Gut microbiota dysbiosis links chronic apical periodontitis to liver fibrosis in nonalcoholic fatty liver disease: Insights from a mouse model.

AIM: In this study, we investigated the systemic implications of chronic apical periodontitis (CAP). CAP may contribute to the nonalcoholic fatty liver disease (NAFLD) progression through the gut microbiota and its metabolites, which are related to the degree of fibrosis. METHODOLOGY: Sixteen 7-week-old male apolipoprotein E knockout (apoE-/-) mice were randomly divided into two groups: the CAP and Con groups. A CAP model was established by sealing the first- and second-maxillary molars with bacterium-containing cotton balls. Apical lesions were evaluated by micro-CT. Histological evaluations of NAFLD were performed using second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) assays. Additionally, we comprehensively analyzed the gut microbiota using 16S rRNA gene sequencing and explored metabolic profiles by liquid chromatography-mass spectrometry (LC-MS). Immunofluorescence analysis was used to examine the impact of CAP on tight junction proteins and mucin expression. Transcriptome assays have elucidated gene expression alterations in liver tissues. RESULTS: Micro-CT scans revealed an evident periapical bone loss in the CAP group, and the total collagen percentage was increased (Con, 0.0361 ± 0.00510%, CAP, 0.0589 ± 0.00731%, p < .05). 16S rRNA sequencing revealed reduced diversity and distinct taxonomic enrichment in the CAP group. Metabolomic assessments revealed that differentially enriched metabolites, including D-galactosamine, were enriched and that 16-hydroxyhexadecanoic acid and 3-methylindole were depleted in the CAP group. Immunofluorescence analyses revealed disruptions in tight junction proteins and mucin production, indicating intestinal barrier integrity disruption. Liver transcriptome analysis revealed upregulation of Lpin-1 expression in the CAP group. CONCLUSION: This study provides comprehensive evidence of the systemic effects of CAP on liver fibrosis in NAFLD patients by elucidating alterations in the gut microbiota composition and metabolism.

Portable Photoacoustic Analytical System Combined with Wearable Hydrogel Patch for pH Monitoring in Chronic Wounds.

Timely diagnosis, monitoring, and management of chronic wounds play crucial roles in improving patients' quality of life, but clinical evaluation of chronic wounds is still ambiguous and relies heavily on the experience of clinician, resulting in increased social and financial burden and delay of optimal treatment. During the different stages of the healing process, specific and dynamic changes of pH values in the wound exudate can be used as biomarkers to reflect the wound status. Herein, a pH-responsive agent with well-behaved photoacoustic (PA) properties, nitrazine yellow (NY), was incorporated in poly(vinyl alcohol)/sucrose (PVA/Suc) hydrogel to construct a wearable pH-sensing patch (PVA/Suc/NY hydrogel) for monitoring of pH values during chronic wound healing. According to Rosencwaig-Gersho theory and the combination of 3D printing technology, the PA chamber volume and chopping frequency were systematically optimized to improve the sensitivity of the PA analytical system. The prepared PVA/Suc/NY hydrogel patch had excellent mechanical properties and flexibility and could maintain conformal contact with skin. Moreover, combined with the miniaturized PA analytical device, it had the potential to detect pH values (5.0-9.0) free from the color interference of blood and therapeutic drugs, which provides a valuable strategy for wound pH value monitoring by PA quantitation. This strategy of combining the wearable hydrogel patch with portable PA analysis offers broad new prospects for the treatment and management of chronic wounds due to its features of simple operation, time savings, and anti-interference.

TBC1D4 antagonizes RAB2A-mediated autophagic and endocytic pathways.

Macroautophagic/autophagic and endocytic pathways play essential roles in maintaining homeostasis at different levels. It remains poorly understood how both pathways are coordinated and fine-tuned for proper lysosomal degradation of diverse cargoes. We and others recently identified a Golgi-resident RAB GTPase, RAB2A, as a positive regulator that controls both autophagic and endocytic pathways. In the current study, we report that TBC1D4 (TBC1 domain family member 4), a TBC domain-containing protein that plays essential roles in glucose homeostasis, suppresses RAB2A-mediated autophagic and endocytic pathways. TBC1D4 bound to RAB2A through its N-terminal PTB2 domain, which impaired RAB2A-mediated autophagy at the early stage by preventing ULK1 complex activation. During the late stage of autophagy, TBC1D4 impeded the association of RUBCNL/PACER and RAB2A with STX17 on autophagosomes by direct interaction with RUBCNL via its N-terminal PTB1 domain. Disruption of the autophagosomal trimeric complex containing RAB2A, RUBCNL and STX17 resulted in defective HOPS recruitment and eventually abortive autophagosome-lysosome fusion. Furthermore, TBC1D4 inhibited RAB2A-mediated endocytic degradation independent of RUBCNL. Therefore, TBC1D4 and RAB2A form a dual molecular switch to modulate autophagic and endocytic pathways. Importantly, hepatocyte- or adipocyte-specific tbc1d4 knockout in mice led to elevated autophagic flux and endocytic degradation and tissue damage. Together, this work establishes TBC1D4 as a critical molecular brake in autophagic and endocytic pathways, providing further mechanistic insights into how these pathways are intertwined both in vitro and in vivo.Abbreviations: ACTB: actin beta; ATG9: autophagy related 9; ATG14: autophagy related 14; ATG16L1: autophagy related 16 like 1; CLEM: correlative light electron microscopy; Ctrl: control; DMSO: dimethyl sulfoxide; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FL: full length; GAP: GTPase-activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and protein sorting; IP: immunoprecipitation; KD: knockdown; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; OE: overexpression; PG: phagophore; PtdIns3K: class III phosphatidylinositol 3-kinase; SLC2A4/GLUT4: solute carrier family 2 member 4; SQSTM1/p62: sequestosome 1; RUBCNL/PACER: rubicon like autophagy enhancer; STX17: syntaxin 17; TAP: tandem affinity purification; TBA: total bile acid; TBC1D4: TBC1 domain family member 4; TUBA1B: tubulin alpha 1b; ULK1: unc-51 like autophagy activating kinase 1; VPS39: VPS39 subunit of HOPS complex; WB: western blot; WT: wild type.

Biomimetic Phthalocyanine-Based Covalent Organic Frameworks with Tunable Pendant Groups for Electrocatalytic CO2 Reduction.

Electrocatalytic carbon dioxide reduction reaction (CO2RR) is an effective way of converting CO2 into value-added products using renewable energy, whose activity and selectivity can be in principle maneuvered by tuning the microenvironment near catalytic sites. Here, we demonstrate a strategy for tuning the microenvironment of CO2RR by learning from the natural chlorophyll and heme. Specifically, the conductive covalent organic frameworks (COFs) linked by piperazine serve as versatile supports for single-atom catalysts (SACs), and the pendant groups modified on the COFs can be readily tailored to offer different push-pull electronic effects for tunable microenvironment. As a result, while all the COFs exhibit high chemical structure stability under harsh conditions and good conductivity, the addition of -CH2NH2 can greatly enhance the activity and selectivity of CO2RR. As proven by experimental characterization and theoretical simulation, the electron-donating group (-CH2NH2) not only reduces the surface work function of COF, but also improves the adsorption energy of the key intermediate *COOH, compared with the COFs with electron-withdrawing groups (-CN, -COOH) near the active sites. This work provides insights into the microenvironment modulation of CO2RR electrocatalysts at the molecular level.

GmHXK2 promotes the salt tolerance of soybean seedlings by mediating AsA synthesis, and auxin synthesis and distribution.

BACKGROUND: Salt is an important factor that affects crop productivity. Plant hexokinases (HXKs) are key enzymes in the glycolytic pathway and sugar signaling transduction pathways of plants. In previous studies, we identified and confirmed the roles of GmHXK2 in salt tolerance. RESULTS: In this study, we analyzed the tissue-specific expression of GmHXK2 at different growth stages throughout the plant's life cycle. The results showed that GmHXK2 was expressed significantly in all tissues at vegetative stages, including germination and seedling. However, no expression was detected in the pods, and there was little expression in flowers during the later mature period. Arabidopsis plants overexpressing the GmHXK2 (OE) had more lateral roots. The OE seedlings also produced higher levels of auxin and ascorbic acid (AsA). Additionally, the expression levels of genes PMM, YUC4/YUC6/YUC8, and PIN/LAX1,LAX3, which are involved respectively in the synthesis of AsA and auxin, as well as polar auxin transport, were upregulated in OE plants. This upregulation occurred specifically under exogenous glucose treatment. AtHKT1, AtSOS1, and AtNHX1 were up-regulated in OE plants under salt stress, suggesting that GmHXK2 may modulate salt tolerance by maintaining ion balance within the cells and alleviating damage caused by salt stress. Additionally, we further confirmed the interaction between GmHXK2 and the protein GmPMM through yeast two-hybridization and bimolecular fluorescence complementation assays, respectively. CONCLUSION: The expression of GmHXK2 gene in plants is organ-specific and developmental stage specific. GmHXK2 not only regulates the synthesis of AsA and the synthesis and distribution of auxin, but also promotes root elongation and induces lateral root formation, potentially enhancing soil water absorption. This study reveals the crosstalk between sugar signaling and hormone signaling in plants, where GmHXK2 acts as a glucose sensor through its interaction with GmPMM, and sheds light on the molecular mechanism by which GmHXK2 gene is involved in salt tolerance in plants.

Causal relationship between endometrial cancer and risk of breast cancer: A 2-sample Mendelian randomization study.

Several studies have confirmed the important role of endometrial cancer (EC) in the development and progression of breast cancer (BC), and this study will explore the causal relationship between EC and BC by 2-sample Mendelian randomization analysis. Pooled data from published genome-wide association studies were used to assess the association between EC and BC risk in women using 5 methods, namely, inverse variance weighting (IVW), MR-Egger, weighted median (WME), simple multimaximetry (SM) and weighted multimaximetry (WM) with the EC-associated genetic loci as the instrumental variables (IV) and sensitivity analyses were used to assess the robustness of the results. The statistical results showed a causal association between EC and BC (IVW: OR = 1.07, 95% CI = 1.01-1.32, P = .02; MR-Egger: OR = 1.21, 95% CI = 0.71-1.51, P = .11; weighted median: OR = 1.05, 95% CI = 0.97-1.31, P = .19; simple plurality method: OR = 0.98, 95% CI = 0.81-1.15, P = .78; weighted plurality method: OR = 0.98, 95% CI = 0.81-1.14, P = .75), and the results of the sensitivity analyses showed that there was no significant heterogeneity or multiplicity, and the results were stable. EC is associated with an increased risk of developing BC. The results of this MR analysis can be used as a guideline for screening for BC in women with EC and to help raise awareness of screening for early detection and treatment.

Integrated-omics profiling unveils the disparities of host defense to ECM scaffolds during wound healing in aged individuals.

Extracellular matrix (ECM) scaffold membranes have exhibited promising potential to better the outcomes of wound healing by creating a regenerative microenvironment around. However, when compared to the application in younger individuals, the performance of the same scaffold membrane in promoting re-epithelialization and collagen deposition was observed dissatisfying in aged mice. To comprehensively explore the mechanisms underlying this age-related disparity, we conducted the integrated analysis, combing single-cell RNA sequencing (scRNA-Seq) with spatial transcriptomics, and elucidated six functionally and spatially distinctive macrophage groups and lymphocytes surrounding the ECM scaffolds. Through intergroup comparative analysis and cell-cell communication, we characterized the dysfunction of Spp1+ macrophages in aged mice impeded the activation of the type Ⅱ immune response, thus inhibiting the repair ability of epidermal cells and fibroblasts around the ECM scaffolds. These findings contribute to a deeper understanding of biomaterial applications in varied physiological contexts, thereby paving the way for the development of precision-based biomaterials tailored specifically for aged individuals in future therapeutic strategies.

Rft1 catalyzes lipid-linked oligosaccharide translocation across the ER membrane.

The eukaryotic asparagine (N)-linked glycan is pre-assembled as a fourteen-sugar oligosaccharide on a lipid carrier in the endoplasmic reticulum (ER). Seven sugars are first added to dolichol pyrophosphate (PP-Dol) on the cytoplasmic face of the ER, generating Man5GlcNAc2-PP-Dol (M5GN2-PP-Dol). M5GN2-PP-Dol is then flipped across the bilayer into the lumen by an ER translocator. Genetic studies identified Rft1 as the M5GN2-PP-Dol flippase in vivo but are at odds with biochemical data suggesting Rft1 is dispensable for flipping in vitro. Thus, the question of whether Rft1 plays a direct or an indirect role during M5GN2-PP-Dol translocation has been controversial for over two decades. We describe a completely reconstituted in vitro assay for M5GN2-PP-Dol translocation and demonstrate that purified Rft1 catalyzes the translocation of M5GN2-PP-Dol across the lipid bilayer. These data, combined with in vitro results demonstrating substrate selectivity and rft1∆ phenotypes, confirm the molecular identity of Rft1 as the M5GN2-PP-Dol ER flippase.

Insights into the Correlation between Microbial Community Succession and Pericarp Degradation during Pepper (Piper nigrum L.) Peeling Process via Retting.

White pepper, used both as a seasoning in people's daily diets and as a medicinal herb, is typically produced by removing the pericarp of green pepper through the retting process. However, the mechanism of the retting process for peeling remains unclear. Therefore, this study aimed to investigate the changes in physicochemical factors, microbial community succession effects, and metabolites of the pepper pericarp during the pepper peeling process. The findings indicated that pre-treatment involving physical friction before the retting process effectively reduced the production time of white pepper. During the retting process, the pectinase activity increased, leading to a decrease in the pectin content in the pepper pericarp. There was a significant correlation observed between the changes in pH, pectin content, and peeling rate and the Shannon diversity index of bacteria and fungi. Prevotella, Lactococcus, and Candida were the dominant microbial genera during the retting. The functional predictions suggested that the monosaccharides degraded from the pepper pericarp could have been utilized by microbes through sugar metabolism pathways. Metabolomic analysis showed that the metabolic pathways of carbohydrates and amino acids were the main pathways altered during the pepper peeling process. The verification experiment demonstrated that the degradation of pectin into galacturonic acid by polygalacturonase was identified as the key enzyme in shortening the pepper peeling time. The structure of the pepper pericarp collapsed after losing the support of pectin, as revealed by scanning electron microscopy. These results suggest that the decomposition of the pepper pericarp was driven by key microbiota. The succession of microbial communities was influenced by the metabolites of the pepper pericarp during retting. These findings provide new insights into the retting process and serve as an important reference for the industrial production of white pepper.

Pan-cancer analysis of the disulfidptosis-related gene RPN1 and its potential biological function and prognostic significance in gliomas.

Background: Numerous studies have shown a strong correlation between disulfidptosis and various cancers. However, the expression and function of RPN1, a crucial gene in disulfidptosis, remain unclear in the context of cancer. Methods: Gene expression and clinical information on lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. RPN1 expression was analyzed using the Timer2.0 and the Human Protein Atlas (HPA) databases. Prognostic significance was assessed using Cox regression analysis and Kaplan-Meier curves. Genetic mutations and methylation levels were examined using the cBioPortal and UALCAN platforms, respectively. The relationship between RPN1 and tumor mutation burden (TMB) and microsatellite instability (MSI) across different cancer types was analyzed using the Spearman correlation coefficient. The relationship between RPN1 and immune cell infiltration was analyzed using the Timer2.0 database, whereas variations in drug sensitivity were explored using the CellMiner database. Receiver operating characteristic curves validated RPN1's diagnostic potential in glioma, and its correlation with immune checkpoint inhibitors (ICIs) was assessed using Spearman's correlation coefficient. Single-sample gene set enrichment analysis elucidated a link between RPN1 and immune cells and pathways. In addition, a nomogram based on RPN1 was developed to predict patient prognosis. The functional impact of RPN1 on glioma cells was confirmed using scratch and Transwell assays. Result: RPN1 was aberrantly expressed in various cancers and affected patient prognosis. The main mutation type of RPN1 in the cancer was amplified. RPN1 exhibited a positive correlation with myeloid-derived suppressor cells, neutrophils, and macrophages, and a negative correlation with CD8+ T cells and hematopoietic stem cells. RPN1 expression was associated with TMB and MSI in various cancers. The expression of RPN1 affected drug sensitivity in cancer cells. RPN1 was positively correlated with multiple ICIs in gliomas. RPN1 also affected immune cell infiltration into the tumor microenvironment. RPN1 was an independent prognostic factor for gliomas, and the nomogram demonstrated excellent predictive performance. Interference with RPN1 expression reduces the migratory and invasive ability of glioma cells. Conclusion: RPN1 exerts multifaceted effects on different stages of cancer, including immune infiltration, prognosis, and treatment outcomes. RPN1 expression affects the prognosis and immune microenvironment infiltration in patients with glioma, making RPN1 a potential target for the treatment of glioma.

CDK4/6 inhibition enhances T-cell immunotherapy on hepatocellular carcinoma cells by rejuvenating immunogenicity.

Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC.

Correlation between environmental nickel exposure and the development of arthritis: A large-sample cross-sectional investigation.

BACKGROUND: Nickel is a common metallic element in orthopedic implanted devices and living environment exposures. It is associated with varieties of diseases. The purpose of this investigation was to explore the correlation between nickel exposure and the prevalence of arthritis. METHODS: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database from 2017 to 2018. Multivariate logistic regression was utilized to analyze the relationship between urinary nickel levels and arthritis. In addition, hierarchical modeling further explored the interactions and trends between urinary nickel levels and arthritis. Propensity score matching (PSM) method was used to reduce the effect of confounders. Additionally, restricted cubic spline curve (RCS) was used to assess the possible nonlinear association between urinary nickel and arthritis. RESULTS: The investigation was comprised of 139 arthritis patients and 547 healthy participants. After correction by PSM, there was a positive correlation between arthritis and Nickel exposure levels. The risk of developing arthritis was significantly increased when nickel exposure levels were in the Q4 interval (OR=2.25, 95 % CI=1.03-5.02). When stratified by age and sex, nickel exposure was significantly and positively associated with arthritis in the subgroup aged over 65 years. (OR=2.78,95 %CI=1.20-6.46). Also, the difference between nickel exposure and arthritis was significant in the different gender subgroups (interaction P<0.05). Restricted cubic spline (RCS) results showed a significant linear association between nickel exposure levels and arthritis. In addition, there was a non-linear association between nickel exposure and arthritis across gender and age subgroups. CONCLUSION: A significant positive association between nickel exposure levels and arthritis was showed by the experimental data. Controlling the use of nickel-containing medical prostheses and reducing exposure to nickel-containing daily necessity could help to slow the onset of arthritis.

Safety assessment of tranexamic acid: real-world adverse event analysis from the FAERS database.

Background: In recent years, with the continuous expansion of the application scope of Tranexamic acid (TXA), its usage has surged. Despite numerous studies demonstrating its powerful efficacy, concerns regarding its adverse reactions persist, necessitating comprehensive safety assessment. This study analyzed real-world data from the U.S. Food and Drug Administration to investigate TXA-related adverse events, aiming to elucidate its safety and optimize patient treatment. Methods: The adverse drug event data concerning TXA from 2004 Q1 to 2023 Q3 were collected. Following data standardization, a variety of signal quantification techniques, including the reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and empirical Bayes geometric mean were used for analysis. Results: After analyzing 16,692,026 adverse event reports, a total of 1,574 cases of adverse events related to TXA were identified, spanning 23 system organ classes and 307 preferred terms. In addition to the common thrombosis-related Vascular disorders (n = 386) and Cardiac disorders (n = 377), adverse reactions in the Nervous system disorders category were also observed (n = 785), including Myoclonus (n = 70), Status epilepticus (n = 43), and Myoclonic epilepsy (n = 17). Furthermore, this study uncovered adverse effects such as Renal cortical necrosis, Hepatic cyst rupture, and Vascular stent stenosis, which were not previously mentioned in the instructions. Although these occurred infrequently, they exhibited high signal strength. Both Retinal artery occlusion and Vascular stent thrombosis disorder were frequent and exhibited high signal strength as well. It is worth noting that 78 cases of adverse reactions were caused by confusion between incorrect product administration. Conclusion: Our research suggests that TXA has some adverse reactions that are being overlooked. As a cornerstone medication in hemorrhage treatment, it's crucial to monitor, identify, and address these adverse reactions effectively.

Efficient high-resolution fluorescence projection imaging over an extended depth of field through optical hardware and deep learning optimizations.

Optical microscopy has witnessed notable advancements but has also become more costly and complex. Conventional wide field microscopy (WFM) has low resolution and shallow depth-of-field (DOF), which limits its applications in practical biological experiments. Recently, confocal and light sheet microscopy become major workhorses for biology that incorporate high-precision scanning to perform imaging within an extended DOF but at the sacrifice of expense, complexity, and imaging speed. Here, we propose deep focus microscopy, an efficient framework optimized both in hardware and algorithm to address the tradeoff between resolution and DOF. Our deep focus microscopy achieves large-DOF and high-resolution projection imaging by integrating a deep focus network (DFnet) into light field microscopy (LFM) setups. Based on our constructed dataset, deep focus microscopy features a significantly enhanced spatial resolution of ∼260 nm, an extended DOF of over 30 µm, and broad generalization across diverse sample structures. It also reduces the computational costs by four orders of magnitude compared to conventional LFM technologies. We demonstrate the excellent performance of deep focus microscopy in vivo, including long-term observations of cell division and migrasome formation in zebrafish embryos and mouse livers at high resolution without background contamination.

Two new cases with the UBQLN2 gene mutation in Han Chinese.

Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. 18F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.

TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity.

Energy status is linked to the production of reactive oxygen species (ROS) in macrophages, which is elevated in obesity. However, it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity. Here, we show that the Rab-GTPase activating protein (RabGAP) TBC1D1, a substrate of the energy sensor AMP-activated protein kinase (AMPK), is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development. TBC1D1 deletion decreases, whereas an energy overload-mimetic non-phosphorylatable TBC1D1S231A mutation increases, ROS production and M1-like polarization in macrophages. Mechanistically, TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation. Transplantation of TBC1D1S231A bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable TtSOD for removal of ROS selectively in macrophages alleviates both TBC1D1S231A mutation- and diet-induced obesity. Our findings therefore have implications for drug discovery to combat obesity.

A review of the present methods used to remediate soil and water contaminated with organophosphate esters and developmental directions.

Organophosphate esters (OPEs) are widely used commercial additives, but their environmental persistence and toxicity raise serious concerns necessitating associated remediation strategies. Although there are various existing technologies for OPE removal, comprehensive screening for them is urgently needed to guide further research. This review provides a comprehensive overview of the techniques used to remove OPEs from soil and water, including their related influencing factors, removal mechanisms/degradation pathways, and practical applications. Based on an analysis of the latest literature, we concluded that (1) methods used to decontaminate OPEs include adsorption, hydrolysis, photolysis, advanced oxidation processes (AOPs), activated sludge processes, and microbial degradation; (2) factors such as the quantity/characteristics of the catalysts/additives, pH value, inorganic ion concentration, and natural organic matter (NOM) affect OPE removal; (3) primary degradation mechanisms involve oxidation induced by reactive oxygen species (ROS) (including •OH and SO4•-) and degradation pathways include hydrolysis, hydroxylation, oxidation, dechlorination, and dealkylation; (5) interference from the pH value, inorganic ion and the presence of NOM may limit complete mineralization during the treatment, impacting practical application of OPE removal techniques. This review provides guidance on existing and potential OPE removal methods, providing a theoretical basis and innovative ideas for developing more efficient and environmentally friendly techniques to treat OPEs in soil and water.

Enhanced diabetic wound healing with injectable hydrogel containing self-assembling nanozymes.

To build a smart system in response to the variable microenvironment in infected diabetic wounds, a multifunctional wound dressing was constructed by co-incorporating glucose oxidase (GOx) and a pH-responsive self-assembly Cu2-xSe-BSA nanozyme into a dual-dynamic bond cross-linked hydrogel (OBG). This composite hydrogel (OBG@CG) can adhere to the wound site and respond to the acidic inflammatory environment, initiating the GOx-catalyzed generation of H2O2 and the self-assembly activated peroxidase-like property of Cu2-xSe-BSA nanozymes, resulting in significant hydroxyl radical production to attack the biofilm during the acute infection period and alleviate the high-glucose microenvironment for better wound healing. During the wound recovery phase, Cu2-xSe-BSA aggregates disassembled owing to the elevated pH, terminating catalytic reactive oxygen species generation. Simultaneously, Cu2+ released from the Cu2-xSe-BSA not only promotes the production of mature collagen but also enhances the migration and proliferation of endothelial cells. RNA-seq analysis demonstrated that OBG@CG exerted its antibacterial property by damaging the integrity of the biofilm by inducing radicals and interfering with the energy supply, along with destroying the defense system by disturbing thiol metabolism and reducing transporter activities. This work proposes an innovative glucose consumption strategy for infected diabetic wound management, which may inspire new ideas in the exploration of smart wound dressing.