Optineurin promotes myogenesis during muscle regeneration in mice by autophagic degradation of GSK3ß.

Skeletal muscle regeneration is essential for maintaining muscle function in injury and muscular disease. Myogenesis plays key roles in forming new myofibers during the process. Here, through bioinformatic screen for the potential regulators of myogenesis from 5 independent microarray datasets, we identify an overlapping differentially expressed gene (DEG) optineurin (OPTN). Optn knockdown (KD) delays muscle regeneration in mice and impairs C2C12 myoblast differentiation without affecting their proliferation. Conversely, Optn overexpression (OE) promotes myoblast differentiation. Mechanistically, OPTN increases nuclear levels of ß-catenin and enhances the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription activity, suggesting activation of Wnt signaling pathway. The activation is accompanied by decreased protein levels of glycogen synthase kinase 3ß (GSK3ß), a negative regulator of the pathway. We further show that OPTN physically interacts with and targets GSK3ß for autophagic degradation. Pharmacological inhibition of GSK3ß rescues the impaired myogenesis induced by Optn KD during muscle regeneration and myoblast differentiation, corroborating that GSK3ß is the downstream effector of OPTN-mediated myogenesis. Together, our study delineates the novel role of OPTN as a potential regulator of myogenesis and may open innovative therapeutic perspectives for muscle regeneration.

Structurally diverse amides from Chloranthus henryi var. hupehensis and their anti-inflammatory activities by blocking Akt phosphorylation.

Eleven new amides, four racemic pairs of (±)-chlorahupetamides A, B, D, E (1, 2, 4, 5) and chlorahupetamides C, F, G (3, 6, 7), have been isolated from Chloranthus henryi var. hupehensis. Compounds 1-3 are the first naturally occurring dimers via an unprecedented [2 + 2] cycloaddition derived from two dissimilar cinnamic acid amides, while compounds 4 and 5 represent the first examples of lignanamides in Chloranthus; together with two new hydroxycinnamic acid amide monomers (6-7), these compounds were obtained. Their structures were characterized by nuclear magnetic resonance (NMR), electronic circular dichroism (ECD), and X-ray diffraction analysis. Meanwhile, an LPS-induced BV-2 cell inflammatory model was used to determine the potential anti-inflammatory activity of all the isolated compounds. Intriguingly, compound -1 treatment showed a much greater inhibition of TNF-α expression with an EC50 value of 1.80 µM, while compound + 1 had more advantages in reducing IL-1ß expression with an EC50 value of 19.93 µM. Moreover, compounds + 1 and -1 could significantly suppress inflammation and inhibit the Akt signaling pathway by decreasing the phosphorylated protein levels of Akt.

Optimal assessment of the glomerular filtration rate in older chinese patients using the equations of the Berlin Initiative Study.

AIM: To evaluate the performances of the various estimated glomerular filtration rate (eGFR) equations of the Chronic Kidney Disease Epidemiology Collaboration, the Berlin Initiative Study (BIS), and the Full Age Spectrum (FAS) in older Chinese. METHODS: This study enrolled Chinese adults aged ≥ 65 years who underwent GFR measurements (via 99Tcm-DTPA renal dynamic imaging) in our hospital from 2011 to 2022. Using the measured glomerular filtration rate (mGFR) as the reference, we derived the bias, precision, accuracy, and consistency of each equation. RESULTS: We enrolled 519 participants, comprising 155 with mGFR ≥ 60 mL/min/1.73 m2 and 364 with mGFR < 60 mL/min/1.73 m2. In the total patients, the BIS equation based on creatinine and cystatin C (BIScr-cys) exhibited the lowest bias [median (95% confidence interval): 1.61 (0.77-2.18)], highest precision [interquartile range 11.82 (10.32-13.70)], highest accuracy (P30: 81.12%), and best consistency (95% limit of agreement: 101.5 mL/min/1.73 m2). In the mGFR ≥ 60 mL/min/1.73 m2 subgroup, the BIScr-cys and FAS equation based on creatinine and cystatin C (FAScr-cys) performed better than the other equations; in the mGFR < 60 mL/min/1.73 m2 subgroup, all equations exhibited relatively large deviations from the mGFR. Of all eight equations, the BIScr-cys performed the best. CONCLUSIONS: Although no equation was fully accurate in the mGFR < 60 mL/min/1.73 m2 subgroup, the BIScr-cys (of the eight equations) assessed the eGFRs of the entire population best. A new equation is urgently required for older Chinese and even East Asians, especially those with moderate-to-severe renal insufficiency.

Highly Conductive Topologically Chiral Molecular Knots as Efficient Spin Filters.

Knot-like structures were found to have interesting magnetic properties in condensed matter physics. Herein, we report on topologically chiral molecular knots as efficient spintronic chiral material. The discovery of the chiral-induced spin selectivity (CISS) effect opens the possibility of manipulating the spin orientation with soft materials at room temperature and eliminating the need for a ferromagnetic electrode. In the chiral molecular trefoil knot, there are no stereogenic carbon atoms, and chirality results from the spatial arrangements of crossings in the trefoil knot structures. The molecules show a very high spin polarization of nearly 90%, a conductivity that is higher by about 2 orders of magnitude compared with that of other chiral small molecules, and enhanced thermal stability. A plausible explanation for these special properties is provided, combined with model calculations, that supports the role of electron-electron interaction in these systems.

Photoresponsive Rotaxane-Branched Dendrimers: From Nanoscale Dimension Modulation to Macroscopic Soft Actuators.

Aiming at the construction of novel soft actuators through the amplified motions of molecular machines at the nanoscale, the design and synthesis of a new family of photoresponsive rotaxane-branched dendrimers through an efficient controllable divergent approach was successfully realized for the first time. In the third-generation rotaxane-branched dendrimers, up to 21 azobenzene-based rotaxane units located at each branch, thus making them the first successful synthesis of light-control integrated artificial molecular machines. Notably, upon alternative irradiation with UV and visible light, photoisomerization of the azobenzene stoppers leads to the collective and amplified motions of the precisely arranged rotaxane units, resulting in controllable and reversible dimension modulation of the integrating photoresponsive rotaxane-branched dendrimers in solution. Moreover, novel macroscopic soft actuators were further constructed based on these photoresponsive rotaxane-branched dendrimers, which revealed fast shape transformation behaviors with an actuating speed up to 21.2 ± 0.2° s-1 upon ultraviolet irradiation. More importantly, the resultant soft actuators could produce mechanical work upon light control that has been further successfully employed for weight-lifting and cargo transporting, thus laying the foundation toward the construction of novel smart materials that can perform programmed events.

Chlorahupetenes A-D, Four Eudesmane-Type Sesquiterpenoid Dimer Enantiomers with Two Unusual Carbon Skeletons from Chloranthus henryi Var. hupehensis.

(+)- and (-)-Chlorahupetenes A (1a and 1b), B (2a and 2b), C (3a and 3b), and D (4a and 4b), four unique enantiomeric pairs of eudesmane-type sesquiterpenoid dimers with two new carbon skeletons, were isolated from the aerial parts of Chloranthus henryi var. hupehensis. Compounds 1 and 2 possess an unprecedented 6/6/5/6/6 pentacyclic carbon skeleton with a new dimerization pattern of two eudesmane-type sesquiterpenoids. Compounds 3 and 4, which are fused with two eudesmane-type sesquiterpenoids via an unprecedented five-membered O-heterocyclic ring, represent a new 6/6/5/5/6/6/5 heptacyclic ring system. The structures of the compounds were determined through spectroscopic data and X-ray crystallography. Compounds 1a-3b significantly inhibited NO production with IC50 values ranging from 9.62 to 12.91 µM. Moreover, compounds 1b and 3a suppressed the production of a proinflammatory mediator (TNF-α) and enzyme expression (iNOS) at the mRNA level.

Artificial Light-Harvesting Systems Based on AIEgen-branched Rotaxane Dendrimers for Efficient Photocatalysis.

Aiming at the construction of novel platform for efficient light harvesting, the precise synthesis of a new family of AIEgen-branched rotaxane dendrimers was successful realized from an AIEgen-functionalized [2]rotaxane through a controllable divergent approach. In the resultant AIE macromolecules, up to twenty-one AIEgens located at the tails of each branches, thus making them the first successful example of AIEgen-branched dendrimers. Attributed to the solvent-induced switching feature of the rotaxane branches, the integrated rotaxane dendrimers displayed interesting dynamic feature upon the aggregation-induced emission (AIE) process. Moreover, novel artificial light-harvesting systems were further constructed based on these AIEgen-branched rotaxane dendrimers, which revealed impressive generation-dependent photocatalytic performances for both photooxidation reaction and aerobic cross-dehydrogenative coupling (CDC) reaction.

AIE-Active Chiral [3]Rotaxanes with Switchable Circularly Polarized Luminescence.

The construction of circularly polarized luminescence (CPL) switches with multiple switchable emission states and high dissymmetry factors (glum ) has attracted increasing attention due to their broad applications in diverse fields such as the development of smart devices and sensors. Herein, a new family of AIE-active chiral [3]rotaxanes were designed and synthesized, from which a novel CPL switching system was successfully constructed. The switching process was realized through the controlled motions of the chiral pillar[5]arene macrocycles along the axle through the addition or removal of the acetate anions, which not only modulated the chirality information transfer but also tuned the aggregations of the integrated [3]rotaxanes, thus resulting in reversible transformations between two emission states with both high photoluminescence quantum yields (PLQYs) and high dissymmetry factors (glum ) values.

Rotaxane-Branched Dendrimers with Enhanced Photosensitization.

During the past few decades, fabrication of functional rotaxane-branched dendrimers has become one of the most attractive yet challenging topics within supramolecular chemistry and materials science. Herein, we present the successful fabrication of a family of new rotaxane-branched dendrimers containing up to 21 platinum atoms and 42 photosensitizer moieties through an efficient and controllable divergent approach. Notably, the photosensitization efficiencies of these rotaxane-branched dendrimers gradually increased with the increase of dendrimer generation. For example, third-generation rotaxane-branched dendrimer PG3 revealed 13.3-fold higher 1O2 generation efficiency than its corresponding monomer AN. The enhanced 1O2 generation efficiency was attributed to the enhancement of intersystem crossing (ISC) through the simple and efficient incorporation of multiple heavy atoms and photosensitizer moieties on the axles and wheels of the rotaxane units, respectively, which has been validated by UV-visible and fluorescence techniques, time-dependent density functional theory calculations, photolysis model reactions, and apparent activation energy calculations. Therefore, we develop a new promising platform of rotaxane-branched dendrimers for the preparation of effective photosensitizers.

[Study on chemical constituents of Codonopsis pilosula].

A new neolignan, (-)-(7R,8S,7'E)-3',4-dihydroxy-3-methoxy-8,4'-oxyneoligna-7'-ene-7,9,9'-triol(1), and seven known compounds, 9-(tetrahydropyran-2-yl)-nona-trans,trans-2,8-diene-4,6-diyn-1-ol (2), 9-(tetrahydropyran-2-yl)-trans-non-8-ene-4,6-diyn-1-ol (3), lobetyol (4), lobetyolin (5),dehydrodieoniferyl alcohol (6), 5-hydroxymethylfurfural (7), and 4, 4'-dihydroxy-3, 3'-dimethoxy-trans-stilbene (8), were isolated from the H2O extract of Codonopsis pilosula. The structures of 1-8 were elucidated by spectroscopic methods including NMR, HR-ESI-MS, and CD. In addition, compounds 2 and 3 were isolated from the genus Codonopsis for the first time.

Development of a machine learning-based model for predicting risk of early postoperative recurrence of hepatocellular carcinoma.

BACKGROUND: Surgical resection is the primary treatment for hepatocellular carcinoma (HCC). However, studies indicate that nearly 70% of patients experience HCC recurrence within five years following hepatectomy. The earlier the recurrence, the worse the prognosis. Current studies on postoperative recurrence primarily rely on postoperative pathology and patient clinical data, which are lagging. Hence, developing a new pre-operative prediction model for postoperative recurrence is crucial for guiding individualized treatment of HCC patients and enhancing their prognosis. AIM: To identify key variables in pre-operative clinical and imaging data using machine learning algorithms to construct multiple risk prediction models for early postoperative recurrence of HCC. METHODS: The demographic and clinical data of 371 HCC patients were collected for this retrospective study. These data were randomly divided into training and test sets at a ratio of 8:2. The training set was analyzed, and key feature variables with predictive value for early HCC recurrence were selected to construct six different machine learning prediction models. Each model was evaluated, and the best-performing model was selected for interpreting the importance of each variable. Finally, an online calculator based on the model was generated for daily clinical practice. RESULTS: Following machine learning analysis, eight key feature variables (age, intratumoral arteries, alpha-fetoprotein, pre-operative blood glucose, number of tumors, glucose-to-lymphocyte ratio, liver cirrhosis, and pre-operative platelets) were selected to construct six different prediction models. The XGBoost model outperformed other models, with the area under the receiver operating characteristic curve in the training, validation, and test datasets being 0.993 (95% confidence interval: 0.982-1.000), 0.734 (0.601-0.867), and 0.706 (0.585-0.827), respectively. Calibration curve and decision curve analysis indicated that the XGBoost model also had good predictive performance and clinical application value. CONCLUSION: The XGBoost model exhibits superior performance and is a reliable tool for predicting early postoperative HCC recurrence. This model may guide surgical strategies and postoperative individualized medicine.

Letter to editor 'Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness'.

This letter to the editor relates to the study entitled "Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness". Acute bleeding caused by esophageal varices is a life-threatening complication in patients with liver cirrhosis. Due to the discomfort, contraindications, and associated complications of upper gastrointestinal endoscopy screening, it is crucial to identify an imaging-based non-invasive model for predicting high-risk esophageal varices in patients with cirrhosis.

Co-culture of Aspergillus sydowii and Bacillus subtilis induces the production of antibacterial metabolites.

The co-culture strategy, which mimics natural ecology by constructing an artificial microbial community, is a useful tool to activate the biosynthetic gene clusters to generate new compounds. However, without optimization of fermentation conditions, the antagonism between the microbes often interferes with the production of secondary metabolites. In this study, the fermentation conditions of co-culture of Aspergillus sydowii and Bacillus subtilis were optimized by response surface methodology to increase the production of active metabolites against Staphylococcus aureus. After optimization, the inhibitory rate of the co-culture extract was 74.62%, which was 29.20% higher than that of the initial conditions. Meanwhile, a total of 15 newly biosynthesized metabolites were detected only in optimized co-culture, occupying 13.2% of all detected metabolites. The structures of the 12 metabolites with high variable importance in projection score were elucidated by the established LC-MS/MS approach integrated with various metabonomic tools. Among them, 7 metabolites were newly induced and the content of other 5 metabolites increased by 1.1-2.4 folds in optimized co-culture. The bioassay of metabolites in co-culture against S. aureus indicated that compounds (-)- (7S)- 10-hydroxysydonic acid, serine sydonate and macrolactin U' contributed much to the increment of antibacterial activity. This study demonstrated that optimizing the fermentation conditions of co-culture was beneficial to changing the metabolite profile and effective to induce the biosynthesis of active metabolites.

Isorhapontigenin Improves Diabetes in Mice via Regulating the Activity and Stability of PPARγ in Adipocytes.

Isorhapontigenin is a natural bioactive stilbene isolated from various plants and fruits. It has been reported to exhibit several physiological activities including anticancer and anti-inflammation activity in vitro and in experimental animal models. This study aimed to investigate whether isorhapontigenin exerts antidiabetic effects in vivo. To this end, diabetic db/db mice were treated with either 25 mg kg-1 of isorhapontigenin or vehicle intraperitoneally for a period of 5 weeks. The results show that isorhapontigenin treatment significantly reduced postprandial levels of glucose, insulin, as well as free fatty acid, three markers of diabetes. Further studies show that isorhapontigenin treatment markedly improves insulin sensitivity and glucose tolerance of db/db mice as shown by ITT and GTT. Together, these physiological results show that isorhapontigenin possesses antidiabetic properties in vivo. Mechanistically, the isorhapontigenin-mediated antidiabetic effect is caused by favorable changes in adipose tissue, including reductions in adipocyte diameter and improved adipose insulin sensitivity. Further studies with 3T3-L1 cells show that isorhapontigenin treatment promotes preadipocyte differentiation by upregulation of the activity of the master adipogenic regulator PPARγ and deceleration of its proteasomal degradation. Together, our results establish for the first time an important role of isorhapontigenin as a potential nutraceutical agent for diabetes treatment.

A Potential Nutraceutical Candidate Lactucin Inhibits Adipogenesis through Downregulation of JAK2/STAT3 Signaling Pathway-Mediated Mitotic Clonal Expansion.

The prevalence of obesity has increased dramatically worldwide in the past ~50 years. Searching for safe and effective anti-obesity strategies are urgently needed. Lactucin, a plant-derived natural small molecule, is known for anti-malaria and anti-hyperalgesia. The study is to investigate whether lactucin plays a key role in adipogenesis. To this end, in vivo male C57BL/6 mice fed a high-fat diet (HFD) were treated with 20 mg/kg/day of lactucin or vehicle by gavage for seven weeks. Compared with vehicle-treated controls, Lactucin-treated mice showed lower body mass and mass of adipose tissue. Consistently, in vitro 3T3-L1 cells were treated with 20 µM of lactucin. Compared to controls, lactucin-treated cells showed significantly less lipid accumulation during adipocyte differentiation and lower levels of lipid synthesis markers. Mechanistically, we showed the anti-adipogenic property of lactucin was largely limited to the early stage of adipogenesis. Lactucin-treated cells fail to undergo mitotic clonal expansion (MCE). Further studies demonstrate that lactucin-induced MCE arrests might result from reduced phosphorylation of JAK2 and STAT3. We then asked whether activation of JAK2/STAT3 would restore the inhibitory effect of lactucin on adipogenesis with pharmacological STAT3 activator colivelin. Our results revealed similar levels of lipid accumulation between lactucin-treated cells and controls in the presence of colivelin, indicating that inactivation of STAT3 is the limiting factor for the anti-adipogenesis of lactucin in these cells. Together, our results provide the indication that lactucin exerts an anti-adipogenesis effect, which may open new therapeutic options for obesity.

Neolignan and phenylpropanoid compounds from the fruits of Illicium simonsii Maxim.

One new sesqui-neolignan compound, namely, sesqui-illisimonan A (1), one new neolignan, illisimonan A (2), and one new phenylpropanoid compound, illisimoid A (3) were isolated from the fruits of Illicium simonsii Maxim. The structures and absolute configurations of these compounds were determined by extensive spectroscopic, including NMR, circular dichroism and calculated electronic circular dichroism methods. The antioxidant activities of compounds 1-3 were also evaluated. Vitamin E was selected as the positive control (IC50 = 49.73 ± 0.88 µM). Compounds 1 and 2 exhibited in vitro antioxidant activity with an IC50 value of 55.76 ± 1.30 and 59.36 ± 0.50 µM, respectively. However, the compound 3 didn't show obvious antioxidant activity.