Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein.

DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50 = 643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies.

A case report on atypical presentations of Dyke-Davidoff-Masson syndrome.

Dyke-Davidoff-Masson Syndrome (DDMS) is a rare neurological disease with an unknown incidence. The manifestations of DDMS are variable, while typical symptoms are seizures, hemiparesis, and mental retardation. Here, we present a case involving a 19-year-old male patient who presents with headaches, mood changes, and a history of seizures during childhood. Based on the neuroimages, a diagnosis of DDMS was established. The application of sertraline hydrochloride as a therapeutic intervention has alleviated the symptoms. This case report illustrates the importance of understanding the clinical features of DDMS based on imaging.

Sodium Tanshinone IIA Sulfonate alleviates vascular senescence in diabetic mice by modulating the A20-NFκB-NLRP3 inflammasome-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Insight to starch retrogradation through fine structure models: A review.

The retrogradation of starch is crucial for the texture and nutritional value of starchy foods products. There is mounting evidence highlighting the significant impact of starch's fine structures on starch retrogradation. Because of the complexity of starch fine structure, it is a formidable challenge to study the structure-property relationship of starch retrogradation. Several models have been proposed over the years to facilitate understanding of starch structure. In this review, from the perspective of starch models, the intricate structure-property relationship is sorted into the correlation between different types of structural parameters and starch retrogradation performance. Amylopectin B chains with DP 24-36 and DP ≥36 exhibit a higher tendency to form ordered crystalline structures, which promotes starch retrogradation. The chains with DP 6-12 mainly inhibit starch retrogradation. Based on the building block backbone model, a longer inter-block chain length (IB-CL) enhances the realignment and reordering of starch. The mathematical parameterization model reveals a positive correlation between amylopectin medium chains, amylose short chains, and amylose long chains with starch retrogradation. The review is structured according to starch models; this contributes to a clear and comprehensive elucidation of the structure-property relationship, thereby providing valuable references for the selection and utilization of starch.

Effects of synergistic action on rheological and thermal properties of potato starch complexes co-gelatinized with caffeic acid and squash polysaccharides extracted with water and subcritical water.

In order to broaden the application range of squash polysaccharide (WESP/SWESP) and caffeic acid (CAA) and improve the quality of potato starch (PS) products, the effects of WESP/SWESP and CAA on the gelatinization, rheology, thermodynamics, microstructure and in vitro digestion of PS were investigated. Meanwhile, the synergistic effect of WESP/SWESP and CAA on PS was further analyzed. Differently, due to WESP and SWESP had different monosaccharide composition and structure, they had different effects on the system. Pasting properties results showed that the presence of WESP/SWESP and CAA significantly reduced the peak viscosity, trough viscosity, breakdown viscosity and final viscosity of PS, especially under the combined action. In rheological tests, all sample gels belonged to the pseudoplastic fluids and weak gel system (tan δ < 1). Besides, thermodynamic properties revealed that WESP/SWESP and CAA synergistic effect had better retrogradation delay effect. In the ternary system, WESP/SWESP, CAA and PS can form a new network structure and improve the stability of the gel system. In addition, the results of infrared spectroscopy, Raman spectroscopy, x-ray diffraction and scanning electron microscopy exhibited that the ternary system can promote the accumulation and winding of the spiral structure of PS chain, and make the structure of PS gel network more orderly and stable. Furthermore, compared with PS gel, the ternary system had lower RDS and higher SDS and RS content, suggesting that the addition of WESP/SWESP and CAA at the same time was more conducive to reducing the hydrolysis rate of PS. This work revealed the interaction between WESP/SWESP, CAA and PS, which improved the physicochemical and digestive properties of PS. It will provide a theoretical basis for improving the quality of potato starch-related products and developing functional foods.

Structural characterization of squash polysaccharide and its effect on STZ-induced diabetes mellitus model in MIN6 cells.

A novel natural water-soluble acidic polysaccharide (PWESP-3) was isolated from squash with a molecular mass of 140.519 kDa, which was composed of arabinose (Ara, 35.30 mol%), galactose (Gal, 61.20 mol%), glucose (Glc, 1.80 mol%), and Mannuronic acid (ManA, 1.70 mol%) and contained Araf-(1→, →3)-Araf-(1→, →5)-Araf-(1→, Glcp-(1→, Galp-(1→, →3,5)-Araf-(1→, →2)-Glcp-(1→, →2)-Manp-(1→, →3)-Glcp-(1→, →4)-Galp-(1→, →3)-Galp-(1→, →6)-Galp-(1→, →3,4)-Galp-(1→, →4,6)-Galp-(1→ residues in the backbone. Moreover, the structure of PWESP-3 was identified by NMR spectra. The branch chain was connected to the main chain by the O-3 and O-4 atom of Gal. In addition, the effect of PWESP-3 on STZ-induced type I diabetes mellitus model in MIN6 cells was investigated. The results showed that PWESP-3 can increase the viability and insulin secretion of MIN6 cells and reduce the oxidative stress caused by ROS and NO. Meanwhile, PWESP-3 can also reduce the content of ATP, Ca2+, mitochondrial membrane potential and Caspase-3 activity in MIN6 cells. Furthermore, treatment with PWESP-3 can prevent single or double stranded DNA breaking to form DNA fragments and improve DNA damage in MIN6 cells, thereby avoiding apoptosis. Therefore, the above data highlight that PWESP-3 can improve the function of insulin secretion in STZ-induced MIN6 cells in vitro and can be used as an alternative food supplement to diabetes drugs.

FGF21 overexpression alleviates VSMC senescence in diabetic mice by modulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-ß-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-ß-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.

Performance of ATT and UDFF in the diagnosis of non-alcoholic fatty liver: An animal experiment.

Objective: To establish a Bama minipigs model with Non-Alcoholic Fatty Liver (NAFL) induced by a high-fat diet and investigate the application of attenuation coefficient (ATT) and ultrasound-derived fat fraction (UDFF) in the diagnosis of NAFL. Methods: Six-month-old male Bama minipigs were randomly divided into normal control and high-fat groups (n = 3 pigs per group), and fed with a control diet and high-fat diet for 32 weeks. Weight and body length were measured every four weeks, followed by quantitative ultrasound imaging (ATT and UDFF), blood biochemical markers, and liver biopsies on the same day. Using the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) as a reference, we analyzed the correlation between ATT, UDFF, and their score results. Results: Compared with the normal control group, the body weight, body mass index (BMI), and serum levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the High-fat group were significantly different at Week 12 (P < 0.05). Spearman correlation analysis showed that the ATT value was significantly correlated with NAS score (r = 0.76, P < 0.001), and the UDFF value was significantly correlated with NAS score (r = 0.80, P < 0.001). The optimal cut-off value of ATT and UDFF were 0.59 dB/cm/MHz and 5.5%, respectively. These values are optimal for diagnosis of NAFL in Bama minipig model. Conclusion: ATT and UDFF have a high correlation with steatosis, and can be used as a non-invasive method for early screening of hepatic steatosis, which can dynamically monitor the change of disease course.

Advancements in Single-Cell RNA Sequencing Research for Neurological Diseases.

Neurological diseases are a major cause of the global burden of disease. Although the mechanisms of the occurrence and development of neurological diseases are not fully clear, most of them are associated with cells mediating neuroinflammation. Yet medications and other therapeutic options to improve treatment are still very limited. Single-cell RNA sequencing (scRNA-seq), as a delightfully potent breakthrough technology, not only identifies various cell types and response states but also uncovers cell-specific gene expression changes, gene regulatory networks, intercellular communication, and cellular movement trajectories, among others, in different cell types. In this review, we describe the technology of scRNA-seq in detail and discuss and summarize the application of scRNA-seq in exploring neurological diseases, elaborating the corresponding specific mechanisms of the diseases as well as providing a reliable basis for new therapeutic approaches. Finally, we affirm that scRNA-seq promotes the development of the neuroscience field and enables us to have a deeper cellular understanding of neurological diseases in the future, which provides strong support for the treatment of neurological diseases and the improvement of patients' prognosis.

Comprehensive Assessment of Polysaccharides Extracted from Squash by Subcritical Water under Different Conditions.

The effects of subcritical water microenvironment on the physiochemical properties, antioxidant activity and in vitro digestion of polysaccharides (SWESPs) from squash were investigated. After single-factor experiments, twenty samples were successfully prepared at different extraction temperatures (110, 130, 150, 170 and 190 °C) and extraction times (4, 8, 12 and 16 min). Under a low temperature environment, the whole process was mainly based on the extraction of SWESP. At this time, the color of SWESP was white or light gray and the molecular mass was high. When the temperature was 150 °C, since the extraction and degradation of SWESP reached equilibrium, the maximum extraction rate (18.67%) was reached at 150 °C (12 min). Compared with traditional methods, the yield of squash SWESP extracted by subcritical water was 3-4 times higher and less time consuming. Under high temperature conditions, SWESPs were degraded and their antioxidant capacity and viscosity were reduced. Meanwhile, Maillard and caramelization reactions turned the SWESPs yellow-brown and produced harmful substances. In addition, different SWESPs had different effects on in vitro digestion. In brief, SWESPs prepared under different conditions have different structures and physicochemical properties, allowing the obtainment of the required polysaccharide. Our results show that squash polysaccharides prepared in different subcritical water states had good development potential and application in the food industry.

Effect of ubiquinol on electrophysiology during high-altitude acclimatization and de-acclimatization: A substudy of the Shigatse CARdiorespiratory fitness (SCARF) randomized clinical trial.

BACKGROUND: High-altitude exposure changes the electrical conduction of the heart. However, reports on electrocardiogram (ECG) characteristics and potent prophylactic agents during high-altitude acclimatization and de-acclimatization are inadequate. This study aimed to investigate the effects of ubiquinol on electrophysiology after high-altitude hypoxia and reoxygenation. METHODS: The study was a prospective, randomized, double-blind, placebo-controlled trial. Forty-one participants were randomly divided into two groups receiving ubiquinol 200 mg daily or placebo orally 14 days before flying to high altitude (3900 m) until the end of the study. Cardiopulmonary exercise testing was performed at baseline (300 m), on the third day after reaching high altitude, and on the seventh day after returning to baseline. RESULTS: Acute high-altitude exposure prolonged resting ventricular repolarization, represented by increased corrected QT interval (455.9 ± 23.4 vs. 427.1 ± 19.1 ms, P < 0.001) and corrected Tpeak-Tend interval (155.5 ± 27.4 vs. 125.3 ± 21.1 ms, P < 0.001), which recovered after returning to low altitude. Ubiquinol supplementation shortened the hypoxia-induced extended Tpeak-Tend interval (-7.7 ms, [95% confidence interval (CI), -13.8 to -1.6], P = 0.014), Tpeak-Tend /QT interval (-0.014 [95% CI, -0.027 to -0.002], P = 0.028), and reserved maximal heart rate (11.9 bpm [95% CI, 3.2 to 20.6], P = 0.013) during exercise at high altitude. Furthermore, the decreased resting amplitude of the ST-segment in the V3 lead was correlated with decreased peak oxygen pulse (R = 0.713, P < 0.001) and maximum oxygen consumption (R = 0.595, P < 0.001). CONCLUSIONS: Our results illustrated the electrophysiology changes during high-altitude acclimatization and de-acclimatization. Similarly, ubiquinol supplementation shortened the prolonged Tpeak-Tend interval and reserved maximal heart rate during exercise at high altitude. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR2200059900.

Advances in protein-based microcapsules and their applications: A review.

Due to their excellent emulsification, biocompatibility, and biological activity, proteins are widely used as microcapsule wall materials for encapsulating drugs, natural bioactive substances, essential oils, probiotics, etc. In this review, we summarize the protein-based microcapsules, discussing the types of proteins utilized in microcapsule wall materials, the preparation process, and the main factors that influence their properties. Additionally, we conclude with examples of the vital role of protein-based microcapsules in advancing the food industry from primary processing to deep processing and their potential applications in the biomedical, chemical, and textile industries. However, the low stability and controllability of protein wall materials lead to degraded performance and quality of microcapsules. Protein complexes with polysaccharides or modifications to proteins are often used to improve the thermal instability, pH sensitivity, encapsulation efficiency and antioxidant capacity of microcapsules. In addition, factors such as wall material composition, wall material ratio, the ratio of core to wall material, pH, and preparation method all play critical roles in the preparation and performance of microcapsules. The application area and scope of protein-based microcapsules can be further expanded by optimizing the preparation process and studying the microcapsule release mechanism and control strategy.

Solution blow spun bilayer chitosan/polylactic acid nanofibrous patch with antibacterial and anti-inflammatory properties for accelerating acne healing.

The quercetin (QC) loaded chitosan (CS) nanofibrous patch (CSQC) was designed and fabricated successfully by solution blow spinning (SBS). And it was employed to explore a functional double-layer nanofibrous patch (CSQC/PLA) with polylactic acid (PLA) for overcoming the resistance of acne-causing bacteria to antibiotics and local cutaneous irritation. The nanofibrous patch possessed a fluffy bilayer structure with good air permeability, which may be befitted from the SBS method. The 10 % QC loaded CSQC0.10/PLA had sustained release ability of QC for 24 h. A high free radical clearance rate (91.18 ± 2.26 %) and robust antibacterial activity against P. acnes (94.4 %) were achieved for CSQC0.10/PLA with excellent biocompatibility. Meanwhile, E. coli and S. aureus were also suppressed with 99.4 % and 99.2 %, respectively. Moreover, the expression of pro-inflammatory cytokines (IL-6 and TNF-α) was significantly reduced, conducive to acne healing. Therefore, the CSQC0.10/PLA bilayer nanofibrous patch designed here may shed some light on developing multifunctional materials for treating acne infectious wounds.

Effects of zucchini polysaccharide on pasting, rheology, structural properties and in vitro digestibility of potato starch.

Zucchini polysaccharide (ZP) has a unique molecular structure and a variety of biological activities. This study aimed to evaluate the effects of ZP (1, 2, 3, 4 and 5 %, w/w) on the properties of potato starch (PS), including pasting, rheological, thermodynamic, freeze-thaw stability, micro-structure, and in vitro digestibility of the ZP-PS binary system. The results showed that the appearance of ZP significantly reduced the peak, breakdown, final and setback viscosity and prolonged the pasting temperature of PS, whereas increased the trough viscosity. The tests of rheological showed that ZP had a damaging effect on PS gels. Meanwhile, the results of thermodynamic and Fourier transform infrared exhibited that the presence of ZP significantly retarded the retrogradation of PS, especially at a higher levels. The observation of the microstructure exhibited that ZP significantly altered the microscopic network structure of the PS gels, and ZP reduced the formation of the gel structure. Besides, ZP postponed the retrogradation process of PS gels. Moreover, ZP weakened the freeze-thaw stability of the PS gel. Furthermore, ZP also can decrease the digestibility and estimated glycemic index (eGI) value of PS from 86.04 % and 70.89 to 77.67 % and 65.22, respectively. Simultaneously, the addition of ZP reduced the rapidly digestible starch content (from 25.09 % to 16.59 %) and increased the slowly digestible starch (from 24.99 % to 26.77 %) and resistant starch content (from 49.92 % to 56.64 %). These results have certain guiding significance for the application of ZP in starch functional food.

MiR-146a-5p deficiency in extracellular vesicles of glioma-associated macrophages promotes epithelial-mesenchymal transition through the NF-κB signaling pathway.

Glioma-associated macrophages (GAMs) are pivotal chains in the tumor immune microenvironment (TIME). GAMs mostly display M2-like phenotypes with anti-inflammatory features related to the malignancy and progression of cancers. Extracellular vesicles derived from immunosuppressive GAMs (M2-EVs), the essential components of the TIME, greatly impact the malignant behavior of GBM cells. M1- or M2-EVs were isolated in vitro, and human GBM cell invasion and migration were reinforced under M2-EV treatment. Signatures of the epithelial-mesenchymal transition (EMT) were also enhanced by M2-EVs. Compared with M1-EVs, miR-146a-5p, considered the key factor in TIME regulation, was deficient in M2-EVs according to miRNA-sequencing. When the miR-146a-5p mimic was added, EMT signatures and the invasive and migratory abilities of GBM cells were correspondingly weakened. Public databases predicted the miRNA binding targets and interleukin 1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were screened as miR-146a-5p binding genes. Bimolecular fluorescent complementation and coimmunoprecipitation confirmed interactions between TRAF6 and IRAK1. The correlation between TRAF6 and IRAK1 was evaluated with immunofluorescence (IF)-stained clinical glioma samples. The TRAF6-IRAK1 complex is the switch and the brake that modulates IKK complex phosphorylation and NF-κB pathway activation, as well as the EMT behaviors of GBM cells. Furthermore, a homograft nude mouse model was explored and mice transplanted with TRAF6/IRAK1-overexpressing glioma cells had shorter survival times while mice transplanted with glioma cells with miR-146a-5p overexpression or TRAF6/IRAK1 knockdown lived longer. This work indicated that in the TIME of GBM, the deficiency of miR-146a-5p in M2-EVs enhances tumor EMT through disinhibition of the TRAF6-IRAK1 complex and IKK-dependent NF-κB signaling pathway providing a novel therapeutic strategy targeting the TIME of GBM.

Targeting Pericytes for Functional Recovery in Ischemic Stroke.

Pericytes surrounding endothelial cells in the capillaries are emerging as an attractive cell resource, which can show a large variety of functions in ischemic stroke, including preservation of the blood-brain barrier, regulation of immune function, and support for cerebral vasculature. These functions have been fully elucidated in previous studies. However, in recent years, increasing evidence has shown that pericytes play an important role in neurological recovery after ischemic stroke due to their regenerative function which can be summarized in two aspects according to current discoveries, one is that pericytes are thought to be multipotential themselves, and the other is that pericytes can promote the differentiation of oligodendrocyte progenitor cells (OPCs). Considering the neuroprotective treatment for stroke has not been much progressed in recent years, new therapies targeting pericytes may be a future direction. Here, we will review the beneficial effects of pericytes in ischemic stroke from two directions: the barrier and vascular functions and the regenerative functions of pericytes.

Compromised browning in white adipose tissue of ageing people.

BACKGROUND: Adipose tissue plays a pivotal role in the pathology of metabolic disorders. In the past decade, brown and brown-like adipose tissues were detected in adult humans and show therapeutic potential in ageing-related metabolic diseases. OBJECTIVE: This study investigated expressions of major brown adipose markers in white adipose tissue (WAT) of different ages. Their associations with metabolic parameters and key adipokines were interrogated. DESIGN: Cross-sectional study, 2019-2021. METHODS: We recruited 21 young, 67 middle-aged, and 34 older patients. Omental adipose tissues were collected, and expressions of key brown markers and adipokines and the adipocyte size were evaluated. The fat depot distribution was evaluated by computed tomography. RESULTS: UCP1 and PRDM16 mRNA expressions declined with ageing in WAT and were more associated with age, than with the body mass index (BMI). The increased visceral adipose tissue (VAT) amount, as well as the VAT to subcutaneous adipose tissue (SAT) ratio, was decreased in the highest tertile of UCP1 expression, while individuals in different PRDM16 mRNA tertiles exhibited similar fat distribution. UCP1 mRNA was positively correlated with ADIPOQ and the strength of the correlation declined with ageing. In contrast, the association between UCP1 and LEP was insignificant in young and middle-aged groups but became significantly correlated in the older-people group. We also found a positive correlation between UCP1 and PRDM16. CONCLUSIONS: PRDM16 and UCP1, despite their key functions in adipose browning, exhibit differential clinical correlations with metabolic features in human WAT in an age-dependent manner. These two genes may participate in the pathogenesis of ageing-related metabolic diseases, but with distinct mechanisms.

Reproducibility of functional lung parameters derived from free-breathing non-contrast-enhanced 2D ultrashort echo-time.

Background: Imaging the lung parenchyma with magnetic resonance imaging (MRI) is challenging due to cardiac and respiratory motion, the low proton density and short T2* relaxation time, and therefore not well established in the clinical routine. As a further step in facilitating lung MRI for longitudinal monitoring, this study aimed to assess the reproducibility of 2D ultrashort echo time (UTE)-derived lung function parameters in healthy subjects. Methods: In this study, a 2D UTE technique was combined with tiny golden angle (tyGA) ordering. Data were acquired either during breath-holds (BH) or continuously during free-breathing (FB) at a field strength of 3T. Retrospective self-gating (image- and k-space-based) was used to reconstruct respiratory and cardiac multistage images from the FB acquisitions. The reproducibility of functional lung parameters derived from BH and FB acquisitions was assessed for three independent examinations (M1-3). M1 and M2 were acquired within 2 h, whereas M3 was acquired at least 14 d after M1/2. Different respiratory and cardiac phases were reconstructed for three coronal slices. Quantitative analysis including proton fraction (fP ), apparent signal-to-noise ratio (apparent SNR), fractional ventilation (FV), and perfusion (f) was performed by two independent observers, and inter-measurement and inter-observer repeatability were assessed. Results: All scans could be performed successfully in all volunteers. Intraclass correlation coefficients (ICC) of inter-measurement and inter-observer variability, and Bland-Altman analysis showed good to very good reproducibility. Larger breathing amplitudes were observed in the BH acquisitions, which also showed lower reproducibility when compared with the FB acquisitions. For the FB approach, the ICC ranged between 0.70 and 0.98 for all measurements, and ranged between 0.86 and 0.97 for the two observers. No bias or significant differences were observed between the three measurements or the two observers in healthy volunteers. Conclusions: The study proves the feasibility of FB 2D tyGA UTE for lung imaging. Functional parameters derived from FB acquisitions are reproducible in healthy volunteers, allowing for further investigation of this technique in patients with various underlying diseases.

Host-microbiota interactions: The aryl hydrocarbon receptor in the acute and chronic phases of cerebral ischemia.

The relationship between gut microbiota and brain function has been studied intensively in recent years, and gut microbiota has been linked to a couple of neurological disorders including stroke. There are multiple studies linking gut microbiota to stroke in the "microbiota-gut-brain" axis. The aryl hydrocarbon receptor (AHR) is an important mediator of acute ischemic damage and can result in subsequent neuroinflammation. AHR can affect these responses by sensing microbiota metabolites especially tryptophan metabolites and is engaged in the regulation of acute ischemic brain injury and chronic neuroinflammation after stroke. As an important regulator in the "microbiota-gut-brain" axis, AHR has the potential to be used as a new therapeutic target for ischemic stroke treatment. In this review, we discuss the research progress on AHR regarding its role in ischemic stroke and prospects to be used as a therapeutic target for ischemic stroke treatment, aiming to provide a potential direction for the development of new treatments for ischemic stroke.