CD36 regulates LPS-induced acute lung injury by promoting macrophages M1 polarization.

M1 polarization of macrophages works as a promoter in pathogenesis of acute lung injury / acute respiratory distress syndrome (ALI/ARDS) by the secretion of pro-inflammatory cytokines and recruiting other inflammatory cells. Lipopolysaccharide (LPS), a critical component of the wall of gram-negative bacteria, can induce M1 polarization and ALI. Recently, cluster of differentiation 36 (CD36) has been reported to be associated with inflammatory responses. However, it has not yet been clarified whether CD36 in macrophages is involved in LPS-induced ALI. Herein, we demonstrated that in macrophages, LPS-induced ALI was regulated by CD36. Loss of CD36 attenuated LPS-induced ALI by reducing M1 polarization. Mechanistically, CD36 promoted macrophage M1 polarization by regulating CD14 associated with TLR4 during LPS stimulation. The findings of this study, clarified the mechanism of LPS-induced ALI through CD36 in macrophages, which provides a potential target for the prevention and treatment of ALI.

Lenvatinib enhances T cell immunity and the efficacy of adoptive chimeric antigen receptor-modified T cells by decreasing myeloid-derived suppressor cells in cancer.

BACKGROUND: Lenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated. METHODS: The antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells targeted carbonic anhydrase IX (CAIX) in a murine renal cancer model. RESULTS: The antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model. CONCLUSION: Our study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.

The Association between Urinary Glucose and Renal Uric Acid Excretion in Non-diabetic Patients with Stage 1-2 Chronic Kidney Disease.

Aims: To test the hypothesis that in non-diabetic patients with early-stage chronic kidney disease (CKD), the renal excretion of urate and glucose transportation are coupled and interconnected. Methods: A cross-sectional study of 255 non-diabetic participants with stage 1-2 CKD recruited from our department was conducted. Spearman's correlation and multiple linear regression analyses were used to study the correlation between urinary glucose and renal uric acid excretion. ANOVA was used to compare urinary uric acid excretion among three tertiles of urinary glucose (UG; UG1: UG<0.24 mmol/24 h/1.73 m2, UG2: 0.24 mmol/24 h/1.73 m2≤ UG≤0.55 mmol/24 h/1.73 m2, and UG3: UG>0.55 mmol/24 h/1.73 m2), the fractional excretion of glucose (FEG; FEG1: FEG<0.04%, FEG2: 0.04%≤FEG≤0.09%, and FEG3: FEG>0.09%) and the excretion of glucose per volume of glomerular filtration (EgGF; EgGF1: EgGF<1.95 µmol/L, EgGF2: 1.95 µmol/L≤ EgGF≤3.99 µmol/L, and EgGF3: EgGF>3.99 µmol/L). Results: According to the multiple linear regression analysis, FEG and EgGF were positively correlated with the excretion of uric acid per volume of glomerular filtration (EurGF) after adjusting for confounding factors. The EurGF levels in the highest tertiles of UG, FEG and EgGF were higher than those in the lowest tertiles of UG, FEG and EgGF. Conclusion: Urinary glucose excretion is closely related to renal excretion of uric acid in non-diabetic patients with stage 1-2 CKD.

Comparison and development of machine learning tools in the prediction of chronic kidney disease progression.

BACKGROUND: Urinary protein quantification is critical for assessing the severity of chronic kidney disease (CKD). However, the current procedure for determining the severity of CKD is completed through evaluating 24-h urinary protein, which is inconvenient during follow-up. OBJECTIVE: To quickly predict the severity of CKD using more easily available demographic and blood biochemical features during follow-up, we developed and compared several predictive models using statistical, machine learning and neural network approaches. METHODS: The clinical and blood biochemical results from 551 patients with proteinuria were collected. Thirteen blood-derived tests and 5 demographic features were used as non-urinary clinical variables to predict the 24-h urinary protein outcome response. Nine predictive models were established and compared, including logistic regression, Elastic Net, lasso regression, ridge regression, support vector machine, random forest, XGBoost, neural network and k-nearest neighbor. The AU-ROC, sensitivity (recall), specificity, accuracy, log-loss and precision of each of the models were evaluated. The effect sizes of each variable were analysed and ranked. RESULTS: The linear models including Elastic Net, lasso regression, ridge regression and logistic regression showed the highest overall predictive power, with an average AUC and a precision above 0.87 and 0.8, respectively. Logistic regression ranked first, reaching an AUC of 0.873, with a sensitivity and specificity of 0.83 and 0.82, respectively. The model with the highest sensitivity was Elastic Net (0.85), while XGBoost showed the highest specificity (0.83). In the effect size analyses, we identified that ALB, Scr, TG, LDL and EGFR had important impacts on the predictability of the models, while other predictors such as CRP, HDL and SNA were less important. CONCLUSIONS: Blood-derived tests could be applied as non-urinary predictors during outpatient follow-up. Features in routine blood tests, including ALB, Scr, TG, LDL and EGFR levels, showed predictive ability for CKD severity. The developed online tool can facilitate the prediction of proteinuria progress during follow-up in clinical practice.

[Land Use Change Driving and Optimization of Carbon Budget in Hangzhou Metropolitan Area].

As climate change, such as global warming, has become a global environmental issue, clarifying the mechanism driving the carbon budget based on land use change has become an inevitable path to realize the "double carbon" goal. Based on the land use change characteristics in the Hangzhou Metropolitan Area from 1995 to 2020, this study employed the inventory accounting method, concentration index, and panel regression models to investigate the driving mechanisms of carbon budget dynamics influenced by land use changes. Moreover, the study utilized a "scenario-actor" policy analysis framework to propose low-carbon strategies through the integration of land use management within territorial spatial planning. The research findings were as follows： ① The carbon source capacity in the study area significantly surpassed its carbon sink capacity. The overall carbon budget concentration index had yet to exceed the 0.4 "alert threshold," with spatial concentration levels as follows： Hangzhou > Huangshan > Shaoxing > Quzhou > Jiaxing ≈ Huzhou. ② For croplands, larger areas and greater shape regularity contributed to a reduction in carbon budgets. Conversely, for constructed lands, expansive areas and increased fragmentation intensified the carbon budget levels, primarily driven by other urban land categories. ③ An increased proportion of croplands and higher land use heterogeneity promoted spatial equilibrium in carbon budgets, whereas the larger coverage and fragmentation of industrial and other urban lands led to an uneven spatial distribution of carbon budgets. ④ Low-carbon optimization of territorial space needs to adjust for the structure and form of carbon source functional land use as a key driver. At the policy implementation level, the central government and urban residents demonstrated strong support for low-carbon territorial control. However, cooperation from local governments, enterprises, and rural residents was suboptimal, necessitating complementary policies for effective guidance. This study holds practical significance for enhancing land use efficiency and promoting low-carbon urban development.

[Impacts of Urban Form on Carbon Emissions Under the Goal of Carbon Emission Peak and Carbon Neutrality: A Case Study of the Yangtze River Economic Belt].

Clarifying the mechanism of influence of urban form on carbon emissions is an important prerequisite for achieving urban carbon emission reduction. Taking the Yangtze River Economic Belt as an example, this study elaborated on the general mechanism of urban form on carbon emissions, used multi-source data to quantitatively evaluate the urban form, and explored the impacts of urban form indicators on carbon emissions from 2005 to 2020 at global and sub-regional scales with the help of spatial econometric models and geodetector, respectively. The results showed that:① The carbon emissions of the Yangtze River Economic Belt increased from 2 365.31 Mt to 4 230.67 Mt, but the growth rate gradually decreased. Its spatial distribution pattern was bipolar, with high-value areas mainly distributed in core cities such as Shanghai and Chongqing and low-value areas concentrated in the western regions of Sichuan and Yunnan. ② The area of construction land in the study area expanded over the past 15 years, but the population density of construction land had been decreasing. The degree of urban fragmentation was decreasing, and the difference between cities was also progressively narrowing. The average regularity of urban shape improved, and the compactness increased significantly. ③ All indicators of urban scale had significant positive effects on carbon emissions at the global scale, urban fragmentation had a significant negative effect in 2005, and the effective mesh size (MESH) indicator of urban compactness showed a significant negative correlation with carbon emissions in the study period. ④ Total class area, patch density, and effective mesh size had the most significant impacts on carbon emissions in upstream cities. Effective mesh size, mean perimeter-area ratio, and total class area had higher influences in midstream cities. Effective mesh size, percentage of like adjacencies, and largest patch index were the key factors to promote carbon reduction in downstream cities. Cities in different regions should comprehensively consider the impacts of various urban form indicators on carbon emissions and then optimize their urban form to promote sustainable development.

Impacts of land use transitions on ecosystem services: A research framework coupled with structure, function, and dynamics.

Rapid urbanization in China has resulted in drastic land use transitions (LUT) and has had a severe impact on the supply of regional ecosystem services (ESs). To improve ecosystem security and promote sustainable development regionally, it is essential to clarify spatial correlations between the multi-dimensional characteristics of LUT and ESs. We developed a theoretical framework to examine how LUT influenced regional ESs in three dimensions: land use structure, function, and dynamics. Using the Taihu Lake Rim urban agglomeration (TLRUA) as an example, we explored the process by which LUT affected the change in regional ESs. The results indicated that the TLRUA experienced accelerated urbanization between 2000 and 2018, with LUT and ESs exhibiting distinct characteristics in urban, suburban, and rural areas in different regions. The impact of LUT on ESs, as we analyzed them from different dimensions, embraced interactive effects and significant spatial spillover effects. The land use structural transitions were globally positively correlated with habitat maintenance, carbon sequestration, and recreation potential, whereas land use intensity and dynamics transitions exhibited negative correlations. Given their interactions at the local scale, we propose corresponding land management strategies, which can offer practical guidance for coordinating regional land resource development and ecosystem conservation.

Syntheses, Characterization and Crystal Structures of Dicyanamide Bridged Polynuclear Copper(II) and Zinc(II) Complexes with Urease Inhibitory Activity.

A pair of structurally similar dicyanamide bridged copper(II) and zinc(II) complexes [CuL(dca)]n (1) and [ZnL(dca)]n (2), were prepared from the fluorine containing Schiff base 5-fluoro-2-(((2-hydroxyethyl)imino)methyl)phenol (HL). The compounds were characterized by physico-chemical methods. Structures of the complexes were confirmed by single crystal X-ray diffraction. The Cu atom in complex 1 is in square pyramidal coordination, whereas the Zn atom in complex 2 is in trigonal bipyramidal coordination. The copper complex has effective Jack bean urease inhibitory activity, with IC50 value of 0.14±0.12 µmol L-1.

The urinary ß2 microglobulin-creatinine ratio is inversely associated with lumbar spine bone mineral density in the elderly Chinese males.

Renal tubule cells play a pivotal role in maintaining bone homeostasis. Hence, renal tubular function may be associated with bone mineral density. Our study found that urinary ß2 microglobulin-creatinine ratio (UBCR) levels correlated negatively with lumbar spine bone mineral density (BMD) and T and Z values, and may be a marker for osteoporosis in Chinese elderly male adults. PURPOSE: To study the association of UBCR levels with BMD and the predictive value of UBCR for osteoporosis in elderly Chinese male adults. METHODS: A cross-sectional study of 149 (65 to 85 years, 69.7 ± 4.6) Chinese male adults who underwent health checkups in Huadong Hospital in Shanghai China was conducted. BMD was measured by dual-energy X-ray absorptiometry. The clinical variables and BMD of the participants in the low UBCR group (B1, UBCR < 300 µg/g) and the high UBCR group (B2, UBCR ≥ 300 µg/g) were compared. Associations between UBCR with clinical variables and BMD were analyzed by Pearson's correlation coefficient and multiple regression analysis. BMD and T and Z values were compared between the B1 and B2 groups. The odds ratios (ORs) for dose-dependent increases in osteoporosis between B1 and B2 were analyzed by binary logistic regression analysis. The area under the receiver operating characteristic (ROC) curve was used to analyze the capacity of UBCR to predict osteoporosis. RESULTS: UBCR was significantly higher in the osteoporosis group. After adjusting for multiple confounders, UBCR levels correlated negatively with BMD and T and Z values of the lumbar spine. Lumbar spine BMD and T and Z values were significantly lower in the B2 UBCR group than in the B1 UBCR group. Compared with the B1 participants, the ORs for "osteoporosis" were 12.401 times higher in B2 participants (P = 0.005) by binary logistic regression analysis after adjusting for potential confounders. The UBCR index (cutoff = 362.48 µg/g) had a sensitivity of 78.6% and a specificity of 68.7% for identifying osteoporosis, with an area under the ROC curve of 0.760. CONCLUSIONS: These results suggest that UBCR levels correlate negatively with lumbar spine BMD and T and Z values and may serve as a marker for osteoporosis in Chinese elderly male adults.

Copper-catalyzed enantioselective beta-boration of acyclic enones.

The enantioselective beta-boration of various acyclic enones has been studied by using chiral diphosphine-copper complexes. Good to excellent yields and enantioselectivities (up to 97 % ee (enantiomeric excess)) were observed for a range of substrates under optimized conditions. In this transformation, the addition of a controlled amount of alcohol, especially methyl alcohol, is critical to obtain products in high ee and yield. This methodology accommodates structural variation of acyclic enones and provides access to a range of functionalized chiral organoboronates in high enantiomeric purity.

Serum uric acid is associated with lumbar spine bone mineral density in healthy Chinese males older than 50 years.

OBJECTIVES: We aimed to investigate the association of serum uric acid (UA) levels with bone mineral density (BMD) at all skeletal sites in healthy Chinese males >50 years of age. METHODS: A cross-sectional study of 385 Chinese males >50 years of age who underwent health checkup in Huadong Hospital Affiliated to Fudan University in Shanghai, China, was conducted. Clinical and bone characteristics were compared in different UA tertiles (UA1: UA <4.7 mg/dL, UA2: 4.7 mg/dL ≤ UA <6 mg/dL and UA3: UA ≥6 mg/dL). Pearson correlation and multiple regression analysis were used to study the correlation of UA with BMD at various skeletal sites. RESULTS: Serum UA levels were positively associated with higher BMD and T-values at the lumbar spine, but not at other skeletal sites, after adjusting for multiple confounding factors. Lumbar spine BMD; the T- and Z-values at the lumbar spine, total hip and femoral neck; as well as intact parathyroid hormone (iPTH) levels are higher in the highest tertile of UA than in the second tertile of UA. CONCLUSION: Our results provide epidemiological evidence in Chinese Han males aged >50 years that serum UA levels are positively correlated with lumbar spine BMD and T-values, suggesting that UA may exert protective effect on bone density at the lumbar spine in Chinese males >50 years of age.

Peroxisome proliferator-activated receptor γ prevents the production of NOD-like receptor family, pyrin domain containing 3 inflammasome and interleukin 1ß in HK-2 renal tubular epithelial cells stimulated by monosodium urate crystals.

Recent evidence showed that peroxisome proliferator­activated receptor γ (PPARγ) ameliorates a variety of inflammatory conditions. The present study aimed to investigate the role of PPARγ in regulating NOD-like receptor family, pyrin domain containing 3 (NALP3) inflammasome and interleukin (IL)­1ß levels during monosodium urate (MSU) crystal­induced inflammation. HK­2 cells were incubated with or without 200 µg/ml MSU crystals, and mRNA and protein levels of PPARγ were determined using reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. To verify the role of PPARγ, HK­2 cells were pre­treated with PPARγ agonist pioglitazone, and the levels of NALP3 inflammasome and IL­1ß were detected by western blot analysis and ELISA. The results showed that MSU crystals increased PPARγ expression in HK­2 cells at 24 h, while the expression decreased to normal levels at 48 h. It was also demonstrated that although the PPARγ agonist pioglitazone did not alter the mRNA and protein levels of PPARγ, it significantly reduced the MSU crystal­induced production of NALP3 inflammasome and IL­1ß in HK­2 cells, possibly by increasing the level of PPARγ activity. In conclusion, the results of the present study indicated that PPARγ prevented NALP3 inflammasome formation and IL­1ß production in HK­2 cells stimulated by MSU crystals, which indicated that PPARγ may represent a novel target for the treatment of hyperuricemic nephropathy.

Catalytic enantioselective boron conjugate addition to cyclic carbonyl compounds: a new approach to cyclic beta-hydroxy carbonyls.

The highly enantioselective conjugate boration of six-membered and seven-membered cyclic enones and unsaturated esters was achieved by the use of a copper-(R,S)-Taniaphos complex with up to 99% ee under optimal conditions.