Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity.

Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 µM against IL-1ß release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 µM) against IL-1ß release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1ß release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.

Pituitary Apoplexy Leading to Cerebral Infarction: A Systematic Review.

BACKGROUND: Cerebral infarction caused by pituitary apoplexy (PA) is rare. To characterize the clinical features of cerebral infarction caused by PA, we performed a systematic review. SUMMARY: The clinical symptoms are mainly sudden headache, hemiplegia, visual impairment, disturbance of consciousness, and ophthalmalgia in patients with cerebral infarction caused by PA. Treatment for this type of infarction is different from treatment for general acute cerebral infarction. Compared to patients who underwent emergency surgery and conservative treatment, patients treated with delayed surgery showed a better prognosis and a lower mortality rate. Compared to patients who underwent craniotomy or conservative treatment, patients who underwent transsphenoidal surgery (TSS) not only improved well but also showed a lower mortality rate. Key Messages: PA rarely causes cerebral infarction, which is a critical condition with a poor prognosis and is more common in men. Delayed surgery and TSS appear to confer a better prognosis in patients with this condition.

CircRNA hsa_circRNA_101996 increases cervical cancer proliferation and invasion through activating TPX2 expression by restraining miR-8075.

In recent years, circular RNAs have been shown to serve as essential regulators in several human cancers. Nevertheless, the function and mechanism of CircRNA in cervical cancer remain elusive. In the present study, we showed that hsa_circRNA_101996 was highly expressed in cervical cancer tissues compared with matched normal tissues by bioinformatics analysis. We showed that the expression level of hsa_circRNA_101996 in cervical cancer tissues was positively correlated with TNM stage, tumor size, and lymph node metastasis. Moreover, higher levels of hsa_circRNA_101996 were related to poor outcomes of cervical cancer patients. We found that knockdown of hsa_circRNA_101996 significantly inhibited the proliferation, cell cycle, migration, and invasion of cervical cancer cells. Mechanistically, we demonstrated that hsa_circRNA_101996 served as a sponge of miR-8075, which targeted TPX2 in cervical cancer cells. We showed that miR-8075 that was downregulated in cervical cancer tissues repressed cervical cancer cell proliferation, migration, and invasion. Furthermore, we validated that upregulation of TPX2 by hsa_circRNA_101996-mediated inhibition of miR-8075 contributed to cervical cancer proliferation, migration, and invasion. Taken together, our findings revealed a novel mechanism that hsa_circRNA_101996-miR-8075-TPX2 network promoted cervical cancer progression.

RNA interference-based therapy and its delivery systems.

RNA interference (RNAi) is considered a highly specific approach for gene silencing and holds tremendous potential for treatment of various pathologic conditions such as cardiovascular diseases, viral infections, and cancer. Although gene silencing approaches such as RNAi are widely used in preclinical models, the clinical application of RNAi is challenging primarily because of the difficulty in achieving successful systemic delivery. Effective delivery systems are essential to enable the full therapeutic potential of RNAi. An ideal nanocarrier not only addresses the challenges of delivering naked siRNA/miRNA, including its chemically unstable features, extracellular and intracellular barriers, and innate immune stimulation, but also offers "smart" targeted delivery. Over the past decade, great efforts have been undertaken to develop RNAi delivery systems that overcome these obstacles. This review presents an update on current progress in the therapeutic application of RNAi with a focus on cancer therapy and strategies for optimizing delivery systems, such as lipid-based nanoparticles.

Minocycline protects against myocardial ischemia/reperfusion injury in rats by upregulating MCPIP1 to inhibit NF-κB activation.

Minocycline is a tetracycline antibiotic and has been shown to play a protective role in cerebral and myocardial ischemia/reperfusion (I/R). However, the underlying mechanism remains unclear. Herein, we investigated whether monocyte chemotactic protein-induced protein-1 (MCPIP1), a negative regulator of inflammation, was involved in the minocycline-induced cardioprotection in myocardial I/R in vivo and in vitro models. Myocardial ischemia was induced in rats by left anterior descending coronary artery occlusion for 1 h and followed by 48 h reperfusion. Minocycline was administered prior to ischemia (45 mg/kg, ip, BID, for 1 d) and over the course of reperfusion (22.5 mg/kg, ip, BID, for 2 d). Cardiac function and infarct sizes were assessed. Administration of minocycline significantly decreased the infarct size, alleviated myocardial cell damage, elevated left ventricle ejection fraction, and left ventricle fractional shortening following I/R injury along with significantly decreased pro-inflammatory cytokine IL-1ß and monocyte chemoattractant protein-1 (MCP-1) levels in heart tissue. H9c2 cardiomyocytes were subjected to oxygen glucose deprivation (OGD) followed by reoxygenation (OGD/R). Pretreatment with minocycline (1-50 µmol/L) dose-dependently increased the cell viability and inhibited OGD/R-induced expression of MCP-1 and IL-6. Furthermore, minocycline dose-dependently inhibited nuclear translocation of NF-κB p65 in H9c2 cells subjected to OGD/R. In both the in vivo and in vitro models, minocycline significantly increased MCPIP1 protein expression; knockdown of MCPIP1 with siRNA in H9c2 cells abolished all the protective effects of minocycline against OGD/R-induced injury. Our results demonstrate that minocycline alleviates myocardial I/R injury via upregulating MCPIP1, then subsequently inhibiting NF-κB activation and pro-inflammatory cytokine secretion.

The Effect of Winter Temperature on Patients with Ischemic Stroke.

BACKGROUND The incidence of ischemic stroke increases in winter. This study aimed to explore the effect of winter temperatures on the risk factors, etiology, coagulation, and degree of neurological impairment in patients with ischemic stroke using temperature and rainfall data from the Guangzhou Meteorological Bureau during the winter months of December, January, and February. MATERIAL AND METHODS We divided 112 patients with ischemic stroke into low-temperature and non-low-temperature groups. The low-temperature group experienced an average daily winter temperature of <13°C for five consecutive days within the 14 days before hospital admission and an average temperature of <13°C on admission. The non-low-temperature group experienced an average daily temperature of >13°C in the 14 days before hospital admission and an average daily temperature of >13°C on admission. Neurological deficits were scored and monitored using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) for disability in stroke. Blood pressure and coagulation indices of prothrombin time (PT) and thromboplastin time (TT) were recorded. RESULTS Compared with the non-low-temperature group, the low-temperature group showed a significantly increased proportion of patients with hypertension and large artery atherosclerotic stroke, more prolonged PT, and higher NIHSS scores. However, TT was reduced in the low-temperature group (P<0.05). CONCLUSIONS When the average winter temperature was <13°C, the risk factors, etiology, coagulation factors, and degree of neurological impairment of patients with ischemic stroke were significantly different from patients with ischemic stroke during warmer temperature.

The Therapeutic Effect of ICAM-1-Overexpressing Mesenchymal Stem Cells on Acute Graft-Versus-Host Disease.

BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) do not readily migrate to appropriate sites, and this creates a major obstacle for their use in the treatment of graft-versus-host disease (GVHD). Intercellular adhesion molecule-1 (ICAM-1) can guide the homing of various immune cells to the proper anatomical location within secondary lymphoid organs (SLOs), which are the major niches for generating immune responses or tolerance. MSCs rarely migrate to SLOs after intravenous infusion, and are constitutively low expression of ICAM-1. So in our previous work, ICAM-1 was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (ICAM-1MSCs). Here, we hypothesized that ICAM-1highMSCs may significantly improve their immunomodulatory effect. METHODS: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate ICAM-1highMSCs immunomodulatory effect on dendritic cells (DCs) and T cells in vitro and in vivo. MSCs were labeled with carboxyfluorescein diacetate succinimidylester (CFSE) to detect its distribution in mouse model. RESULTS: Our in vitro analyses revealed ICAM-1 MSCs could suppress DCs maturation according to co-culture methods and suppress the T cell immune response according to the mixed lymphocyte response (MLR) and lymphoblast transformation test (LTT) tests. We found that infusion of ICAM-1highMSCs potently prolonged the survival of GVHD mouse model. The infused ICAM-1highMSCs migrate to SLOs in vivo, and suppressed DCs maturation, suppressed CD4+ T cell differentiation to Th1 cells, and increased the ratios of Treg cells. CONCLUSIONS: Taken together, these data demonstrate that ICAM-1highMSCs had an enhanced immunosuppressive effect on DCs and T cells, which may help explain the protective effect in a GVHD model. This exciting therapeutic strategy may improve the clinical efficacy of MSC-based therapy for GVHD.

Prognostic significance of glutathione peroxidase 2 in gastric carcinoma.

Increasing evidence suggests that the glutathione peroxidase 2 may actually play important roles in tumorigenesis and progression in various human cancers such as colorectal carcinomas and lung adenocarcinomas. However, the role of glutathione peroxidase 2 in gastric carcinoma remains to be determined. In this study, the expression and prognostic significance of glutathione peroxidase 2 in gastric carcinoma were investigated and the well-known prognostic factor Ki-67 labeling index was also assessed as positive control. Glutathione peroxidase 2 expression levels in the tumor tissue specimens, the matched adjacent normal tissue specimens, and the lymph node metastases of 176 patients with gastric carcinoma were evaluated by quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The associations between glutathione peroxidase 2 expression levels, as determined by immunohistochemical staining, and multiple clinicopathological characteristics were determined by Pearson's chi-square test and Spearman's correlation analysis. The relationships between glutathione peroxidase 2 expression and other clinicopathological variables and patient prognoses were analyzed further by the Kaplan-Meier method, the log-rank test, and Cox multivariate regression. The quantitative polymerase chain reaction, western blotting, and immunohistochemical staining results showed that glutathione peroxidase 2 expression levels were upregulated in both the primary tumor foci and the lymph node metastases of patients with gastric carcinoma (all p values < 0.05). Furthermore, Pearson's chi-square tests, as well as Spearman's correlation analysis, revealed that glutathione peroxidase 2 expression levels were strongly correlated with the Ki-67 labeling index, differentiation, histological patterns, Lauren classifications, lymph node metastasis, vascular invasion, tumor-node-metastasis stages, Helicobacter pylori infection, and overall survival (all p values < 0.05). Kaplan-Meier analysis, as well as the log-rank test and multivariate Cox regression analysis, showed that multiple clinicopathological risk factors and glutathione peroxidase 2 expression were novel independent prognostic factors for gastric carcinoma (all p values < 0.05). Glutathione peroxidase 2 expression is a novel independent prognostic biomarker for gastric carcinoma that may be used to devise personalized therapeutic regimens and precision treatments for this disease.

Epileptic seizures in nonalcoholic Wernicke's encephalopathy: a case report and literature review.

Wernicke encephalopathy (WE) is characterized by eye signs, cerebellar dysfunction, and confusion. Epileptic seizures are rare in nonalcoholic WE. We reviewed the clinical, laboratory, radiological, and prognostic characteristics of nonalcoholic WE accompanied by epileptic seizures. We reported 1 case and searched similar cases using PubMed, WoK, Ovid, and Embase. WE was diagnosed according to dietary deficiencies, clinical symptoms and brain magnetic resonance imaging (MRI). We reviewed 13 patients (median age, 27 years; 5 men) with clear histories of thiamine deficiency and symptoms of typical WE. The type of epileptic seizures reported in the 13 cases reviewed was generically reported as seizures or convulsions in 4 patients; 7 patients had generalized tonic-clonic seizures, 1 partial seizure, and 1 generalized convulsive status epileptics. Two patients had epileptic seizures as the first symptom of WE. Laboratory tests mainly indicated metabolic acidosis and electrolyte disturbances. Electroencephalography may present as normal patterns, increased slow waves or epileptic discharge. Six patients had cortical lesions on brain MRI. These lesions were usually diffuse and band-like, and sometimes involved all lobes either symmetrically or asymmetrically, with the frontal lobe as the most susceptible area. All cortical lesions were accompanied by non-cortical lesions typical of WE. Brain MRI abnormalities, after thiamine treatment, mostly disappeared on follow-up MRIs. The patients had good prognoses. Only 1 patient had repeated seizures, and there were no comas or deaths. Patients with nonalcoholic WE accompanied by seizures are young and generally have good prognoses. Most patients experienced generalized convulsive seizures, which may have been related to abnormal cerebral cortical metabolism due to subacute thiamine deficiency.

[Effects of virtual reality training on limb movement in children with spastic diplegia cerebral palsy].

OBJECTIVE: To study the effects of virtual reality (VR) training on the gross motor function of the lower limb and the fine motor function of the upper limb in children with spastic diplegia cerebral palsy. METHODS: Thirty-five children with spastic diplegia cerebral palsy were randomly assigned to VR training group (n=19) and conventional training group (n=16). The conventional training group received conventional physical therapy and occupational therapy for three months. The VR training group received VR training and occupational therapy for three months. Grip and visual-motor integration subtests in Peabody Developmental Motor Scales-2 were used to evaluate the fine movement in patients before and after treatment. The D and E domains of the 88-item version of the Gross Motor Function Measure (GMFM-88), Modified Ashworth Scale (MAS), and Berg Balance Scale (BBS) were used to evaluate the gross movement in patients before and after treatment. RESULTS: Before treatment, there were no significant differences in grip, visual-motor integration, fine motor development quotient, scores of D and E domains of GMFM-88, MAS score, or BBS score between the two groups (P>0.05). After treatment, all the indices were significantly improved in the VR training group compared with the conventional training group (P<0.05). CONCLUSIONS: VR training can effectively improve the gross motor function of the lower limb and the fine motor function of the upper limb in children with spastic diplegia cerebral palsy.

Targeting the NLRP3 inflammasome in psoriasis.

The NLRP3 inflammasome, a complex consisting of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3, has emerged as a critical mediator of pathological inflammation and a significant therapeutic target for various inflammatory diseases. Psoriasis, a chronic inflammatory skin condition without a definitive cure, has shown promising results in animal models through the inhibition of the NLRP3 inflammasome. This review aims to explore the development of the NLRP3 inflammasome in psoriasis and the molecular mechanisms responsible for its inhibition by natural products and small molecules currently being developed for psoriasis treatment. Furthermore, we are examining clinical trials using agents that block the NLRP3 pathway for the treatment of psoriasis. This study is timely to provide a new perspective on managing psoriasis.

Development and verification of a newly established cuproptosis-associated lncRNA model for predicting overall survival in uterine corpus endometrial carcinoma.

Background: Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecologic malignant tumor with high recurrence and mortality rates. This study aimed to develop and validate a prognostic model for patients with UCEC based on cuproptosis-related long non-coding RNA (lncRNA) signature. Methods: Transcriptome and clinical UCEC data were obtained from The Cancer Genome Atlas (TCGA) database. Correlation analysis was conducted to screen out the cuproptosis-related lncRNAs, and univariate regression analysis was performed to determine prognostic factors associated with overall survival (OS). A cuproptosis-related lncRNA risk model was constructed through least absolute shrinkage and selection operator (LASSO) regression and cross-validation. The accuracy and reliability of the model were verified through Kaplan-Meier (KM), proportional hazards model (Cox) regression, nomogram, principal component analysis (PCA), and stage analysis. Gene Ontology (GO) enrichment, immune function, and tumor mutation burden (TMB) analyses were conducted between low-risk and high-risk groups, and antineoplastic drugs were predicted. Results: By correlation analysis, 155 cuproptosis-related lncRNAs were acquired, and 9 lncRNAs were identified as independent prognostic factors. A 6-cuproptosis-related lncRNA model was established. The results revealed that patients in the high-risk group were more inclined to have a poor OS than those in the low-risk group. Risk score was an independent prognostic factor and had a high accuracy and predictive value. The extracellular structure and anchored components of membrane-related GO terms were significantly enriched. Immune function and TMB results were assumed to be different from each other, which might explain a better outcome in the low-risk group than that in the high-risk group. Eighteen compounds were predicted as chemotherapy drugs with high half maximal inhibitory concentration (IC50) in the high-risk group. Conclusions: We successfully developed a cuproptosis-related lncRNA risk model for the prediction of prognosis, while simultaneously providing insights on new approaches for immunotherapy and chemotherapy for patients with UCEC.

Comparative proteomic analysis of the mitochondria of menstrual stem cells and ovarian cancer cells.

Mitochondrial transplantation is a popular field of research in cell-free therapy. Menstrual stem cells (MenSCs) are potential donor cells for provision of foreign mitochondria. The present study aimed to investigate the potential effects of MenSC-derived mitochondria on ovarian cancer from the perspective of protein expression profiling. MenSCs were harvested from menstrual blood. The mitochondria were isolated from MenSCs and ovarian cancer cell line SKOV3. A label-free mitochondria proteomics and analysis were performed by comparing the protein expression in mitochondria of MenSCs and SKOV3 cells. The differentially expressed proteins with fold-change >2 were analyzed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein domain enrichment, protein interaction networks and parallel reaction monitoring (PRM) analysis. In total, 592 proteins that were found to have increased expression in the mitochondria of MenSCs were analyzed. Functional enrichment analysis revealed these proteins were enriched in metabolism-associated pathway entries including 'oxidative phosphorylation' (OXPHOS) pathway. PRM analysis confirmed that four of 6 candidate proteins in the OXPHOS pathway showed similar increasing trends. The protein domain enrichment analysis showed that domains such as 'thioredoxin domain' were significantly enriched. Based on these findings, it was hypothesized that mitochondria from MenSCs have the potential to enhance progression of ovarian cancer likely mediated by the enrichment of OXPHOS-associated metabolic pathways.

Identification of the Active Compound of Liu Wei Di Huang Wan for Treatment of Gestational Diabetes Mellitus via Network Pharmacology and Molecular Docking.

Liu Wei Di Huang Wan (LWDHW) is a well-known Chinese herbal compound, which has been prescribed for the treatment of gestational diabetes mellitus (GDM). We sought to clarify the potential therapeutic effects of LWDHW against GDM. Differentially expressed genes (DEGs) in GDM were firstly identified from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to reveal the biological functions of the DEGs. Subsequently, the LWDHW-compound-target network was constructed based on public databases to identify the relationship between the active components in LWDHW and the corresponding targets. Furthermore, gene functional analysis and protein-protein interaction (PPI) network construction were applied to investigate the function of potential targets and to evaluate hub genes. Finally, molecular docking was used to verify the binding activities between active ingredients and hub targets. Thirteen active components and 39 corresponding therapeutic target genes were obtained via network pharmacology analysis. The enrichment analysis demonstrated that the anti-GDM effect of LWDHW included oxidoreductase activity, involvement in renal system process, and regulation of blood pressure, which may be achieved through regulation of serotonergic synapses, vascular smooth muscle contraction, and neuroactive ligand-receptor interaction pathways. Additionally, molecular docking revealed that the main active component, Mu Dan Pi, exhibited the best affinity for proteins encoded by hub genes. This study applied network pharmacology analysis and molecular docking to display the multicomponent and multitarget characteristics of LWDHW in the treatment of GDM. Our findings provide novel insights into the pathogenesis of GDM and the therapeutic mechanisms of LWDHW against GDM.

Expression and prognostic analysis of BGN in head and neck squamous cell carcinoma.

OBJECTIVE: BGN belongs to class of small leucine rich proteoglycans, which is high expression in plenty of human cancers. However, the detailed role of BGN remains unclear in Head and neck squamous cell carcinoma (HNSC). MATERIALS AND METHODS: In this study, we assessed the transcriptional expression, protein expression, prognosis, co-expressed genes, functional enrichment, and hub genes in HNSC patients based on the data published in the following databases: ONCOMINE, GEPIA, GEO, LinkedOmics, and HPA databases. Data from the TCGA database was used to analyze the correlations between BGN expression and different clinicopathological features, as well as prognostic analysis. RESULTS: We found that the expression of BGN is higher in patients with HNSC than in control tissues. Pathologically, high BGN expression was significantly correlated with T3 and T4 stage. Besides, high expression of BGN is a poor prognostic factor for overall surviva, not disease free survival. The co-expression genes associated with BGN expression exhibited enriched in various function and pathway, such as extracellular matrix, mitochondrion, PI3K-Akt signaling pathway. A total of 10 hub genes were identified from the co-expressed genes, within which five genes, including FSTL1, LAMB1, SDC2, VCAN, and IGFBP7, were significantly increased in patient's with HNSC. BGN exhibited weak correlations with tumor-infiltrating CD4+ T, macrophages cell, and dendritic cells. Futhermore, many markers of infiltrating immune cells, such as Treg, showed different BGN-related immune infiltration patterns. BGN expression showed strong correlations with diverse immune marker sets in COAD and STAD. CONCLUSIONS: Our results demonstrated that BGN is high expression in HNSC and is a poor prognostic factor for clinical outcome in patients with HNSC. It could serve as a potential prognostic biomarker for patients survival in HNSC.

Ciclopirox inhibits NLRP3 inflammasome activation via protecting mitochondria and ameliorates imiquimod-induced psoriatic inflammation in mice.

The maturation and secretion of interleukin-1ß (IL-1ß) mediated by NLRP3 inflammasome activation plays an important role in the progression of many inflammatory diseases. Inhibition of NLRP3 inflammasome activation may be a promising strategy to treat these inflammation-driven diseases, such as psoriasis. As a broad-spectrum antifungal agent, ciclopirox (CPX) is widely used in the treatment of dermatomycosis. Although CPX has been reported to have anti-inflammatory effects in many studies, there has been little research into its underlying mechanisms. In our study, CPX reduced lipopolysaccharide (LPS)/nigericin-induced NLRP3 inflammasome activation (IC50: 1.684 µM). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-γ coactivator-1α expression (by 82.7% at 5 µM and 87.5% at 10 µM) to protect mitochondria. Our studies showed that CPX reduced mitochondrial reactive oxygen species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level. Furthermore, treatment with CPX promoted the up-regulation of mRNA expression, which involved mitochondrial biosynthesis (NRF1, NRF2, TFAM) and antioxidation (SOD1 and CAT). In addition, CPX ameliorated inflammatory response in imiquimod-induced psoriasis mice. This study provides a potential pharmacological mechanism for CPX to treat psoriasis and other NLRP3-driven inflammatory diseases.

Bortezomib inhibits NLRP3 inflammasome activation and NF-κB pathway to reduce psoriatic inflammation.

The abnormal activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the pathogenesis of psoriasis. Accordingly, the inhibition of NLRP3 inflammasome may be an effective strategy for psoriasis treatment. However, the NLRP3 inflammasome inhibitors are not available in the clinic. Repurposing FDA-approved drugs is a highly attractive way for identifying new drugs. Here, proteasome inhibitor bortezomib, a marketed drug for treating multiple myeloma, was found to specifically inhibit NLRP3 inflammasome activation at nanomolar concentrations. Mechanistically, bortezomib did not inhibit reactive oxygen species generation, ion efflux, NLRP3 oligomerization, and NLRP3-ASC interactions. Bortezomib reduced ASC oligomerization and ASC speck formation. In addition, bortezomib inhibited the activity of the core subunit ß5i in the immunoproteasome and reduced ß5i binding to NLRP3. Bortezomib reduced the production of interleukin-1ß and attenuated the severity of skin lesions in the imiquimod-induced psoriatic mouse model. Thus, bortezomib is a potential therapeutic drug for psoriasis. Our study also revealed that ß5i may be an indirect target for regulating NLRP3 inflammasome activation and treating psoriasis and other NLRP3 inflammasome-related diseases.

Artemisinin-derived artemisitene blocks ROS-mediated NLRP3 inflammasome and alleviates ulcerative colitis.

Artemisinins are well-known antimalarial drugs with clinical safety. In addition to antimalarial effects, their anti-inflammatory and immunoregulatory properties have recently attracted much attention in the treatment of inflammatory diseases. However, these artemisinins only have sub-millimolar anti-inflammatory activity in vitro, which may pose a high risk of toxicity in vivo with high doses of artemisinins. Here, we identified another derivative, artemisitene, which can increase the activity of inhibiting the NLRP3 pathway by more than 200-fold through introducing a covalent binding group while retaining the peroxide bridge structure. Mechanistically, artemisitene inhibits the production of ROS (especially mtROS) and prevents the assembly and activation of NLRP3 inflammasome, thereby inhibiting IL-1ß production. In addition, it can also block IL-1ß secretion mediated by NLRC4 and AIM2 inflammasome and IL-6 production. Furthermore, treatment with artemisitene significantly attenuated inflammatory response in DSS-induced ulcerative colitis. Our work provides a potential artemisinin derivative, which is worthy of further structural optimization based on pharmacokinetic properties as a drug candidate for inflammatory disorders.

Chlorquinaldol inhibits the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome and ameliorates imiquimod-induced psoriasis-like dermatitis in mice.

Psoriasis is a common chronic autoinflammatory/autoimmune skin disease associated with elevated pro-inflammatory cytokines. The pivotal role of interleukin (IL)-1ß and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of psoriasis has been widely described. Accordingly, the suppression of NLRP3-dependent IL-1ß release is a potential therapy for psoriasis. Repurposing marketed drugs is a strategy for identifying new inhibitors of NLRP3 inflammasome activation. Herein, chlorquinaldol (CQD), a historic antimicrobial agent used as a topical treatment for skin and vaginal infections, was found to have a distinct effect by inhibiting NLRP3 inflammasome activation at concentrations ranging from 2 to 6 µM. CQD significantly suppressed apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) oligomerization, NLRP3-ASC interaction, and pyroptosis in macrophages. The levels of cleaved IL-1ß and caspase-1 were reduced by CQD in the cell lysates of macrophages, suggesting that CQD acted on upstream of pore formation in the cell membrane. Mechanistically, CQD reduced mitochondrial reactive oxygen species production but did not affect the nuclear factor-κB (NF-κB) pathway. Intraperitoneal administration of CQD (15 mg/kg) for 6 days was found to improve the skin lesions in the imiquimod-induced psoriatic mouse model (male C57BL/6 mice), while secretion of pro-inflammatory cytokines (IL-17 and IL-1ß) and keratinocyte proliferation were significantly suppressed by CQD. In conclusion, CQD exerted inhibitory effects on NLRP3 inflammasome activation in macrophages and decreased the severity of psoriatic response in vivo. Such findings indicate that the repurposing of the old drug, CQD, is a potential pharmacological approach for the treatment of psoriasis and other NLRP3-driven diseases.

Endothelial p130cas confers resistance to anti-angiogenesis therapy.

Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.