Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.

A logic-incorporated gene regulatory network deciphers principles in cell fate decisions.

Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.

Measuring Patient-Reported Use and Outcomes From Complementary and Integrative Health Therapies: Development of the Complementary and Integrative Health Therapy Patient Experience Survey.

Background: Assessing the use and effectiveness of complementary and integrative health (CIH) therapies via survey can be complicated given CIH therapies are used in various locations and formats, the dosing required to have an effect is unclear, the potential health and well-being outcomes are many, and describing CIH therapies can be challenging. Few surveys assessing CIH therapy use and effectiveness exist, and none sufficiently reflect these complexities. Objective: In a large-scale Veterans Health Administration (VA) quality improvement effort, we developed the "Complementary and Integrative Health Therapy Patient Experience Survey", a longitudinal, electronic patient self-administered survey to comprehensively assess CIH therapy use and outcomes. Methods: We obtained guidance from the literature, subject matter experts, and Veteran patients who used CIH therapies in designing the survey. As a validity check, we completed cognitive testing and interviews with those patients. We conducted the survey (March 2021-April 2023), inviting 15,608 Veterans with chronic musculoskeletal pain with a recent CIH appointment or referral identified in VA electronic medical records (EMR) to participate. As a second validity check, we compared VA EMR data and patient self-reports of CIH therapy utilization a month after survey initiation and again at survey conclusion. Results: The 64-item, electronic survey assesses CIH dosing (amount and timing), delivery format and location, provider location, and payor. It also assesses 7 patient-reported outcomes (pain, global mental health, global physical health, depression, quality of life, stress, and meaning/purpose in life), and 3 potential mediators (perceived health competency, healthcare engagement, and self-efficacy for managing diseases). The survey took 17 minutes on average to complete and had a baseline response rate of 45.3%. We found high degrees of concordance between self-reported and EMR data for all therapies except meditation. Conclusions: Validly assessing patient-reported CIH therapy use and outcomes is complex, but possible.

Arsenic exposure causes decline in sperm motility accompanied by energy metabolism disorders in mouse testes.

Arsenic (As) is a notorious environmental toxicant widely present in various natural environments. As exposure has been correlated with the decline in sperm motility. Yet, the mechanism has not been fully elucidated. Adult male C57 mice were given 0, 1, or 15 mg/L NaAsO2 for 10 weeks. The mature seminiferous tubules and sperm count were decreased in As-exposed mice. Sperm motility and several sperm motility parameters, including average path velocity (VAP), straight-line velocity (VSL), curvilinear velocity (VCL), beat-cross frequency (BCF), linearity (LIN), straightness (STR), and amplitude of lateral head displacement (ALH), were declined in As-exposed mice. RNA sequencing and transcriptomics analyses revealed that differentially expressed genes (DEGs) were mainly enriched in metabolic pathways. Untargeted metabolomics analyses indicated that energy metabolism was disrupted in As-exposed mouse testes. Gene set enrichment analysis showed that glycolysis and oxidative phosphorylation were disturbed in As-exposed mouse testes. As-induced disruption of testicular glucose metabolism and oxidative phosphorylation was further validated by RT-PCR and Western blotting. In conclusion, As exposure causes decline in sperm motility accompanied by energy metabolism disorders in mouse testes.

Long-term variations in surface ozone at the Longfengshan Regional Atmosphere Background Station in Northeast China and related influencing factors.

Surface ozone (O3) is a crucial air pollutant that affects air quality, human health, agricultural production, and climate change. Studies on long-term O3 variations and their influencing factors are essential for understanding O3 pollution and its impact. Here, we conducted an analysis of long-term variations in O3 during 2006-2022 at the Longfengshan Regional Atmosphere Background Station (LFS; 44.44°N, 127.36°E, 330.5 m a.s.l.) situated on the northeastern edge of the Northeast China Plains. The maximum daily 8-h average (MDA8) O3 fluctuated substantially, with the annual MDA8 decreasing significantly during 2006-2015 (-0.62 ppb yr-1, p < 0.05), jumping during 2015-2016 and increasing clearly during 2020-2022. Step multiple linear regression models for MDA8 were obtained using meteorological variables, to decompose anthropogenic and meteorological contributions to O3 variations. Anthropogenic activities acted as the primary drivers of the long-term trends of MDA8 O3, contributing 73% of annual MDA8 O3 variability, whereas meteorology played less important roles (27%). Elevated O3 at LFS were primarily associated with airflows originating from the North China Plain, Northeast China Plain, and coastal areas of North China, primarily occurring during the warm months (May-October). Based on satellite products of NO2 and HCHO columns, the O3 photochemical regimes over LFS revealed NOx-limited throughout the period. NO2 increased first, reaching peak in 2011, followed by substantial decrease; while HCHO exhibited significant increase, contributing to decreasing trend in MDA8 O3 during 2006-2015. The plateauing NO2 and decreasing HCHO may contribute to the increase in MDA8 O3 in 2016. Subsequently, both NO2 and HCHO exhibited notable fluctuations, leading to significant changes in O3. The study results fill the gap in the understanding of long-term O3 trends in high-latitude areas in the Northeast China Plain and offer valuable insights for assessing the impact of O3 on crop yields, forest productivity, and climate change.

Gastrointestinal Tract Granular Cell Tumor in the Pediatric Population: A Multicenter Experience.

BACKGROUND: Pediatric granular cell tumors (GCT) involving the gastrointestinal tract (GIT) are rare with limited case report/series reported to date. METHODS: Multicenter retrospective study of pediatric GIT GCT. RESULTS: A total of 10 cases were included in the study with a median age of 13.5 years (range: 7-18 years) and were predominantly female patients (60%). In half of the patients no significant medical history was present with the remaining 5 having Crohn disease (10%), eosinophilic esophagitis (EoE) (10%), Crohn disease and EoE (10%), growth hormone deficiency (10%), and aplasia cutis congenita (10%). The GCT median size was 1.3 cm (range: 1-1.6 cm) and were more commonly located in the esophagus (70%) followed by the stomach (20%) and rectum (10%). Most of the cases showed round/polygonal tumor cells with abundant granular cytoplasm, and none of the cases had nuclear atypia, increased mitotic activity, or tumor cell necrosis. None of our cases received specific therapy for GCT other than clinical follow-up, and none of the patients had evidence of local recurrence or metastatic disease. CONCLUSION: We present our multicenter experience with GIT GCT, all cases had a benign course. Interestingly, 4 of the esophageal GCT cases (including 2 patients with EoE) showed an eosinophil-rich esophagitis in the underlying mucosa.

Self-powered molecularly imprinted photoelectrochemical sensor based on Ppy/QD/HOF heterojunction for the detection of bisphenol A.

As an emerging porous material, hydrogen-bonded organic framework materials (HOFs) still pose application challenges. In this work, the designed type "I + II" heterojunction extracted hot electrons from HOFs using quantum dots (QDs) and polypyrrole (Ppy), improving the stability and photoelectrochemical performance of materials. In addition to serving as a potential well, electropolymerized Ppy was used as a recognition element for bisphenol A (BPA), and a novel self-powered molecularly imprinted photoelectrochemical (MIP-PEC) sensor was designed. The sensing platform showed a linear relationship from 1 × 10-10 to 1 × 10-7 mol∙L-1 and from 1 × 10-7 to 1 mol∙L-1 with an acceptable detection limit of 4.2 × 10-11 mol∙L-1. This is the first application of HOFs in constructing MIP-PEC sensors and a new attempt to improve the stability of HOFs for the application of porous crystal materials in the sensing field.

Outcomes of antiretroviral treatment for 0-14-year-old children living with HIV in Ganzhou, China, 2006-2023.

BACKGROUND: Studies on antiretroviral therapy (ART) in children living with HIV (CLHIV) are limited due to the small population and low accession rate of ART. METHODS: All 0-14-year-old CLHIV admitted to the Ganzhou Center for Disease Control and Prevention from January 2006 to June 2023 were included retrospectively. The information of treatment regimens, disease progression, and laboratory tests of the patients under ART were used to explore the outcomes and impacts of long-term ART. The normality of all the data was tested by the Shapiro-Wilk test. RESULTS: From 2006 to 2023, 18 CLHIV were reported in Ganzhou. Among them, 11 received ART and were followed up for 60.0 ± 48.4 months. After receiving ART, the median viral load of them decreased from 89,600 copies/ml to 22 copies/ml (P = 0.007), the median CD4+ T cell count increased from 380.7 cells/µL to 661.9 cells/µL (P = 0.028), and the median CD8+ T cell count decreased from 1065.8 cells/µL to 983.3 cells/µL (P = 0.584). The laboratory test results regarding liver function, renal function, blood cell count, and glucolipid metabolism tended to be within normal reference ranges, and the mean height-for-age z-score and weight-for-age z-score increased. However, all the three CLHIV who received cotrimoxazole developed pneumocystis carinii pneumonia, upper respiratory infection, skin lesions, bacterial pneumonia and/or thrush; the mean body-mass-index-for-age z-score decreased from 0.52 to -0.63. CONCLUSION: For CLHIV, ART could effectively inhibit the replication of HIV and improve the immune function of patients. More studies that focus on ART in CLHIV are urgently needed.

Laparoscopic pyelotomy combined with ultrasonic lithotripsy via a nephroscope for the treatment of complex renal stones.

The purpose of the study was to introduce a novel surgical approach of combining laparoscopic pyelotomy with ultrasonic lithotripsy via a nephroscope for the treatment of complex renal stones. Between May 2021 and April 2023, 32 patients underwent laparoscopic pyelotomy combined with ultrasonic lithotripsy via a nephroscope and their perioperative variables were retrospectively collected and outcomes were assessed. Dissection and incision of the anterior renal pelvis wall was performed via a laparoscope. A 19.5 F nephroscope was introduced into the renal pelvis through a laparoscopic trocar from the incision. Stones were fragmented and sucked out using a 3.3 mm ultrasonic probe placed through the nephroscope. All operations were completed successfully and the stone-free rate at 3 days after operation was 87.5% (28/32). Four (12.5%, 4/32) patients with staghorn stones had a small residual stone in the lower calyx after operation and did not require reintervention. No patient required perioperative transfusion and four (12.5%, 4/32) patients with struvite stones developed postoperative fever, which was successfully treated with intravenous antibiotics. The mean follow-up time was 14.0 ± 7.2 months, with no patient developing long-term complications. This approach offers a safe and effective treatment option for complex renal stones, as the method exhibits a high clearance rate with few complications.

Alpha-Emitter Radium-223 Induces STING-Dependent Pyroptosis to Trigger Robust Antitumor Immunity.

Radium-223 (223 Ra) is the first-in-class alpha-emitter to mediate tumor eradication, which is commonly thought to kill tumor cells by directly cleaving double-strand DNA. However, the immunogenic characteristics and cell death modalities triggered by 223 Ra remain unclear. Here, it is reported that the 223 Ra irradiation induces the pro-inflammatory damage-associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223 Ra retards tumor progression by triggering pyroptosis, an immunogenic cell death. Mechanically, 223 Ra-induced DNA damage leads to the activation of stimulator of interferon genes (STING)-mediated DNA sensing pathway, which is critical for NLRP3 inflammasome-dependent pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha-emitter 223 Ra-induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy.

The mitochondrial-endoplasmic reticulum co-transfer in dental pulp stromal cell promotes pulp injury repair.

Dental pulp injury remains a clinical challenge with limited therapeutic approaches. In the present study, we sought to prove that dental pulp stromal cells (DPSCs) mitochondrial transfer could promote dental pulp injury repair and endoplasmic reticulum (ER)-mitochondrial contacts have a significant regulatory effect on mitochondrial transfer. Healthy DPSCs were co-cultured directly or indirectly with injured DPSCs in the first molar of 1-2 month SD rats or in vitro. Mitochondrial transfer was observed after 24 h of co-culture using fluorescence microscopy and live cell workstation. After co-culture for 1W, 8-OhdG immunofluorescence, mitochondrial membrane potential and total oxidant status/total antioxidant status were used to detect the mitochondrial function of injured DPSCs before and after mitochondrial transfer. Subsequently, mitochondria-ER co-transfer was regulated by modulating mitochondria-ER binding in healthy DPSCs, and the results of GRP78 and CHOP in DPSCs, and PDI immunofluorescence and haematoxylin and eosin staining of pulp tissue were analysed to clarify the effects of modulating mitochondria-ER co-transfer on endoplasmic reticulum stress (ERS), and on pulp injury repair. Fluorescence microscopy and live cell workstation results showed significant mitochondrial transfer between DPSCs. Meanwhile, mitochondrial transfer significantly restored mitochondrial function in injured DPSCs. By modulating mitochondrial-ER binding, the efficiency of mitochondrial transfer between DPSCs was significantly affected and had an impact on ERS in injured cells. Mitochondrial transfer of DPSCs significantly promotes pulpal injury repair and functional recovery of damaged DPSCs, and mitochondrial transfer of DPSCs is regulated by mitochondria-ER binding.

Medulla Tetrapanacis water extract alleviates inflammation and infection by regulating macrophage polarization through MAPK signaling pathway.

Medulla Tetrapanacis (MT) is a commonly used herb to promote lactation and manage mastitis in lactating mothers. However, its anti-inflammatory and anti-bacterial effects are currently unknown. We hypothesized that MT water extract possesses anti-inflammatory and anti-bacterial effects by modulating macrophage polarization to reduce the release of inflammatory mediators and phagocytosis via inactivation of MAPKs pathways. The chemical composition of the MT water extract was analyzed by UPLC-Orbitrap-mass spectrometry. The anti-inflammatory and anti-bacterial properties of the MT water extract were examined using LPS-stimulated inflammation and Staphylococcus aureus infection model in RAW 264.7 cells, respectively. The underlying mechanism of action of the MT water extract was also investigated. We identified eight compounds by UPLC-Orbitrap-mass spectrometry that are abundant within the MT water extract. MT water extract significantly suppressed LPS-induced nitric oxide, TNF-α and IL-6 secretion in RAW 264.7 cells which was accompanied by the promotion of macrophage polarization from pro-inflammatory towards anti-inflammatory phenotypes. MT water extract significantly suppressed the LPS-induced MAPK activation. Finally, MT water extract decreased the phagocytic capacity of the RAW 264.7 cells against S. aureus infection. MT water extract could suppress LPS-induced inflammation by promoting macrophages towards an anti-inflammatory phenotype. In addition, MT also inhibited the growth of S. aureus.

Severe photochemical pollution formation associated with strong HONO emissions from dew and guttation evaporation.

The unknown daytime source of HONO has been extensively investigated due to unexplained atmospheric oxidation capacity and current modelling bias, especially during cold seasons. In this study, abrupt morning increases in atmospheric HONO at a rural site in the North China Plain (NCP) were observed almost on daily basis, which were closely linked to simultaneous rises in atmospheric water vapor content and NH3 concentrations. Dew and guttation water formation was frequently observed on wheat leaves, from which water samples were taken and chemically analyzed for the first time. Results confirmed that such natural processes likely governed the daily nighttime deposition and daytime release of HONO and NH3, which have not been considered in the numerous HONO budget studies investigating its large missing daytime source in the NCP. The dissolved HONO and NH3 in leaf surface water droplets reached 1.4 and 23 mg L-1 during the morning on average, resulting in averaged atmospheric HONO and NH3 increases of 0.89 ± 0.61 and 43.7 ± 29.3 ppb during morning hours, with relative increases of 186 ± 212 % and 233 ± 252 %, respectively. The high atmospheric oxidation capacity contained within HONO was stored in near surface liquid water (such as dew, guttation and soil surface water) during nighttime, which prevented its atmospheric dispersion after sunset and protected it from photodissociation during early morning hours. HONO was released in a blast during later hours with stronger solar radiation, which triggered and then accelerated daytime photochemistry through the rapid photolysis of HONO and subsequent OH production, especially under high RH conditions, forming severe secondary gaseous and particulate pollution. Results of this study demonstrate that global ecosystems might play significant roles in atmospheric photochemistry through nighttime dew formation and guttation processes.

Network evolution of diffusion in enterprise digitalization and intellectualization transformation: A technology-organization-environment framework perspective.

Enterprise digitalization and intellectualization (EDI) is a crucial aspect of China's modernization process. However, uncertainty in market and business decisions hinders the EDI diffusion process in China. Therefore, this research aims to solve the uncertainty problem of EDI diffusion by examining market demand and government policy coordination. First, we utilize complex network game theory and establish a technology-organization-environment framework for the factors that influence the elements of EDI transformation by combining evidence from existing studies. Second, the network game model is constructed to analyze and optimize the updating rules in the network as a diffusion strategy that enterprises under the uncertain market can adopt. Finally, the impact of adjusting government subsidies and different premiums on the diffusion of EDI transformation strategies is examined. The degree of market diffusion and average revenue of EDI are higher after the optimization of network node strategy updating rules compared to before optimization. Further analysis reveals that only the premium effect of product pricing and inverted U-shaped subsidy support from the government affect the degree of market diffusion and the average revenue of EDI, while the other premium effects are not significant. These findings enrich research related to complex networks and nonlinear dynamic strategies. They also indicate recommendations for government policies to enhance diffusion efficiency and reasonable pricing for enterprises to promote returns.

Government intervention, industrial structure, and energy eco-efficiency: an empirical research on new energy demonstration in cities.

This study investigates the relationships among government intervention, industrial structure, and energy eco-efficiency (EE). Energy eco-efficiency was measured based on a non-radial directional distance function for 236 cities in China from 2005 to 2019. Additionally, the difference-in-difference model (DID) method and spatial econometric models were used to analyse the impact of government intervention and industrial structure on energy eco-efficiency and their spatial spill-over effects. Government intervention includes fiscal expenditures and policy orientation for new energy demonstration construction. Our results indicate that: China's EE has a fluctuating upward trend and increased 17.85% in the period, and its spatial distribution imbalance gradually developed into a regional distribution balance. Moreover, government intervention and adjustment of the industrial structure improved urban energy eco-efficiency by 7.43% and 0.92%, respectively, which also has spatial spill-over effects in neighbouring regions. Furthermore, economic development, technological innovation, and foreign direct investment enable EE. However, urbanisation hinders the improvement of energy eco-efficiency. Finally, heterogeneity analysis showed that the policy of the new energy demonstration city has better effects on eastern and western cities in promoting EE.

Single-cell RNA-sequencing atlas reveals an FABP1-dependent immunosuppressive environment in hepatocellular carcinoma.

BACKGROUND: Single-cell RNA sequencing, also known as scRNA-seq, is a method profiling cell populations on an individual cell basis. It is particularly useful for more deeply understanding cell behavior in a complicated tumor microenvironment. Although several previous studies have examined scRNA-seq for hepatocellular carcinoma (HCC) tissues, no one has tested and analyzed HCC with different stages. METHODS: In this investigation, immune cells isolated from surrounding normal tissues and cancer tissues from 3 II-stage and 4 III-stage HCC cases were subjected to deep scRNA-seq. The analysis included 15 samples. We distinguished developmentally relevant trajectories, unique immune cell subtypes, and enriched pathways regarding differential genes. Western blot and co-immunoprecipitation were performed to demonstrate the interaction between fatty acid binding protein 1 (FABP1) and peroxisome proliferator-activated receptor gamma(PPARG). In vivo experiments were performed in a C57BL/6 mouse model of HCC established via subcutaneous injection. RESULTS: FABP1 was discovered to be overexpressed in tumor-associated macrophages (TAMs) with III-stage HCC tissues compared with II-stage HCC tissues. This finding was fully supported by immunofluorescence detection in significant amounts of HCC human samples. FABP1 deficiency in TAMs inhibited HCC progression in vitro. Mechanistically, FABP1 interacted with PPARG/CD36 in TAMs to increase fatty acid oxidation in HCC. When compared with C57BL/6 mice of the wild type, tumors in FABP1-/- mice consistently showed attenuation. The FABP1-/- group's relative proportion of regulatory T cells and natural killer cells showed a downward trend, while dendritic cells, M1 macrophages, and B cells showed an upward trend, according to the results of mass cytometry. In further clinical translation, we found that orlistat significantly inhibited FABP1 activity, while the combination of anti-programmed cell death 1(PD-1) could synergistically treat HCC progression. Liposomes loaded with orlistat and connected with IR780 probe could further enhance the therapeutic effect of orlistat and visualize drug metabolism in vivo. CONCLUSIONS: ScRNA-seq atlas revealed an FABP1-dependent immunosuppressive environment in HCC. Orlistat significantly inhibited FABP1 activity, while the combination of anti-PD-1 could synergistically treat HCC progression. This study identified new treatment targets and strategies for HCC progression, contributing to patients with advanced HCC from new perspectives.

Pushing the heterometal doping limit while preserving long-lived charge separation in a Ti-based MOF photocatalyst.

This study explores the nature, dynamics, and reactivity of the photo-induced charge separated excited state in a Fe3+-doped titanium-based metal organic framework (MOF), xFeMIL125-NH2, as a function of iron concentration. The MOF is synthesized with doping levels x = 0.5, 1 and 2 Fe node sites per octameric Ti-oxo cluster and characterized by powder x-ray diffraction, UV-vis diffuse reflectance, atomic absorption, and steady state Fe K-edge X-ray absorption spectroscopy. For each doping level, time-resolved X-ray transient absorption spectroscopy studies confirm the electron trap site role of the Fe sites in the excited state. Time scan data reveal multiexponential decay kinetics for the charge recombination processes which extend into the microsecond range for all three concentrations. A series of dye photodegradation studies, based on the oxidative decomposition of Rhodamine B, demonstrates the reactivity of the charge separated excited state and the photocatalytic capacity of these MOF materials compared to traditional heterometal-doped semiconductor photocatalysts.

3-Hydroxypyridin-4(1H)-one Derivatives as pqs Quorum Sensing Inhibitors Attenuate Virulence and Reduce Antibiotic Resistance in Pseudomonas aeruginosa.

The development of quorum sensing inhibitors capable of decreasing the production of virulence factors is an effective strategy to overcome resistance in Pseudomonas aeruginosa due to the less selective pressure exerted on bacteria. In this study, a series of 3-hydroxypyridin-4(1H)-one derivatives bearing a 4-aminomethyl-1,2,3-triazole linker were designed and synthesized as antivirulence agents against P. aeruginosa. The most potent derivative 16e was identified as a selective inhibitor of the pqs system (IC50 = 3.7 µM) and its related virulence factor pyocyanin (IC50 = 2.7 µM). In addition, 16e exhibited moderate biofilm inhibition and significant inhibition of P. aeruginosa motility phenotypes with low cytotoxicity. Compound 16e showed an obvious antibacterial synergistic effect in combination with antibiotics such as ciprofloxacin and tobramycin in in vitro and in vivo Caenorhabditis elegans infection models. Overall, the excellent antivirulence properties of compound 16e make it a potential antibiotic adjuvant for the treatment of P. aeruginosa infections that may be advanced into preclinical development in the future.

Electronic Tuning of Photoexcited Dynamics in Heteroleptic Cu(I) Complex Photosensitizers.

Photoexcited dynamics of heteroleptic Cu(I) complexes as noble-metal-free photosensitizers are closely intertwined with the nature of their ligands. By utilizing ultrafast optical and X-ray transient absorption spectroscopies, we characterized a new set of heteroleptic Cu(I) complexes [Cu(PPh3)2(BPyR)]+ (R = CH3, H, Br to COOCH3), with an increase in the electron-withdrawing ability of the functional group (R). We found that after the transient photooxidation of Cu(I) to Cu(II), the increasing electron-withdrawing ability of R barely affects the internal conversion (IC) (e.g., Jahn-taller (JT) distortion) between singlet MLCT states. However, it does accelerate the dynamics of intersystem crossing (ISC) between singlet and triplet MLCT states and the subsequent decay from the triplet MLCT state to the ground state. The associated lifetime constants are reduced by up to 300%. Our understanding of the photoexcited dynamics in heteroleptic Cu(I) complexes through ligand electronic tuning provides valuable insight into the rational design of efficient Cu(I) complex photosensitizers.