Design, synthesis and biological evaluation of tanshinone IIA derivatives as NLRP3 inflammasome inhibitors.

Natural product structures have long provided valuable pharmacophores and even candidates for drug discovery. Tanshinone scaffold showed moderately inhibitory activity in NLRP3 inflammasome/IL-1ß pathway. Herein, we designed a series of derivatives on different regions of Tanshinone IIA (TNA) scaffold. The biological evaluation identified compound T10, a scaffold hybrid of TNA and salicylic acid, as a potent NLRP3 inflammasome inhibitor. Mechanistically, T10 inhibits the production of ROS and prevents NLRP3 inflammasome-dependent IL-1ß production. In addition, treatment with T10 significantly attenuated inflammatory response in DSS-induced peritonitis. Our work describes a potential tanshinone-based derivative, which needs to be further structurally optimized as NLRP3 inflammasome inhibitors for treating inflammatory disorders.

Discovery of a selective NLRP3-targeting compound with therapeutic activity in MSU-induced peritonitis and DSS-induced acute intestinal inflammation.

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is known to contribute to the pathogenesis of various human inflammation-related diseases. However, to date, no small-molecule NLRP3 inhibitor has been used in clinical settings. In this study, we have identified SB-222200 as a novel direct NLRP3 inhibitor through the use of drug affinity responsive target stability assay, cellular thermal shift assay, and surface plasmon resonance analysis. SB-222200 effectively inhibits the activation of the NLRP3 inflammasome in macrophages, while having no impact on the activation of NLRC4 or AIM2 inflammasome. Furthermore, SB-222200 directly binds to the NLRP3 protein, inhibiting NLRP3 inflammasome assembly by blocking the NEK7 - NLRP3 interaction and NLRP3 oligomerization. Importantly, treatment with SB-222200 demonstrates alleviation of NLRP3-dependent inflammatory diseases in mouse models, such as monosodium urate crystal-induced peritonitis and dextran sulfate sodium-induced acute intestinal inflammation. Therefore, SB-222200 holds promise as a lead compound for the development of NLRP3 inhibitors to combat NLRP3-driven disease and serves as a versatile tool for pharmacologically investigating NLRP3 biology.

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.

Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent.

Targeting the SMAD3 protein is an attractive therapeutic strategy for treating cancer, as it avoids the potential toxicities due to targeting the TGF-ß signaling pathway upstream. Compound SIS3 was the first selective SMAD3 inhibitor developed that had acceptable activity, but its poor water solubility limited its development. Here, a series of SIS3 analogs was created to investigate the structure-activity relationship for inhibiting the activation of SMAD3. On the basis of this SAR, further optimization generated a water-soluble compound, 16d, which was capable of effectively blocking SMAD3 activation in vitro and had similar NK cell-mediated anticancer effects in vivo to its parent SIS3. This study not only provided a preferable lead compound, 16d, for further drug discovery or a potential tool to study SMAD3 biology, but also proved the effectiveness of our strategy for water-solubility driven optimization.

Synthesis and biological evaluation of parthenolide derivatives with reduced toxicity as potential inhibitors of the NLRP3 inflammasome.

Parthenolide (PTL) can target NLRP3 inflammasome to treat inflammation and its related disease, but its cytotoxicity limits further development as an anti-inflammatory drug. A series of PTL analogs and their Michael-type adducts were designed and synthesized, and most of them showed high activities against the NLRP3 inflammasome pathway. The most potent compound 8b inhibited the release of IL-1ß with IC50 values of 0.3 µM in J774A.1 cell and 1.0 µM in primary glial cells, respectively. Moreover, 8b showed low toxicity against J774A.1 cell (IC50 = 24.1 µM) and HEK-293T (IC50 = 69.8 µM) with a ~8 folds increase of therapeutic index compared to its parent PTL. The preliminary mechanism study revealed that 8b mediated anti-inflammation is associated with the NLRP3 inflammasome signal pathway. Based on these investigations, we propose that 8b might be a potential drug candidate for ultimate development of the anti-inflammation drug.

Synthesis and biological evaluation of dithiocarbamate esters of parthenolide as potential anti-acute myelogenous leukaemia agents.

A series of dithiocarbamate esters of parthenolide (PTL) was designed, synthesised, and evaluated for their anti- acute myelogenous leukaemia (AML) activities. The most promising compound 7l showed greatly improved potency against AML progenitor cell line KG1a with IC50 value of 0.7 µM, and the efficacy was 8.7-folds comparing to that of PTL (IC50 = 6.1 µM). Compound 7l induced apoptosis of total primary human AML cells and leukaemia stem cell (LSCs) of primary AML cells while sparing normal cells. Furthermore, 7l suppressed the colony formation of primary human leukaemia cells. Moreover, compound 12, the salt form of 7l, prolonged the lifespan of mice in two patient-derived xenograft models and had no observable toxicity. The preliminary molecular mechanism study revealed that 7l-mediated apoptosis is associated with mitogen-activated protein kinase signal pathway. On the basis of these investigations, we propose that 12 might be a promising drug candidate for ultimate discovery of anti-LSCs drug.

Hyperbaric oxygen therapy modulates serum OPG/RANKL in femoral head necrosis patients.

Hyperbaric oxygen therapy (HBOT) has beneficial effects on avascular necrosis of femoral head (ANFH), but its mechanism of action is still unclear. We investigated if HBOT upregulates serum osteoprotegerin (OPG) and/or inhibits osteoclast activation. 23 patients with unilateral ANFH at stage I, II and III consented to the study: the patients received standard HBOT. Serum OPG levels were obtained at the beginning of HBOT (T0), after 15 sessions (T1), 30 sessions (T2), after a 30-day break (T3), and after 60 sessions (T4). Magnetic resonance imaging (MRI) was obtained at T0 and about one year from the end of HBO treatments. Lesion size was compared between pre- and post-HBOT. 19 patients completed the study. HBOT reduced pain symptoms in all patients. HBOT significantly reduced lesion size in all stage I and II patients and in 2 of 11 stage III patients. HBOT increased serum OPG levels but receptor activator of nuclear factor kappa-B ligand (RANKL) levels did not change.

Effects of oxygen concentration and pressure on Drosophila melanogaster: oxidative stress, mitochondrial activity, and survivorship.

Organisms are known to be equipped with an adaptive plasticity as the phenotype of traits in response to the imposed environmental challenges as they grow and develop. In this study, the effects of extreme changes in oxygen availability and atmospheric pressure on physiological phenotypes of Drosophila melanogaster were investigated to explore adaptation mechanisms. The changes in citrate synthase activity (CSA), lifespan, and behavioral function in different atmospheric conditions were evaluated. In the CAS test, hyperoxia significantly increased CSA; both hypoxia and hyperbaric conditions caused a significant decrease in CSA. In the survivorship test, all changed atmospheric conditions caused a significant reduction in lifespan. The lifespan reduced more after hypoxia exposure than after hyperbaria exposure. In behavioral function test, when mechanical agitation was conducted, bang-sensitive flies showed a stereotypical sequence of initial muscle spasm, paralysis, and recovery. The percentage of individuals that displayed paralysis or seizure was measured on the following day and after 2 weeks from each exposure. The majority of flies showed seizure behavior 15 days after exposure, especially after 3 h of exposure. The percentage of individuals that did not undergo paralysis or seizure and was able to move in the vial, was also tested. The number of flies that moved and raised the higher level of the vial decreased after exposure. Animal's speed decreased significantly 15 days after exposure to extreme environmental conditions. In summary, the alteration of oxygen availability and atmospheric pressure may lead to significant changes in mitochondria mass, lifespan, and behavioral function in D. melanogaster.

Effects of alpha lipoic acid and its R+ enantiomer supplemented to hyperbaric oxygen therapy on interleukin-6, TNF-α and EGF production in chronic leg wound healing.

CONTEXT: Lipoic acid (LA) and hyperbaric oxygenation therapy (HBOT) improve chronic wound healing. OBJECTIVE: We compared the effects of LA or its enantiomer R-(+)-lipoic acid (RLA) on wound healing. MATERIALS AND METHODS: Groups LA + HBOT (L), RLA + HBOT (R) and placebo + HBOT (P). Lesion areas measured before treatment and on 20th and 40th day. The biopsies and plasma were harvested before treatment and on 7th and 14th (measurements of VEGF, vascular endothelial growth factor; EGF, epidermal growth factor, TNF-α and IL-6). RESULTS: Ulcers improved more on RLA. In both L and R groups, EGF and VEFG increased in time. RLA decreased IL-6 on T7 and T14, which did not happen with LA. TNF-α levels decreased on T14 in both LA and RLA. DISCUSSION: The improved wound healing is associated with increased EGF and VEGF and reduced plasma TNF-α and IL-6. CONCLUSION: RLA may be more effective than LA in improving chronic wound healing in patients undergoing HBO therapy.

Risk factors for delayed extubation in thoracic and lumbar spine surgery: a retrospective analysis of 135 patients.

PURPOSE: Extubation may be delayed after spine surgery mainly for the concerns of airway safety. Risk factors for delayed extubation in cervical spine surgery have been described to include prolonged surgery time and amount of crystalloids or blood transfused. To date, risk factors for delayed extubation in thoracic or lumbar spine surgery have not been investigated. We retrospectively reviewed 135 consecutive patients from 2006 to 2009 who underwent thoracic or lumbar spine surgery by one particular surgeon to identify risk factors for delayed extubation. METHODS: Data including patient factors, surgical time, anesthetic technique, blood loss, crystalloid and colloid administration, transfusion requirements, time to transfusion, and time to extubation were collected and analyzed. Delayed extubation was defined as the patient was not extubated in the operating room at completion of the surgery. RESULTS: One hundred and eight patients were extubated in the OR. Delayed extubation occurred in 27 patients. Delayed extubation was significantly related to total operative time (6.6 ± 0.4 vs. 5.2 ± 0.1 h), volume of crystalloid replacement (6,018 ± 408 vs. 4,186 ± 130 cm3), volume of total colloids infused (787 ± 93 vs. 442 ± 36 cm3), intraoperative blood transfused (3.7 ± 0.5 vs. 0.7 ± 0.1 units); blood loss (2,137 ± 286 vs. 832 ± 50 cm3), and time to starting blood transfusion (106 ± 12 vs. 199 ± 9 min). CONCLUSIONS: Our study suggests that intraoperative factors including prolonged surgical time, significant blood loss, larger volume of crystalloid and colloid infusion, and blood transfusion may be risk factors for delayed extubation following thoracic or lumbar spine surgery. Early blood transfusion may also increase the risk of delayed extubation. Patient factors did not affect extubation time.

Antagonizing interleukin-5 receptor ameliorates dextran sulfate sodium-induced experimental colitis in mice through reducing NLRP3 inflammasome activation.

Inflammatory bowel disease (IBD) is a condition characterized by inflammation in the gastrointestinal tract. Reducing intestinal inflammation is a promising approach for treating IBD. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, a critical component of the innate immune system, is implicated in the pathogenesis of IBD. Therefore, inhibiting NLRP3 inflammasome activation is a potential therapeutic strategy for IBD. In this study, we investigated the effects of the interleukin-5 (IL-5) receptor antagonist YM-90709 on dextran sulfate sodium-induced experimental colitis in mice. We found that YM-90709 reduced the expressions of IL-1ß and caspase-1 p20 in the colon and ameliorated colitis. Furthermore, we identified YM-90709 as an effective agent for inhibiting NLRP3 inflammasome activation. Knockdown of IL-5 receptor or using an inhibitor of STAT5, a key transcription factor downstream of the IL-5/IL-5 receptor signal pathway, also reduced NLRP3 inflammasome-dependent IL-1ß release and ASC speck formation. Our study is the first to demonstrate that the NLRP3 inflammasome may be a downstream signal of IL-5/IL-5 receptor and that YM-90709 protects against IBD by inhibiting IL-5 receptor. These findings suggest a new strategy for regulating intestinal inflammation and managing IBD.

Discovery of a dual-acting inhibitor of interleukin-1ß and STATs for the treatment of inflammatory bowel disease.

Currently, a significant proportion of inflammatory bowel disease (IBD) patients fail to respond to conventional drug therapy such as immunosuppressants and biologic agents. Interference with the JAK/STAT pathway and blocking of IL-1 signaling are two promising therapeutic strategies for these unresponsive IBD patients. This work describes the discovery of an inhibitor 10v that not only blocks NLRP3 and AIM-2 inflammasome-mediated IL-1ß signaling, but also reduces the expression of STAT1 and STAT5 in the JAK/STAT pathway. Importantly, 10v exhibits a significant anti-IL-1ß effect and decreases the levels of STAT1 and STAT5 in a mouse model of colitis. As a result, a novel small molecule is identified with a dual inhibitory capacity towards both inflammasomes/IL-1ß and STAT pathways, which supports further exploration of the therapeutic potential for IBD patients that do not respond to current drug therapy.

Chlorquinaldol Alleviates Lung Fibrosis in Mice by Inhibiting Fibroblast Activation through Targeting Methionine Synthase Reductase.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Thus, it is essential to investigate potential druggable targets to improve IPF treatment outcomes. By screening a curated library of 201 small molecules, we have identified chlorquinaldol, a known antimicrobial drug, as a potential antifibrotic agent. Functional analyses have demonstrated that chlorquinaldol effectively inhibits the transition of fibroblasts to myofibroblasts in vitro and mitigates bleomycin-induced pulmonary fibrosis in mice. Using a mass spectrometry-based drug affinity responsive target stability strategy, we revealed that chlorquinaldol inhibited fibroblast activation by directly targeting methionine synthase reductase (MTRR). Decreased MTRR expression was associated with IPF patients, and its reduced expression in vitro promoted extracellular matrix deposition. Mechanistically, chlorquinaldol bound to the valine residue (Val-467) in MTRR, activating the MTRR-mediated methionine cycle. This led to increased production of methionine and s-adenosylmethionine, counteracting the fibrotic effect. In conclusion, our findings suggest that chlorquinaldol may serve as a novel antifibrotic medication, with MTRR-mediated methionine metabolism playing a critical role in IPF development. Therefore, targeting MTRR holds promise as a therapeutic strategy for pulmonary fibrosis.

Artemisitene shows superiority over artemisinin in preventing Schistosoma japonica-induced liver disease.

BACKGROUND: Artemisinin (ART) analogs, such as dihydroartemisinin, arteether, artemether, and artesunate, all featuring an endoperoxide bridge, have demonstrated efficacy against schistosomiasis. Artemisitene (ATT), which contains an additional α, ß-unsaturated carbonyl structure, has shown enhanced biological activities. This study aims to evaluate the anti-schistosomaiasis japonica activity of ATT and compare it with ART. METHODS: We assessed liver inflammation and fibrosis in mice using hematoxylin and eosin staining and Sirius red staining, respectively. RNA sequencing analyzed transcriptomics in female and male Schistosoma japonicum (S. japonicum) adult worms and mice livers, with cytokine profiling and flow cytometry to study immune responses under ART or ATT treatment. RESULTS: ATT exhibits a marked reduction in female S. japonicum adult worms and egg numbers, damaging the adult worms' surface. It also influences the transcription of genes related to cellular anatomical structures. Notably, ATT treatment resulted in significant reductions in liver granuloma size and collagen area, alongside lowering serum levels of glutamic pyruvic and glutamic oxaloacetic transaminase more effectively than ART. Both ART and ATT markedly decreased neutrophil frequency in the liver and elevated eosinophil counts. However, only ATT treatment significantly reduced the M1/M2 and Th1/Th2 indices, indicating a pronounced shift in immune response profiles. ATT-affected host immunity correlated with the extent of liver fibrosis and the count of single males more strongly than ART. CONCLUSION: ATT, as a novel preventive strategy for schistosomiasis japonica in mice, significantly outperforms ART.

Seratrodast, a thromboxane A2 receptor antagonist, inhibits neuronal ferroptosis by promoting GPX4 expression and suppressing JNK phosphorylation.

More than 30 % of individuals with epilepsy are refractory to currently available drugs, highlighting the urgent need to develop novel candidate drugs. Accumulating evidence implicates the key role of ferroptosis in the pathophysiology of epileptic seizuresand its potential as a new drug target. Drug repurposing is a promising strategy for the rapid generation of new candidate drugs from the market drugs with new therapeutic indications, such as the best-selling drug thalidomide. Herein, we reported the discovery of Seratrodast, a market drug of thromboxane A2 receptor antagonist as a new ferroptosis inhibitor (IC50: 4.5 µmol·L-1). Seratrodast could reduce lipid ROS production, regulate the system xc-/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, and inhibit JNK phosphorylation and p53 expression. In addition, Seratrodast elevated GPX4 expression and decreased JNK phosphorylation in pentylenetetrazole-induced seizures in mice. Seratrodast increased the latency of seizures and reduced seizure duration in pentylenetetrazole-induced seizures. Our results suggest Seratrodast might be either a ferroptosis inhibitor or a novel lead compound for further optimization of novel drug discovery.

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.

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.

Discovery of a Novel Oral Proteasome Inhibitor to Block NLRP3 Inflammasome Activation with Anti-inflammation Activity.

NLRP3 inflammasome activation plays a critical role in inflammation-related disorders. More small-molecule entities are needed to study the mechanism of NLRP3 inflammasome activation and to validate the efficacy and safety of the NLRP3 pathway. Herein, we report the discovery of an orally bioavailable proteasome inhibitor NIC-0102 (27) that specifically prevents NLRP3 inflammasome activation but has no effect on NLRC4 or AIM2 inflammasomes. In vitro studies revealed that NIC-0102 induced the polyubiquitination of NLRP3, interfered with the NLRP3-ASC interaction, and blocked ASC oligomerization, thereby resulting in the inhibition of NLRP3 inflammasome activation. In addition, NIC-0102 also inhibited the production of pro-IL-1ß. Importantly, NIC-0102 showed potent anti-inflammatory effects on DSS-induced ulcerative colitis model in vivo. As a result of these studies, a potential small molecule is identified to demonstrate the possible link between the proteasome and NLRP3 pathway, which supports further exploration of potentially druggable nodes to modulate NLRP3 inflammasome activation.

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.

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.