Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium ...urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.
A finite‐element method based on a weak formulation of the Takagi–Taupin equations was adopted to study the X‐ray diffraction of crystals with surface undulations. A general diffraction geometry was ...simulated to investigate the diffraction features caused by the surface undulations. The numerical results reveal that the effects of surface undulations on Bragg diffraction are local for those limited in the low‐frequency range and physically result from the refractive effect, brought on by the variation of the local asymmetry angle. Thus, a formula based on the local perfect flat crystal approximation was introduced to efficiently evaluate the change in the direction of the diffracted wave caused by surface undulations.
Takagi–Taupin dynamical X‐ray diffraction simulations of crystals with surface undulations show that the influence of the surface undulations is local for those in the low‐frequency range and can be predicted by classical X‐ray dynamical theory.
To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives (4a∼4m) were designed and synthesized. Compounds 4a and 4b were ...determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-α, NO through NF-κB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints.
New arylpyrazole-coumarins with anti-inflammatory activity were designed and synthesized. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and NO production LPS-stimulated. The further study showed that title compound could significantly suppress LPS-induced iNOS, COX-2 expression and IL-6, TNF-α, NO production through NF-κB/MAPK signaling pathway. Display omitted
•Trifluoromethylphenyl-dihydropyrazole coumarin compounds were synthesized.•Compound showed the highest anti-inflammatory activity against IL-6, TNF-α.•Preliminary mechanisms of anti-inflammatory action were discovered.
•Five synovial tissue-specific genes involved in RA were identified and validated.•The predictive and diagnostic value of these potential biomarkers were analyzed.•The characteristic genes were ...associated with excessive immune-infiltration and cell proliferation.•Eight suggestive compounds with anti-RA potential were obtained.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. It is well known that the formation of positive feedback between synovial hyperplasia and inflammatory infiltration is intimately associated with the occurrence and development of RA. However, the exact mechanisms still remain unknown, making the early diagnosis and therapy of RA difficult. This study was designed to identify prospective diagnostic and therapeutic biomarkers, as well as their-mediated biological mechanisms in RA.
Three microarray datasets (GSE36700, GSE77298 and GSE153015) and two RNA-sequencing datasets (GSE89408 and GSE112656) of synovial tissues, as well as three other microarray datasets (GSE101193, GSE134087 and GSE94519) of peripheral blood were downloaded for integrated analysis. The differently expressed genes (DEGs) were identified by “limma” package of R software. Then, weight gene co-expression analysis and gene set enrichment analysis were performed to investigate synovial tissue-specific genes and their-mediated biological mechanisms in RA. The expression of candidate genes and their diagnostic value for RA were verified by quantitative real-time PCR and receiver operating characteristic (ROC) curve, respectively. Relevant biological mechanisms were explored through cell proliferation and colony formation assay. The suggestive anti-RA compounds were discovered by CMap analysis.
We identified a total of 266 DEGs, which were mainly enriched in cellular proliferation and migration, infection and inflammatory immune signaling pathways. Bioinformatics analysis and molecular validation revealed 5 synovial tissue-specific genes, which exhibited excellent diagnostic value for RA. The infiltration level of immune cells in RA synovial tissue was significantly higher than that in control individuals. Moreover, preliminary molecular experiments suggested that these characteristic genes may be responsible for the high proliferation potential of RA fibroblast-like synoviocytes (FLSs). Finally, 8 small molecular compounds with anti-RA potential were obtained.
We have proposed 5 potential diagnostic and therapeutic biomarkers (CDK1, TTK, HMMR, DLGAP5, and SKA3) in synovial tissues that may contribute to the pathogenesis of RA. These findings may shed light on the early diagnosis and therapy of RA.
Innate immunity activates the corresponding immune response relying on multiple pattern recognition receptors (PRRs) that includes pattern recognition receptors (PRRs), like NOD-like receptors ...(NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs), which could accurately recognize invasive pathogens. In particular, NLRs belong to a large protein family of pattern recognition receptors in the cytoplasm, where they are highly correlated with activation of inflammatory response system followed by rapid clearance of invasive pathogens. Among the NLRs family, NLRC5, also known as NOD4 or NOD27, accounts for a large proportion and involves in immune responses far and wide. Notably, in the above response case of inflammation, the expression of NLRC5 remarkably increased in immune cells and immune-related tissues. However, the evidence for higher expression of NLRC5 in immune disease still remains controversial. It is noted that the growing evidence further accounts for the participation of NLRC5 in the innate immune response and inflammatory diseases. Moreover, NLRC5 has also been confirmed to exert a critical role in the control of regulatory diverse signaling pathways. Together with its broad participation in the occurrence and development of immune diseases, NLRC5 can be consequently treated as a potential therapeutic target. Nevertheless, the paucity of absolute understanding of intrinsic characteristics and underlying mechanisms of NLRC5 still make it hard to develop targeting drugs. Therefore, current summary about NLRC5 information is indispensable. Herein, current knowledge of NLRC5 is summarized, and research advances in terms of NLRC5 in characteristics, biological function, and regulatory mechanisms are reviewed.
Alcohol use disorder (AUD) is one of the most prevalent neuropsychological disorders worldwide, and its pathogenesis is convoluted and poorly understood. There is considerable evidence demonstrating ...significant associations between multiple heritable factors and the onset and progression of AUD. In recent years, a substantial body of research conducted by emerging biotechnologies has increasingly highlighted the crucial roles of noncoding RNAs (ncRNAs) in the pathophysiology of mental diseases. As in-depth understanding of ncRNAs and their mechanisms of action, they have emerged as prospective diagnostic indicators and preclinical therapeutic targets for a variety of psychiatric illness, including AUD. Of note, dysregulated expression of ncRNAs such as circRNAs, lncRNAs and miRNAs was routinely found in AUD individuals, and besides, exogenous regulation of partial ncRNAs has also been shown to be effective in ameliorating alcohol preference and excessive alcohol consumption. However, the exact molecular mechanism still remains elusive. Herein, we systematically summarized current knowledge regarding alterations in the expression of certain ncRNAs as well as their-mediated regulatory mechanisms in individuals with AUD. And finally, we detailedly reviewed the potential theranostics applications of gene therapy agents targeting ncRNAs in AUD mice. Overall, a deeper comprehension of functional roles and biological mechanisms of ncRNAs may make significant contributions to the accurate diagnosis and effective treatment of AUD.
To determine the reliability of dynamic magnetic resonance imaging (MRI) perfusion parameters for the evaluation of blood supply to spinal metastatic tumors.
A total of 36 patients with spinal ...metastasis who underwent dynamic contrast-enhanced magnetic resonance spinal perfusion imaging at Tianjin Hospital from December 2018 to December 2020 were reviewed. Subsequently, the patients underwent corresponding preoperative examination using digital subtraction angiography of the spine at the hospital and were divided into 2 groups accordingly. Differences in dynamic MRI perfusion parameters between the 2 groups were analyzed.
There were statistically significant differences between the 2 groups in the quantitative dynamic contrast-enhanced MRI perfusion parameters vascular permeability and plasma volume, as well as semi-quantitative peak enhancement and blood flow ratio parameters.
Dynamic MRI perfusion may distinguish spinal metastatic lesions with rich blood supply from those with poor blood supply and may help clinicians identify patients that can benefit from invasive spinal angiography and preoperative embolization. This technique may also provide guidance on decision taking for surgery basing on dynamic MRI perfusion parameters.
Type I interferon (IFN) inhibits viruses by inducing the expression of antiviral proteins. The IFN-induced myxovirus resistance B (MxB) protein has been reported to inhibit a limited number of ...viruses, including HIV-1 and herpesviruses, but its antiviral coverage remains to be explored further. Here we show that MxB interferes with RNA replication of hepatitis C virus (HCV) and significantly inhibits viral replication in a cyclophilin A (CypA)-dependent manner. Our data further show that MxB interacts with the HCV protein NS5A, thereby impairing NS5A interaction with CypA and NS5A localization to the endoplasmic reticulum, two events essential for HCV RNA replication. Interestingly, we found that MxB significantly inhibits two additional CypA-dependent viruses of the
family, namely, Japanese encephalitis virus and dengue virus, suggesting a potential link between virus dependence on CypA and virus susceptibility to MxB inhibition. Collectively, these data have identified MxB as a key factor behind IFN-mediated suppression of HCV infection, and they suggest that other CypA-dependent viruses may also be subjected to MxB restriction.
Viruses of the
family cause major illness and death around the world and thus pose a great threat to human health. Here we show that IFN-inducible MxB restricts several members of the
, including HCV, Japanese encephalitis virus, and dengue virus. This finding not only suggests an active role of MxB in combating these major pathogenic human viruses but also significantly expands the antiviral spectrum of MxB. Our study further strengthens the link between virus dependence on CypA and susceptibility to MxB restriction and also suggests that MxB may employ a common mechanism to inhibit different viruses. Elucidating the antiviral functions of MxB advances our understanding of IFN-mediated host antiviral defense and may open new avenues to the development of novel antiviral therapeutics.
► A new flow injection CL method was developed for timolol maleate. ► AuNPs with the sizes in the range of 6–99nm was found to catalyze the CL reaction of luminol with N-bromosuccinimide. ► The CL ...signal was furtherly increased by timolol maleate significantly. ► A thorough discussion on CL reaction mechanism was presented.
A new chemiluminescence (CL) method combined with flow injection technique was developed for the determination of timolol maleate. Gold nanoparticles was found to catalyze the CL reaction of luminol with N-bromosuccinimide in an alkaline condition. The CL signal was furtherly enhanced significantly when timolol maleate was presented in the reaction system. But timolol maleate alone inhibited the CL signal from luminol–N-bromosuccinimide reaction slightly. Under the selected conditions, the enhanced CL intensity was linearly related to timolol maleate concentration in the range of 0.01–5.0mg/L with a detection limit of 7.6μg/L. The relative standard deviation was 2.7% for 11 repeated measurements of 0.1mg/L timolol maleate solution. The proposed method was applied to the determination of timolol maleate in eye drops and in spiked human urine. A discussion on the possible CL reaction mechanism was also presented.
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