IKKα-STAT3-S727 axis: a novel mechanism in DOX-induced cardiomyopathy.

Doxorubicin (DOX) is an effective chemotherapeutic drug, but its use can lead to cardiomyopathy, which is the leading cause of mortality among cancer patients. Macrophages play a role in DOX-induced cardiomyopathy (DCM), but the mechanisms undlerlying this relationship remain unclear. This study aimed to investigate how IKKα regulates macrophage activation and contributes to DCM in a mouse model. Specifically, the role of macrophage IKKα was evaluated in macrophage-specific IKKα knockout mice that received DOX injections. The findings revealed increased expression of IKKα in heart tissues after DOX administration. In mice lacking macrophage IKKα, myocardial injury, ventricular remodeling, inflammation, and proinflammatory macrophage activation worsened in response to DOX administration. Bone marrow transplant studies confirmed that IKKα deficiency exacerbated cardiac dysfunction. Macrophage IKKα knockout also led to mitochondrial damage and metabolic dysfunction in macrophages, thereby resulting in increased cardiomyocyte injury and oxidative stress. Single-cell sequencing analysis revealed that IKKα directly binds to STAT3, leading to the activation of STAT3 phosphorylation at S727. Interestingly, the inhibition of STAT3-S727 phosphorylation suppressed both DCM and cardiomyocyte injury. In conclusion, the IKKα-STAT3-S727 signaling pathway was found to play a crucial role in DOX-induced cardiomyopathy. Targeting this pathway could be a promising therapeutic strategy for treating DOX-related heart failure.

Combined GWAS and eGWAS reveals the genetic basis underlying drought tolerance in emmer wheat (Triticum turgidum L.).

Drought is one of the major environmental constraints for wheat production world-wide. As the progenitor and genetic reservoir of common wheat, emmer wheat is considered as an invaluable gene pool for breeding drought-tolerant wheat. Combining GWAS and eGWAS analysis of 107 accessions, we identified 86 QTLs, 105 462 eQTLs as well as 68 eQTL hotspots associating with drought tolerance (DT) in emmer wheat. A complex regulatory network composed of 185 upstream regulator and 2432 downstream drought-responsive candidates was developed, of which TtOTS1 was found to play a negative effect in determining DT through affecting root development. This study sheds light on revealing the genetic basis underlying DT, which will provide the indispensable genes and germplasm resources for elite drought tolerance wheat improvement and breeding.

Prediction of cerebral infarction after bypass surgery in adult moyamoya disease: using pulsatility index on TCD.

BACKGROUND: At present, the most effective treatment for symptomatic moyamoya disease (MMD) is surgery. However, the high incidence of postoperative complications is a serious problem plaguing the surgical treatment of MMD, especially the acute cerebral infarction. Decreased cerebrovascular reserve is an independent risk factor for ischemic infarction, and the pulsatility index (PI) of transcranial Doppler (TCD) is a common intuitive index for evaluating intracranial vascular compliance. However, the relationship between PI and the occurrence of ischemic stroke after operation is unclear. OBJECTIVE: To explore whether the PI in the middle cerebral artery (MCA) could serve as a potential predictor for the occurrence of ischemic infarction after bypass surgery in MMD. METHODS: We performed a retrospective analysis of data from 71 patients who underwent combined revascularization surgery, including superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis and encephalo-duro-myo-synangiosis (EDMS). The patients were divided into two groups according to the median of ipsilateral MCA-PI before operation, low PI group (MCA-PI < 0.614) and high PI group (MCA-PI ≥ 0.614). Univariate and multivariate regression analysis were used to explore risk factors affecting the occurrence of postoperative cerebral infarction. RESULTS: Among the 71 patients with moyamoya disease, 11 patients had cerebral infarction within one week after revascularization. Among them, 10 patients' ipsilateral MCA-PI were less than 0.614, and another one's MCA- PI is higher than 0.614. Univariate analysis showed that the lower ipsilateral MCA-PI (0.448 ± 0.109 vs. 0.637 ± 0.124; P = 0.001) and higher Suzuki stage (P = 0.025) were linked to postoperative cerebral infarction. Multivariate analysis revealed that lower ipsilateral MCA-PI was an independent risk factor for predicting postoperative cerebral infarction (adjusted OR = 14.063; 95% CI = 6.265 ~ 37.308; P = 0.009). CONCLUSIONS: A lower PI in the ipsilateral MCA may predict the cerebral infarction after combined revascularization surgery with high specificity. And combined revascularization appears to be safer for the moyamoya patients in early stages.

Wide-Range Excitation-Dependent Phosphorescence of Coordination Polymers Exhibiting Dynamic Anticounterfeiting, White-Light Emission, and Antibacterial Performance.

Multicolor-tunable room-temperature phosphorescence (RTP) is attracting wide attention in optoelectronic applications. Here, we propose a coordination-oriented assembly approach to achieve wide-range RTP with a benzimidazole derivative (2,7-diazabenzimidazole, DZBIM) as a luminogen. These two compounds exhibit unexpected excitation-responsive RTP emission, and the phosphorescence emission nearly covers the entire visible region with the change of the excitation wavelength from 360 to 620 nm. To the best of our knowledge, this is the first report of coordination polymers with such a full-color-tunable RTP. Compound 1 also shows white-light emission upon excitation at 280 nm. Experimental and theoretical results demonstrate that multiple intermolecular interactions and emission centers from different aggregates are responsible for the generation of multicolor emission. The white-light emission and multiple anticounterfeiting are explored. Besides, compound 1 exhibits high antibacterial activity benefiting from efficient 1O2 generation. This work provides an efficient way to prepare a color-tunable RTP.

Intramolecular interaction induced C-C cleavages in fructose conversion in polar aprotic solvents-origin of the formation of excess formic acid and oligomers.

Understanding the mechanism of excess formic acid formation in the dehydration of fructose to HMF would be beneficial to improve HMF selectivity and carbon efficiency. The production of formic acid from keto-D-fructose in polar aprotic solvents, such as THF, DIO, and MTHF, and MIBK solvents without a catalyst was investigated via DFT calculations. It was found that in THF, DIO and MTHF solvents, fructose tended to generate formic acid directly with the catalysis of the intramolecular hydroxyls, especially C6-OH (terminal hydroxyl), while in MIBK, the solvent molecule could react with the intermediates produced in the process, making the barrier of production of acetic acid lower than that of formic acid. Molecular dynamics simulations showed that the lower dielectric polar aprotic solvents (THF, DIO and MTHF) could not destroy the intramolecular H-bonds of hydroxyls in fructose, which could promote the keto-enol tautomerization and hydration steps, facilitating the formation of six-member-ring transition states, which reduced the ring tension and decreased the activation energy greatly, leading to the overproduction of formic acid and oligomers. ETS-NOCV analysis further indicated that the donated electrons from C-O σ-bonds on the carbon chain of fructose made the intramolecular hydroxyls more basic, which could catalyse keto-enol tautomerization with a lower energy barrier than water molecules. To obtain more target products, such as HMF, suitable reaction environments, such as a higher polar aprotic solvent with a low boiling point or restriction of the activity of hydroxyls of fructose, might be selected to destroy the intramolecular interaction and then reduce the overproduction of formic acid and the formation of oligomers.

CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Rationale: Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. Objectives: To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Methods: Four cohorts were investigated: 1) sputum samples (healthy, n = 4; COPD, n = 37), 2) lung tissue samples (healthy, n = 13; smokers without COPD, n = 10; smoker+COPD, n = 17), 3) pulmonary lobectomy tissue samples (no/mild emphysema, n = 6), and 4) blood samples (healthy, n = 6; COPD, n = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. Measurements and Main Results: 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.

Biocontrol activity and potential mechanism of Bacillus cereus G5 against Meloidogyne graminicola.

Root-knot nematodes (Meloidogyne spp.) are highly destructive pests that cause significant yield losses annually. Biological control of nematodes has emerged as a potential alternative in sustainable agriculture. In this study, we originally isolated Bacillus cereus G5 from the rhizosphere soil of rice (Oryza sativa). Treatment with the fermentation supernatant of G5 in vitro demonstrated high toxicity to second-stage juveniles (J2) of Meloidogyne graminicola and remarkably inhibited egg hatching. Moreover, G5 steadily colonized rhizosphere soil and rice seedlings, and exhibited excellent biocontrol efficacy against M. graminicola under greenhouse conditions. Notably, the volatile organic compounds (VOCs) produced by G5 displayed high fumigant activity against M. graminicola. The G5 VOCs efficiently reduced the gall index and nematode population in rice roots, while also promoting rice growth in double-layered pot tests. Additionally, the expression of defense genes involved in the salicylic acid (OsNPR1, OsWRKY45, OsPAL1), jasmonic acid (OsJaMYB, OsAOS2) and ethylene (OsACS1) signalling pathways was significantly upregulated in rice seedlings treated with G5 VOCs. This suggests that G5 VOCs contribute to eliciting plant defense responses. Furthermore, we identified 14 major VOCs produced by G5 using solid-phase micro-extraction gas chromatography and mass spectrometry (SPEM-GC-MS). Notably, allomatrine, morantel, 1-octen-3-ol and 3-methyl-2-butanol displayed strong contact nematicidal activity. Among these, only 1-octen-3-ol demonstrated fumigant activity against J2s of M. graminicola, with an LC50 value of 758.95 mg/L at 24 h. Overall, these results indicated that the B. cereus G5 and its synthetic VOCs possess high potential as biocontrol agents for managing root-knot nematodes.

6-Gingerol Inhibits De Novo Lipogenesis by Targeting Stearoyl-CoA Desaturase to Alleviate Fructose-Induced Hepatic Steatosis.

Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), is a worldwide liver disease without definitive or widely used therapeutic drugs in clinical practice. In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)-proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis.

Molecular Dynamics Simulation Combined with Neural Relationship Inference and Markov Model to Reveal the Relationship between Conformational Regulation and Bioluminescence Properties of Gaussia Luciferase.

Gaussia luciferase (Gluc) is currently known as the smallest naturally secreted luciferase. Due to its small molecular size, high sensitivity, short half-life, and high secretion efficiency, it has become an ideal reporter gene and is widely used in monitoring promoter activity, studying protein-protein interactions, protein localization, high-throughput drug screening, and real-time monitoring of tumor occurrence and development. Although studies have shown that different Gluc mutations exhibit different bioluminescent properties, their mechanisms have not been further investigated. The purpose of this study is to reveal the relationship between the conformational changes of Gluc mutants and their bioluminescent properties through molecular dynamics simulation combined with neural relationship inference (NRI) and Markov models. Our results indicate that, after binding to the luciferin coelenterazine (CTZ), the α-helices of the 109-119 residues of the Gluc Mutant2 (GlucM2, the flash-type mutant) are partially unraveled, while the α-helices of the same part of the Gluc Mutant1 (GlucM1, the glow-type mutant) are clearly formed. The results of Markov flux analysis indicate that the conformational differences between glow-type and flash-type mutants when combined with luciferin substrate CTZ mainly involve the helicity change of α7. The most representative conformation and active pocket distance analysis indicate that compared to the flash-type mutant GlucM2, the glow-type mutant GlucM1 has a higher degree of active site closure and tighter binding. In summary, we provide a theoretical basis for exploring the relationship between the conformational changes of Gluc mutants and their bioluminescent properties, which can serve as a reference for the modification and evolution of luciferases.

Saponins from Chenopodium quinoa Willd. husks alleviated high-fat-diet-induced hyperlipidemia via modulating the gut microbiota and multiple metabolic pathways.

BACKGROUND: Hyperlipidemia is characterized by abnormally elevated blood lipids. Quinoa saponins (QS) have multiple pharmacological activities, including antitumor, bactericidal and immune-enhancing effects. However, the lipid-lowering effect and mechanisms of QS in vivo have been scarcely reported. METHODS: The effect of QS against hyperlipidemia induced by high-fat diet in rats was explored based on gut microbiota and serum non-targeted metabolomics. RESULTS: The study demonstrated that the supplementation of QS could reduce serum lipids, body weight, liver injury and inflammation. 16S rRNA sequencing demonstrated that QS mildly increased alpha-diversity, altered the overall structure of intestinal flora, decreased the relative richness of Firmicutes, the ratio of Firmicutes/Bacteroidetes (P < 0.05) and increased the relative richness of Actinobacteria, Bacteroidetes, Bifidobacterium, Roseburia and Coprococcus (P < 0.05). Simultaneously, metabolomics analysis showed that QS altered serum functional metabolites with respect to bile acid biosynthesis, arachidonic acid metabolism and taurine and hypotaurine metabolism, which were closely related to bile acid metabolism and fatty acid ß-oxidation. Furthermore, QS increased protein levels of farnesoid X receptor, peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1, which were related to the screened metabolic pathways. Spearman correlation analysis showed that there was a correlation between gut microbiota and differential metabolites. CONCLUSION: QS could prevent lipid metabolism disorders in hyperlipidemic rats, which may be closely associated with the regulation of the gut microbiota and multiple metabolic pathways. This study may provide new evidence for QS as natural active substances for the prevention of hyperlipidemia. © 2023 Society of Chemical Industry.

Development of a two-beveled-fiber polarized fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy.

We report on the development of a two-beveled-fiber polarized (TBFP) fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy. The two-beveled fibers positioned symmetrically along a ball lens, in synergy with paired parallel-polarized polarizers integrated between the fibers and the ball lens, maximize the Raman signal excitation and collection from the superficial epithelium where gastrointestinal (GI) precancer arises. Monte Carlo (MC) simulations and two-layer tissue phantom experiments show that the probe developed detects ∼90% of the Raman signal from the superficial epithelium. The suitability of the probe developed for rapid (<3 s) superficial epithelial Raman measurements is demonstrated on fresh swine esophagus, stomach, and colon tissues, followed by their differentiation with high accuracies (92.1% for esophagus [sensitivity: 89.3%, specificity: 93.2%], 94.1% for stomach [sensitivity: 86.2%, specificity: 97.2%], and 94.1% for colon [sensitivity: 93.2%, specificity: 94.7%]). The presented results suggest the great potential of the developed probe for enhancing in vivo superficial epithelial Raman measurements in endoscopy.

Response time characteristics of a transmissive uniformly doped GaAsP photocathode.

In this paper, the matrix difference method is used to calculate the photoelectron continuity equation and the outgoing electron flux density equation. The effects of the GaAsP/AlGaAsP recombination rate, electron diffusion coefficient, and activation layer thickness on the time-resolved characteristics and quantum efficiency of a GaAsP photocathode are systematically studied, and the accuracy of the theoretical calculation is verified by experiments. The response speed and quantum efficiency of the GaAsP photocathode can be greatly improved by adjusting the thickness of the GaAsP activation layer reasonably.

Plastic mulching, and occurrence, incorporation, degradation, and impacts of polyethylene microplastics in agroecosystems.

Polyethylene microplastics have been detected in farmland soil, irrigation water, and soil organisms in agroecosystems, while plastic mulching is suggested as a crucial source of microplastic pollution in the agroecosystem. Plastic mulch can be broken down from plastic mulch debris to microplastics through environmental aging and degradation process in farmlands, and the colonization of polyethylene-degrading microorganisms on polyethylene microplastics can eventually enzymatically depolymerize the polyethylene molecular chains with CO2 release through the tricarboxylic acid cycle. The selective colonization of microplastics by soil microorganisms can cause changes in soil microbial community composition, and it can consequently elicit changes in enzyme activities and nutrient element content in the soil. The biological uptake of polyethylene microplastics and the associated disturbance of energy investment are the main mechanisms impacting soil-dwelling animal development and behavior. As polyethylene microplastics are highly hydrophobic, their presence among soil particles can contribute to soil water repellency and influence soil water availability. Polyethylene microplastics have been shown to cause impacts on crop plant growth, as manifested by the effects of polyethylene microplastics on soil properties and soil biota in the agroecosystems. This review reveals the degradation process, biological impacts, and associated mechanisms of polyethylene microplastics in agroecosystems and could be a critical reference for their risk assessment and management.

Safety evaluation of rare ginsenosides of stems and leaves from American ginseng: 90-day exposure toxicity study combined with intestinal flora analysis and metabonomics in rats.

Rare ginsenosides have already been widely applied in many fields, including health food and bio-medicine. The human being can expose to rare ginsenosides directly or indirectly increasingly. However, there are few studies on the safety assessment of rare ginsenoside mixtures. In the present study, the sub-chronic toxicity of rare ginsenosides for 90 days on SD rats was performed by combining the intestinal flora analysis and urine metabonomics aiming to illustrate the safety of long-term consumption of rare ginsenosides and the potential damage for liver and intestinal. 48 adult rats were divided into four groups: control (0 mg/kg), low-dose (60 mg/kg), medium-dose (200 mg/kg), and high-dose (600 mg/kg). Rats in the high-dose group showed inflammatory changes in their livers and intestines. The strong bactericidal effect of rare ginsenosides caused intestinal flora disorder and changed the structure of intestinal flora in rats, thus inducing intestinal damage in rats. In the high-dose group, levels of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (AKP) increased significantly. As a result of the high-dose treatment, certain metabolic pathways were altered, such as vitamin B6 metabolism, methionine metabolism, glutathione metabolism, and others. These results indicated that high doses of rare ginsenosides induced liver injury by affecting the above metabolic pathways. Rare ginsenosides with no observed adverse effect level (NOAEL) were below 200 mg/kg/day in vivo. Thus, this present study provides insight into the rational use of rare ginsenosides.

Oxidative damage induced by combined exposure of titanium dioxide nanoparticles and cypermethrin in rats for 90 days.

Titanium dioxide nanoparticles (TiO2NPs) and cypermethrin (CPM) are widely used in various fields, and they can enter the environment in different ways. Combined exposure of TiO2NPs and CPM may increase the accumulation of pollutants in organisms and affect human health. This study was undertaken to evaluate the oxidative and inflammatory parameters associated with the combined exposure of TiO2NPs and CPM in rats. Twenty-four healthy male adult SD rats were randomly divided into four groups. The first group served as the control, while groups 2, 3, and 4 were treated with TiO2NPs (450 mg/m3); CPM (6.67 mg/m3) or combined exposure of TiO2NPs and CPM by inhalation for 90 days. We investigated the oxidative damage induced through combined exposure of TiO2NPs and CPM in rats by evaluating hematology of the rats and determining the blood biochemical index. Our results demonstrated that inhalation of TiO2NPs and CPM increased the levels of oxidative stress markers such as malondialdehyde and alkaline phosphatase in the serum of rats. These were accompanied by a decreased glutathione peroxidase and total superoxide dismutase levels. Furthermore, the level of glutathione peroxidase was further decreased while malondialdehyde was increased in the combined exposure of TiO2NPs and CPM. Interestingly, pathological sections showed that different degrees of tissue injury could be seen in the liver and lung tissues of each exposure group. In summary, the combined exposure of TiO2NPs and CPM can cause increased oxidative damage in rats and damage the tissue structure of the liver and lung.

Resistive Sensing of Seed Cotton Moisture Regain Based on Pressure Compensation.

The measurement of seed cotton moisture regain (MR) during harvesting operations is an open and challenging problem. In this study, a new method for resistive sensing of seed cotton MR measurement based on pressure compensation is proposed. First, an experimental platform was designed. After that, the change of cotton bale parameters during the cotton picker packaging process was simulated through the experimental platform, and the correlations among the compression volume, compression density, contact pressure, and conductivity of seed cotton were analyzed. Then, support vector regression (SVR), random forest (RF), and a backpropagation neural network (BPNN) were employed to build seed cotton MR prediction models. Finally, the performance of the method was evaluated through the experimental platform test. The results showed that there was a weak correlation between contact pressure and compression volume, while there was a significant correlation (p < 0.01) between contact pressure and compression density. Moreover, the nonlinear mathematical models exhibited better fitting performance than the linear mathematical models in describing the relationships among compression density, contact pressure, and conductivity. The comparative analysis results of the three MR prediction models showed that the BPNN algorithm had the highest prediction accuracy, with a coefficient of determination (R2) of 0.986 and a root mean square error (RMSE) of 0.204%. The mean RMSE and mean coefficient of variation (CV) of the performance evaluation test results were 0.20% and 2.22%, respectively. Therefore, the method proposed in this study is reliable. In addition, the study will provide a technical reference for the accurate and rapid measurement of seed cotton MR during harvesting operations.

Icariin Alleviates Nonalcoholic Fatty Liver Disease in Polycystic Ovary Syndrome by Improving Liver Fatty Acid Oxidation and Inhibiting Lipid Accumulation.

(1) Background: Icariin is the main component of the Chinese herb Epimedium. A number of studies have shown that it alleviates abnormal lipid metabolism. However, it is not clear whether and how icariin can ameliorate hepatic steatosis with polycystic ovary syndrome (PCOS). This study was designed to explore the anti-hepatosteatosis effect of icariin in rats with polycystic ovary syndrome. (2) Methods: Female Sprague Dawley(SD)rats were treated with a high-fat diet and letrozole for 21 days to make nonalcoholic fatty liver disease (NAFLD) in the polycystic ovary syndrome model. Then model rats were treated with icariin (by gavage, once daily) for 28 days. Serum hormones and biochemical variables were determined by ELISA or enzyme. RNA-sequence analysis was used to enrich related target pathways. Then, quantitative Real-time PCR (qRT-PCR) and Western blot were performed to verify target genes and proteins. (3) Results: Icariin treatment reduced excess serum levels of Testosterone (T), Estradiol (E2), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), LH/FSH ratio, insulin, triglycerides (TG), and aspartate aminotransferase (AST) in high-fat diet (HFD) and letrozole fed rats. Meanwhile, icariin ameliorated HFD and letrozole-induced fatty liver, as evidenced by a reduction in excess triglyceride accumulation, vacuolization, and Oil Red O staining area in the liver of model rats. Results of RNA-sequencing, western blotting, and qRT-PCR analyses indicated that icariin up-regulated fatty acid translocase (CD36), in mitochondria, and peroxisome proliferator-activated receptor α (PPARα) expression, which led to the enhancement of fatty acid oxidation molecules, such as cytochrome P450, family 4, subfamily a, polypeptide 3 (CYP4A3), carnitine palmitoyltransferase 1 α (CPT1α), acyl-CoA oxidase 1 (ACOX1), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD). Besides, icariin reduced lipid synthesis, which elicited stearoyl-Coenzyme A desaturase 1 (SCD1), fatty acid synthase (FASN), and acetyl-CoA (ACC). (4) Conclusion: Icariin showed an ameliorative effect on hepatic steatosis induced by HFD and letrozole, which was associated with improved fatty acid oxidation and reduced lipid accumulation in the liver.

Discovery of a SHP2 Degrader with In Vivo Anti-Tumor Activity.

Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for cancer therapy due to its multifaceted roles in both tumor and immune cells. Herein, we designed and synthesized a novel series of proteolysis targeting chimeras (PROTACs) using a SHP2 allosteric inhibitor as warhead, with the goal of achieving SHP2 degradation both inside the cell and in vivo. Among these molecules, compound P9 induces efficient degradation of SHP2 (DC50 = 35.2 ± 1.5 nM) in a concentration- and time-dependent manner. Mechanistic investigation illustrates that the P9-mediated SHP2 degradation requires the recruitment of the E3 ligase and is ubiquitination- and proteasome-dependent. P9 shows improved anti-tumor activity in a number of cancer cell lines over its parent allosteric inhibitor. Importantly, administration of P9 leads to a nearly complete tumor regression in a xenograft mouse model, as a result of robust SHP2 depletion and suppression of phospho-ERK1/2 in the tumor. Hence, P9 represents the first SHP2 PROTAC molecule with excellent in vivo efficacy. It is anticipated that P9 could serve not only as a new chemical tool to interrogate SHP2 biology but also as a starting point for the development of novel therapeutics targeting SHP2.

A Supported Catalyst that Enables the Synthesis of Colorless CO2 -Polyols with Ultra-Low Molecular Weight.

Ultra-low molecular weight (ULMW) CO2 -polyols with well-defined hydroxyl end groups represent useful soft segments for the preparation of high-performance polyurethane foams. However, owing to the poor proton tolerance of catalysts towards CO2 /epoxide telomerization, it remains challenging to synthesize ULMW yet colorless CO2 -polyols. Herein, we propose an immobilization strategy of constructing supported catalysts by chemical anchoring of aluminum porphyrin on Merrifield resin. The resulting supported catalyst displays both extremely high proton tolerance (≈8000 times the equivalents of metal centers) and independence of cocatalyst, affording CO2 -polyols with ULMW (580 g mol-1 ) and high polymer selectivity (>99 %). Moreover, the ULMW CO2 -polyols with various architectures (tri-, quadra-, and hexa-arm) can be obtained, suggesting the wide proton universality of supported catalysts. Notably, benefiting from the heterogeneous nature of the supported catalyst, colorless products can be facilely achieved by simple filtration. The present strategy provides a platform for the synthesis of colorless ULMW polyols derived from not only CO2 /epoxides, but also lactone, anhydrides etc. or their combinations.

An Integrated Proteomic Strategy to Identify SHP2 Substrates.

Protein phosphatases play an essential role in normal cell physiology and the development of diseases such as cancer. The innate challenges associated with studying protein phosphatases have limited our understanding of their substrates, molecular mechanisms, and unique functions within highly coordinated networks. Here, we introduce a novel strategy using substrate-trapping mutants coupled with quantitative proteomics methods to identify physiological substrates of Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) in a high-throughput manner. The technique integrates three parallel mass spectrometry-based proteomics experiments, including affinity isolation of substrate-trapping mutant complex using wild-type and SHP2 KO cells, in vivo global quantitative phosphoproteomics, and in vitro phosphatase reaction. We confidently identified 18 direct substrates of SHP2 in the epidermal growth factor receptor signaling pathways, including both known and novel SHP2 substrates. Docking protein 1 was further validated using biochemical assays as a novel SHP2 substrate, providing a mechanism for SHP2-mediated Ras activation. This advanced workflow improves the systemic identification of direct substrates of protein phosphatases, facilitating our understanding of the equally important roles of protein phosphatases in cellular signaling.