Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a condition characterized by functional deterioration with sustained inflammation and progressive fibrosis of the kidneys affecting over 800 million people worldwide. The P2X7 receptor (P2X7R) plays a key role in CKD progression. Our previous P2X7R antagonists demonstrated good efficacy for treating kidney injury but were limited by low oral exposure and short half-life, restricting their application. This study reports the optimization of P2X7R antagonists for better oral pharmacokinetics. The candidate compound 13a with the respective IC50 of 34.86 and 25.28 nM against human and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits a remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55 µg·h/L. Oral administration of 13a (0.3 or 1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis in unilateral ureteral obstruction and adenine diet-induced mice models, highlighting its potential for delaying the progression of CKD.

A risk prediction model for new-onset chronic kidney disease in the elderly.

INTRODUCTION: Worsening renal function poses a significant health risk to elderly individuals. This study aimed to construct a simple risk prediction model for new-onset chronic kidney disease (CKD) among elderly populations. METHODS: In this retrospective cohort study, 5,416 elderly residents (aged ≥ 65 years) who underwent physical examinations as part of the National Basic Public Health Service project at least twice between January 2017 and July 2021 were included. The endpoint was new-onset CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² during the follow-up period. Predictors of new-onset CKD were selected using multivariable Cox regression and a stepwise approach. A risk prediction model based on the selected predictors was constructed and evaluated using the concordance index (C-index) and area under curve (AUC). External validation was conducted to verify the model's performance. RESULTS: During the median follow-up period of 2.3 years, the incident of new-onset CKD was 20.1% (n = 1,088). Age, female gender, diabetes, elevated triglyceride levels, and baseline eGFR were selected as predictors. The model demonstrated good predictive performance across the cohort, with a C-index of 0.802. The AUCs for 2-year, 3-year, and 4-year predictions were 0.831, 0.829, and 0.839, respectively. External validation confirmed the model's efficacy, with a 2-year AUC of 0.735. CONCLUSION: This study developed a simple yet effective risk prediction model for new-onset CKD among elderly populations. The model facilitates prompt identification of elderly individuals at risk of renal function decline in primary care, enabling timely interventions.

Dual-enzyme inhibiting nanomedicines for enhanced cancer chemodynamic therapy by inducing intratumoral acidosis.

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Reducing intrusive memories and promoting posttraumatic growth with Traveler: A randomized controlled study.

Over recent decades, serious games have become a promising intervention approach for addressing psychological problems by providing users with computerized, engaging, and interactive experiences. An innovative serious game, Traveler, has been developed specifically as an intervention tool for managing posttraumatic responses immediately after trauma. The game incorporates the principle of visuospatial interference, the core elements of Tetris, such as spatial displacement and mental rotation, and the critical phases of eye movement desensitization and reprocessing. To test the intervention efficacy and feasibility of Traveler, we conducted a randomized controlled trial involving 105 young adults. Participants were randomly assigned into three groups: a wait-list control group, a group undergoing five-session written exposure therapy, or a group engaging in one session of Traveler gameplay. Outcome measures included intrusive memories (i.e. vividness of traumatic images, disgust at traumatic images, flashback frequency, and flashback impact) and posttraumatic growth measured by the Posttraumatic Growth Inventory. Traveler significantly outperformed the control and written exposure therapy groups in reducing intrusive memories and enhancing posttraumatic growth, with effects persisting at a 30-day follow-up. Thus, Traveler offers a promising brief and early intervention technique for addressing posttraumatic responses. Yet, its clinical applicability requires further investigation.

High average output power, dual-wavelength synchronously self-mode-locked Ho:LLF laser operating at 2068.5 and 2069.2†nm.

A dual-wavelength synchronously self-mode-locked Ho:LLF laser operating at 2068.5 and 2069.2 nm was demonstrated. The maximum average output power was as high as 2.6 W with a pulse repetition frequency of 3.03 GHz. Meanwhile, the output power ratio of the dual-wavelength lasers can be effectively controlled by varying the incident pump power. To the best of our knowledge, this is the first dual-wavelength synchronously self-mode-locked Ho-doped fluoride solid state laser; moreover, our current experimental results represent the highest average output power from a GHz self-mode-locked oscillator in the 2 µm wave band.

LncRNA MFRL regulates the phenotypic switch of vascular smooth muscle cells to attenuate arterial remodeling by encoding a novel micropeptide MFRLP.

BACKGROUND: Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells (VSMC) plays an important role. Recently, an increasing number of long non-coding RNAs(lncRNAs) have been shown to encode micropeptides that play biological roles and have great clinical transformation potential. However, the role of micropeptides encoded by lncRNAs in arterial remodeling has not been well studied and requires further exploration. METHODS AND RESULTS: Through bioinformatic analysis and experimental verification, we found that a new lncRNA, the mitochondrial function-related lncRNA (MFRL), encodes a 64-amino acid micropeptide, MFRLP. MFRL and MFRLP play important roles in the phenotypic switch of VSMC. Further experiments showed that MFRLP interacts with mitochondrial cytochrome b to reduce accumulation of reactive oxygen species, suppress mitophagy and inhibit the VSMC switch from contractile to synthetic phenotype. CONCLUSIONS: LncRNA MFRL encodes the micropeptide MFRLP, which interacts with mitochondrial cytochrome b to inhibit the VSMC switch from contractile to synthetic phenotype and improve arterial remodeling.

Glutathione-depleting polyprodrug nanoparticle for enhanced photodynamic therapy and cascaded locoregional chemotherapy.

Nanomedicines that combine reactive oxygen species (ROS)-responsive polyprodrug and photodynamic therapy have shown great potential for improving treatment efficacy. However, the consumption of ROS by overexpressed glutathione in tumor cells is a major obstacle for achieving effective ROS amplification and prodrug activation. Herein, we report a polyprodrug-based nanoparticle that can realize ROS amplification and cascaded drug release. The nanoparticle can respond to the high level of hydrogen peroxide in tumor microenvironment, achieving self-destruction and release of quinone methide. The quinone methide depletes intracellular glutathione and thus decreases the antioxidant capacity of cancer cells. Under laser irradiation, a large amount of ROS will be generated to induce cell damage and prodrug activation. Therefore, the glutathione-depleting polyprodrug nanoparticles can efficiently inhibit tumor growth by enhanced photodynamic therapy and cascaded locoregional chemotherapy.

Watt-level output power and near-diffraction-limit beam quality mid-infrared Ho:GdVO4 self-Raman laser at 2.5†µm.

We demonstrate an efficient active Q-switched Ho:GdVO4 self-Raman laser at 2500 nm for the first time, to our knowledge. Using Ho:GdVO4 crystal as the gain medium for both the 2048nm fundamental laser and the 2500 nm Raman laser, the output performances of a new mid-infrared self-Raman laser were investigated. The maximum average output power of 1.45 W was achieved at an incident pump power of 22.5 W, with a slope efficiency of 25.8%, for an output transmittance of 30% and a pulse repetition frequency of 15 kHz. The maximum single pulse energy of 96.7 µJ with a pulse width of 11.35 ns was obtained, corresponding to the peak power of 8.5 kW. The beam quality was near diffraction limited with the M2 factors of 1.15 and 1.06 along the x and y directions. Moreover, adopting the two-end output way of the fundamental laser and the Raman laser, the Raman gain coefficient of Ho:GdVO4 crystal was estimated to be 1.14 cm/GW at 2048nm. This work shows that Ho:GdVO4 is an excellent self-Raman laser crystal for the generation of high power Raman laser at 2.5 µm.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

High-power, gigahertz repetition frequency self-mode-locked Ho:GdVO4 laser resonantly pumped by a Tm-doped fiber laser.

A self-mode-locked Ho:GdVO4 laser with the GHz pulse repetition frequency oscillation near 2.06 µm was demonstrated for the first time to our knowledge. The output performances of the self-mode-locked Ho:GdVO4 laser were investigated for a few output coupler transmittances at the pulse repetition frequency of 1.89 GHz. At the incident pump power of 8.12 W, the maximum average output power was as high as 2.28 W, corresponding to the slope efficiency and optical-to-optical efficiency of 36.3% and 28.1%, respectively. This is the maximum average output for the 2 µm self-mode-locked solid-state laser with a GHz pulse repetition frequency. This work provides a new way for generating an efficient and a high-power ultrafast pulse laser with a GHz repetition frequency in the 2 µm wave band.

14-Electron Redox Chemistry Enabled by Salen-Based π-Conjugated Framework Polymer Boosting High-Performance Lithium-Ion Storage.

A paucity of redox centers, poor charge transport properties, and low structural stability of organic materials obstruct their use in practical applications. Herein, these issues have been addressed through the use of a redox-active salen-based framework polymer (RSFP) containing multiple redox-active centers in π-conjugated configuration for applications in lithium-ion batteries (LIBs). Based on its unique architecture, RSFP exhibits a superior reversible capacity of 671.8 mAh g-1 at 0.05 A g-1 after 168 charge-discharge cycles. Importantly, the lithiation/de-lithiation performance is enhanced during operation, leading to an unprecedented reversible capacity of 946.2 mAh g-1 after 3500 cycles at 2 A g-1. The structural evolution of RSFP is studied ex situ using X-ray photoelectron spectroscopy, revealing multiple active C═N, C─O, and C═O sites and aromatic sites such as benzene rings. Remarkably, the emergence of C═O originated from C─O is triggered by an electrochemical process, which is beneficial for improving reversible lithiation/delithiation behavior. Furthermore, the respective strong and weak binding interactions between redox centers and lithium ions, corresponding to theoretical capacities of 670.1 and 938.2 mAh g-1, have been identified by density functional theory calculations manifesting 14-electron redox reactions. This work sheds new light on routes for the development of redox-active organic materials for energy storage applications.

One-step growth of ultrathin CoSe2 nanobelts on N-doped MXene nanosheets for dendrite-inhibited and kinetic-accelerated lithium-sulfur chemistry.

The practical application of lithium-sulfur (Li-S) batteries is inhibited by the shuttle effect of lithium polysulfides (LiPSs) and slow polysulfide redox kinetics on the S cathode as well as the uncontrollable growth of dendrites on the Li metal anode. Therefore, both cathode and anode sides must be considered when modifying Li-S batteries. Herein, two-dimensional (2D) ultrathin CoSe2 nanobelts are in situ grown on 2D N-doped MXene nanosheets (CoSe2@N-MXene) via one-step solvothermal process for the first time. Owing to its unique 2D/2D structure, CoSe2@N-MXene can be processed to crumpled nanosheets by freeze-drying and flexible and freestanding films by vacuum filtration. These crumpled CoSe2@N-MXene nanosheets with abundant active sites and inner spaces can act as S hosts to accelerate polysulfide redox kinetics and suppress the shuttle effect of LiPSs owing to their strong adsorption ability and catalytic conversion effect with LiPSs. Meanwhile, the CoSe2@N-MXene film (CoSe2@NMF) can act as a current collector to promote uniform Li deposition because it contains lithiophilic CoSe2 and N sites. Under the systematic effect of CoSe2@N-MXene on S cathode and Li metal anode, the electrochemical and safety performance of Li-S batteries are improved. CoSe2@NMF also shows excellent storage performances in flexible energy storage devices.

Genetic association of lipid-lowering drugs with aortic aneurysms: a Mendelian randomization study.

AIMS: The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. METHODS AND RESULTS: Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. CONCLUSION: This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.

KEY FINDINGS: High expression of HMGCR, PCSK9, and CETP was positively correlated with the risk of aortic aneurysms, highlighting that the corresponding lipid-lowering drugs may be preferred for preventing arterial aneurysms in high-risk individuals with dyslipidemia. We found that genetically predicted HMGCR inhibitors were positively associated with smaller aortic lumen size, which is the first time to support the causal association of gene HMGCR on the lumen size of aortic aneurysms.

This Mendelian randomization study used publicly available data involving over 1 million individuals to demonstrate the causal relationship between five target genes of LDL-C-lowering medicines and the risk of aortic aneurysms, and implied one lipid-lowering drug may link with the lumen size of aortic aneurysms.

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate-induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

NQO1-activated multifunctional theranostic probe for imaging-guided mitochondria-targeted photodynamic therapy and boosting immunogenic cell death.

NAD(P)H: quinine oxidoreductase (NQO1) is overexpressed in many types of cancer cells, and have been used as a biomarker for cancer diagnosis and targeted therapy. The development of activatable theranostic agents is highly desirable for precise cancer diagnosis and therapy. Herein, a NQO1-activated near-infrared multifunctional theranostic probe I-HCy-Q is successfully developed for imaging guided photodynamic therapy. The NIR fluorescence (λex/em = 685/703 nm) and capacity of reactive oxygen species generation are sensitive controllable by the level of NQO1, the linear detection range of NQO1 and limit of detection are 0.05-1.5 µg/mL and 5.66 ng/mL, respectively. On the one hand, I-HCy-Q can monitor the activity of NQO1 and distinguish the NQO1 positive cancer cells; on the other hand, the capacity of mitochondria-targeted photodynamic therapy makes I-HCy-Q an effective inducer of apoptosis and immunogenic cell death. Attribute to its complementary advantages, I-HCy-Q holds potential for the imaging and treatment of tumors in complex organisms.

Comparison of clinical features and outcomes of proliferative, fibrotic, and mixed subtypes of IgG4-related disease: A retrospective cohort study.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated disorder that can affect almost any organ in the human body. IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients' clinicopathological characteristics. This study aimed to compare the clinical manifestations, laboratory findings, and treatment outcomes of IgG4-RD among different subtypes. METHODS: We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021. The patients were divided into three groups according to their clinicopathological characteristics: proliferative, fibrotic, and mixed subtypes. We compared demographic features, clinical manifestations, organ involvement, laboratory tests, and treatment agents across three subtypes. We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants. Moreover, risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis. RESULTS: We classified the 622 patients into three groups consisting of 470 proliferative patients, 55 fibrotic patients, and 97 mixed patients, respectively. We found that gender distribution, age, disease duration, and frequency of allergy history were significantly different among subgroups. In terms of organ involvement, submandibular and lacrimal glands were frequently involved in the proliferative subtype, while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype. The comparison of laboratory tests revealed that eosinophils ( P = 0.010), total IgE ( P = 0.006), high-sensitivity C-reactive protein ( P <0.001), erythrocyte sedimentation rate ( P <0.001), complement C4 ( P <0.001), IgG ( P = 0.001), IgG1 (P <0.001), IgG4 (P <0.001), and IgA ( P <0.001), at baseline were significantly different among three subtypes. Compared with proliferative and mixed subtypes, the fibrotic subtype showed the lowest rate of relapse (log-rank P = 0.014). CONCLUSIONS: Our study revealed the differences in demographic characteristics, clinical manifestations, organ involvement, laboratory tests, treatment agents, and outcomes across proliferative, fibrotic, and mixed subtypes in the retrospective cohort study. Given significant differences in relapse-free survival among the three subtypes, treatment regimens, and follow-up frequency should be considered separately according to different subtypes.

MXene-Based Current Collectors for Advanced Rechargeable Batteries.

As an indispensable component of rechargeable batteries, the current collector plays a crucial role in supporting the electrode materials and collecting the accumulated electrical energy. However, some key issues, like uneven resources, high weight percentage, electrolytic corrosion, and high-voltage instability, cannot meet the growing need for rechargeable batteries. In recent years, MXene-based current collectors have achieved considerable achievements due to its unique structure, large surface area, and high conductivity. The related research has increased significantly. Nonetheless, a comprehensive review of this area is seldom. Herein the applications and progress of MXene in current collector are systematically summarized and discussed. Meanwhile, some challenges and future directions are presented.

Associations of serum carotenoids with visceral adiposity index and lipid accumulation product: a cross-sectional study based on NHANES 2001-2006.

BACKGROUND: Visceral adiposity index (VAI) and lipid accumulation product (LAP) are comprehensive indicators to evaluate visceral fat and determine the metabolic health of individuals. Carotenoids are a group of naturally occurring antioxidants associated with several diseases. The purpose of this investigation was to explore the association between serum carotenoid concentration and VAI or LAP. METHODS: The data were obtained from the National Health and Nutrition Examination Survey between 2001 and 2006. The levels of serum carotenoids were evaluated using high-performance liquid chromatography. Multivariate linear regression models were employed to investigate the relationship between levels of serum carotenoids and VAI or LAP. The potential non-linear relationship was determined using threshold effect analysis and fitted smoothing curves. Stratification analysis was performed to investigate the potential modifying factors. RESULTS: In total, 5,084 participants were included in this population-based investigation. In the multivariate linear regressions, compared to the lowest quartiles of serum carotenoids, the highest quartiles were significantly associated with VAI, and the effect size (ß) and 95% CI was - 0.98 (- 1.34, - 0.62) for α-carotene, - 1.39 (- 1.77, - 1.00) for ß-carotene, - 0.79 (- 1.18, - 0.41) for ß-cryptoxanthin, - 0.68 (- 0.96, - 0.39) for lutein/zeaxanthin, and - 0.88 (- 1.50, - 0.27) for trans-lycopene. Using piece-wise linear regression models, non-linear relationships were found between ß-carotene and trans-lycopene and VAI with an inflection point of 2.44 (log2-transformed, ug/dL) and 3.80 (log2-transformed, ug/dL), respectively. The results indicated that α-carotene, ß-cryptoxanthin, and lutein/zeaxanthin were linearly associated with VAI. An inverse association was also found between serum carotenoids and LAP after complete adjustments. CONCLUSION: This study revealed that several serum carotenoids were associated with VAI or LAP among the general American population. Further large prospective investigations are warranted to support this finding.

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition.

NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1ß and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.