Correlation between oxygenation status of extra-synovial tissue of wrist and disease activity in rheumatoid arthritis: a photoacoustic imaging study.

OBJECTIVES: Rheumatoid arthritis (RA) is characterized by hypoxia in the synovial tissue. While photoacoustic imaging (PA) offers a method to evaluate tissue oxygenation in RA patients, studies exploring the link between extra-synovial tissue of wrist oxygenation and disease activity remain scarce. We aimed to assess synovial oxygenation in RA patients using a multimodal photoacoustic-ultrasound (PA/US) imaging system and establish its correlation with disease activity. METHODS: A retrospective study was conducted on 111 patients with RA and 72 healthy controls from 2022 to 2023. Dual-wavelength PA imaging quantified oxygen saturation (So2) levels in the synovial membrane and peri-wrist region. Oxygenation states were categorised as hyperoxia, intermediate oxygenation, and hypoxia based on So2 values. The association between oxygenation levels and the clinical disease activity index was evaluated using a one-way analysis of variance, complemented by the Kruskal-Wallis test with Bonferroni adjustment. RESULTS: Of the patients with RA, 39 exhibited hyperoxia, 24 had intermediate oxygenation, and 48 had hypoxia in the wrist extra-synovial tissue. All of the control participants exhibited the hyperoxia status. Oxygenation levels in patients with RA correlated with clinical metrics. Patients with intermediate oxygenation had a lower disease activity index compared with those with hypoxia and hyperoxia. CONCLUSION: A significant correlation exists between wrist extra-synovial tissue oxygenation and disease activity in patients with RA.

Characteristics and Correlations of Wall Shear Stress and Flow Turbulence in the Carotid Bifurcation Evaluated Using an Ultrasound Vector Flow Imaging.

INTRODUCTION: The aim of the study was to evaluate characteristics and provide the normal values of wall shear stress (WSS) and flow turbulence (Tur), and the relationship between them in the carotid bifurcation based on an ultrasound vector flow imaging (V Flow) in healthy adults. METHODS: Max and mean WSS and Tur values at three segments (initial segments of internal and external carotid arteries [IICA and IECA]; distal segment of common carotid artery [DCCA]), both in anterior and posterior walls, were successfully obtained in 56 healthy adults, using ultrasound V Flow function. Relationship between mean WSS and Tur was further explored. RESULTS: The mean WSS value was 0.71 Pa, 0.86 Pa, and 0.96 Pa at IICA, IECA, and DCCA, respectively (IICA < IECA < DCCA, p < 0.05). The mean Tur value was 13.85%, 5.46%, and 4.17% at IICA, IECA, and DCCA, respectively (IICA > IECA > DCCA, p < 0.05). A cutoff value (WSS = 0.4 Pa) was selected and Tur values were significantly higher in group with WSS cutoff value <0.4 Pa than group with WSS cutoff value ≥0.4 Pa (p < 0.01). CONCLUSION: WSS and Tur are moderately negatively correlated, which can be used in the quantitative evaluation of carotid bifurcation and could be a potential dual-parameter tool in the clinical research for early detection of carotid atherosclerosis.

Molecular Modeling of the Fluorination Effect on the Penetration of Nanoparticles across Lipid Bilayers.

The fluorinated decorations have recently been widely used in many biomedical applications. However, the potential mechanism of the fluorination effect on the cellular delivery of nanoparticles (NPs) still remains elusive. In this work, we systemically explore the penetration of a perfluoro-octanethiol-coated gold NP (PF-Au NP) and, for comparison, an octanethiol-coated gold NP (OT-Au NP) across lipid bilayers. We also investigated the effect of these two types of NPs on the properties of lipid bilayers. Our findings indicate that the lipid type and the surface tension of the lipid bilayer significantly impact the penetration capabilities of the fluorinated gold NP. By examining the distribution of ligands on the surface of the two types of NPs in water and during the penetration process, we unveil their distinct penetration characteristics. Specifically, the PF-Au NP exhibits amphiphobic behavior (both hydrophobic and lipophobic), while the OT-Au NP exhibits solely hydrophobic characteristics. Finally, we observe that the penetration capabilities can be increased by adjusting the degree of fluorination of the ligands on the NP surface. Overall, this study provides useful physical insights into the unique properties of the fluorinated decorations in NP permeation.

Cost-utility analysis of treating mild stage normal tension glaucoma by surgery in China: a decision-analytic Markov model.

BACKGROUND: Many individuals suffer from normal tension glaucoma (NTG) in China. This study utilized Markov models to evaluate the cost-utility of applying many medications and surgery for mild-stage NTG when disease progression occurred at a mild stage. METHODS: A 10-year decision-analytic Markov model was developed for the cost-utility analysis of treating mild-stage NTG with surgery and increased application of medication. We hypothesized that all 100,000 samples with a mean age of 64 were in mild stages of NTG. Transitional probabilities from the mild to moderate to severe stages and the basic parameters acquired from the CNTGS were calculated. Incremental cost-utility ratios (ICUR) were calculated for treating all patients with NTG by probabilistic sensitivity analysis (PSA) and Monte Carlo simulation. One-way sensitivity analysis were conducted by adjusting the progression rate, cost of medications or trabeculectomy, cost of follow-up, and surgical acceptance rate. RESULTS: The ICUR of treating mild stage NTG with medication over 10 years was $12743.93 per quality-adjusted life years (QALYs). The ICUR for treating mild stage NTG patients with a 25% and 50% surgery rate with medication were $8798.93 and $4851.93 per QALYs, respectively. In this model, the cost-utility of treating NTG was sensitive to disease progression rate, surgical treatment rate, and medication costs. CONCLUSIONS: According to the results of the cost-utility analysis, it was a reasonable and advantageous strategy to administer a lot of medication and surgery for NTG in the mild stages of the disease. In the model, the greater the probability of patients undergoing surgery, the strategy becomes more valuable.

Theoretical Study on the Reaction between Carcinogenic 2,5-Dichloro-1,4-benzoquinone and tert-Butyl Hydroperoxide: Self-Catalysis and Water Catalysis.

The potentially carcinogenic halobenzoquinones (HBQs) have been recently identified in drinking water as disinfection byproducts. Several radical intermediates in the reaction of 2,5-dichloro-1,4-benzoquinone (DCBQ) and t-butyl hydroperoxide (t-BuOOH), which may induce DNA damage, were detected experimentally, and metal-independent decomposition reactions of t-BuOOH by DCBQ were proposed. It has not yet been confirmed by theoretical calculations. The theoretical study in this work provides insights into the details of the reaction. An unprecedented self-catalysis mechanism of organic hydroperoxides, that is, the reactant t-BuOOH also has a catalytic effect, was uncovered at the molecular level. Moreover, as the solvent, water molecules also clearly have an efficient catalytic effect. Due to the catalysis of t-BuOOH and water, the metal-independent reaction of t-BuOOH and DCBQ can occur under moderate conditions. Our findings about the novel catalytic effect of organic hydroperoxides t-BuOOH could offer a unique perspective into the design of new catalysts and an understanding of the catalytic biological, environmental, and air pollution reactions. Furthermore, organic hydroperoxide t-BuOOH could serve as a proton shuttle, where the proton transfer process is accompanied by simultaneous charge transfer. Therefore, organic hydroperoxides may disrupt the vital proton transfer process in biological systems and may give rise to unexpected toxicity.

Catalytic PMS oxidation universality of CuFe2O4/MnO2 heterojunctions at multiple application scenarios.

The magnetic CuFe2O4/MnO2 heterojunctions were prepared by hydrothermal method, and the effect of different reaction temperature on the physicochemical properties and catalytic activity was investigated. The CuFe2O4/MnO2 heterojunctions prepared at 100 °C can effectively activate peroxymonosulfate (PMS) at multiple application scenarios for degradation and mineralization of tetracycline, o-nitrophenol and ceftriaxone sodium under indoor light, visible light and dark condition. Additionally, the CuFe2O4/MnO2-PMS system showed high catalytic activity and anti-interference ability for degradation of pharmaceutical pollutants in natural water bodies and industrial wastewater. The TC removal efficiency in Qianhu Lake water, Ganjiang River water and tap water was about 88%, 92% and 89%, respectively. The CuFe2O4/MnO2-PMS system is also effective for actual pharmaceutical wastewater treatment with 77.9% of COD removal efficiency. Interestingly, the reactive species of CuFe2O4/MnO2-PMS system under visible light are different from those in dark condition, and the different catalytic mechanisms at multiple application scenarios were proposed. This work provides new insights into mechanism exploration of heterojunction catalyst for PMS activation.

24-Hour movement behaviors and executive functions in preschoolers: A compositional and isotemporal reallocation analysis.

This cross-sectional study explored the relationship between 24-hour movement behaviors and executive function (EF) in preschool children. A total of 426 Han Chinese preschoolers (231 males; 3.8 ± 0.6 years old) from Zhuhai, Guangdong Province, China were selected from October 2021 to December 2021. Accelerometers were used to measure physical activity (PA) and sedentary behavior (SB), while sleep duration was obtained via a parent-report questionnaire. Components of EF (cognitive flexibility, inhibitory control, and working memory) were assessed using computerized behavioral tasks. The daily composition was significantly associated with inhibitory control and working memory. Inhibitory control improvements were linked to the addition of moderate-to-vigorous physical activity (MVPA) at the expense of SB and sleep. The reallocation between MVPA, SB, sleep, and light physical activity yielded a significant association with working memory.

Mortality of Peritoneal Dialysis versus Hemodialysis in Older Adults: An Updated Systematic Review and Meta-Analysis.

INTRODUCTION: The optimal choice of dialysis modality remains contentious in older adults threatened by advanced age and high risk of comorbidities. METHODS: We conducted a systematic review and meta-analysis of cohort and case-control studies to assess mortality risk between peritoneal dialysis (PD) and hemodialysis (HD) in older adults using PubMed, Embase, and the Cochrane Library database from inception to June 1, 2022. The outcome of interest is all-cause mortality. RESULTS: Thirty-one eligible studies with >774,000 older patients were included. Pooled analysis showed that PD had a higher mortality rate than HD in older dialysis population (HR 1.17, 95% CI: 1.10-1.25). When stratified by co-variables, our study showed an increased mortality risk of PD versus HD in older patients with diabetes mellitus or comorbidity who underwent longer dialysis duration (more than 3 years) or who started dialysis before 2010. However, definitive conclusions were constrained by significant heterogeneity. CONCLUSION: From the survival point of view, caution is needed to employ PD for long-term use in older populations with diabetes mellitus or comorbid conditions. However, a tailored treatment choice needs to take account of what matters to older adults at an individual level, especially in the context of limited survival improvements and loss of quality of life. Further research is still awaited to conclude this topic.

The association between mammographic density and breast cancer risk in Chinese women: a systematic review and meta-analysis.

PURPOSE: Breast density has consistently been shown to be an independent risk factor for breast cancer in Western populations; however, few studies have evaluated this topic in Chinese women and there is not yet a unified view. This study investigated the association between mammographic density (MD) and breast cancer risk in Chinese women. METHODS: The PubMed, Cochrane Library, Embase, and Wanfang databases were systematically searched in June 2023 to include all studies on the association between MD and breast cancer risk in Chinese women. A total of 13,977 breast cancer cases from 14 studies were chosen, including 10 case-control/cross-sectional studies, and 4 case-only studies. For case-control/cross-sectional studies, the odds ratios (ORs) of MD were combined using random effects models, and for case-only studies, relative odds ratios (RORs) were combinations of premenopausal versus postmenopausal breast cancer cases. RESULTS: Women with BI-RADS density category II-IV in case-control/cross-sectional studies had a 0.93-fold (95% confidence interval [CI] 0.55, 1.57), 1.08-fold (95% CI 0.40, 2.94), and 1.24-fold (95% CI 0.42, 3.69) higher risk compared to women with the lowest density category. Combined RORs for premenopausal versus postmenopausal women in case-only studies were 3.84 (95% CI 2.92, 5.05), 22.65 (95% CI 7.21, 71.13), and 42.06 (95% CI 4.22, 419.52), respectively, for BI-RADS density category II-IV versus I. CONCLUSIONS: For Chinese women, breast cancer risk is weakly associated with MD; however, breast cancer risk is more strongly correlated with mammographic density in premenopausal women than postmenopausal women. Further research on the factors influencing MD in premenopausal women may provide meaningful insights into breast cancer prevention in China.

A deep learning-based calculation system for plaque stenosis severity on common carotid artery of ultrasound images.

OBJECTIVES: Assessment of plaque stenosis severity allows better management of carotid source of stroke. Our objective is to create a deep learning (DL) model to segment carotid intima-media thickness and plaque and further automatically calculate plaque stenosis severity on common carotid artery (CCA) transverse section ultrasound images. METHODS: Three hundred and ninety images from 376 individuals were used to train (235/390, 60%), validate (39/390, 10%), and test (116/390, 30%) on a newly proposed CANet model. We also evaluated the model on an external test set of 115 individuals with 122 images acquired from another hospital. Comparative studies were conducted between our CANet model with four state-of-the-art DL models and two experienced sonographers to re-evaluate the present model's performance. RESULTS: On the internal test set, our CANet model outperformed the four comparative models with Dice values of 95.22% versus 90.15%, 87.48%, 90.22%, and 91.56% on lumen-intima (LI) borders and 96.27% versus 91.40%, 88.94%, 91.19%, and 92.88% on media-adventitia (MA) borders. On the external test set, our model still produced excellent results with a Dice value of 92.41%. Good consistency of stenosis severity calculation was observed between CANet model and experienced sonographers, with Intraclass Correlation Coefficient (ICC) of 0.927 and 0.702, Pearson's Correlation Coefficient of 0.928 and 0.704 on internal and external test set, respectively. CONCLUSIONS: Our CANet model achieved excellent performance in the segmentation of carotid IMT and plaques as well as automated calculation of stenosis severity.

Persistence of dissolved organic matter in sediments influenced by environmental factors：Implication for nutrition and carbon cycle.

The persistence of dissolved organic matter (DOM) plays a crucial role in the cycling and distribution of carbon and nutrients. Nonetheless, our understanding of how environmental alterations affect the persistence of sedimentary DOM remains incomplete. Excitation Emission Fluorescence Matrix-Parallel Factor Analysis (EEM-PARAFAC) was used to examine the fluorescence and compositional characteristics of hydrophilic and hydrophobic DOM (separated using XAD-8 resin) within sediments from twelve lakes and reservoirs. Fluorescence analysis indicated that DOM persistence is dependent on the proportions of the three components derived from PARAFAC. The Mantel test showed that climatic factors had the most significant impact on DOM persistence (Mantel's r = 0.46-0.54, Mantel's p = 0.001-0.007), while anthropogenic (Mantel's r = 0.24-0.32, Mantel's p = 0.03-0.05) and hydrological factors (Mantel's r = 0.03-0.22, Mantel's p = 0.06-0.40) had a somewhat lesser influence. Environmental changes resulted in a consistent decline in DOM persistence from Northeast to Southwest China, accompanied by an increase in gross primary productivity (GPP). Reduced DOM persistence due to climate, hydrological, and anthropogenic factors may lead to elevated concentrations of total phosphorus (TP), contributing to deteriorating water quality and events such as algal blooms. The decline in water quality due to reduced DOM persistence in lakes with high GPP can exacerbate the transition from carbon sinks to carbon sources. Consequently, the persistence of sedimentary DOM significantly influences nutrient and carbon cycling in lakes. Investigating DOM persistence in lakes across diverse geographic locations offers a new perspective on lake eutrophication and carbon emissions. Furthermore, it is crucial to develop targeted recommendations for lake restoration and management.

Impact of primary glaucoma on health-related quality of life in China: the handan eye study.

BACKGROUND: We assessed health-related quality of life (HRQOL) and its determinants among rural glaucoma participants compared to age-matched normal controls in the population-based Handan Eye Study (HES), in rural Yongnian County, northern China. METHODS: We enrolled 99 adults with glaucoma (mean age 63.0 ± 11.0 years), including primary open-angle glaucoma (POAG, n = 67) and primary angle-closure glaucoma (PACG, n = 32) and 102 controls (mean age 58.5 ± 5.3 years) with normal visual acuity and visual field and no history of glaucoma. Results of ophthalmic examinations and socioeconomic data were recorded. HRQOL was measured using the EQ-5D (converted to utility valves, UVs), and visual function (VF) and vision-related quality of life (VRQOL) were evaluated using the visual function-quality of life (VF-QOL) instrument. PRIMARY AND SECONDARY OUTCOME MEASURES: EQ-5D and VF-QOL scores. RESULTS: The mean UVs, VF, and VRQOL scores for glaucoma cases were 0.98 ± 0.04, 87.9 ± 15.2, and 95.5 ± 12.8, respectively, significantly worse than VF (94.4 ± 4.4) and VRQOL (100.0 ± 0.0) among controls, even after adjusting for age, gender, educational level, and family income (P = 0.015, P = 0.033). UVs were significantly lower among glaucoma participants with impaired VRQOL (55.4 ± 11.5) compared to those with normal VRQOL scores (99.1 ± 2.8) (UVs: 0.92 ± 0.08 vs. 0.99 ± 0.03, P = 0.036), also after adjustment for age and family income (P = 0.006). Participants with PACG had significantly lower VF and VRQOL scores compared to POAG (77.8 ± 21.4 vs. 92.9 ± 6.8, P < 0.001; 89.0 ± 18.1 vs. 98.7 ± 7.5, P < 0.001). CONCLUSION: Participants with glaucoma have worse visual function and related quality of life compared to age-matched normal population controls. Participants with PACG have lower VF and VRQOL compared to those with POAG. UVs can be used for cost-effectiveness research and to support public health strategies for glaucoma in rural China.

Blood Flow Turbulence Quantification of Carotid Artery With a High-Frame Rate Vector Flow Imaging.

OBJECTIVES: To assess the feasibility and performance of Turbulence (Tur) index as a quantitative tool for carotid artery flow turbulence; to detect and compare the blood flow patterns of common carotid artery (CCA) and carotid bulb (CB) at different ages and cardiac phases in healthy adults, and thus interpret the evolvement of etiology difference between CCA and CB. METHODS: Carotid flow characteristics of 40 healthy volunteers were evaluated quantitatively by a high-frame rate vector flow imaging. Three types of flow patterns were defined depending on the distributive range of complex flow during systole in CB. Comparison of mean Tur value in CCA and CB at different age groups and cardiac phases was performed. And the correlation between Tur value and the diameter ratio of proximal internal carotid artery to common carotid artery (DRpro-ica/cca) was tested. RESULTS: Mean Tur values in CB were remarkably higher than that in CCA, whether during systole or diastole (P < .001). Meanwhile Tur values in CB during systole were significantly higher than that during diastole (P < .001). Flow complexity of CB showed variations among 40 participants especially in systole, whereas the flow pattern of CCA was relatively consistent. Mean Tur values were positively correlated with DRpro-ica/cca in CB (ρ = 0.69, P < .05). CONCLUSIONS: V Flow imaging provided a reliable method-Tur, for quantitative analysis of carotid blood flow. It had potential to be further applied in distinguishing complex hemodynamic characteristics in high-risk people of carotid diseases for the risk stratification of cardiovascular events.

Precise evaluation of blood flow patterns in human carotid bifurcation based on high-frame-rate vector flow imaging.

PURPOSE: To investigate the feasibility of high-frame-rate vector flow imaging (HiFR-VFI) compared to ultrasound color Doppler flow imaging (CDFI) for precisely evaluating flow characteristics in the carotid bifurcation (CB) of presumed healthy adults. METHODS: Forty-three volunteers were assessed for flow characteristics and their extensions using HiFR-VFI and CDFI in CBs. The flow patterns were classified according to the streamlines in HiFR-VFI and quantitatively measured using an innovative turbulence index (Tur-value). Interobserver agreement was also assessed. RESULTS: HiFR-VFI was consistent with CDFI in detecting laminar and nonlaminar flow in 81.4% of the cases; however, in 18.6% of the cases, only HiFR-VFI identified the nonlaminar flow. HiFR-VFI showed a larger extension of complex flow (0.37 ± 0.26 cm2 ) compared to CDFI (0.22 ± 0.21 cm2 ; p < 0.05). The flow patterns were classified into four types: 3 type-I (laminar flow), 35 type-II (rotational flow), 27 type-III (reversed flow), and 5 type-IV (complex flow). The Tur-value of type-IV (50.03 ± 14.97)% is larger than type-III (44.57 ± 8.89)%, type-II (16.30 ± 8.16)%, and type-I (1.48 ± 1.43)% (p < 0.05). Two radiologists demonstrated almost perfect interobserver agreement on recognizing the change of streamlines (κ = 0.81, p < 0.001). The intraclass correlation coefficient of the Tur-value was 0.98. CONCLUSION: HiFR-VFI can reliably characterize complex hemodynamics with quantitative turbulence measurement and may be an auxiliary diagnostic tool for assessing atherosclerotic arterial disease.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation.

Mediator of IRF3 activation (MITA, also named as STING/ERIS/MPYS/TMEM173), is essential to DNA virus- or cytosolic DNA-triggered innate immune responses. In this study, we demonstrated the negative regulatory role of RING-finger protein (RNF) 90 in innate immune responses targeting MITA. RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation. Overexpression of RNF90 inhibited HSV-1- or cytosolic DNA-induced immune responses whereas RNF90 knockdown had the opposite effects. Moreover, RNF90-deficient bone marrow-derived dendritic cells (BMDCs), bone marrow-derived macrophages (BMMs) and mouse embryonic fibroblasts (MEFs) exhibited increased DNA virus- or cytosolic DNA-triggered signaling and RNF90 deficiency protected mice from DNA virus infection. Taken together, our findings suggested a novel function of RNF90 in innate immunity.

Vision-related quality of life in patients with glaucoma: the role of illness perceptions.

PURPOSE: To explore the predictive effects of illness perceptions on vision-related quality of life (VRQoL) in Chinese glaucoma patients. METHODS: In this cross-sectional study, 97 patients with glaucoma completed the brief illness perception questionnaire (BIPQ), the glaucoma quality of life-15 (GQL-15) questionnaire, and a questionnaire regarding sociodemographic and clinical information. A correlation analysis and hierarchical linear regression analysis were performed. RESULTS: The BIPQ total score was positively correlated with the total score of the GQL-15 questionnaire and the scores of its four dimensions. Chronic comorbidities, the type of glaucoma, the best-corrected visual acuity (BCVA), the mean defect (MD) of visual field in the better eye, and identity in the BIPQ were critical predictors of VRQoL. Illness perceptions independently accounted for 7.8% of the variance in the VRQoL of glaucoma patients. CONCLUSIONS: Patients with stronger illness perceptions and those who perceive themselves as having more glaucoma symptoms are likely to experience worse VRQoL. Illness perceptions in glaucoma patients deserve clinical attention, and further studies are needed to examine whether cognitive interventions targeting illness perceptions can improve VRQoL.

Rational design and synthesis of Oreoch-2 analogues as efficient broad-spectrum antimicrobial peptides.

In recent years, bacterial resistance has risen sharply, which seriously endangers public health due to the abuse of antibiotics and the lack of new antibiotics. Therefore, there is an urgent need for new antimicrobial agents to combat multidrug-resistant (MDR) bacterial infections. In this paper, six Oreoch-2 analogues were rationally designed and efficiently synthesized by using the truncation strategy with Oreoch-2 as the lead compound. Evaluation of these analogues against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed. Among them, ZN-5 and ZN-6 were identified to be broad-spectrum effective analogues, which were superior to their parent peptide Oreoch-2. In addition, ZN-5 and ZN-6 had good stability to the physiological environment, and much higher selectivity to bacterial cells than to mammalian cells. Time-kill kinetics and transmission electron microscope (TEM) studies suggested that these analogues were typical bactericidal agents and quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. Moreover, ZN-5 and ZN-6 could inhibit biofilm formation of Staphylococcus aureus ATCC25923. Compared with their parent peptide Oreoch-2, ZN-5 and ZN-6 not only possessed shortened peptide chains, but also showed slightly improved antibacterial activity and greatly reduced hemolysis. This indicates that they are ideal lead compounds of antimicrobial peptides, which can be developed as substitutes for traditional antibiotics.

Acridinium-conjugated aromatic heterocycles as highly potent FtsZ inhibitors: Design, synthesis, and biological evaluation.

The epidemic of multidrug resistance (MDR) is a serious threat to public health, and new classes of antibiotics with novel mechanisms of action are in critical need. We rationally designed and efficiently synthesized three series of new chemical entities with potential antibacterial activity targeting filamenting temperature-sensitive mutant Z (FtsZ). Evaluation of these compounds against a panel of Gram-positive bacteria including MDR and vancomycin-resistant Enterococcus strains indicated that most compounds showed enhanced antibacterial efficacy, comparable or even superior to the reference drugs. The newly synthesized compounds proved to be substrates of the Escherichia coli efflux pump AcrB, thus affecting the activity. Their structure-activity relationships were summarized in detail. The most potent compound 10f quickly eliminated bacteria in a bactericidal mode, with low susceptibility to induce bacterial resistance. Further mechanistic studies with the BsFtsZ protein revealed that 10f functioned as an effective FtsZ inhibitor through altering the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which leads to inhibition of cell division and cell death. Besides, 10f not only displayed no obvious cytotoxicity to mammalian cells but also had a high efficacy in a murine model of bacteremia in vivo. Regarded as a whole, our findings highlight 10f as a promising new FtsZ-targeting bactericidal agent.

Sulfur-Doped Quintuple [9]Helicene with Azacorannulene as Core.

Herein, a hetero(S,N)-quintuple [9]helicene (SNQ9H) molecule with an azacorannulene core was synthesized, currently representing the highest hetero-helicene reported in the field of multiple [n]helicenes. X-ray crystallography indicated that SNQ9H includes not only a propeller-shaped conformer SNQ9H-1, but also an unforeseen quasi-propeller-shaped conformer SNQ9H-2. Different conformers were observed for the first time in multiple [n≥9]helicenes, likely owing to the doping of heteroatomic sulfurs in the helical skeletons. Remarkably, the ratio of SNQ9H-1 to SNQ9H-2 can be regulated in situ by the reaction temperature. Experimental studies on the photophysical and redox properties of SNQ9H and theoretical calculations clearly demonstrated that the electronic structures of SNQ9H depend on their molecular conformations. The strategy of introducing heteroatomic sulfurs into the helical skeleton may be useful in constructing various conformers of higher multiple [n]helicenes in the future.