Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in ...astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects ...with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.
Ten hexahydropyrimido4,5-
d
pyrimidine derivatives have been synthesized by using a green and time-efficient microwave method. The synthesized motifs were evaluated for their anticancer activity, ...antimicrobial activity, molecular docking, drug likeliness and ADMET studies. Comparatively, the hetero-aromatic pyrazole substituted compound
4a
exhibited the highest anticancer activity Mean growth percent: 35.57, while EDG –N(CH
3
)
2
substituted compound
4i
indicated very good activity Mean growth percent: 60.92 against various cell lines. From the computational studies, Compound
4a
passed the drug-likeness and ADME properties, fewer toxic properties, and potent inhibitory potential against the RIPK2 with significant binding affinity. In-silico molecular docking revealed that the compound
4a
has significant binding energy (− 9.8 kcal/mol) and dissociation constant (0.54 µM) properties. Additionally, synthesized motifs were evaluated for antimicrobial activity by MIC referencing the standards. According to the SAR evaluations, the compounds
4f
(4-NO
2
),
4g
(3-NO
2
), and
4h
(2-Cl) that include EWGs substituted aldehydes performed well as antimicrobials against selected bacterial and fungal strains. Thus, the synthesized pyrimido4,5-
d
pyrimidine with the heterocyclic and EWGs substituents could act as a potential candidate after further structural optimization for anticancer and antimicrobial drug discovery, respectively.
Graphical abstract
Foxp3+ T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. ...Here we identified Foxp3+ T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT+ Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.
•TIGIT defines a distinct Foxp3+ Treg cell subset•TIGIT induces transcription and secretion of the effector molecule Fgl2 in Treg cells•TIGIT+ Treg cells suppress proinflammatory Th1 and Th17 not Th2 cell responses•Selective suppression by TIGIT+ Treg cells is Fgl2 dependent
Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by ...β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.
The functioning, Pot, Atom, and Step Economic (PASE) green chemistry proposition has been approached for the synthesis of pyrimido4,5-dpyrimidines by the multicomponent reaction (MCR) of barbituric ...acid, guanidine, and aldehyde derivatives using water solvent and iodine catalyst through ultrasound and microwave irradiation methods. Reaction optimization was performed by varying solvents, reaction time, the concentration of catalyst, and reaction methods. Microwave irradiation approach using water solvent and iodine catalyst (8 mol%) with 5 min led to offer the highest yield. EWG substituted compound 4 g (4-NO
2
, guanidine) 87% (U.S.), 93% (M.W.) was found to be the highest yielded compound in this study. The greenness of the reaction was estimated by calculating some green chemistry metrics. The metrics approved the proposed protocol as an ideal, green, and sustainable approach.
Objective
MicroRNAs (miRNAs) are single‐stranded, small noncoding RNAs that regulate gene expression. Because they are stable in serum, they are being developed as biomarkers for cancer and other ...diseases. In multiple sclerosis (MS), miRNAs have been studied in cell populations but not in the circulation. In MS, a major challenge is to develop immune biomarkers to monitor disease. We asked whether circulating miRNAs could be identified in MS and whether they are linked to disease stage and/or disability.
Methods
A total of 368 miRNAs were measured in ethylenediaminetetraacetic acid plasma in 10 relapsing–remitting MS (RRMS) patients, 9 secondary progressive MS (SPMS) patients, and 9 healthy controls (HCs) using miRCURY LNA™ Universal RT microRNA polymerase chain reaction panels. Nineteen miRNAs from this discovery set were validated using qPCR on an independent set of 50 RRMS patients, 51 SPMS patients, and 32 HCs.
Results
We found that circulating miRNAs are differentially expressed in RRMS and SPMS versus HCs and in RRMS versus SPMS. We also found miRNAs to be linked to Expanded Disability Status Scale (EDSS). hsa‐miR‐92a‐1* was identified in the largest number of comparisons. It was different in RRMS versus SPMS, and RRMS versus HCs, and showed an association with EDSS and disease duration. miR‐92 has target genes involved in cell cycle regulation and cell signaling. The let‐7 family of miRNAs differentiated SPMS from HCs and RRMS from SPMS. let‐7 miRNAs regulate stem cell differentiation and T cell activation, activate Toll‐like receptor 7, and are linked to neurodegeneration. hsa‐miR‐454 differentiated RRMS from SPMS, and hsa‐miR‐145 differentiated RRMS from HCs and RRMS from SPMS. Interestingly, the same circulating miRNAs (let‐7 and miR‐92) that were differentially expressed in RRMS versus SPMS also differentiated amyotrophic lateral sclerosis (ALS) from RRMS subjects, but were not different between SPMS and ALS, suggesting that similar processes may occur in SPMS and ALS.
Interpretation
Our results establish circulating miRNAs as a readily accessible blood biomarker to monitor disease in MS. ANN NEUROL 2013;73:729–740
Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors ...influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
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•Melatonin levels negatively correlate with multiple sclerosis relapses in humans•Melatonin treatment ameliorates pathology in a mouse model of multiple sclerosis•Melatonin blocks ROR-γt expression and Th17 differentiation•Melatonin boosts Tr1 development via Erk1/2 and ROR-α
Melatonin affects the differentiation and function of effector and regulatory T cells in vitro and in vivo, representing an environmental cue that contributes to the seasonality of multiple sclerosis relapses and a potential target for therapeutic intervention in immune-mediated diseases.
•8-Methyl-2-phenyl quinazolinone Schiff's base series has been synthesized.•Efficacy of 7b and 7 h against MDA-MB-435 and NCI-H522 cell lines, respectively.•7 g was effective against breast cancer ...(HS-578T) and CNS cancer (SNB-19) cell lines.•7d (4-Br) and 7j (4-Cl) potent against selected bacterial and fungal microorganisms.•7d and 7j show target affinities with −8 to −12.5 kcal/mol binding energies.
A series of new compounds based on 8-methyl-2-phenyl quinazolinone Schiff's base were synthesized from 3-amino quinazolinone intermediates. These compounds were evaluated for their potential as anticancer and antimicrobial agents through docking analysis. Anticancer evaluation was done against sixty different cancer cell lines. Compounds 7b and 7 h showed strong efficacy against Melanoma (MDA-MB-435 Cell lines) and Non-Small Cell Lung Cancer (NCI-H522), respectively. Compound 7 g was found to be predominantly effective against both breast cancer (HS-578T) and central nervous system cancer (SNB-19). The antimicrobial activity results showed that the newly synthesized compounds 7d and 7j, which contain halogen, exhibited potential inhibiting action against selected bacterial and fungal microorganisms. The SAR study revealed that compounds with EDGs like hydroxyl and meta-substituted chloro group were found to be more potent in anticancer studies; while compounds with EWGs substituted in the para position (7d and 7j) demonstrated higher antimicrobial activity. Moreover, Antimicrobial docking analysis indicated that compounds 7d and 7j have a high affinity towards molecular targets found in both bacteria and fungi, with negative binding energies ranging from -8 to -12.5 kcal/mol. We endorse further evaluation of these compounds in combination with standard antibiotics to potentially increase their synergistic effect.
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The present investigation is in the interest of some synthesized novel derivatives containing (5-(2-chloroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1
H
-pyrazol-1-yl)(pyridin-4-yl)methanones (
4a–o
) ...moieties incorporated with different biological active heterocycles such as quinoline, pyrazoline and pyridine derivatives. For the determination of the compounds reported in this paper was based on IR,
1
H NMR,
13
C NMR and mass spectral data and same compounds were screened for their antibacterial and antifungal activity on four bacteria (
Staphylococcus aureus
,
Streptococcus pyogenes
,
Escherichia coli
,
Pseudomonas aeruginosa
) and three fungi (
Candida albicans
,
Aspergillus niger
,
Aspergillus clavatus
) using ampicillin and griseofulvin as the standard drugs. Cytotoxicity study was carried out using MTT colorimetric assay (HeLa cell line). Among the screened compounds,
4e
,
4f
and
4n
showed most potent antibacterial activity, while compounds
4d
and
4g
emerged as the most active against fungal strains. The results demonstrated that compound
4o
was remarkably active against all microbial strains. From the viewpoint of SAR studies, it was observed that the presence of electron withdrawing groups remarkably enhanced the antimicrobial activity of synthesized compounds. Additionally, preliminary MTT cytotoxicity studies on HeLa cells suggested that effective antimicrobial activity of
4e
–
g
,
4n
and
4o
was accompanied by low cytotoxicity.
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