Design, synthesis and evaluation of pyrimidine derivatives as sedative-hypnotic agents.

Insomnia is a mental disorder in which drugs only alleviate the symptoms but also produce adverse effects. Therefore, developing innovative sedative-hypnotic agents is urgent. In this work, twenty-five novel heteroatomic compounds were designed, synthesized, and screened for their sedative activities, structurally featuring the fusion of pyrimidine and carbazole or benzothiazole.

Compound FLZ attenuates neuroinflammation through inhibiting Src/PTEN/Akt signaling pathway.

Compound FLZ has neuroprotective effects on Parkinson's disease (PD), while the precise mechanism remains unclear. In this study, we found that FLZ decreased PTEN/Akt activity in LPS-challenged BV2 cells. Neuroinflammatory responses suppressed by FLZ were abolished when PTEN or Src was inhibited.

White matter lesions contribute to motor and non-motor disorders in Parkinson's disease: a critical review.

Parkinson's disease (PD) is a prevalent neurodegenerative disease, characterized by movement disorders and non-motor symptoms like cognitive impairment and depression. Degeneration of dopaminergic neurons in the substantia nigra and Lewy bodies have long been considered as main neuropathological changes. However, recent magnetic resonance imaging (MRI) studies have shown that white matter lesions (WMLs) were present in PD patients.

Natural products and their derivatives alleviating cerebral white matter lesions.

White matter lesions (WMLs), characterized by focal demyelination or myelination disorders, are commonly present in cerebral small vessel disease and various neurological diseases. Multiple etiologies lead to WMLs. However, there is no specific therapy or effective drugs for relieving WMLs.

Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies.

HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson's disease models.

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses.

Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-B pathway through microbiota-gut-brain axis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet.

TLR2 Potentiates SR-Marco-Mediated Neuroinflammation by Interacting with the SRCR Domain.

Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes.

Autoimmune polyendocrine syndrome induced by immune checkpoint inhibitors: a systematic review.

Objective: To summarize the clinical characteristics and immunological and genetic features of patients who developed autoimmune polyendocrine syndrome type II (APS-2) after treatment with immune checkpoint inhibitors (ICIs).

Design And Methods: Several databases (MEDLINE/EMBASE/Cochrane) were searched for studies published between January 2000 and February 2020 involving patients with two or more endocrine disorders after ICI therapy.

Results: Our final review included 22 articles comprising 23 patients (median age 56 years; 65.

Novel phloroglucinol derivative Compound 21 protects experimental autoimmune encephalomyelitis rats via inhibiting Th1/Th17 cell infiltration.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory infiltration and demyelination in the central nervous system (CNS). Among the factors involved in the immunological mechanisms of MS, T helper 1 (Th1) cells and T helper 17 (Th17) cells play a critical role. Compound 21, a novel phloroglucinol derivative, significantly protected myelin from damage in our previous study.

Highly oxidized sesquiterpenes from the fruits of Illicium lanceolatum A. C. Smith.

Ten undescribed highly oxidized sesquiterpenes and six known sesquiterpenes were isolated from HO-soluble part of the fruits of Illicium lanceolatum A. C. Smith.

Induction of glial cell line-derived neurotrophic factor by the squamosamide derivative FLZ in astroglia has neuroprotective effects on dopaminergic neurons.

Glial cell line-derived neurotrophic factor (GDNF) has neurotrophic activity for the survival of dopaminergic neurons, which is under active investigation for Parkinson's disease (PD) therapy. FLZ is a potential new drug for PD treatment. However, it is unclear whether neurotrophic activity contributes to the neuroprotective effects of FLZ.

Phloroglucinol derivative compound 21 attenuates cuprizone-induced multiple sclerosis mice through promoting remyelination and inhibiting neuroinflammation.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease in the central nervous system. The myelin loss is mainly caused by dysfunction of oligodendrocytes and inflammatory responses of microglia and astrocytes further aggravate the demyelination. Current therapies for MS focus on suppressing the overactivated immune response but cannot halt the disease progress, so effective drugs are urgently needed.

New hexalactone derivatives and a pair of new oxaspiro-carbon epimeric glycosides from the fruits of Illicium lanceolatum.

Five new compounds (1-5), including three hexalactone derivatives (1-3) and a pair of new oxaspiro-carbon epimeric glycosides (4 and 5), and six known compounds (6-11) were obtained from the fruits of Illicium lanceolatum. The structures of the new compounds were elucidated using extensive spectroscopic data. The absolute configurations of compounds 1-3 were determined by an analysis of their CD spectra.

Discovery of coumarin Mannich base derivatives as multifunctional agents against monoamine oxidase B and neuroinflammation for the treatment of Parkinson's disease.

Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies.

The Protective Effects of Gardenia jasminoides (Fructus Gardenia) on Amyloid-β-Induced Mouse Cognitive Impairment and Neurotoxicity.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Although the exact causes of AD have not yet been fully elucidated, cholinergic dysfunction, mitochondrial damage, oxidative stress and neuroinflammation have been recognized as influential factors. Current drugs that are designed to address only a single target are unable to mitigate or prevent the progression of this complicated disease, so new disease-modifying drugs are urgently needed.

Heat shock protein 70 suppresses neuroinflammation induced by α-synuclein in astrocytes.

Neuroinflammation triggered by activation of glial cells plays an important role in the pathophysiology of several neurodegenerative diseases including Parkinson's disease (PD). Besides microglia, astrocytes are also critical in initiating and perpetuating inflammatory process associated with PD. Heat shock protein 70 (Hsp70) is originally described as intracellular chaperone, however, recent study revealed that it had anti-inflammatory effects as well.

Mechanism of Non-receptor Tyrosine Kinase Src Regulating Neuroinflammation Through Phosphatase and Tensin Homology Protein in Microglia.

Objective To investigate the mechanism of non-receptor tyrosine kinase Src regulating neuroinflammation through phosphatase and tensin homology protein(PTEN)in microglia. Methods BV2 cells were incubated with PTEN inhibitor bpv(HOpic)for 2 hours,and then added with lipopolysaccharide(LPS)to induce neuroinflammation,Western blot was performed to determine the expression of phosphorylated protein kinase B(Akt)to investigate the activity of PTEN. Enzyme-linked immunosorben assay(ELISA)was used to determine the release of tumor necrosis factor α(TNF-α)to assess neuroinflammation.

Three new coumarin glycosides from the stems of Hydrangea paniculata.

Three new coumarin glycosides (1-3), together with three known compounds (4-6), have been obtained from the stems of Hydrangea paniculata Sieb. Their structures were elucidated based on spectroscopic data and chemical evidence. In addition, compounds 1-3 were screened for their neuroprotective effects against serum deprivation-induced PC12 cell damage, hepatoprotective activities against DL-galactosamine-induced toxicity in HL-7702 cells and their ability to inhibit LPS-induced nitric oxide production in the murine microglia BV2 cell line, but they were inactive.

A novel synthetic derivative of squamosamide FLZ inhibits the high mobility group box 1 protein-mediated neuroinflammatory responses in murine BV2 microglial cells.

High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson's disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses.

Anti-inflammatory pentacyclic triterpenes from the stems of Euonymus carnosus.

Three new lupane-type triterpenoids (1-3), three new oleane-type triterpenoids (4-6), as well as two known compounds (7-8) were isolated from Euonymus carnosus. The structures of the compounds were elucidated on the basis of spectroscopic data analyses, including UV, IR, MS, and NMR experiments. The inhibitory on LPS-induced NO production in microglia BV2 cells of compounds 1-8 were also evaluated.