Catalyst-Free Cascade Annulation of Enaminones and Aryl Diazonium Tetrafluoroboronates for Cinnoline Synthesis and the Anti-Inflammatory Activity Study.

A simple and concise method for the synthesis of cinnolines has been developed by the reactions of readily available enaminones and aryl diazonium tetrafluoroboronates. The reactions run efficiently to provide cinnolines with broad diversity in the substructure by heating in dimethyl sulfoxide without using any catalyst or additive. In addition, the primary investigation of the anti-inflammatory activity of these products leads to the observation of p-chlorobenzoyl (3f) and p-nitrobenzoyl (3j) cinnolines as attractive anti-inflammatory compounds in vitro.

Assessing the relationship between gut microbiota and irritable bowel syndrome: a two-sample Mendelian randomization analysis.

BACKGROUND: Growing evidence has suggested that gut microbiota is closely related to the risk of irritable bowel syndrome (IBS), but whether there is a causal effect remains unknown. We adopted a Mendelian randomization (MR) approach to evaluate the potential causal relationships between gut microbiota and the risk of IBS. METHODS: Genetic instrumental variables for gut microbiota were identified from a genome-wide association study (GWAS) of 18,340 participants. Summary statistics of IBS were drawn from a GWAS including 53,400 cases and 433,201 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, reverse MR analysis was performed to evaluate the possibility of reverse causation. RESULTS: We identified suggestive associations between three bacterial traits and the risk of IBS (odds ratio (OR): 1.08; 95% confidence interval (CI): 1.02, 1.15; p = 0.011 for phylum Actinobacteria; OR: 0.95; 95% CI: 0.91, 1.00; p = 0.030 for genus Eisenbergiella and OR: 1.10; 95% CI: 1.03, 1.18; p = 0.005 for genus Flavonifractor). The results of sensitivity analyses for these bacterial traits were consistent. We did not find statistically significant associations between IBS and these three bacterial traits in the reverse MR analysis. CONCLUSIONS: Our systematic analyses provide evidence to support a potential causal relationship between several gut microbiota taxa and the risk of IBS. More studies are required to show how the gut microbiota affects the development of IBS.

Metal-free three-component assemblies of anilines, α-keto acids and alkyl lactates for quinoline synthesis and their anti-inflammatory activity.

A new and metal-free three-component method for the synthesis of 2,4-disubstituted quinolines via the reactions of anilines, α-keto acids and alkyl lactates is reported. The reactions proceed in the presence of p-toluene sulfonic acid (p-TSA) and tert-butyl peroxybenzoate (TBPB) to provide diverse quinoline products via the construction of new CC double, C-C single and CN double bonds without producing any organic mass-based side product. Notably, the anti-inflammatory activity of the quinolines has been investigated by measuring their ability to inhibit NO release by lipopolysaccharide (LPS) induced RAW264.7 cells, leading to the identification of 4i, 4t and 4x as potent anti-inflammatory compounds in vitro.

Gut microbiota mediated the therapeutic efficiency of Simiao decoction in the treatment of gout arthritis mice.

BACKGROUND: Gut microbiota plays a significant role in the development and treatment of gouty arthritis. Simiao decoction has been shown to alleviate gouty arthritis by inhibiting inflammation, regulating NLRP3 inflammasome, and altering gut microbiota. However, there is no evidence to prove whether gut microbiota directly mediates the therapeutic efficiency of Simiao decoction in treating gout arthritis. METHODS: In this study, fecal microbiota transplantation (FMT) was used to transfer the gut microbiota of gout arthritis mice treated with Simiao decoction or allopurinol to blank gout arthritis mice, in order to investigate whether FMT had therapeutic effects on gout arthritis. RESULTS: Both Simiao decoction and allopurinol effectively reduced the levels of serum uric acid, liver XOD activity, foot thickness, serum IL-1ß, and G-CSF in gout arthritis mice. However, Simiao decoction also had additional benefits, including raising the pain threshold, reducing serum TNF-α and IL-6, alleviating gut inflammation, and repairing intestinal pathology, which were not observed with allopurinol treatment. Moreover, Simiao decoction had a greater impact on gut microbiota than allopurinol, as it was able to restore the abundance of phylum Proteobacteria and genus Helicobacter. After transplantation into gout arthritis mice, gut microbiota altered by Simiao decoction exhibited similar therapeutic effects to those of Simiao decoction, but gut microbiota altered by allopurinol showed no therapeutic effect. CONCLUSIONS: These findings demonstrates that Simiao decoction can alleviate gout arthritis symptoms by regulating gut microbiota.

Lipidomics analysis facilitate insight into the molecular mechanisms of urate nephropathy in a gout model induced by combination of MSU crystals injection and high-fat diet feeding.

Renal injury is one of the most common clinical manifestations of patients with hyperuricaemia/gout. The precise pathophysiological mechanism(s) for the renal injury is still unknown. Furthermore, it is also unclear whether the clinical therapies (e.g., colchicine and febuxostat) could prevent its progression or not. Lipids are involved in almost all of important biological processes and play critical roles in maintaining the renal functions. Herein, shotgun lipidomics was performed for class-targeted lipid analysis of cellular lipidomes in renal tissue of a gouty model induced by combination of monosodium urate crystals injection and high-fat diet feeding with/without treatment with either colchicine or febuxostat. Serum uric acid (UA), proinflammatory cytokines (i.e., TNF-α and IL-6), xanthine oxidase activity, footpad swelling, and pain threshold were determined to evaluate the gouty severity. Renal histopathological changes, blood urea nitrogen, creatinine, and kidney index were used to reflect renal injury. Lipidomics analysis revealed that altered triacylglycerol (TAG) profile, impaired mitochondrial function resulted by decreased tetra 18:2 cardiolipin, reduced 4-hydroxyalkenal (HNE) species, and elevated lysophospholipids were already present in the kidneys at early stage of renal injury, probably contributing to its occurrence and development. In addition to significantly reduce the UA level and relief the gouty severity, treatment with either colchicine or febuxostat could restore HNE bioavailability, thereby delaying the progression of renal injury. However, both of them could not recover the altered TAG profile and the impaired mitochondrial function, indicating that treatment with either of them could not completely prevent the development of renal injury in the gouty model.

Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling.

Optineurin (OPTN) has important functions in diverse biological processes and diseases, but its effect on dendritic cell (DC) differentiation and functionality remains elusive. Here we show that OPTN is upregulated in human and mouse DC maturation, and that deletion of Optn in mice via CD11c-Cre attenuates DC maturation and impairs the priming of CD4+ T cells, thus ameliorating autoimmune symptoms such as experimental autoimmune encephalomyelitis (EAE). Mechanistically, OPTN binds to the JH1 domain of JAK2 and inhibits JAK2 dimerization and phosphorylation, thereby preventing JAK2-STAT3 interaction and inhibiting STAT3 phosphorylation to suppress downstream transcription of IL-10. Without such a negative regulation, Optn-deficient DCs eventually induce an IL-10/JAK2/STAT3/IL-10 positive feedback loop to suppress DC maturation. Finally, the natural product, Saikosaponin D, is identified as an OPTN inhibitor, effectively inhibiting the immune-stimulatory function of DCs and the disease progression of EAE in mice. Our findings thus highlight a pivotal function of OPTN for the regulation of DC functions and autoimmune disorders.

Correction: Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Relationship of auditory verbal hallucinations with cerebral asymmetry in patients with schizophrenia: an event-related fMRI study.

The purpose of this study was to explore whether there are differences in cerebral asymmetry between subgroups of schizophrenic patients with or without auditory verbal hallucinations (AVHs) and normal controls by using event-related functional magnetic resonance imaging (efMRI). A total of 26 Chinese Han male patients with paranoid schizophrenia (diagnosed by DSM IV, including 13 patients with AVHs and 13 patients without) and 13 matched normal controls were recruited for the present study. The participants had been instructed to listen to short sentences from left or right side and to indicate laterality during efMRI scanning. Functional data were acquired using a 1.5T MR, and were analyzed using statistical parametric mapping. A random-effect model was employed to asses the difference in blood oxygen level dependent response between "left-sided" and "right-sided" conditions. The results from the present study have shown (1) within group comparisons: right precuneus and right superior parietal lobule were significantly activated showed significantly greater activation by left-sided voices than right-sided ones in controls. However, no significant difference in activation was found in any brain region between left and right-sided voices in either of the two patient subgroups, (2) between group comparisons: in comparison with AVHs patients, right middle frontal gyrus (MFG) was markedly activated when control subjects were differentiating right-sided voices. In comparison with patients without AVHs, right-side stimuli significantly activated bilateral MFG and left postcentral gyrus in control group. Furthermore, compared to the non-hallucination group, left Wernicke's area, including supramarginal gyrus, angular gyrus and superior temporal gyrus, was significantly activated by both left and right-sided voices in the hallucination group. In summary, auditory-related asymmetry in control subjects is attenuated in schizophrenic patients. The symptoms of AVHs in schizophrenia are possibly correlated with left hemispheric, particularly auditory and language-related areas dysfunction.

Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization.

Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide-treated IL10-/- BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS.

[The neural substrates for voice familiarity in schizophrenic patients with auditory verbal hallucinations: an event-related functional magnetic resonance imaging study].

OBJECTIVE: To study the physiologic base of voice familiarity (VF) and the mechanism of auditory verbal hallucination (AVH) in the patients with schizophrenia (SCH). METHODS: Twenty-six schizophrenic patients, 13 with and 13 without AVH, and 13 healthy control subjects were instructed to passively listen to familiar or unfamiliar voices and to give their judgment and underwent event-related functional magnetic resonance imaging (efMRI) based on blood oxygenation level-dependent (BOLD) signal efficacy. The functional images were collected by using a 1.5-T MRI and were analyzed by using statistical parametric mapping 2 (SPM2). RESULTS: The total score of positive symptoms of the SCH patients with AVH was (45.5 +/- 13.2), significantly higher than that of the SCH patients without AVH [(22.2 +/- 6.7), P < 0.05]. In comparison with unfamiliar voices, familiar voices elicited greater responses in the left superior temporal gyrus, right frontal lobe and limbic lobe among the SCH patients with AVH (P < 0.005, K(E) > 10). IN comparison with healthy control group, when the patients with AVH discriminated the familiar voices their left precuneus lobes were activated more significantly, and when they discriminated unfamiliar voices their right frontal lobes were activated more significantly (P < 0.005, K(E) > 10). In comparison with the SCH patients without AVH when the SCH patients with AVH discriminated the familiar voices their right frontal lobe were activated more significantly (P < 0.005, K(E) > 10), however, when they discriminated unfamiliar voices there was not significantly difference in the activation of the right frontal lobe between these groups. CONCLUSION: The efMRI results of the inter-group comparison support the inner speech disorder hypothesis that the activation of inner speech in the SCH patients with AVH inhibits the activation of external voice on the corresponding cerebral areas. In addition, hallucinating patients may have significant change of VF neurocognitive model.

TNFAIP3 rs2230926 polymorphisms in rheumatoid arthritis of southern Chinese Han population: a case-control study.

Polymorphism of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) has been be related to various auto-immune diseases. Based on previous studies that the single nucleotide polymorphism (SNP) of rs2230926 was association with rheumatoid arthritis (RA) of Japanese, Caucasian population and the northern Chinese Han population, we tested the alleles and geno-type frequencies of rs2230926 in TNFAIP3 to investigate whether rs2230926 is susceptible to RA of southern Chinese Han population. In our case-control association study, 207 RA patients fulfilling the American College of Rheumatology (ACR) 1987 criteria were compared with 199 unrelated healthy subjects. After testing the alleles and genotype frequencies of rs2230926, the airwise linkage disequilibrium (LD) was computed and odd ration (OR) and 95% confidence intervals (95% CI) were used for evaluating the susceptibility to RA. The SNP of rs2230926 of the cases and control subjects were conformed to the Hardy-Weinberg equilibrium (P = 0.02257). The significantly statistical differences in alleles of T, G were founded in the cases and controls (P = 0.0027, OR 0.417, 95% CI 0.232-0.749); the genetic types of rs2230926 were associated with a susceptibility to RA, with OR 0.375 (95% CI 0.198-0.707, P = 0.0018). In the present study, our results indicated that the genetic polymorphism of rs2230926 in TNFAIP3 may be a susceptible factor conferring risk for RA in southern Chinese Han population.

Association of HLA-DQA1 (rs9272219) with susceptibility to rheumatoid arthritis in a Han Chinese population.

HLA-DQA1 (rs9272219) has been previously reported that it is a susceptibility locus in rheumatoid arthritis (RA) of UK Caucasian population and North American; however, it has not reported in RA of Chinese population. Our study was to identify whether or not this relationship is reside between rs9272219 and RA in a Han Chinese population. 207 patients with RA and 199 control subjects were recruited. The single nucleotide polymorphism (SNP) of rs9272219 was tested in alleles and genotype frequencies and the data was analyzed by doing the statistic analysis of odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses after pairwise linkage disequilibrium (LD) was estimated. Finally, the Alleles and genotype frequencies distribution of rs9272219 locus among RA patients and control subjects were in accordance with Hardy-Weinberg equilibrium. We found significant association between rs9272219 and RA of Chinese population (OR 0.494, 95% confidence interval [95% CI] 0.354-0.688, P = 0 and OR 2.541, 95% CI 1.695-3.808, P = 0, respectively). In this study, we found that the SNP of rs9272219 in HLA-DQA1 is a potential susceptibility locus in RA of Han Chinese population; the results suggest that HLA-DQA1 may be related to the development of RA.

Voice recognition and altered connectivity in schizophrenic patients with auditory hallucinations.

Auditory verbal hallucination (AVH) is a pathological hallmark of schizophrenia; however, their neural basis is unclear. Voice identity is an important phenomenological feature of AVHs. Certain voice identity recognition deficits are specific to schizophrenic patients with AVHs. We tested our hypothesis that among schizophrenia patients with hallucination, dysfunctional voice identity recognition is associated with poor functional integration in the neural networks involved in the evaluation of voice identity. Using functional magnetic resonance imaging (fMRI) during a voice recognition task, we examined the modulation of neural network connectivity in 26 schizophrenic patients with or without AVHs, and 13 healthy controls. Our results showed that the schizophrenic patients with AVHs had altered frontotemporal connectivity compared to the schizophrenic patients without AVHs and healthy controls. The latter two groups did not show any differences in functional connectivity. In addition, the strength of frontotemporal connectivity was correlated with the accuracy of voice recognition. These findings provide preliminary evidence that impaired functional integration may contribute to the faulty appraisal of voice identity in schizophrenic patients with AVHs.