1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidin-2-amine derivatives (BPMs, 20–33) were synthesized and screened the anti-neuroinflamamtion effects. 3,5-bis-trifluoromethylphenyl-substituted BPM 29 showed more potent anti-neuroinflammatory activity and no toxicity to BV2 microglia cells in vitro. 29 significantly reduced the number of M1 phenotype of microglia cells, but significantly increased the number of M2 phenotype of microglia cells in lipopolysaccharide (LPS)-induced BV2 microglia cells. 29 significantly reduced the secretion of inflammatory cytokines (IL-18, IL-1β, TNF-α), but increased the secretion of anti-inflammatory cytokines (IL-10) from LPS-induced BV2 microglia cells. Also, 29 inhibited the NOD-like receptor NLRP3 inflammasome formation, and down-regulated the expression of M2 isoform of pyruvate kinase in LPS-induced BV2 microglia cells. In vivo, 29 reduced the neuroinflammation in cuprizone-induced inflammatory and demyelinating mice by reducing the expression of inducible nitric-oxide synthase, but increased the expression of CD206. Taken together, 29 might be a prospective anti-neuroinflammatory compound for neuroinflammatory and demyelinating disease by alleviating microglia activation.

Labdane diterpenoids from Lagopsis supina and their anti-neuroinflammatory activity

In this study, ten labdane-type diterpenoids 1–10 were isolated from a methanol extract of the whole plant Lagopsis supina, including three undescribed compounds 1–3. Their structures were determined by spectroscopic data analyses such as HR-ESI-MS, 1D, and 2D NMR, as well as comparison with literature data. At the same time, the absolute configuration of five compounds 2–5 and 10 was confirmed for the first time by the single crystal X-ray diffraction method. All the compounds were isolated from L. supina for the first time. The CCK-8 assay showed that all compounds had no significant damage to BV-2 microglial cells, and then screened their inhibitory effects of nitric oxide production stimulated by lipopolysaccharide in BV-2 microglial cells. The pharmacological results showed that compound 4 greatly inhibited LPS-stimulated NO release at the concentration of 10 μM, indicating that it has potential anti-neuroinflammatory activity.

Degradation Profiling of Nardosinone at High Temperature and in Simulated Gastric and Intestinal Fluids.

Nardosinone, a predominant bioactive product from Nardostachys jatamansi DC, is well-known for its promising therapeutic applications, such as being used as a drug on anti-inflammatory, antidepressant, cardioprotective, anti-neuroinflammatory, anti-arrhythmic, anti-periodontitis, etc. However, its stability under varying environmental conditions and its degradation products remain unclear. In this study, four main degradation products, including two previously undescribed compounds [2-deoxokanshone M (64.23%) and 2-deoxokanshone L (1.10%)] and two known compounds [desoxo-narchinol A (2.17%) and isonardosinone (3.44%)], were firstly afforded from the refluxed products of nardosinone in boiling water; their structures were identified using an analysis of the extensive NMR and X-ray diffraction data and the simulation and comparison of electronic circular dichroism spectra. Compared with nardosinone, 2-deoxokanshone M exhibited potent vasodilatory activity without any of the significant anti-neuroinflammatory activity that nardosinone contains. Secondly, UPLC-PDA and UHPLC-DAD/Q-TOF MS analyses on the degradation patterns of nardosinone revealed that nardosinone degraded more easily under high temperatures and in simulated gastric fluid compared with the simulated intestinal fluid. A plausible degradation pathway of nardosinone was finally proposed using nardosinonediol as the initial intermediate and involved multiple chemical reactions, including peroxy ring-opening, keto-enol tautomerization, oxidation, isopropyl cleavage, and pinacol rearrangement. Our findings may supply certain guidance and scientific evidence for the quality control and reasonable application of nardosinone-related products.

The extracts of Dracaena cochinchinensis stemwood suppress inflammatory response and phagocytosis in lipopolysaccharide-activated microglial cells

BackgroundNeuroinflammation is a pivotal process in the brain that contributes to the development of neurodegenerative diseases, such as Alzheimer's disease (AD). During neuroinflammation, the over-activation of microglial cells can drive the pathological processes underlying AD, including an increase in amyloid β (Aβ) production and accumulation, ultimately leading to neuronal and synaptic loss. Dracaena cochinchinensis (Lour.) S.C. Chen, also known as “Chan-daeng” in Thai, belongs to the Asparagaceae family. In Thai traditional medicine, it has been used as an antipyretic, pain reliever, and anti-inflammatory agent. However, the effects of D. cochinchinensis on neuroinflammation are yet to be determined. PurposeWe aimed to evaluate the anti-neuroinflammatory activities of D. cochinchinensis stemwood extract in activated microglia. MethodsIn this study, lipopolysaccharide (LPS), a potent pro-inflammatory stimulus, was used to activate microglial BV2 cells, as a cell model of neuroinflammation. Our investigation included several techniques, including qRT-PCR, ELISA, Western blotting, phagocytosis, and immunofluorescence staining, to examine the potential anti-inflammatory effects of D. cochinchinensis stemwood. ResultsD. cochinchinensis stemwood, named DCS, was extracted with ethanol and water. The extracts of DCS showed dose-dependent anti-inflammatory effects, markedly suppressing the LPS-mediated mRNA expression of pro-inflammatory factors, including IL-1β, TNF-α, and iNOS, while increasing expression of the anti-inflammatory biomarker Arg1 in both BV2 microglia and RAW264.7 macrophages. DCS extracts also decreased the protein levels of IL-1β, TNF-α, and iNOS. These findings were correlated with the suppression of phosphorylated proteins of p38, JNK, and Akt in the LPS-activated microglia. Moreover, DCS extracts significantly attenuated excessive phagocytosis of beads and Aβ fibrils during the LPS-mediated microglial activation. ConclusionTaken together, our results indicated that DCS extracts had anti-neuroinflammatory properties by suppressing the expression of pro-inflammatory factors, increasing the expression of the anti-inflammatory biomarker Arg1, and modulating excessive phagocytosis in activated microglia. These findings suggested that DCS extract could be a promising natural product for the treatment of neuroinflammatory and neurodegenerative diseases, like AD.

Evaluation of Anti-Neuroinflammatory Activity of Isatin Derivatives in Activated Microglia.

Neuroinflammation plays a crucial role in the progression of Alzheimer's disease and other neurodegenerative disorders. Overactivated microglia cause neurotoxicity and prolong the inflammatory response in many neuropathologies. In this study, we have synthesised a series of isatin derivatives to evaluate their anti-neuroinflammatory potential using lipopolysaccharide activated microglia as a cell model. We explored four different substitutions of the isatin moiety by testing their anti-neuroinflammatory activity on BV2 microglia cells. Based on the low cytotoxicity and the activity in reducing the release of nitric oxide, pro-inflammatory interleukin 6 and tumour necrosis factor α by microglial cells, the N1-alkylated compound 10 and the chlorinated 20 showed the best results at 25 µM. Taken together, the data suggest that 10 and 20 are promising lead compounds for developing new neuroprotective agents.

Structural identification of pyridinopyrone compounds with anti-neuroinflammatory activity from streptomyces sulphureus DSM 40104.

This study investigated the chemical composition and biosynthesis pathway of compounds produced by Streptomyces sulphureus DSM 40104. With the guild of molecular networking analysis, we isolated and identified six uncommon structural characteristics of compounds, including four newly discovered pyridinopyrones. Based on genomic analysis, we proposed a possible hybrid NRPS-PKS biosynthesis pathway for pyridinopyrones. Notably, this pathway starts with the use of nicotinic acid as the starting unit, which is a unique feature. Compounds 1-3 exhibited moderate anti-neuroinflammatory activity against LPS-induced BV-2 cell inflammation. Our study demonstrates the diversity of polyene pyrone compounds regarding their chemical structure and bioactivity while providing new insights into their biosynthesis pathway. These findings may lead to the development of new treatments for inflammation-related diseases.