Erratum: Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis: Erratum.

[This corrects the article DOI: 10.7150/ijbs.46153.

Macrophage P2YR activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses.

Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2YR mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study. Here, the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2YR, while the cell-chat algorithm showed there was a correlation between macrophage P2YR and Th1 cells mediated by IL-27.

Identification of 6-Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer.

Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound , which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y receptor antagonists based on the scaffold hopping strategy. The optimized compound (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC: 0.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cβ/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

Background And Aims: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways.

Network pharmacology-based analysis of Jin-Si-Wei on the treatment of Alzheimer's disease.

Ethnopharmacological Relevance: Jin-Si-Wei (JSW), a traditional Chinese medicine (TCM) formula, have cognitive enhancing effect and delay the memory decline in an animal model of AD， which has been reported. However, the therapeutic mechanism of JSW in the treatment of AD remains unclear.

Aim Of The Study: This study aimed to verify the pharmacodynamics of JSW in the treatment of AD, and to explore its potential mechanism based on network pharmacology, molecular docking and experimental validation both in vitro and in vivo.

Polysaccharide from Strongylocentrotus nudus eggs regulates intestinal epithelial autophagy through CD36/PI3K-Akt pathway to ameliorate inflammatory bowel disease.

Sea urchin is a popular food all over the world, of which eggs are main edible part. Previous studies suggested that polysaccharides from eggs of Strongylocentrotus nudus (SEP) exhibited immunomodulatory activities during anti-tumor therapy, nevertheless, effects of SEP on inflammatory bowel disease and its underlying mechanisms have never been reported. In the present study, we showed that the SEP inhibited dextran sodium sulfate-induced ulcerative colitis characterized by decreased disease activity index, restored colon length and body weight, improved histopathological changes, down-regulation of inflammatory cytokines levels and Th17/Treg ratios in C57BL/6 J mice.

Discovery of Selective P2YR Antagonists with High Affinity and Efficacy for Inflammatory Disease Therapy.

As a member of purinoceptors, the P2Y receptor (P2YR) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2YR, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2YR antagonist (compound ) was identified to possess excellent antagonistic activity (IC = 5.

HQL6 serves as a novel P2Y receptor antagonist to ameliorate acute gouty arthritis through inhibiting macrophage pyroptosis.

Acute gouty arthritis (AGA) has been classified as an autoinflammatory disease caused by deposition of monosodium urate crystals (MSU), accompanied by swellingofjoint and severe pain. Limited clinical therapy and highincidence indicate that the development of effective drugs for AGA is an urgent need. Our previous study found that P2Y receptor (P2YR) was a potential target in anti-gout treatment through regulating pyroptosis of macrophages under exposure of MSU.

Discovery of a Series of 5-Amide-1-pyrazole-3-carboxyl Derivatives as Potent P2YR Antagonists with Anti-Inflammatory Characters.

UDPG/P2YR signaling pathway has been considered as a potential therapeutic target for innate immune system diseases. Based on the scaffold hopping strategy, a series of pyrazole analogues were designed and synthesized as novel P2YR antagonists with improved physicochemical properties, together with potential anti-inflammatory activities. Additionally, we designed and synthesized a fluorescent probe based on highly selective and potent PPTN to study the affinity of synthesized compounds.

GPR105-Targeted Therapy Promotes Gout Resolution as a Switch Between NETosis and Apoptosis of Neutrophils.

The fate of infiltrating neutrophils in inflamed joints determines the development of acute gouty arthritis (AGA). GPR105 highly expressed in human neutrophils is sensitive to monosodium urate crystals (MSU); nevertheless, the roles of GPR105 in AGA remain unclear. Here, we show that GPR105 is significantly upregulated in peripheral polymorphonuclear neutrophils of AGA patients.

Cardiovascular Protective Effects of Plant Polysaccharides: A Review.

Cardiovascular disease is a kind of heart, brain, and blood vessel injury disease by the interaction of various pathological factors. The pathogenesis of cardiovascular disease is complex with various risk factors, including abnormally elevated blood pressure, glucose, and lipid metabolism disorders, atherosclerosis, thrombosis, etc. Plant polysaccharides are a special class of natural products derived from plant resources, which have the characteristics of wide sources, diverse biological activities, and low toxicity or side effects.

Discovery and computational studies of 2-phenyl-benzoxazole acetamide derivatives as promising P2YR antagonists with anti-gout potential.

The P2Y nucleotide receptor, a subtype of P2Y receptors, is implicated in many human inflammatory diseases. Based on the identification of favorable residues of two screening hits in the almost symmetrical P2Y binding domain, we describe the structural optimization of previously identified virtual screening hits 6 and 7 that result in the development of P2YR antagonists with a novel 2-phenyl-benzoxazole acetamide chemical scaffold. Notably, compound 52 showed potent P2YR antagonistic activity (IC = 2 nM), and a stronger inhibitory effect on MSU-induced inflammatory in vitro, better than a previously described P2YR antagonist PPTN.

Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis.

Acute gouty arthritis is a common inflammatory arthropathy resulting from urate deposition in joints during persistent hyperuricemia. Nevertheless, effective therapeutic strategies are still unavailable. Here, we propose the crucial role of bromodomain-containing protein 4 (BRD4) in acute gouty arthritis.

Silencing of Gasdermin D by siRNA-Loaded PEI-Chol Lipopolymers Potently Relieves Acute Gouty Arthritis through Inhibiting Pyroptosis.

Gasdermin D (GSDMD) plays a causal role in NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis eruption, which has been regarded as a potential therapeutic target for pyroptosis-related diseases including acute gouty arthritis. In the present study, the synthesized PEI-Chol (cholesterol grafted polyethylenimine) was assembled with GSDMD small interfering RNA (siRNA) to form PEI-Chol/siGSDMD polyplexes, which provided high transfection efficiency for siRNA-mediated GSDMD knockdown. Then we evaluated the effect of GSDMD siRNA-loaded PEI-Chol on inflammatory cascades in bone-marrow-derived macrophages (BMDMs) and acute gouty arthritis animal models under MSU exposure.

P2Y receptor has a critical role in acute gouty arthritis by regulating pyroptosis of macrophages.

Nod-like receptor protein 3 (NLRP3)-mediated pyroptosis has a causal role in the pathogenesis of gout. P2Y receptor (P2YR) distributed in immune cells including macrophages is a Gi-coupled receptor that inhibits the synthesis of cAMP, which has been regarded as a potential regulator of inflammatory response. Nevertheless, the role of P2YR in MSU-induced pyroptosis of macrophages involved in acute gouty arthritis is still unclear.

HJ22, a Novel derivative of piperine, Attenuates ibotenic acid-induced cognitive impairment, oxidativestress, apoptosis and inflammation via inhibiting the protein-protein interaction of Keap1-Nrf2.

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests.

The role of P2YR in cardiovascular diseases and recent development of P2YR antagonists.

As a member of the P2Y receptor family with a typical 7-transmembrane structure, P2Y purinergic receptor (P2YR) belongs to the G-protein-coupled nucleotide receptor activating the phospholipase-C signaling pathway. P2YR is widely involved in a range of human diseases, including atherosclerosis and other cardiovascular diseases, gradually attracting attention owing to its inappropriate or excessive activation. In addition, it was reported that P2YR might regulate inflammatory responses by governing the maturation and secretion of proinflammatory cytokines.

Development of novel NLRP3-XOD dual inhibitors for the treatment of gout.

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms.

Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y receptor antagonists.

The P2Y receptor (P2YR) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2YR antagonists. The most potent antagonist, 16c, showed comparable activity (IC = 1.

4-(2-(4-chlorophenyl)-1-((4-chlorophenyl)amino)ethyl)benzene-1, 3-diol is a potential agent for gout therapy as a dual inhibitor of XOD and NLRP3.

Backgound: Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Both anti-hyperuricemia and anti-inflammation could be gout therapeutic strategies, whereas ideal drugs for gout treatment are deficient.

Purpose: 4-(2-(4-chlorophenyl)-1-((4-chlorophenyl)amino)ethyl)benzene-1, 3-diol (CBED) was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti-hyperuricemic and anti-inflammatory activities, which was expected to be a dual inhibitor of xanthine oxidase (XOD) and NOD-like receptor protein 3 (NLRP3).

Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout.

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway.

Emodinol ameliorates urate nephropathy by regulating renal organic ion transporters and inhibiting immune inflammatory responses in rats.

Emodinol, 1β, 3β, 23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our Research Group, was identified with apparent uricosuric and nephroprotective effects in hyperuricemia mice in our previous study. This study aimed to investigate the renal protective effect of emodinol in urate nephropathy rats. Rats were orally administrated by combined adenine and ethambutol to induce urate nephropathy.