Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy.

Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.

Isotope Effect-Enabled Crystal Enlargement in Metal-Organic Frameworks.

Synthesizing large metal-organic framework (MOF) single crystals has garnered significant research interest, although it is hindered by the fast nucleation kinetics that gives rise to numerous small nuclei. Given the different chemical origins inherent in various types of MOFs, the development of a general approach to enhancing their crystal sizes presents a formidable challenge. Here, we propose a simple isotopic substitution strategy to promote size growth in MOFs by inhibiting nucleation, resulting in a substantial increase in the crystal volume ranging from 1.7- to 165-fold. Impressively, the crystals prepared under optimized conditions by normal approaches can be further enlarged by the isotope effect, yielding the largest MOF single crystal (2.9 cm × 0.48 cm × 0.23 cm) among the one-pot synthesis method. Detailed in situ characterizations reveal that the isotope effect can retard crystallization kinetics, establish a higher nucleation energy barrier, and consequently generate fewer nuclei that eventually grow larger. Compared with the smaller crystals, the isotope effect-enlarged crystal shows 33% improvement in the X-ray dose rate detection limit. This work enriches the understanding of the isotope effect on regulating the crystallization process and provides inspiration for exploring potential applications of large MOF single crystals.

Deep learning-aided respiratory motion compensation in PET/CT: addressing motion induced resolution loss, attenuation correction artifacts and PET-CT misalignment.

PURPOSE: Respiratory motion (RM) significantly impacts image quality in thoracoabdominal PET/CT imaging. This study introduces a unified data-driven respiratory motion correction (uRMC) method, utilizing deep learning neural networks, to solve all the major issues caused by RM, i.e., PET resolution loss, attenuation correction artifacts, and PET-CT misalignment. METHODS: In a retrospective study, 737 patients underwent [18F]FDG PET/CT scans using the uMI Panorama PET/CT scanner. Ninety-nine patients, who also had respiration monitoring device (VSM), formed the validation set. The remaining data of the 638 patients were used to train neural networks used in the uRMC. The uRMC primarily consists of three key components: (1) data-driven respiratory signal extraction, (2) attenuation map generation, and (3) PET-CT alignment. SUV metrics were calculated within 906 lesions for three approaches, i.e., data-driven uRMC (proposed), VSM-based uRMC, and OSEM without motion correction (NMC). RM magnitude of major organs were estimated. RESULTS: uRMC enhanced diagnostic capabilities by revealing previously undetected lesions, sharpening lesion contours, increasing SUV values, and improving PET-CT alignment. Compared to NMC, uRMC showed increases of 10% and 17% in SUVmax and SUVmean across 906 lesions. Sub-group analysis showed significant SUV increases in small and medium-sized lesions with uRMC. Minor differences were found between VSM-based and data-driven uRMC methods, with the SUVmax was found statistically marginal significant or insignificant between the two methods. The study observed varied motion amplitudes in major organs, typically ranging from 10 to 20 mm. CONCLUSION: A data-driven solution for respiratory motion in PET/CT has been developed, validated and evaluated. To the best of our knowledge, this is the first unified solution that compensates for the motion blur within PET, the attenuation mismatch artifacts caused by PET-CT misalignment, and the misalignment between PET and CT.

Mechanochemical Synthesis of Silylcyclopentenes via Ball Milling.

The development of innovative methods for synthesizing silylcyclopentene compounds is particularly important for enriching and improving the synthetical toolbox of organosilicon compounds. Herein, a facile approach has been developed for the synthesis of silylcyclopentenes promoted by mechanochemically generated organolithium species as silicon nucleophiles under ball milling conditions, avoiding the requirement of large amounts of bulk solvent. This operationally simple method demonstrates good functional group compatibility, which provides a great opportunity for further exploration of the synthetic applications of silylcyclopentenes. Density functional theory calculations indicated that the transient lithiosilole intermediates undergo a stepwise nucleophilic addition process, which governs this mechanic-force-promoted [4+1] cycloaddition reaction.

Activation and modulation of the AGEs-RAGE axis: Implications for inflammatory pathologies and therapeutic interventions - A review.

Chronic inflammation is a common foundation for the development of many non-communicable diseases, particularly diabetes, atherosclerosis, and tumors. The activation of the axis involving Advanced Glycation End products (AGEs) and their receptor RAGE is a key promotive factor in the chronic inflammation process, influencing the pathological progression of these diseases. The accumulation of AGEs in the body results from an increase in glycation reactions and oxidative stress, especially pronounced in individuals with diabetes. By binding to RAGE, AGEs activate signaling pathways such as NF-κB, promoting the release of inflammatory factors, exacerbating cell damage and inflammation, and further advancing the formation of atherosclerotic plaques and tumor development. This review will delve into the molecular mechanisms by which the AGEs-RAGE axis activates chronic inflammation in the aforementioned diseases, as well as strategies to inhibit the AGEs-RAGE axis, aiming to slow or halt the progression of chronic inflammation and related diseases. This includes the development of AGEs inhibitors, RAGE antagonists, and interventions targeting upstream and downstream signaling pathways. Additionally, the early detection of AGEs levels and RAGE expression as biomarkers provides new avenues for the prevention and treatment of diabetes, atherosclerosis, and tumors.

Maternal secretin ameliorates obesity by promoting white adipose tissue browning in offspring.

Our knowledge of the coordination of intergenerational inheritance and offspring metabolic reprogramming by gastrointestinal endocrine factors is largely unknown. Here, we showed that secretin (SCT), a brain-gut peptide, is downregulated by overnutrition in pregnant mice and women. More importantly, genetic loss of SCT in the maternal gut results in undesirable phenotypes developed in offspring including enhanced high-fat diet (HFD)-induced obesity and attenuated browning of inguinal white adipose tissue (iWAT). Mechanistically, loss of maternal SCT represses iWAT browning in offspring by a global change in genome methylation pattern through upregulation of DNMT1. SCT functions to facilitate ubiquitination and degradation of DNMT1 by activating AMPKα, which contributes to the observed alteration of DNMT1 in progeny. Lastly, we showed that SCT treatment during pregnancy can reduce the development of obesity and improve glucose tolerance and insulin resistance in offspring of HFD-fed females, suggesting that SCT may serve as a novel biomarker or a strategy for preventing metabolic diseases.

Global trends in the burden of chronic kidney disease attributable to type 2 diabetes: An age-period-cohort analysis.

AIM: To assess temporal trends of chronic kidney disease (CKD) attributable to type 2 diabetes (T2D) globally and in five sociodemographic index (SDI) regions. MATERIALS AND METHODS: We extracted the population data and CKD burden attributable to T2D from the Global Burden of Disease Study 2019. We evaluated the trends of disability-adjusted life years (DALYs), mortality, prevalence and incidence through age-period-cohort modelling, and calculated net drifts (overall annual percentage changes), local drifts (annual percentage changes in each age group), longitudinal age curves (fitted longitudinal age-specific rates), period relative risks (RRs) and cohort RRs. RESULTS: From 1990 to 2019, the global burden of CKD attributable to T2D showed increasing trends in general. The burden of CKD attributable to T2D was highest in the middle SDI region and lowest in the low SDI region. Age effects increased with age, and peaked at the ages of 75-79 and 80-84 years for incidence and prevalence, respectively. Period RRs in the burden of CKD attributable to T2D increased, with the high SDI being the most remarkable in DALYs and mortality, and the middle SDI being the most notable in incidence. Cohort RRs showed unfavourable trends in incidence and prevalence among recent cohorts. CONCLUSIONS: After a lengthy period of multi-initiative diabetes management, the high-middle SDI region exhibited improvement. However, unresolved issues and improvement gaps were still remarkable. Future efforts to reduce the burden of CKD attributable to T2D in the population should prioritize addressing the unfavourable patterns identified.

Organophotocatalyzed Cross Coupling of C- and Si-Radical to Access Dibenzylic Silanes from para-Quinone Methides and Silanecarboxylic Acids.

Herein we present a catalytic cross-coupling strategy between C-radicals and Si-radicals, enabling the efficient, gentle, and versatile synthesis of dibenzylic silanes from para-quinone methides and silanecarboxylic acids as the stable silyl radical precursors. The reaction is facilitated by an inexpensive organophotocatalyst and exhibits broad compatibility with various electron-donating and electron-withdrawing functional groups. Notably, mechanistic investigations suggest the involvement of dibenzylic and silyl radicals, underscoring a novel radical coupling mechanism that introduces a fresh perspective on C-Si bond formation.

Mechanochemical Activation of Aryl Diazonium Salts: Synthesis of Polycyclic (Hetero)Aromatics.

Although the synthesis of polycyclic (hetero)aromatics via the [4 + 2] benzannulation process has been thoroughly explored, the restricted availability of energy sources (including thermal, light, and electrical energy) mandates the utilization of substantial quantities of organic solvents, inevitably leading to environmental pollution, resource wastage, and low reaction efficiency. Herein, we report a new method for the synthesis of polycyclic (hetero)aromatics from diazonium salts and alkynes under ball-milling conditions. This mechanochemical approach requires only substoichiometric amounts of DMSO as a liquid-assisted grinding additive and furnishes the desired product in a short time.

A Dual-target Fluorescent Chemosensor for Detecting Indium (III) and Hypochlorite with High Selectivity.

A dual-target fluorescent chemosensor BQC (((E)-N-benzhydryl-2-(quinolin-2-ylmethylene)hydrazine-1-carbothioamide) was synthesized for detecting In3+ and ClO-. BQC displayed green and blue fluorescence responses to In3+ and ClO- with low detection limits (0.83 µM for In3+ and 2.50 µM for ClO-), respectively. Importantly, BQC is the first fluorescent chemosensor capable of detecting In3+ and ClO-. The binding ratio between BQC and In3+ was determined to be a 2:1 through Job plot and ESI-MS analysis. BQC could be successfully utilized as a visible test kit to detect In3+. Meanwhile, BQC showed a selective turn-on response to ClO- even in the presence of anions or reactive oxygen species. The sensing mechanisms of BQC for In3+ and ClO- were demonstrated by 1 H NMR titration, ESI-MS and theoretical calculations.

Extracellular vesicle-encapsulated CC16 as novel nanotherapeutics for treatment of acute lung injury.

Acute lung injury (ALI) is still associated with high mortality. Growing evidence suggests that Club Cell Protein 16 (CC16) plays a protective role against ALI. However, the doses of recombinant CC16 (rCC16) used in preclinical studies are supraphysiological for clinical applications. Extracellular vesicles (EVs) are nanovesicles endogenously generated by mammalian cells. Our study demonstrated that CC16 is released via small EVs and EV-encapsulated CC16 (sEV-CC16) and has anti-inflammatory activities, which protect mice from lipopolysaccharide (LPS) or bacteria-induced ALI. Additionally, sEV-CC16 can activate the DNA damage repair signaling pathways. Consistent with this activity, we observed more severe DNA damage in lungs from Cc16 knockout (KO) than wild-type (WT) mice. Mechanistically, we elucidated that CC16 suppresses nuclear factor κB (NF-κB) signaling activation by binding to heat shock protein 60 (HSP60). We concluded that sEV-CC16 could be a potential therapeutic agent for ALI by inhibiting the inflammatory and DNA damage responses by reducing NF-κB signaling.

Value of multiparametric magnetic resonance imaging in distinguishing sinonasal lymphoma from sinonasal carcinoma: a case control study.

BACKGROUND: The study aimed to evaluate the diagnostic efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) parameters in distinguishing sinonasal lymphoma from sinonasal carcinoma. METHODS: Forty-two participants with histologically confirmed sinonasal lymphomas and fifty-two cases of sinonasal carcinoma underwent imaging with a 3.0T MRI scanner. DCE-MRI and DWI were conducted, and various parameters including type of time-intensity curve(TIC), time to peak, peak enhancement, peak contrast enhancement, washout rate, apparent diffusion coefficient (ADC), and relative ADC were measured. Binary logistic regression and receiver operating characteristic (ROC) curve analysis were employed to assess the diagnostic capability of individual and combined indices for differentiating nasal sinus lymphoma from nasal sinus carcinoma. RESULTS: Sinonasal lymphoma predominantly exhibited type II TIC(n = 20), whereas sinonasal carcinoma predominantly exhibited type III TIC(n = 23). Significant differences were observed in all parameters except washout ratio (p < 0.05), and ADC value emerged as the most reliable diagnostic tool in single parameter. Combined DCE-MRI parameters demonstrated superior diagnostic efficacy compared to individual parameters, with the highest efficiency (area under curve = 0.945) achieved when combining all parameters of DCE-MRI and DWI. CONCLUSIONS: Multiparametric evaluation involving contrast-enhanced dynamic MRI and DWI holds considerable diagnostic value in distinguishing sinonasal lymphoma from sinonasal carcinoma.

Rhizosphere-Associated Anammox Bacterial Diversity and Abundance of Nitrogen Cycle-Related Functional Genes of Emergent Macrophytes in Eutrophic Wetlands.

Rhizospheric microbial community of emergent macrophytes plays an important role in nitrogen removal, especially in the eutrophic wetlands. The objective of this study was to identify the differences in anammox bacterial community composition among different emergent macrophytes and investigate revealed the the main factors affecting on the composition, diversity, and abundance of anammox bacterial community. Results showed that the composition, diversity, and abundance of the anammox community were significantly different between the vegetated sediments of three emergent macrophytes and unvegetated sediment. The composition of the anammox bacterial community was different in the vegetated sediments of different emergent macrophytes. Also, the abundance of nitrogen cycle-related functional genes in the vegetated sediments was found to be higher than that in the unvegetated sediment. Canonical correspondence analysis (CCA) and structural equation models analysis (SEM) showed that salinity and pH were the main environmental factors influencing the composition and diversity of the anammox bacterial community and NO2--N indirectly affected anammox bacterial community diversity by affecting TOC. nirK-type denitrifying bacteria abundance had significant effects on the bacterial community composition, diversity, and abundance of anammox bacteria. The community composition of anammox bacteria varies with emergent macrophyte species. The rhizosphere of emergent macrophytes provides a favorable environment and promotes the growth of nitrogen cycling-related microorganisms that likely accelerate nitrogen removal in eutrophic wetlands.

Chronic exposure to tris(1,3-dichloro-2-propyl) phosphate: Effects on intestinal microbiota and serum metabolism in rats.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphate ester that can adversely affect animal or human health. The intestinal microbiota is critical to human health. High-dose exposure to TDCIPP can markedly affect the intestinal ecosystem of mice, but the effects of long-term exposure to lower concentrations of TDCIPP on the intestinal flora and body metabolism remain unclear. In this study, TDCIPP was administered to Sprague-Dawley rats by gavage at a dose of 13.3 mg/kg bw/day for 90 days. TDCIPP increased the relative weight of the kidneys (P = 0.017), but had no effect on the relative weight of the heart, liver, spleen, lungs, testes, and ovaries (P > 0.05). 16 S rRNA gene sequencing revealed that long-term TDCIPP exposure affected the diversity, relative abundance, and functions of rat gut microbes. The serum metabolomics of the rats showed that TDCIPP can disrupt the serum metabolic profiles, result in the up-regulation of 26 metabolites and down-regulation of 3 metabolites, and affect multiple metabolic pathways in rat sera. In addition, the disturbed genera and metabolites were correlated. The functions of some disturbed gut microbes were consistent with the affected metabolic pathways in the sera, and these metabolic pathways were all associated with kidney disease, suggesting that TDCIPP may cause kidney injury in rats by affecting the intestinal flora and serum metabolism.

Nuts and seeds consumption impact on adolescent obesity: sex-specific associations from 2003 to 2018 National Health and Nutrition Examination Survey.

The nutritional benefits and immunological advantages of consuming nuts and seeds are well-established. However, the link between nuts and seeds consumption and the susceptibility of being overweight or obese among adolescents is not clear. This study aims to explore this relationship in adolescents aged 12-19. Using a weighted multiple logistic regression model, we analysed data of the Food Patterns Equivalents Database and the U.S. National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018. We found a significant association between nuts and seeds consumption and a reduced odds of being overweight or obese in females. Specifically, females who habitually consumed nuts and seeds had lower odds of being overweight or obese (OR = 0.55, 95% CI: 0.32-0.94). Additionally, we found an L-shaped relationship between nuts and seeds consumption and appropriate waist-to-height ratio in males. The findings suggest that nuts and seeds consumption may contribute to healthier physical development in adolescents.

Visible-Light-Mediated Ring-Opening Geminal Dibromination of Alkenes via Alkoxy Radicals Enabled by Electron Donor-Acceptor Complex.

An electron donor-acceptor complex was utilized to generate alkoxy radicals from alcohols under mild conditions using visible light. This approach was combined with a hydroxybromination process to achieve the deconstructive functionalization of alkenes, leading to the production of geminal dibromides. Mechanistic investigations indicated the intermediacy of hypervalent iodine (III) compounds.

The Medial Canthus Fibrous Band's Impact on Epicanthal Fold Severity and Classification in Asians: Implications for Epicanthoplasty.

BACKGROUND: The epicanthal fold (EF) is a semilunar skin fold located in the medial canthus in most Asians. The medial canthus fibrous band (MCFB) reportedly plays a critical role in EF formation. Variations in MCFB shape and size affect the severity and type of EF. OBJECTIVES: We aimed to analyze MCFB variations in different types and severities of EF and explore the effect of the MCFB resection epicanthoplasty technique (MCFB epicanthoplasty). METHODS: Surgical videos of 40 patients undergoing MCFB epicanthoplasty in our department were reviewed. The MCFB (area), transverse dimension, vertical dimension, upper eyelid direction length (UEDL), and lower eyelid direction length (LEDL) were measured. For aesthetic assessment, 37 patients were followed up for 6 months; intercanthal distance (ICD) and horizontal lid fissure length (HLFL) were measured. Preoperative and postoperative ICD/HLFL ratios were compared. Postoperative scar recovery was evaluated with the Patient and Observer Scar Assessment Scale. Statistical significance was set at P < .05. RESULTS: The MCFB diameter and area were larger for severe EF than for moderate EF (P < .01). Patients with severe EF had larger LEDL than UEDL (P < .01). The tarsalis type had a larger LEDL than the palpebralis type with the same severity (P < .01). MCFB epicanthoplasty yielded favorable postoperative cosmetic effects and scar recovery. Postoperative ICD decreased, while HLFL increased compared to preoperative values (P < .001). The ICD/HLFL ratio was significantly lower postoperatively than preoperatively (P < .001). Postoperative ICD/HLFL ratio was 1.2:1. CONCLUSIONS: The MCFB affects the severity and type of EF. MCFB epicanthoplasty effectively corrected moderate to severe EF.

A Facile Strategy for Constructing High-Performance Polymer Electrolytes via Anion Modification and Click Chemistry for Rechargeable Magnesium Batteries.

Polymer electrolytes play a crucial role in advancing rechargeable magnesium batteries (RMBs) owing to their exceptional characteristics, including high flexibility, superior interface compatibility, broad electrochemical stability window, and enhanced safety features. Despite these advantages, research in this domain remains nascent, plagued by single preparation approaches and challenges associated with the compatibility between polymer electrolytes and Mg metal anode. In this study, we present a novel synthesis strategy to fabricate a glycerol α,α'-diallyl ether-3,6-dioxa-1,8-octanedithiol-based composite gel polymer electrolyte supported by glass fiber substrate (GDT@GF CGPE) through anion modification and thiol-ene click chemistry polymerization. The developed route exhibits novelty and high efficiency, leading to the production of GDT@GF CGPEs featuring exceptional mechanical properties, heightened ionic conductivity, elevated Mg2+ transference number, and commendable compatibility with Mg anode. The assembled modified Mo6S8||GDT@GF||Mg cells exhibit outstanding performance across a wide temperature range and address critical safety concerns, showcasing the potential for applications under extreme conditions. Our innovative preparation strategy offers a promising avenue for the advancement of polymer electrolytes in high-performance rechargeable magnesium batteries, while also opens up possibilities for future large-scale applications and the development of flexible electronic devices.

Nucleophilic functionalization of thianthrenium salts under basic conditions.

In recent years, S-(alkyl)thianthrenium salts have become an important means of functionalizing alcohol compounds. However, additional transition metal catalysts and/or visible light are required. Herein, a direct thioetherification/amination reaction of thianthrenium salts is realized under metal-free conditions. This strategy exhibits good functional-group tolerance, operational simplicity, and an extensive range of compatible substrates.

Total Syntheses of Rhodomollins A and B.

The first and asymmetric total syntheses of rhodomollins A and B, two rhodomollane type grayanoids featuring a d-homograyanane carbon skeleton and an oxa-bicyclo[3.2.1] core, were accomplished via a convergent strategy. A Stille coupling and a lithium-halogen exchange/intramolecular nucleophilic addition to the aldehyde sequence were employed to assemble two enantioenriched fragments. The oxa-bicyclo[3.2.1] core was achieved through an intramolecular SN2 substitution of cyclic sulfate of 1,2-diols (Williamson ether synthesis). The A ring oxidation states were adjusted by a Payne/Meinwald rearrangement sequence and subsequent redox transformations.