Regulating the Double-Way Traffic of Cations and Anions in Ambipolar Polymer Cathodes for High-Performing Aluminum Dual-Ion Batteries.

The strong Coulombic interactions between Al3+ and traditional inorganic crystalline cathodes present a significant obstacle in developing high-performance rechargeable aluminum batteries (RABs) that hold promise for safe and sustainable stationary energy storage. While accommodating chloroaluminate ions (AlCl4 -, AlCl2+, etc.) in redox-active organic compounds offers a promising solution for RABs, the issues of dissolution and low ionic/electronic conductivities plague the development of organic cathodes. Herein, electron donors are synthetically connected with acceptors to create crosslinked, bipolar-conjugated polymer cathodes. These cathodes exhibit overlapped redox potential ranges for both donors and acceptors in highly concentrated AlCl3-based ionic liquid electrolytes. This approach strategically enables on-site doping of the polymer backbones during redox reactions involving both donor and acceptor units, thereby enhancing the electron/ion transfer kinetics within the resultant polymer cathodes. Based on the optimal donor/acceptor combination, the bipolar polymer cathodes can deliver a high specific capacity of 205 mAh g-1 by leveraging the co-storage of AlCl4 - and AlCl2+. The electrodes exhibit excellent rate performance, a stable cycle life of 60 000 cycles, and function efficiently at high mass loadings, i.e., 100 mg cm-2, and at low temperatures, i.e., -30 °C. The findings exemplify the exploration of high-performing conjugated polymer cathodes for RABs through rational structural design.

Effect of Genotype on Cadmium and Trace Element Accumulation in Wheat from Weakly Alkaline Cadmium-contaminated Soil.

Cadmium (Cd) contamination of farmland soils leads to Cd accumulation in crops and reduced micronutrient uptake, posing grave risks to food safety. Herein, we investigated the enrichment and transportation patterns of Cd and trace elements in different parts of six wheat genotypes grown in weakly alkaline Cd-contaminated soils via pot experiments. The results revealed that the wheat grain variety with high Cd accumulation (Ningmai13) demonstrated a 1.94-fold increase compared to the variety with low accumulation (Yanong0428). The transfer factor of Cd from wheat straw to grain ranged from 0.319 to 0.761, while the transfer factor of Cd from root to straw ranged from 0.167 to 0.461. Furthermore, the concentrations of other metals in wheat grains followed the order of Zn > Mn > Fe > Cu. There was a significant positive correlation between Cd and Mn in grains, indicating a potential synergistic effect. Overall, this study provides valuable insights into the regulation of micronutrient intake to modulate Cd uptake in wheat.

Foliar Application of Nanoparticles Reduced Cadmium Content in Wheat (Triticum aestivum L.) Grains via Long-Distance "Leaf-Root-Microorganism" Regulation.

Foliar application of beneficial nanoparticles (NPs) exhibits potential in reducing cadmium (Cd) uptake in crops, necessitating a systematic understanding of their leaf-root-microorganism process for sustainable development of efficient nano-enabled agrochemicals. Herein, wheat grown in Cd-contaminated soil (5.23 mg/kg) was sprayed with different rates of four commonly used NPs, including nano selenium (SeNPs)/silica (SiO2NPs)/zinc oxide/manganese dioxide. SeNPs and SiO2NPs most effectively reduced the Cd concentration in wheat grains. Compared to the control, Cd concentration in grains was significantly decreased by 35.0 and 33.3% by applying 0.96 mg/plant SeNPs and 2.4 mg/plant SiO2NPs, and the grain yield was significantly increased by 33.9% with SeNPs application. Down-regulated gene expression of Cd transport proteins (TaNramp5 and TaLCT1) and up-regulated gene expression of vacuolar Cd fixation proteins (TaHMA3 and TaTM20) were observed with foliar SeNPs and SiO2NPs use. SeNPs increased the levels of leaf antioxidant metabolites. Additionally, foliar spray of SeNPs resulted in lower abundances of rhizosphere organic acids and reduced Cd bioavailability in rhizosphere soil, and soil microorganisms related to carbon and nitrogen (Solirubrobacter and Pedomicrobium) were promoted. Our findings underscore the potential of the foliar application of SeNPs and SiO2NPs as a plant and rhizosphere soil metabolism-regulating approach to reduce Cd accumulation in wheat grains.

Towards Durable and High-Rate Rechargeable Aluminum Dual-ion Batteries via a Crosslinked Diphenylphenazine-based Conjugated Polymer Cathode.

Rechargeable aluminum battery (RAB) is expected to be a promising energy storage technique for grid-scale energy storage. However, the development of RABs is seriously plagued by the lack of suitable cathode materials. Herein, we report two p-type conjugated polymers of L-PBPz and C-PBPz with the same building blocks of diphenylphenazine but different linkage patterns of linear and crosslinked structures as the cathode materials for Al dual-ion batteries. Compared to the linear polymer skeleton in L-PBPz, the crosslinked structure endows C-PBPz with amorphous nature and low dihedral angles of the polymer chains, which severally contribute to the fast diffusion of AlCl4 - with large size and the electron transfer during the redox reaction of diphenylphenazine. As a result, C-PBPz delivers a much better rate performance than L-PBPz. The crosslinked structure also leads to a stable cyclability with over 80000 cycles for C-PBPz. Benefiting from the fast kinetics, meanwhile, the C-PBPz cathode could realize a high redox activity of 117 mAh g-1, corresponding to an areal capacity of 2.30 mAh cm-2, even under a high mass loading of 19.7 mg cm-2 and a low content of 10 wt% conductive agent. These results might boost the development of polymer cathodes for RABs.

Effectiveness comparison of third-generation EGFR-TKI as initial and sequential therapy in adjuvant treatment for EGFR mutation-sensitive stage IIIA non-small cell lung cancer after surgery.

Introduction: Although third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) Osimertinib has been approved as adjuvant therapy for resected stage IIIA non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations, the optimal treatment sequencing of EGFR-TKIs, particularly whether Osimertinib should be the initial or sequential therapy following the first-generation EGFR-TKIs remains uncertain. Methods: A retrospective analysis was conducted on a cohort of patients with EGFR-mutated stage IIIA NSCLC who received treatment with either first-generation EGFR-TKIs or Osimertinib (third-generation) alone, or in sequential combination, at a single institution. The data analysis involved using the Kaplan-Meier method, log-rank test, and Cox regression. Results: Out of the total 148 patients with stage IIIA NSCLC included in the study, 76 individuals underwent treatment with either first-generation EGFR-TKIs (referred to as subgroup "1″) or exclusively Osimertinib (subgroup "0 + 3″), or a sequential combination of the two (subgroup "1 + 3″) following surgery. Both univariate and multivariate analyses demonstrated that there were no discernible disparities in terms of disease-free survival and overall survival between subgroup " 1″ and " 1 + 3," nor between subgroup " 0 + 3″ and "1 + 3". Conclusion: The findings from this study indicate that the introduction of third-generation EGFR-TKI Osimertinib did not yield enhanced survival benefits when compared to the first-generation drug in patients with stage IIIA completely resected NSCLC who were administered EGFR-TKIs as part of their postoperative adjuvant treatment. Additionally, within the observed sample size of this cohort, the sequential use of Osimertinib alongside first-generation EGFR-TKI did not demonstrate superiority over using either the first-generation EGFR-TKI or Osimertinib alone in terms of postoperative survival.

Foliar application of selenium nanoparticles alleviates cadmium toxicity in maize (Zea mays L.) seedlings: Evidence on antioxidant, gene expression, and metabolomics analysis.

The molecular and metabolic mechanisms of foliar selenium (Se) nanoparticles (SeNPs) application in mitigating cadmium (Cd) toxicity in crops have not been well studied. Herein, hydroponically cultured maize seedlings were exposed to Cd (20 µM) and treated without and with foliar SeNPs application. Effects of SeNPs on Cd transporter genes and plant metabolism were also explored. Results showed that compared to control plants without Cd exposure, Cd exposure decreased shoot height (16.8 %), root length (17.7 %), and fresh weight of root (24.2 %), stem (28.8 %), and foliar-applied leaves (Se-leaves) (15.0 %) via oxidative damage. Compared to Cd exposure alone, foliar SeNPs application at 20 mg/L (0.25 mg/plant) significantly alleviated the Cd toxicity by promoting photosynthesis and antioxidant capacity and fixing Cd in cell wall. Meanwhile, the mineral concentration of Ca (26.0 %), Fe (55.4 %), Mg (27.0 %), Na (28.6 %), and Zn (10.1 %) in Se-leaves was improved via foliar SeNPs application at 20 mg/L. QRT-PCR analysis further revealed that down- and up-regulation of the expression of ZmHMA2 and ZmHMA3 gene in Se-leaves contributed to reduced translocation of Cd in plants and enhanced Cd sequestration in the vacuole, respectively. Metabolomic results further indicated that metabolic pathways including carbohydrate metabolism, membrane transport, translation, amino acid metabolism, and energy metabolism were significantly affected by foliar SeNPs application. In conclusion, foliar SeNPs application at 20 mg/L could be a prospective strategy to mitigate Cd toxicity in maize.

Meta-analysis of the effect and safety of recombinant human interferon α-2b combined with Baofukang suppository in the treatment of HPV infection.

Persistent infection of human papilloma virus (HPV) increases the risk of cervical precancerous lesions turning into cervical cancer, which seriously affects women's reproductive health and quality of life. This meta-analysis analyzed the effect and safety of recombinant human interferon α-2b (rhIFNα-2b) combined with Baofukang suppository in the treatment of HPV infection. Online databases were used to search for randomized clinical trials (RCTs) on the treatment of HPV infection with the deadline of January 2022 and the effects of treatment were analyzed by the odds ratio (OR) of treatment outcomes (total effective rate, HPV clearance rate and adverse reaction rate). The interval estimation was expressed by 95% confidence interval (CI). The searching results showed that there were 15 RCTs, including 1786 HPV-infected cases meeting the criteria for meta-analysis, of which 893 received combination therapy. In terms of total effective rate, combination therapy was superior to monotherapy (OR = 4.82, 95% CI 3.43-6.75, P < 0.001). In terms of increasing the HPV clearance rate and reducing the adverse reaction rate, combination therapy also showed obvious advantages over monotherapy (OR = 4.51, 95% CI 3.18-6.39, P < 0.001; OR = 0.60, 95% CI 0.40-0.91, P < 0.02). Our findings suggested that rhIFNα-2b combined with Baofukang suppository is safe and effective in the treatment of cervical HPV infection. Due to the limited quality of the included studies, the results need to be further studied and validated by more high quality RCTs.

Multi-scale characterization of tumor-draining lymph nodes in resectable lung cancer treated with neoadjuvant immune checkpoint inhibitors.

BACKGROUND: Regional lymph node (LN) acts as a pivotal organ for antitumor immunity. Paradoxically, tumor-draining LNs (TDLNs) are usually the first site of tumor metastasis in lung cancer. It is largely unknown about the association between the status of TDLNs and the response of primary tumor beds to immune checkpoint inhibitors (ICIs) in lung cancer patients. Also, studies characterizing the TDLNs in response to ICIs are scarce. METHODS: We characterized and compared the radiological, metabolic (18F-FDG) and pathologic responses between primary tumor beds and paired TDLNs (invaded/non-invaded) from 68 lung cancer patients who underwent neoadjuvant ICIs plus surgery. Additionally, we performed the spatial profiling of immune and non-immune cells within TDLNs using multiplexed immunofluorescence. Therapy responses (e.g., pathologic complete (pCR) or major response (MPR)) of primary lung tumor beds and paired TDLNs were investigated separately. FINDINGS: We observed that responses of TDLNs to ICIs markedly differ from their paired primary lung tumors regarding the radiological, metabolic (18F-FDG uptake), and pathologic alterations. Neoadjuvant ICIs therapy specifically decreased 18F-FDG-reflected metabolic activity in the primary tumor beds with pCR/MPR but not their TDLNs counterparts. Furthermore, the presence of invaded TDLNs was associated with poor pathologic responses in the matched primary tumor beds and predictive of rapid post-treatment tumor relapse. Spatial profiling demonstrated exclusion of T cell infiltrates within the metastatic lesions of invaded TDLNs, and diminished multiple immune and non-immune compositions in non-involved regions surrounding the metastatic lesions. INTERPRETATION: These results provide the first clinically-relevant evidence demonstrating unique response patterns of TDLNs under ICIs treatment and revealing the underappreciated association of TDLNs status with the response of their paired primary tumors to ICIs in lung cancer. FUNDING: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun), the excellent talent program of Shanghai Chest Hospital (to F.Y), the Basic Foundation Program for Youth of Shanghai Chest Hospital (2021YNJCQ2 to H.Yang), and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20212302 to F. Yao).

The improved success rate and reduced complications of a novel localization device vs. hookwire for thoracoscopic resection of small pulmonary nodules: a single-center, open-label, randomized clinical trial.

Background: In our previous study, we developed a 4-hook claw-suture localization device for pulmonary nodule resection, which acheived satifisfactory results. Following this, we conducted this single-center, open-label, randomized clinical trial to compare the success rate and complication rate of this novel localization device and currently widely-used hookwire. Methods: Patients with small pulmonary nodules (0.4-1 cm) who received preoperative localization and thoracoscopic resection at Shanghai Chest Hospital were randomly assigned (1:2 ratio, via computer-generated randomized numbers) to undergo localization using either a novel claw-suture system (claw group) or classical (hookwire group) localization device. The primary endpoint of this study was localization success rate, and the secondary endpoints included complications, localization-related time, and pain. Results: A total of 411 patients were randomly assigned to the claw group (n=136) or the hookwire group (n=275) before thoracoscopic resection of small pulmonary nodules and analyzed. Compared with the hookwire group, the claw group had a significantly higher success rate (133/136, 97.8% vs. 254/275, 92.4%, P=0.027), less asymptomatic hemorrhage (16.9% vs. 37.5%, P=0.003) and pleural reaction (0% vs. 5.1%, P=0.017), as well as better pain alleviation 10 min after localization (measured using the difference between two visual analog scale scores, 0.84±0.98 vs. 0.35±0.79, P<0.001). In contrast, the hookwire group was associated with a shorter localization procedure duration than the claw group (7.2±2.9 vs. 14.4±6.6 min, P<0.001). In the multiple localization subgroup, the claw group compared to the hookwire group also achieved higher success (32/33, 97.0% vs. 70/86, 81.4%) and less pleural reaction (0% vs. 16.3%). Conclusions: The new claw-suture localization device is superior to traditional hookwire, with a higher success rate, fewer complications, and better patient tolerance for preoperative localization of small pulmonary nodules. Trial Registration: Chinese Clinical Trial Registry ChiCTR1900027346.

Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.

Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype. Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis. Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD.

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients.

BACKGROUND: There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy. Neoadjuvant immunotherapy provides an ideal setting for exploring responsive biomarkers because the pathological responses can be directly and accurately evaluated. METHODS: We retrospectively collected the clinicopathological characteristics and treatment outcomes of non-small cell lung cancer (NSCLC) patients who received neoadjuvant immunotherapy or chemo-immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. Clinicopathological factors associated with pathological response were analyzed. RESULTS: A total of 39 patients (35 males and 4 females) were included. The most common histological subtype was lung squamous cell carcinoma (LUSC) (n=28, 71.8%), followed by lung adenocarcinoma (LUAD) (n=11, 28.2%). After neoadjuvant treatment, computed tomography (CT) scan-based evaluation showed poor agreement with the postoperatively pathological examination (weighted kappa =0.0225; P=0.795), suggesting the poor performance of CT scans in evaluating the response to immunotherapy. Importantly, we found that the smoking signature displayed a better performance than programmed death-ligand 1 (PD-L1) expression in predicting the pathological response (area under the curve: 0.690 vs. 0.456; P=0.0259), which might have resulted from increased tumor mutational burden (TMB) and/or microsatellite instability (MSI) relating to smoking exposure. CONCLUSIONS: These findings suggest that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to PD-L1 expression in predicting the benefit of immunotherapy in NSCLC patients.

Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell cancer.

BACKGROUND: Locally-advanced lung squamous cell carcinoma represents a special subset that is challenging to resect completely with surgery alone. Immunotherapy has achieved great success in treating late-stage lung cancer. However, whether neoadjuvant immunotherapy can facilitate resection of initially locally-advanced and surgically-difficult locally-advanced lung squamous cell carcinoma remains to be investigated. METHODS: We retrospectively collected clinical records of locally-advanced lung squamous cell carcinoma patients who received neoadjuvant immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. RESULTS: A total of 23 patients (22 males, 1 female) with locally-advanced locally-advanced lung squamous cell carcinoma were included, initially clinically staged at IIIA (16, 69.6%), IIIB (n=4, 17.4%), IIB (n=2, 8.7%) and IIIC (n=1, 4.3%). The median interval between final treatment to surgery was 36 days (range, 25-93 days), without treatment-related delay in surgery. The neoadjuvant treatment resulted in a high rate of radical resection (n=20, 87.0%). The final histopathological examination demonstrated 6 (26.1%) cases with pathological complete response and 8 (34.8%) with pathological major response. Comparing with the computed tomography scan-based response, we observed a very low consistency (weighted kappa =0.122, P=0.315) between the computed tomography scan-based and final pathological evaluation. The median follow-up time was 510 days (range, 217-920 days). At the end of the follow-up, 1 patient died. CONCLUSIONS: Our findings showed the clinical promise of neoadjuvant immunotherapy plus surgery for locally-advanced lung squamous cell carcinoma. Computed tomography scan displays a poor role in assessing the resectability after neoadjuvant immunotherapy.

Sinomenine restrains breast cancer cells proliferation, migration and invasion via modulation of miR-29/PDCD-4 axis.

Sinomenine (Sino) is diffusely applied in heal rheumatoid arthritis and neuralgia. Howbeit, the activities of Sino in breast cancer cells remain confused. The research attempted to probe the anti-tumor function of Sino in breast cancer cells and divulge the feasible molecular mechanism. Sion at the 1-16 µM concentrations was exploited for the exposure of MDA-MB-231 or MCF7 cells, and cell growth, migration, invasion, cell cycle-relevant and apoptosis-correlative factors were estimated. Micro RNA (miR)-29 expression was evaluated via enforcing qRT-PCR, and the actions of miR-29 in MDA-MB-231 cells growth, migration and invasion were appraised after the overexpressed or suppressed vectors transfection. The functions of PDCD-4 in JNK and MEK/ERK pathways were estimated by employing western blot. We found that, Sino exposure impeded cell proliferation, provoked cell apoptosis and barricaded cell migration and invasion in MDA-MB-231 and MCF7 cells. Enhancement of miR-29 was observed in Sino-managed cells, and miR-29 overexpression further potentiated the activities of Sino in MDA-MB-231 cells. Additionally, Sino remarkably enhanced PCDC-4 expression via adjusting miR-29 in MDA-MB-231 cells. Beyond that, overexpressed PCDC-4 obstructed JNK and MEK/ERK pathways in MDA-MB-231 cells. Taken together, the explorations unveiled that Sino restrained MDA-MB-231 cells proliferation, migration, invasion, and provoked apoptosis through modulation of miR-29/PDCD-4 axis. Highlight Sino inhibits MDA-MB-231 and MCF7 cells proliferation and provokes apoptosis; Sino restrains MDA-MB-231 and MCF7 cells migration and invasion; Sino ascends miR-29 expression in MDA-MB-231 and MCF7 cells; Sino adjusts cell growth, migration and invasion via modulating miR-29; Sino up-regulates PDCD-4 expression through mediating miR-29; PDCD-4 obstructs JNK and MEK/ERK pathways in MDA-MB-231 cells.

Role of endoplasmic reticulum stress and oxidative stress in vinyl chloride-induced hepatic steatosis in mice.

Vinyl chloride (VC) is a common industrial organochlorine, shown to cause hepatic angiosarcoma and hepatic steatosis. However, the role of endoplasmic reticulum stress (ERS) and oxidative stress (OS) in hepatic steatosis after subchronic exposure to VC in mice, is unclear. Based on body weight, forty healthy SPF male C57BL/6 J mice were randomly divided into a control group and three VC exposure groups (57.3, 286.7, and 1433.6 ppm) (n = 10 each). VC was administered by static inhalation in a 50 L sealed plexiglass inhalation chamber for 2 h per day, five days per week for 16 weeks. Serum and liver tissues were analyzed for liver enzymes and lipids. Hepatic cytochrome P450 2E1 (CYP2E1) and OS related indicators malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured. The mRNA expressions of ERS downstream genes, including glycoregulatory protein-78 (GRP-78), sterol regulatory element binding protein-1 (SREBP-1), Acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were detected by real-time PCR (RT-PCR) and their protein levels examined by western blotting. The CYP2E1 levels increased after VC administration in a dose-dependent manner. MDA levels increased (P < .05) and SOD and GSH levels decreased (P < .05) in the liver of each group with the increase in the dose of VC. ERS and expressions of downstream genes (GRP-78, SREBP-1, ACC, and FAS) were enhanced after VC administration. These results suggested that OS and ERS could be induced by VC, which may lead to an increase in fatty acid synthesis in the liver, further aggravating hepatic steatosis.

Interleukin 33 ameliorates disturbance of regulatory T cells in pulmonary sarcoidosis.

The feature of pulmonary sarcoidosis is characterized by a Th1/Th17/regulatory T cells (Tregs) -driven inflammatory process in lung, resulting in noncaseating granulomas containing CD4+ T cells. Tregs increase in both lung and peripheral blood, with damaged immunoregulatory function. The current study investigated the effects of IL33 or anti-IL23 antibody on restoring the homeostasis and functions of Tregs in mycobacterial superoxide dismutase A (SodA)-induced pulmonary sarcoidosis. IL33 or anti-IL23 antibody was administered to mice with late-stage pulmonary sarcoidosis. The levels of Th1/Th17/Tregs and Tregs' suppressive functions were detected by fluorescence activated cell sorting (FACS) analysis or qPCR. The expressions of key proteins in PI3K/Akt/mTOR and TGF-ß/Smad2/Smad3 signaling pathways were tested by western blot. IL33 administration was associated with the rebalance of Th1/Th2 and Tregs, as well as a superior suppressor activity of Tregs on effector T cells in sarcoidosis, probably through increasing ST2 expressions on Tregs, along with the suppression of PI3K/Akt/mTOR and TGF-ß/Smad2/Smad3 signaling pathways. Small dose of anti-IL23 antibody independently improved Th1/Th2 bias, but had limited effects on the homeostasis and ST2 expressions on Tregs. These results suggested a major anti-inflammatory ability of IL33 to ameliorate the disturbance of Th1/Th2 and Tregs in pulmonary sarcoidosis, and provided rationales for further strategies of targeting the IL33/ST2 signals in the treatment of pulmonary sarcoidosis.

Anti-inflammatory effect of novel andrographolide derivatives through inhibition of NO and PGE2 production.

Andrographolide (1) is a major diterpene lactone exhibiting anti-inflammatory effects and is found in the plant Andrographis paniculata (Burm. f) Nees, which is widely used in Traditional Chinese Medicine. Synthesis of more effective drugs from andrographolide is very interesting and can prove to be highly useful. In this study, we investigated the anti-inflammatory effects of andrographolide and its derivatives (compounds 2-6) through dimethylbenzene-induced ear edema in mice. Substances under study were administrated intragastrically and the structure-activity relationship was analyzed. Results showed that compounds 5 and 6 significantly inhibited ear edema compared with compound 1 (p<0.05), indicating that the introduction of p-Chlorobenzylidene to C-15 of compound 2 enhances the anti-inflammatory effect. Moreover, compound 6 exhibited the strongest anti-inflammatory effect against ear edema in mice (79.4%; 1.35 mmol/kg, ig) and paw edema in rats (50.4%; 0.90 mmol/kg, ig). In addition, compound 6 significantly (p<0.05) inhibited granuloma formation and reduced the increase in vascular permeability induced by peritoneal injection of 0.6% acetic acid solution in mice. Findings indicate that compound 6 exerts its enhanced anti-inflammatory effects by decreasing serum iNOS activity, NO production, and PGE(2) production.