Trim21 Regulates the Postnatal Development and Thermogenesis of Brown Adipose Tissue.

Brown adipose tissue undergoes rapid postnatal development to mature and plays a crucial role in thermoregulation and energy expenditure, which protects against cold and obesity. Herein, it is shown that the expression of Trim21 mRNA level of interscapular brown adipose tissue elevates after birth, and peaks at P14 (postnatal day 14). Trim21 depletion severely impairs the maturation of interscapular brown adipose tissue, decreases the expression of a series of thermogenic genes, and reduces energy expenditure. Consistently, the loss of Trim21 also leads to a suppression of white adipose tissue "browning", in response to cold exposure and a ß-adrenergic agonist, CL316,243. In addition, Trim21-/- mice are more prone to high-fat diet-induced obesity compared with the control littermates. Taken together, the study for the first time reveals a critical role of Trim21 in regulating iBAT postnatal development and thermogenesis.

High-temperature magnetically topological candidate material Mn3Bi2Te6.

The Mn-Bi-Te family displaying magnetism and non-trivial topological properties has received extensive attention. Here, we predict that the antiferromagnetic structure of Mn3Bi2Te6with three MnTe layers is energetically stable and the magnetic energy difference of Mn-Mn is enhanced four times compared with that in the single MnTe layer of MnBi2Te4. The predicted Néel transition point is raised to 102.5 K, surpassing the temperature of liquid nitrogen. The topological properties show that with the variation of the MnTe layer from a single layer to three layers, the system transforms from a non-trivial topological phase to a trivial topological phase. Interestingly, the ferromagnetic state of Mn3Bi2Te6is a topological semimetal and it exhibits a topological transition from trivial to non-trivial induced by the magnetic transition. Our results enrich the Mn-Bi-Te family system, offer a new platform for studying topological phase transitions, and pave a new way to improve the working temperature of magnetically topological devices.

[Characteristics and Sources of PM2.5 Pollution During Winter in Handan City from 2016 to 2020].

To explore the characteristics and sources of PM2.5 pollution in winter of Handan City in the past five years, PM2.5 samples were collected in winter of 2016 to 2020, and eight types of water-soluble inorganic ions were analyzed. The principal component analysis(PCA) model was used to analyze the types of pollution sources, and the backward trajectory and potential source contribution factor(PSCF) were used to simulate the transport trajectory and pollution sources. The results showed that the PM2.5 concentration in winter of 2018 was the highest, increasing by 60.44%, 25.46%, 91.43%, and 21.53% compared with that in 2016, 2017, 2019, and 2020, respectively. In the winter of 2020, the concentration of water-soluble inorganic ions(WSIIs) decreased by 18.86% compared with that in 2016, and WSIIs/PM2.5 decreased to 26.69%. The PM2.5 concentration(110.20-209.65 µg·m-3) at night was higher than that in the daytime(95.21-193.00 µg·m-3). The concentration of NO3- and NH4+ increased more at night. On the contrary, the concentration and proportion of Cl-decreased annually. In the winter of 2020, the daytime concentrations of K+, Ca2+, Na+, and Mg2+ decreased by 69.72%, 97.10%, 90.91%, and 74.51% compared with that of 2018, and the night concentrations decreased by 66.67%, 95.38%, 91.67%, and 77.78%, respectively. In 2020, the concentrations of NO3-, SO42-, and NH4+ on polluted days were 4.90, 5.80, and 5.20 times those on non-polluted days, with the largest increase in five years. PCA results showed that the main sources of pollution were secondary sources, coal sources, biomass combustion sources, and road and building dust. The backward trajectory and PSCF analysis results showed that pollution transport continued to exist between south-central Mongolia and central Inner Mongolia in winter and was influenced by the transport between northern Henan and Handan and central Hebei and Handan in winter of 2016 and 2017, whereas the latter had a greater impact in winter of 2018-2020.

Exploring Solvent Polarity-Dependent Photocatalysis Mechanism of Organic Photoredox Catalysts.

Organic dyads with intramolecular charge-transfer (ICT) character are emerging as viable and more sustainable photocatalysts than metal-based complexes. Herein, a carbazole- and naphthalimide-based organic dyad (Cz-NI) was designed as an efficient organic photocatalyst for the direct C(sp3)-H carbamoylation of saturated aza-heterocycles. Aiming at understanding the effect of environment, especially the solvent polarity on photocatalysis performance, the excited-state dynamics of Cz-NI in different polar solvents were studied by femtosecond (fs) and nanosecond (ns) time-resolved transient absorption (TA) spectroscopy. Fs-TA measurements indicate that the formation of an intramolecular charge separation (ICS) state with twisted structural feature in polar solvents is driven and stabilized by solvation dynamics. Combined with chemical calculations, we found that orbital decoupling, poor conjugation between Cz and NI groups due to intramolecular torsional motion and transition moments associated with ICT emission, limits excited-state deactivation through radiation and nonradiation transition to the ground state. In addition, the orthogonal π-system of the ICS state enables the efficient spin-orbit, charge-transfer intersystem crossing to a triplet state, which is localized on the NI group. Spectroscopic and computational results reveal the formation of an ICS state at an appropriate energy that enables the population of the triplet state with high quantum yield, and the localized triplet state has long lifetime and high reduction potential for subsequent reactions. Therefore, solvent-solute interaction, especially the solvation-coupled excited-state structural relaxation, is the main factor that the photocatalysis efficiency of Cz-NI has a significant polarity correlation.

Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 µM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.

Identifying a prognostic model and screening of potential natural compounds for acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is one of the most common hematologic malignancies with a poor prognosis and high recurrence rate. The discovery of new predictive models and therapeutic agents plays a crucial role. Methods: The differentially expressed gene that was explicitly highly expressed in The Cancer Genome Atlas (TCGA) and GSE9476 transcriptome databases were screened and included in the least absolute shrinkage and selection operator (LASSO) regression model to derive risk coefficients and build a risk score model. Functional enrichment analysis was conducted on the screened hub genes to explore the potential mechanisms. Subsequently, critical genes were incorporated into a nomogram model based on risk scores to analyze prognostic value. Finally, this study combined network pharmacology to find potential natural compounds for hub genes and used molecular docking to verify the binding ability of molecular structures to natural compounds to explore drug development for possible efficacy in AML. Results: A total of 33 highly expressed genes may be associated with poor prognosis of AML patients. After LASSO and multivariate Cox regression analysis of 33 critical genes, Rho-related BTB domain containing 2 (RHOBTB2), phospholipase A2 (PLA2G4A), interleukin-2 receptor-α (IL2RA), cysteine and glycine-rich protein 1 (CSRP1), and olfactomedin-like 2A (OLFML2A) were found to played a significant role in the prognosis of AML patients. CSRP1 and OLFML2A were independent prognostic factors of AML. The predictive power of these 5 hub genes in combination with clinical features was better than clinical data alone in predicting AML in the column line graphs and had better predictive value at 1, 3, and 5 years. Finally, through network pharmacology and molecular docking, this study found that diosgenin in Guadi docked well with PLA2G4A, beta-sitosterol in Fangji docked well with IL2RA, and OLFML2A docked well with 3,4-di-O-caffeoylquinic acid in Beiliujinu. Conclusions: The predictive model of RHOBTB2, PLA2G4A, IL2RA, CSRP1, and OLFML2A combined with clinical features can better guide the prognosis of AML. In addition, the stable docking of PLA2G4A, IL2RA, and OLFML2A with natural compounds may provide new options for treating AML.

Early osteoarthritis diagnosis based on near-infrared spectroscopy combined with aquaphotomics.

Osteoarthritis (OA) is the most common joint disease and the leading cause of disability in elderly individuals. Despite rapid advances in imaging techniques, early OA diagnosis remains a clinical challenge. In the present study, the feasibility of early OA diagnosis was explored via near-infrared spectroscopy (NIRS) combined with aquaphotomics. Synovial fluid samples from 65 cases of OA categorized as mild, moderate, and severe according to theKellgrenandLawrence classification criteria were analyzed via NIRS. The 1st overtone of water (1300-1600 nm) was considered as the research object for an aquaphotomics model, and aquagrams of the mild, moderate, and severe OA cases were generated using 12 water absorption patterns for early OA diagnosis.The aquaphotomics results exhibited clear differences in the region of 1300-1500 nm, and the number of hydrogen bonds of different water species (1412,1424, 1482, and 1496 nm) evidently correlated with OA occurrence and development. With OA progression, the absorption intensity of water molecules without hydrogen bonds (1412 nm/1424 nm) became stronger, while the absorption intensity of water molecules with four hydrogen bonds (1482 nm/1496 nm) decreased.These results together reveal that the established accurate and rapid early OA diagnosis model based on NIRS combined with aquaphotomics is effective and feasible, and that the number of hydrogen bonds can be used as a biomarker for early OA diagnosis.

HSP90-regulated CHIP/TRIM21/p21 Axis Involves in the Senescence of Osteosarcoma Cells.

BACKGROUND: OS is the most frequent malignant bone tumor with a poor prognosis. TRIM21 has been reported to play a critical role in OS by regulating the expression of the TXNIP/p21 axis and inhibiting the senescence of OS cells. AIM: Investigation of the molecular mechanism of tripartite motif 21 (TRIM21) in osteosarcoma (OS) would shed light on the understanding of the pathogenesis of OS. OBJECTIVE: This study aimed to explore the mechanism regulating the protein stability of TRIM21 in the process of OS senescence. METHODS: Human U2 OS cells were used to establish stable cells overexpressing TRIM21 (induced by Dox) or knocking down TRIM21. The co-immunoprecipitation (co-IP) assay was used to examine the interaction between TRIM21 and HSP90. Immunofluorescence (IF) assay was used to observe colocalization in OS cells. Western blot analysis was applied to detect the protein expression, and quantitative real-time PCR (qRT-PCR) assay was used to test the mRNA expression of corresponding genes. SA-ß-gal staining was used to evaluate OS senescence. RESULTS: In this study, we verified the interaction between HSP90 and TRIM21 using a co-IP assay. Knockdown or inhibition of HSP90 with its inhibitor 17-AAG accelerated the degradation of TRIM21 by the proteasome in OS cells. CHIP E3 ligase mediated this degradation of TRIM21, with the knockdown of CHIP rescuing the downregulation of TRIM21 induced by 17-AAG. TRIM21 inhibited OS senescence and downregulated the expression of senescence marker p21, while CHIP exhibited an opposite regulatory role on p21 expression. CONCLUSION: Taken together, our results demonstrated that HSP90 is responsible for the stabilization of TRIM21 in OS and that the CHIP/TRIM21/p21 axis controlled by HSP90 affects the senescence of OS cells.

Organic photoredox catalyzed dealkylation/acylation of tertiary amines to access amides.

A mild metal-free C-N bond activation strategy for the direct conversion of inert tertiary amines with acyl chlorides into tertiary amides via organic photoredox catalysis is presented. In this protocol, a novel organic photocatalyst (Cz-NI-Ph) that showed excellent catalytic performance during C-N bond cleavage is developed. Moreover, this reaction features green and mild conditions, broad substrate scope, and readily available raw materials.

MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII.

Epidermal growth factor receptor variant III (EGFRvIII) is a mutant isoform of EGFR with a deletion of exons 2-7 making it insensitive to EGF stimulation and downstream signal constitutive activation. However, the mechanism underlying the stability of EGFRvIII remains unclear. Based on CRISPR-Cas9 library screening, we found that mucin1 (MUC1) is essential for EGFRvIII glioma cell survival and temozolomide (TMZ) resistance. We revealed that MUC1-C was upregulated in EGFRvIII-positive cells, where it enhanced the stability of EGFRvIII. Knockdown of MUC1-C increased the colocalization of EGFRvIII and lysosomes. Upregulation of MUC1 occurred in an NF-κB dependent manner, and inhibition of the NF-κB pathway could interrupt the EGFRvIII-MUC1 feedback loop by inhibiting MUC1-C. In a previous report, we identified AC1Q3QWB (AQB), a small molecule that could inhibit the phosphorylation of NF-κB. By screening the structural analogs of AQB, we obtained EPIC-1027, which could inhibit the NF-κB pathway more effectively. EPIC-1027 disrupted the EGFRvIII-MUC1-C positive feedback loop in vitro and in vivo, inhibited glioma progression, and promoted sensitization to TMZ. In conclusion, we revealed the pivotal role of MUC1-C in stabilizing EGFRvIII in glioblastoma (GBM) and identified a small molecule, EPIC-1027, with great potential in GBM treatment.

Mortality of Escalation and Modulation Antithrombotic Therapy in Coronary Artery Disease Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The net clinical benefit of antithrombotic therapy (ATT) reflects the concomitant effects of bleeding and ischemic events. OBJECTIVES: We sought to assess the overall effect of the modulation or escalation of ATT on all-cause mortality as well as ischemic and bleeding events. METHODS: We performed a meta-analysis of randomized controlled trials comparing escalation or modulation of ATT versus standard ATT in patients with coronary artery disease. A total of 32 studies with 160,659 subjects were enrolled in this analysis. RESULTS: Neither escalation nor modulation of ATT has significant effect on all-cause mortality (escalation: relative risk [RR]: 0.94, 95% confidence interval [CI]: 0.85-1.04; modulation: RR: 0.90; 95% CI: 0.81-1.01). Compared with standard ATT therapy, escalation of ATT was associated with lower risk of myocardial infarction (MI; RR: 0.84, 95% CI: 0.76-0.94), but had a higher risk of major or minor bleeding (RR: 1.38, 95% CI: 1.15-1.66). Modulation of ATT was associated with a similar risk of MI (RR: 1.07, 95% CI: 0.96-1.19), but a reduced risk for major or minor bleeding (RR: 0.58, 95% CI: 0.51-0.66). Meta-regression combining both escalation and modulation studies found that the heterogeneity of all-cause mortality was mainly attributed to the heterogeneity of major or minor bleeding (adjusted R-squared = 100.00%, p = 0.004), but not to MI. CONCLUSION: Either escalation or modulation of ATT has little benefit in all-cause mortality. The variability of the treatment effects on all-cause mortality was mainly attributed to the variability of major or minor bleeding, but not to MI.

Tanshinone IIA promotes reverse cholesterol transport to improve atherosclerosis / 中国药理学通报

Aim To explore the effect of tanshinone II A (Tan II A) on reverse cholesterol transport in atherosclerosis model mice and RAW264. 7 cells and the underlying mechanism. Methods Thirty-two male LDLR -/- mice were randomly divided into four groups. These mice were fed with normal diet or high fat diet for 12 weeks. The control group and model group were given normal saline. Tan II A group and atorvastatin group were given Tan II A solution and atorvastatin solution for 12 weeks. RAW264. 7 cells were induced with oxidized low-density lipoprotein (ox-LDL) 100 mg • L-

Prognostic significance of multiple triglycerides-derived metabolic indices in patients with acute coronary syndrome.

BACKGROUND: Triglyceride (TG) and its related metabolic indices, all recognized as surrogates of insulin resistance, have been demonstrated to be relevant to clinical prognosis. However, the relative value of these TG-related indices for predicting cardiovascular events among patients with acute coronary syndrome (ACS) has not been examined. METHODS: The TG, the triglyceride-glucose (TyG) index, the atherogenic index of plasma, TG to high-density lipoprotein cholesterol ratio, and the lipoprotein combine index were assessed in 1694 ACS patients undergoing percutaneous coronary intervention. The primary endpoint was major adverse cardiovascular event (MACE), which was the composite of all-cause mortality, stroke, myocardial infarction, or unplanned repeat revascularization. RESULTS: During a median follow-up of 31 months, 345 patients (20.4%) had MACE. The risk of the MACE was increased with higher TG and the four TG-derived metabolic indices [TG-adjusted hazard ratio (HR) = 1.002, 95% CI: 1.001-1.003; TyG index-adjusted HR = 1.736, 95% CI: 1.398-2.156; atherogenic index of plasma-adjusted HR = 2.513, 95% CI: 1.562-4.043; TG to high-density lipoprotein cholesterol ratio-adjusted HR = 1.148, 95% CI: 1.048-1.258; and lipoprotein combine index-adjusted HR = 1.009, 95% CI: 1.004-1.014; P < 0.001 for all indices]. TG and all the four indices significantly improved the predictive ability for MACE in addition to the baseline model. Among them, TyG index showed the best ability for predicting MACE compared with the other three indices from all the three measurements ( P < 0.05 for all comparison). CONCLUSIONS: TG and TG-derived metabolic indices were all strongly associated with MACE among ACS patients undergoing percutaneous coronary intervention. Among all the indices, TyG index showed the best ability to predict the risk of MACE.

Effect of Alirocumab on Coronary Calcification in Patients With Coronary Artery Disease.

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been documented with significantly reduction in LDL cholesterol levels and cardiovascular events. However, evidence regarding the impact of PCSK9 inhibitors on coronary calcification is limited. Methods: Eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard statin therapy. Calcium score based on coronary computed tomographic angiography at baseline and follow up were compared. Results: Compared with baseline levels, LDL cholesterol were significantly decreased in both groups, while the absolute reduction of LDL cholesterol levels were higher in patients treated with alirocumab (1.69 ± 0.52 vs. 0.92 ± 0.60, P < 0.0001). Additionally, patients in alirocumab group demonstrated a significant reduction of Lp(a) levels, whereas it was not observed in the standard statin group. Notably, greater increases in the percentage changes of CAC score (10.6% [6.3-23.3] vs. 2.9% [-6.7-8.3]; P < 0.0001) were observed in the statin group compared to the alirocumab group. Consistently, CAC progression was significantly lower in the alirocumab group than in the standard statin group (0.6 ± 2.2% vs. 2.7 ± 2.3%; P = 0.002). Conclusions: Study indicated that administration of the PCSK9 inhibitors to statins produced significantly lower rate of CAC progression in patients with coronary artery disease. Further studies with CAC progression and their clinical outcomes are needed. Trial Registration: ClinicalTrials.gov, Identifier: NCT04851769.

Understanding paraquat resistance mechanisms in Arabidopsis thaliana to facilitate the development of paraquat-resistant crops.

Paraquat (PQ) is the third most used broad-spectrum nonselective herbicide around the globe after glyphosate and glufosinate. Repeated usage and overreliance on this herbicide have resulted in the emergence of PQ-resistant weeds that are a potential hazard to agriculture. It is generally believed that PQ resistance in weeds is due to increased sequestration of the herbicide and its decreased translocation to the target site, as well as an enhanced ability to scavenge reactive oxygen species. However, little is known about the genetic bases and molecular mechanisms of PQ resistance in weeds, and hence no PQ-resistant crops have been developed to date. Forward genetics of the model plant Arabidopsis thaliana has advanced our understanding of the molecular mechanisms of PQ resistance. This review focuses on PQ resistance loci and resistance mechanisms revealed in Arabidopsis and examines the possibility of developing PQ-resistant crops using the elucidated mechanisms.

Direct Synthesis of Bienzyme-like Carbide-derived Carbons via Mild Electrochemical Oxidation of Ti 3AlC 2 MAX.

Objective: To develop effective alternatives to natural enzymes, it is crucial to develop nanozymes that are economical, resource efficient, and environmentally conscious. Carbon nanomaterials that have enzyme-like activities have been extensively developed as substitutes for traditional enzymes. Methods: Carbide-derived carbons (CDCs) were directly synthesized via a one-step electrochemical method from a MAX precursor using an ammonium bifluoride electrolyte at ambient conditions. The CDCs were characterized by systematic techniques. Results: CDCs showed bienzyme-like activities similar to that of peroxidase and superoxide dismutase. We systematically studied the dependence of CDC enzyme-like activity on different electrolytes and electrolysis times to confirm activity dependence on CDC content. Additionally, the synthesis mechanism and CDC applicability were elaborated and demonstrated, respectively. Conclusion: The demonstrated synthesis strategy eliminates tedious intercalation and delamination centrifugation steps and avoids using high concentrations of HF, high temperatures, and halogen gases. This study paves the way for designing two-dimensional material-based nanocatalysts for nanoenzyme and other applications.

Organic photoredox catalytic amino-heteroarylation of unactivated olefins to access distal amino ketones.

Here we describe a metal-free amino-heteroarylation of unactivated olefins via organic photoredox catalysis, providing a concise and efficient approach for the rapid synthesis of various δ (ß, ε)-amino ketones under mild conditions. This protocol demonstrates that the new photocatalyst Cz-NI developed by our group has an excellent photoredox catalytic performance. Finally, a series of mechanistic experiments and DFT calculations indicate that this transformation undergoes a photoredox catalytic sequential radical addition/functional group migration process.

New oxindole alkaloids with selective osteoclast inhibitory activity from Gelsemium elegans.

A new alkaloid 14-hydroxygelseziridine (1), along with four known oxindoles (2-5), was isolated and characterized from the well-known toxic medicine Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemistry calculations. Structurally, new compound 1 has a three membered oxygen ring at N-4/C-20. All compounds were tested for osteoclast (MOC-1) inhibitory activity in vitro. Compound 2 exhibited the selective osteoclast inhibitory activity. Flow cytometry revealed that the apoptosis of osteoclasts induced by 2. Furthermore, the PCR bioassay suggested that compound 2 may activate the apoptotic pathway of osteoclasts by reducing the expression of IL-6 and c-Jun, and increasing caspase 9. This work provided the evidence for the rationality as the traditional treatment for bone related diseases of G. elegans, and shed a new light on its further research.