Regulating Sulfur Redox Kinetics by Coupling Photocatalysis for High-Performance Photo-Assisted Lithium-Sulfur Batteries.

Challenges such as shuttle effect have hindered the commercialization of lithium-sulfur batteries (LSBs), despite their potential as high-energy-density storage devices. To address these issues, we explore the integration of solar energy into LSBs, creating a photo-assisted lithium-sulfur battery (PA-LSB). The PA-LSB provides a novel and sustainable solution by coupling the photocatalytic effect to accelerate sulfur redox reactions. Herein, a perovskite quantum dot-loaded MOF material serves as a cathode for the PA-LSB, creating built-in electric fields at the micro-interface to extend the lifetime of photo-generated charge carriers. The band structure of the composite material aligns well with the electrochemical reaction potential of lithium-sulfur, enabling precise regulation of polysulfides in the cathode of the PA-LSB system. This is attributed to the selective catalysis of the liquid-solid reaction stage in the lithium-sulfur electrochemical process by photocatalysis. These contribute to the outstanding performance of PA-LSBs, particularly demonstrating a remarkably high reversible capacity of 679 mAh g-1 at 5 C, maintaining stable cycling for 1500 cycles with the capacity decay rate of 0.022 % per cycle. Additionally, the photo-charging capability of the PA-LSB holds the potential to compensate for non-electric energy losses during the energy storage process, contributing to the development of lossless energy storage devices.

[Preliminary Study on the Identification of Aerobic Vaginitis by Artificial Intelligence Analysis System]. / 人工智能分析系统对需氧菌性阴道炎的判读方法初探.

Objective: To develop an artificial intelligence vaginal secretion analysis system based on deep learning and to evaluate the accuracy of automated microscopy in the clinical diagnosis of aerobic vaginitis (AV). Methods: In this study, the vaginal secretion samples of 3769 patients receiving treatment at the Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University between January 2020 and December 2021 were selected. Using the results of manual microscopy as the control, we developed the linear kernel SVM algorithm, an artificial intelligence (AI) automated analysis software, with Python Scikit-learn script. The AI automated analysis software could identify leucocytes with toxic appearance and parabasal epitheliocytes (PBC). The bacterial grading parameters were reset using standard strains of lactobacillus and AV common isolates. The receiver operating characteristic (ROC) curve analysis was used to determine the cut-off value of AV evaluation results for different scoring items were obtained by using the results of manual microscopy as the control. Then, the parameters of automatic AV identification were determined and the automatic AV analysis scoring method was initially established. Results: A total of 3769 vaginal secretion samples were collected. The AI automated analysis system incorporated five parameters and each parameter incorporated three severity scoring levels. We selected 1.5 µm as the cut-off value for the diameter between Lactobacillus and common AV bacterial isolates. The automated identification parameter of Lactobacillus was the ratio of bacteria ≥1.5 µm to those <1.5 µm. The cut-off scores were 2.5 and 0.5, In the parameter of white blood cells (WBC), the cut-off value of the absolute number of WBC was 103 µL－1 and the cut-off value of WBC-to-epithelial cell ratio was 10. The automated identification parameter of toxic WBC was the ratio of toxic WBC toWBC and the cut-off values were 1% and 15%. The parameter of background flora was bacteria<1.5 µm and the cut-off values were 5×103 µL－1 and 3×104 µL－1. The parameter of the parabasal epitheliocytes was the ratio of PBC to epithelial cells and the cut-off values were 1% and 10%. The agreement rate between the results of automated microscopy and those of manual microscopy was 92.5%. Out of 200 samples, automated microscopy and manual microscopy produced consistent scores for 185 samples, while the results for 15 samples were inconsistent. Conclusion: We developed an AI recognition software for AV and established an automated vaginal secretion microscopy scoring system for AV. There was good overall concordance between automated microscopy and manual microscopy. The AI identification software for AV can complete clinical lab examination with rather high objectivity, sensitivity, and efficiency, markedly reducing the workload of manual microscopy.

Real-time tracking of electron transfer at catalytically active interfaces in lithium-ion batteries.

Transition metals and related compounds are known to exhibit high catalytic activities in various electrochemical reactions thanks to their intriguing electronic structures. What is lesser known is their unique role in storing and transferring electrons in battery electrodes which undergo additional solid-state conversion reactions and exhibit substantially large extra capacities. Here, a full dynamic picture depicting the generation and evolution of electrochemical interfaces in the presence of metallic nanoparticles is revealed in a model CoCO3/Li battery via an in situ magnetometry technique. Beyond the conventional reduction to a Li2CO3/Co mixture under battery operation, further decomposition of Li2CO3 is realized by releasing interfacially stored electrons from its adjacent Co nanoparticles, whose subtle variation in the electronic structure during this charge transfer process has been monitored in real time. The findings in this work may not only inspire future development of advanced electrode materials for next-generation energy storage devices but also open up opportunities in achieving in situ monitoring of important electrocatalytic processes in many energy conversion and storage systems.

Toward Simultaneous Dense Zinc Deposition and Broken Side-Reaction Loops in the Zn//V2 O5 System.

The Zn//V2 O5 system not only faces the incontrollable growth of zinc (Zn) dendrites, but also withstands the cross-talk effect of by-products produced from the cathode side to the Zn anode, inducing interelectrode talk and aggravating battery failure. To tackle these issues, we construct a rapid Zn2+ -conducting hydrogel electrolyte (R-ZSO) to achieve Zn deposition modulation and side reaction inhibition in Zn//V2 O5 full cells. The polymer matrix and BN exhibit a robust anchoring effect on SO4 2- , accelerating Zn2+ migration and enabling dense Zn deposition behavior. Therefore, the Zn//Zn symmetric cells based on the R-ZSO electrolyte can operate stably for more than 1500 h, which is six times higher than that of cells employing the blank electrolyte. More importantly, the R-ZSO hydrogel electrolyte effectively decouples the cross-talk effects, thus breaking the infinite loop of side reactions. As a result, the Zn//V2 O5 cells using this modified hydrogel electrolyte demonstrate stable operation over 1,000 cycles, with a capacity loss rate of only 0.028 % per cycle. Our study provides a promising gel chemistry, which offers a valuable guide for the construction of high-performance and multifunctional aqueous Zn-ion batteries.

Giardiasis Combined with Sepsis and DIC in a Chinese Child from Ganzi Tibetan Autonomous Prefecture.

BACKGROUND: We reported a rare case of combined Giardiasis, sepsis, and DIC in a Tibetan Chinese male in this study. METHODS: Multiple fecal routine examinations, blood routine examination, blood culture, coagulation screening, and biochemical tests were done after August 1st, 2022. RESULTS: The child had intermittent diarrhea. Giardia cysts were found in his stool mounts. Sepsis, disseminated intravascular coagulation, fever with blood routine decreasing, low proteinemia, hyperlactemia and hypocalcemia were also found in this case. CONCLUSIONS: It is suggested that improving the resistance, immunity, and personal hygiene is particularly important for children from remote ethnic minority areas of China.

Analysis of Infectious Characteristics of Recurrent Vulvovaginal Candidiasis in Chengdu from 2018 to 2022.

BACKGROUND: The aim was to discover the infectivity characteristics of recurrent vulvovaginal candidiasis (RVVC) in Chengdu, Sichuan Province, and provide a reference for RVVC clinical diagnosis and treatment. METHODS: The clinical data of 500 patients with RVVC were retrospectively analyzed, including life history, clinical symptoms, combined gynecological diseases, age, and distribution of pathogenic fungi, and the in vitro drug sensitivity of isolated fungi to antifungal drugs was assessed. RESULTS: Among the 500 patients with RVVC, 486 (97.20%) had a sexual history, and the main clinical symptoms were vulva pruritus (394, 78.80%) and abnormal discharge (232, 46.40%). Common gynecological diseases were cervicitis (156 patients, 31.20%), human papillomavirus infection (130 patients, 26.00%), and coinfection with oth-er pathogens (127 patients, 25.40%). The high-incidence population was mainly concentrated in the 31 to 40-year-old age group, followed by the 20 to 30- and 41 to 50-year-old age groups. The number of patients gradually increased with time. Fungal culture was dominated by Candida albicans (69.80%), followed by Candida glabrata (28.40%), and Candida cerevisiae (0.60%). In vitro susceptibility testing showed that the highest drug resistance rate to antifungal drugs was to terbinafine (96.40%), followed by voriconazole (32.00%), fluconazole (26.40%), and itraconazole (17.40%), whereas the drug resistance rates to 5-fluorocytosine, caspofungin, amphotericin B, and micafungin were relatively low (1.80%, 0.60%, 0.40%, and 0.00%, respectively); the drug resistance rate to azoles gradually increased with age. CONCLUSIONS: The occurrence of RVVC is closely related to sexual history. The most common cases are in women of childbearing age aged 20 - 50. The main pathogen is C. albicans, and the resistance rate to common azole antifungal drugs is increasing over time.

Molecular recognition effect enabled by novel crown ether as macrocyclic host towards highly reversible Zn anode.

Aqueous Zn2+ ion batteries present notable advantages, including high abundance, low toxicity, and intrinsic nonflammability. However, they exhibit severe irreversibility due to uncontrolled dendrite growth and corrosion reactions, which limit their practical applications. Inspired by their distinct molecular recognition characteristics, supramolecular crown ethers featuring interior cavity sizes identical to the diameter of Zn2+ ions were screened as macrocyclic hosts to optimize the Zn2+ coordination environment, facilitating the suppression of the reactivity of H2O molecules and inducing the in-situ formation of organic-inorganic hybrid dual-protective interphase. The in-situ assembled interphase confers the system with an "ion-sieving" effect to repel H2O molecules and facilitate rapid Zn2+ transport, enabling the suppression of side reactions and uniform deposition of Zn2+ ions. Consequently, we were able to achieve dendrite-free Zn2+ plating/stripping at 98.4% Coulombic efficiency for approximately 300 cycles in Zn||Cu cell, steady charge-discharge for 1360 h in Zn||Zn symmetric cell, and improved cyclability of 70% retention for 200 cycles in Zn||LMO full cell, outlining a promising strategy to challenge lithium-ion batteries in low-cost, and large-scale applications.

Highly Reversible Zn Metal Anodes Enabled by Increased Nucleation Overpotential.

Dendrite formation severely compromises further development of zinc ion batteries. Increasing the nucleation overpotential plays a crucial role in achieving uniform deposition of metal ions. However, this strategy has not yet attracted enough attention from researchers to our knowledge. Here, we propose that thermodynamic nucleation overpotential of Zn deposition can be boosted through complexing agent and select sodium L-tartrate (Na-L) as example. Theoretical and experimental characterization reveals L-tartrate anion can partially replace H2O in the solvation sheath of Zn2+, increasing de-solvation energy. Concurrently, the Na+ could absorb on the surface of Zn anode preferentially to inhibit the deposition of Zn2+ aggregation. In consequence, the overpotential of Zn deposition could increase from 32.2 to 45.1 mV with the help of Na-L. The Zn-Zn cell could achieve a Zn utilization rate of 80% at areal capacity of 20 mAh cm-2. Zn-LiMn2O4 full cell with Na-L additive delivers improved stability than that with blank electrolyte. This study also provides insight into the regulation of nucleation overpotential to achieve homogeneous Zn deposition.

Large Interlayer Distance and Heteroatom-Doping of Graphite Provide New Insights into the Dual-Ion Storage Mechanism in Dual-Carbon Batteries.

Dual-ion batteries (DIBs) is a promising technology for large-scale energy storage. However, it is still questionable how material structures affect the anion storage behavior. In this paper, we synthesis graphite with an ultra-large interlayer distance and heteroatomic doping to systematically investigate the combined effects on DIBs. The large interlayer distance of 0.51 nm provides more space for anion storage, while the doping of the heteroatoms reduces the energy barriers for anion intercalation and migration and enhances rapid ionic storage at interfaces simultaneously. Based on the synergistic effects, the DIBs composed of carbon cathode and lithium anode afford ultra-high capacity of 240 mAh g-1 at current density of 100 mA g-1 . Dual-carbon batteries (DCBs) using the graphite as both of cathode and anode steadily cycle 2400 times at current density of 1 A g-1 . Hence, this work provides a reference to the strategy of material designs of DIBs and DCBs.

Protective effect of Huanglianjiedu Decoction on microcystin-LR induced nerve injury.

Microcystin-LR (MC-LR) presented in eutrophic water has been identified as having the capacity to induce damage to the mammalian nervous system by crossing the blood-brain barrier through organic anion transporting polypeptides. However, the lack of effective preventive and protective strategies remains a concern. Huanglianjiedu Decoction (HLJD), a classical Chinese traditional formula originating from the Tang Dynasty and comprising Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri, and Fructus Gardeniae, has exhibited neuroprotective effects attributed to its antioxidant properties. In this study, we investigated the potential of HLJD in counteracting the neurotoxic effects induced by MC-LR. Our findings revealed that MC-LR dose-dependently inhibited the activity of the PP2A enzyme in PC 12 cells and significantly elevated the phosphorylation levels of JNK, ERK1/2, and p38. Moreover, MC-LR administration resulted in synaptic damage in mouse neurons, hyperphosphorylation of the microtubule-related protein Tau, cognitive impairment, and deficits in learning and memory in C57BL/6J mice. Notably, HLJD effectively reversed the cytotoxicity caused by MC-LR in PC 12 cells, and attenuated MC-LR-induced neuronal damage while improving learning ability in mice. These results highlight the potential of HLJD as a promising protective strategy against MC-LR-induced neurological injury.

Bifunctional Dynamic Adaptive Interphase Reconfiguration for Zinc Deposition Modulation and Side Reaction Suppression in Aqueous Zinc Ion Batteries.

Dendrite growth and electrode/electrolyte interface side reactions in aqueous zinc-ion batteries (AZIBs) not only impair the battery lifetime but also pose serious safety concerns for the battery system, hindering its application in large-scale energy storage systems. Herein, by introducing positively charged chlorinated graphene quantum dot (Cl-GQD) additives into the electrolyte, a bifunctional dynamic adaptive interphase is proposed to achieve Zn deposition regulation and side reaction suppression in AZIBs. During the charging process, the positively charged Cl-GQDs are adsorbed onto the Zn surface, acting as an electrostatic shield layer that facilitates smooth Zn deposition. In addition, the relative hydrophobic properties of chlorinated groups also build a hydrophobic protective interface for the Zn anode, mitigating the corrosion of the Zn anode by water molecules. More importantly, the Cl-GQDs are not consumed throughout the cell operation and exhibit a dynamic reconfiguration behavior, which ensures the stability and sustainability of this dynamic adaptive interphase. Consequently, the cells mediated by the dynamic adaptive interphase enable dendrite-free Zn plating/stripping for more than 2000 h. Particularly, even at 45.5% depth of discharge, the modified Zn//LiMn2O4 hybrid cells still retain 86% capacity retention after 100 cycles, confirming the feasibility of this simple approach for application with limited Zn sources.

Lithium Salt Dissociation Promoted by 18-Crown-6 Ether Additive toward Dilute Electrolytes for High Performance Lithium Oxygen Batteries.

Lithium-oxygen batteries (LOBs) are well known for their high energy density. However, their reversibility and rate performance are challenged due to the sluggish oxygen reduction/evolution reactions (ORR/OER) kinetics, serious side reactions and uncontrollable Li dendrite growth. The electrolyte plays a key role in transport of Li+ and reactive oxygen species in LOBs. Here, we tailored a dilute electrolyte by screening suitable crown ether additives to promote lithium salt dissociation and Li+ solvation through electrostatic interaction. The electrolyte containing 100 mM 18-crown-6 ether (100-18C6) exhibits enhanced electrochemical stability and triggers a solution-mediated Li2 O2 growth pathway in LOBs, showing high discharge capacity of 10 828.8 mAh gcarbon -1 . Moreover, optimized electrode/electrolyte interfaces promote ORR/OER kinetics on cathode and achieve dendrite-free Li anode, which enhances the cycle life. This work casts new lights on the design of low-cost dilute electrolytes for high performance LOBs.

Time­dependent changes in NLRP3 and Nrf2 levels in lipopolysaccharide­induced acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe clinical conditions with a high mortality rate. Nucleotide­binding oligomerization domain (NOD)­like receptor containing pyrin domain 3 (NLRP3) and nuclear factor E2­related factor 2 (Nrf2) have been reported to be associated with ALI. However, the dynamic changes in the levels of these factors in lipopolysaccharide (LPS)­induced lung injury remain unclear. Thus, the present study aimed to determine the LPS­induced activation of immunological cascades, as well as the NLRP3/Nrf2 signaling pathway at different stages of lung injury. For this purpose, mice were divided into six groups as follows: The control, LPS­4 h, LPS­24 h, LPS­48 h, LPS­96 h and LPS­144 h groups. LPS (4 mg/kg) was administered intratracheally to induce lung injury. Flow cytometry was used to determine the changes in macrophages, neutrophils and T­cell subsets in lung tissue, hematoxylin and eosin staining were used to measure the histopathological changes in lung tissues, ELISA was performed to evaluate the levels of cytokines, western blot analysis was used to measure the levels of inflammatory proteins, and reverse transcription­quantitative PCR used to determine the mRNA level of a target gene. Following LPS administration, evident histopathological damage with neutrophil infiltration was observed which peaked at 48 h. The levels of interleukin­1ß, keratinocyte­derived chemokine, macrophage inflammatory protein 2 and tumor necrosis factor a were markedly increased in bronchoalveolar lavage fluid and serum from the mice, and these levels peaked at 4 h. Moreover, LPS promoted Toll like receptor­4 expression and reactive oxygen species production, thus activating NLRP3/Nrf2 signaling and pyroptosis. Collectively, the present study demonstrates that LPS triggers multiple inflammatory molecules and immune cells during ALI, which may be closely involved in the irregular redox status, NLRP3/Nrf2 pathway and pyroptosis.

Characteristics of Vulvo-Vaginal Infections in 9- to 13-Year-Old Girls Undergoing Rapid Puberty.

BACKGROUND: This study was conducted to investigate the characteristics of vulvo-vaginal infections in 9- to 13-year-old girls undergoing rapid puberty. METHODS: Three hundred ninety girls aged 9 - 13 years who experienced vulvo-vaginal infections while undergoing rapid puberty and were treated at West China Second University Hospital from July 2017 to June 2020 were retrospectively analyzed. The incidences of bacterial vaginosis (BV), intermediate BV, and vulvo-vaginal candidiasis (VVC) and the differences in these incidences for patients of different ages were analyzed. RESULTS: The incidences of BV, intermediate BV, VVC, and unknown pathogenic vaginitis were 35.38%, 35.13%, 19.23%, and 10.26%, respectively. The incidence of BV was significantly higher than that of VVC. The positive rates of Candida albicans (C. albicans) and non-albicans Candida infections differed significantly at 80.00% and 20.00%, respectively. The BV and intermediate BV incidences did not significantly differ by age. The VVC incidence was significantly lower for 9-year-old girls than for girls of other ages. CONCLUSIONS: Girls undergoing rapid puberty are more susceptible to BV and intermediate BV infections than to VVC infections. The VVC incidence was lowest in 9-year-old girls. More attention should be paid to the effects of female estrogen levels, the vaginal microecosystem, and menstrual hygiene on vulvo-vaginal infections in girls undergoing rapid puberty.

A Self-Regulated Electrostatic Shielding Layer toward Dendrite-Free Zn Batteries.

Although aqueous Zn batteries have become a more sustainable alternative to lithium-ion batteries owing to their intrinsic security, their practical applications are limited by dendrite formation and hydrogen reactions. The first application of a rare earth metal type addition to Zn batteries, cerium chloride (CeCl3 ), as an effective, low-cost, and green electrolyte additive that facilitates the formation of a dynamic electrostatic shielding layer around the Zn protuberance to induce uniform Zn deposition is presented. After introducing CeCl3 additives, the electrochemical characterizations, in situ optical microscopy observation, in situ differential electrochemical mass spectrometry, along with density functional theory calculations, and finite element method simulations reveal resisted Zn dendritic growth and enhanced electrolyte stability. As a result, the Zn-Zn cells using the CeCl3 additive exhibit a long cycling stability of 2600 h at 2 mA cm-2 , an impressive cumulative areal capacity of 3.6 Ah cm-2 at 40 mA cm-2 , and a high Coulombic efficiency of ≈99.7%. The fact that the Zn-LiFePO4 cells with proposed electrolyte retain capacity significantly better than the additive-free case is even more exciting.

One-pot room temperature synthesis of orange-emitting carbon dots for highly-sensitive vitamin B12 sensing.

Fluorescent carbon dots (CDs) with the long-wavelength emission have received increasing attention due to their promising application prospects in the biological field. The synthesis of CDs with long wavelength emission mainly focuses on the high temperature method, but the room temperature synthesis is still rarely studied. Herein, a simple room temperature strategy is developed for the preparation of orange-emitting CDs (O-CDs) by Schiff base crosslinking reaction between methyl-p-benzoquinone and triethylenetetramine. The proposed O-CDs show a strong excitation-dependent emission with a relative quantum yield of about 6.56%. Because of the strong inner filter effect, O-CDs can be well applied for the highly-sensitive detection of vitamin B12 (VB12). The intensity ratio (F/F0) of O-CDs is linear against the concentration of VB12 from 50 nM to 200 µM with a low detection limit of 10 nM. Therefore, the obtained O-CDs nanoprobes provide a promising platform for pharmaceutical analysis applications.

Huanglianjiedu Decoction as an effective treatment for oral squamous cell carcinoma based on network pharmacology and experimental validation.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of malignant tumors in oral and maxillofacial region with high fatality. Huanglianjiedu Decoction (HLJDD) is a well-known traditional Chinese medicinal prescription, which consists of Coptis chinensis Franch, Scutellaria baicalensis Georgi, Phellodendron amurense Rupr and Gardenia jasminoides J.Ellis. Some clinical studies showed HLJDD had good effectiveness on OSCC, but the mechanism is unclear. METHODS: In this study, potential components of HLJDD and putative targets were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combining with potential targets of OSCC searched from Therapeutic Target Database (TTD) and Online Mendelian Inheritance in Man (OMIM), we drew protein-protein interaction (PPI) network by Cytoscape v3.2.0 software. After topological analysis we got core targets and further did Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then we did the in vitro experiments to verify the major biological processes (cell cycle, apoptosis and proliferation) and signaling pathways (mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), protein kinase B (AKT)) on OSCC cell lines, SCC-25 and CAL-27. RESULTS: The potential component targets number of Coptis chinensis Franch, Scutellaria baicalensis Georgi, Phellodendron amurense Rupr and Gardenia jasminoides J.Ellis were 39, 93, 81and 88, respectively. Then we got 52 core targets which enriched in cell cycle, apoptosis, proliferation, MAPK activation etc. and obtained TOP30 pathways. On SCC-25 and CAL-27, HLJDD suppressed cell proliferation, induced late apoptosis and inhibited cell invasion and migration which were consistent with the results from network pharmacology analysis. Additionally, in cell cycle, we confirmed HLJDD inhibited G1 phase and arrested in S phase to reduce cell proliferation on SCC-25. In signaling pathways, HLJDD inhibited the phosphorylation of extracellular regulatory protein kinase 1/2 (ERK1/2) and NF-κB p65 (S468) on SCC-25 and CAL-27. CONCLUSIONS: HLJDD played a potential therapeutic role on OSCC via inhibiting p-ERK1/2 and p-NF-κB p65 (S468).

Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury.

Acute lung injury (ALI) is associated with overproduction of inflammatory mediators in lung tissue. Previous studies have revealed that inflammation induces activation of phosphodiesterase 4B (PDE4B) accompanied by the production of inflammatory mediators, but the detailed mechanism remains unclear. Here, we focused on the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome complexes to study the crosstalk between PDE4B and NF-E2-related factor 2 (Nrf2). We used global knockout PDE4B or Nrf2 mice to prepare LPS induced acute lung injury model by intratracheally administration, and LPS primed bone marrow-derived macrophages (BMDMs), following overexpression of PDE4B or Nrf2, luciferase activity analysis, and chIP-qPCR analyses. We found that deficiency of PDE4B could potently attenuate the lung histopathological changes, suppress the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, IL-18, and cleaved caspase-1, 8, and GSDMD accompanied with defective activation of the ROS/Nrf2/NLRP3. Meanwhile deficiency of Nrf2 showed the similar results. Furtherly, overexpression by PDE4B or Nrf2 plasmid transfection in MH-S cells could enhance the Nrf2 or PDE4B expression. Luciferase analysis suggested that Nrf2 activated PDE4B promoter activity, while PDE4B could increase Nrf2 substrate ARE activity in MH-S cells in dose dependent manners. ChIP-qPCR analyses showed that Nrf2 bound to the PDE4B promoter region at Ì´ 1532 to Ì´1199 position in macrophages. Altogether, deficiency of PDE4B inhibit the inflammasome activation and pyroptosis in LPS stimulated lung injury model and macrophages by regulating ROS/Nrf2/NLRP3 activation. The study provides new insight that PDE4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2.

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization.

Ulcerative colitis (UC) is a form of inflammatory bowel disease, which manifests as irritation or swelling and sores in the large intestine in a relapsing and remitting manner. In a dextran sulfate sodium sulfate (DSS)-induced UC model in female mice, we found that the levels of cyclic guanosine monophosphate (cGMP) are reduced, while the expression of phosphodiesterase 9A (PDE9A) is highest among all phosphodiesterase (PDEs). Since PDE9 has the highest affinity toward cGMP, we evaluated the selective PDE9 inhibitor PF-04447943 (PF) as a potential candidate for UC treatment. PF has been extensively studies in cognitive function and in sickle cell disease, but not in models for inflammatory bowel disease (IBD). Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or sulfasalazine (SASP) to study the body weight, colon length, histopathology, and measure superoxide dismutase (SOD), malondialdehyde (MDA), and cGMP level, as well as cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12/23 (IL-12/23), interleukin-10 (IL-10), and pathways including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and inflammasome activation. In addition, the number of dendritic cells (DC) and regulatory T cells (Treg cell) was assessed in the spleen, lymph node, and colon using flow cytometry. DSS reduced the number of goblet cells, decreased colon lengths and body weights, all of them were attenuated by PF treatment. It also suppressed the elevated level of inflammatory cytokines and increased level the anti-inflammatory cytokine, IL-10. PF treatment also reduced the DSS-induced inflammation by suppressing oxidative stress, NF-κB, STAT3, and inflammasome activation, by upregulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and its downstream proteins via extracellular signal-regulated kinase (ERK) phosphorylation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in ulcerative colitis by suppressing oxidative stress and inflammation as well as reversing the Treg/Th17 cells imbalance.