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The mechanism regulating cellular senescence of postmitotic muscle cells is still unknown. cGAS-STING innate immune signaling was found to mediate cellular senescence in various types of cells, including postmitotic neuron cells, which however has not been explored in postmitotic muscle cells. Here by studying the myofibers from Zmpste24 −/− progeria aged mice [an established mice model for Hutchinson-Gilford progeria syndrome (HGPS)], we observed senescence-associated phenotypes in Zmpste24 −/− myofibers, which is coupled with increased oxidative damage to mitochondrial DNA (mtDNA) and secretion of senescence-associated secretory phenotype (SASP) factors. Also, Zmpste24 −/− myofibers feature increased release of mtDNA from damaged mitochondria, mitophagy dysfunction, and activation of cGAS-STING. Meanwhile, increased mtDNA release in Zmpste24 −/− myofibers appeared to be related with increased VDAC1 oligomerization. Further, the inhibition of VDAC1 oligomerization in Zmpste24 −/− myofibers with VBIT4 reduced mtDNA release, cGAS-STING activation, and the expression of SASP factors. Our results reveal a novel mechanism of innate immune activation-associated cellular senescence in postmitotic muscle cells in aged muscle, which may help identify novel sets of diagnostic markers and therapeutic targets for progeria aging and aging-associated muscle diseases.

Thiol compounds can serve as markers for the antioxidant and prognostic status of lymphoma, playing a crucial role in early tumor diagnosis. However, their high polarity and lack of chromophores pose challenges for multivariate analysis. This study aims to measure thiols associated proteins and develop novel diagnostic models in serum and cerebrospinal fluid from PCNSL to verify potential association and early warning effectiveness. A highly sensitive and selective method was established for simultaneous determination of 7 different thiols and 340 related proteins based on self-developed mass spectrometry probe, Br-OTPP labeled by UHPLC-HRMS. Furthermore, a novel PCNSL monitoring model was developed based on different those combined with machine learning algorithm. Thiols has good linear relationship with correlation coefficients ≥ 0.9995 and suitable precision with inter-day and intra-day coefficients variation was 2.08–5.49% and 1.58–5.53%. Satisfactory accuracy with recoveries between 85.28 and 97.88% was observed. The limit of detection (S/ N  = 3) was 0.8-9.0 fmol. Ultimately, this method greatly improves discrimination efficiency of model with accuracy of 98.83%. The proposed method could successfully apply into measurement of thiols associated proteins and development of multi-omics clinical evaluation model for PCNSL patients.

Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral hemorrhage (ICH). Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell surface transmembrane protein, is a key factor in neuroinflammation. It is widely elevated in several cell types after stroke. The increased EMMPRIN appears to regulate the expression of matrix metalloproteinases (MMPs) and exacerbate the pathology of stroke-induced blood-brain barrier dysfunction, microvascular thrombosis and neuroinflammation. In light of the neurological effects of EMMPRIN, we present in this review the complex network of roles that EMMPRIN has in brain ischemia and ICH. We first introduce the structural features and biological roles of EMMPRIN, followed by a description of the increased expression of EMMPRIN in brain ischemia and ICH. Next, we discuss the pathophysiological roles of EMMPRIN in brain ischemia and ICH. In addition, we summarize several important treatments for stroke that target the EMMPRIN signaling pathway. Finally, we suggest that EMMPRIN may have prospects as a biomarker of stroke injury. Overall, this review collates experimental and clinical evidence of the role of EMMPRIN in stroke and provides insights into its pathological mechanisms.

Highly sensitive and selective monitoring of amino metabolites such as glutamine, arginine, tryptophan and related proteins played significant roles in early diagnosis and warning of lymphoma. But those limited abundance and lacked chromophore group in vivo were bottleneck of multivariate analysis. This work aims to develop a novel UHPLC-Triple-TOF-HRMS method for simultaneous quantitation of 20 kinds of amino metabolites and tracing different proteins based on a new mass spectrometry probe (3-bromopropyl) triphenylphosphonium (3-BMP) with ability of enhance ionization efficiency and targeted labeling amino functional groups. An excellent linearity with R 2  ≥ 0.9995 and inter- and intra-day RSD were 1.43-5.22% and 1.22-5.87%, respectively. Satisfactory recoveries were 87.09-95.82%. Limit of detection (S/ N  = 3) was 4.0–12.0 fmol. Further, up-regulated haptoglobin, coagulation factor VII and catalase could directly negatively regulate Ala, Lys and Phe, which caused Trp, His, Ser, Asp and Pro expression decreased significantly in lymphoma patients ( p  < 0.05). Ultimately, a machine learning model was established to predict lymphoma with accuracy rate of 93.68%. Above all, this study would provide multivariate analysis strategy for in-depth explore relationship aminos associated proteins and pathogenesis and helpful for early warning of lymphoma patients under free-disease state.

In vivo and in vitro toxicity tests of JointAlive.sup.® were studied in animal models to support the safe use of JointAlive.sup.® as a drug for knee osteoarthritis treatment. The acute toxicity study in Sprague Dawley (SD) rats was conducted at a 20 g/kg bw/day dose of JointAlive.sup.® . For 13-week subchronic toxicity tests, SD rats were orally dosed daily with 0.5, 1.5 and 5 g/kg bw/day of JointAlive.sup.® . To assess the potential genotoxicity, Ames test, cellular chromosome aberration and mouse micronucleus test in vivo were carried out. Based on a lack of notable findings other than histopathology finding of co-incidental prostate inflammation at the high dose, the \"No Observed Adverse Effect Level (NOAEL)\" of JointAlive.sup.® was concluded as 5 g/kg bw/day in males and females. Results also indicated that JointAlive.sup.® has no risk of genotoxicity. General toxicity and genotoxicity studies empirically demonstrated that JointAlive.sup.® poses a low risk of potential health risks, providing safety supports for the application of JointAlive.sup.® as a potential drug candidate to treat knee osteoarthritis.

Glutamine synthetase plays an essential role in regulating plant growth and development. However, few studies have analyzed the roles of TaGS in wheat under abiotic stress conditions. In this study, we identified and analyzed the members of the TaGS gene family in Triticum aestivum L., focusing on their gene characteristics, phylogenetic evolution, cis-elements, transcriptional and post-translational modifications, and expression profiling in response to abiotic stress. Twelve TaGS genes were divided into four subfamilies. The synteny analysis revealed that wheat and the five other species share GS homologs. Several potential transcription factors were identified as regulators of TaGS genes. TaGS contains 19 microRNA binding sites, phosphorylation sites, and ubiquitination sites. TaGS genes exhibited tissue-specific expression across various developmental stages and were differentially expressed in response to abiotic stress. For instance, TaGS1-3-4A/4B/4D were upregulated in the leaves and roots of wheat seedlings under abiotic stress conditions. Furthermore, gene ontology annotation was performed on the TaGS-interacting proteins screened by immunoprecipitation–mass spectrometry to elucidate the regulatory network associated with TaGS. This study lays a foundation for further functional research of TaGS genes in response to abiotic stress and provides potential information for enhancing stress tolerance in wheat.

Chlorogenic acid (CGA) has been reported to have various biological activities, such as anti-inflammatory, anti-oxidant and anti-apoptosis effects. However, the role of CGA in intracerebral hemorrhage (ICH) and the underlying mechanisms remain undiscovered. The current study aims to investigate the effect of CGA on neuroinflammation and neuronal apoptosis after inhibition of EMMPRIN in a collagenase-induced ICH mouse model. Dose optimization data showed that intraperitoneal administration of CGA (30 mg/kg) significantly attenuated neurological impairments and reduced brain water content at 24 h and 72 h compared with ICH mice given vehicle. Western blot and immunofluorescence analyses revealed that CGA remarkably decreased the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in perihematomal areas at 72 h after ICH. CGA also reduced the expression of matrix metalloproteinases-2/9 (MMP-2/9) at 72 h after ICH. CGA diminished Evans blue dye extravasation and reduced the loss of zonula occludens-1 (ZO-1) and occludin. CGA-treated mice had fewer activated Iba-1-positive microglia and MPO-positive neutrophils. Finally, CGA suppressed cell death around the hematoma and reduced overall brain injury. These outcomes highlight that CGA treatment confers neuroprotection in ICH likely by inhibiting expression of EMMPRIN and MMP-2/9, and alleviating neuroinflammation, blood–brain barrier (BBB) disruption, cell death and brain injury.

Vascular calcification is a process similar to bone formation, which is highly adjustable and active. Currently, there are no specific drugs to delay or reverse vascular calcification. Through the screening of 44 coumarin compounds synthesised by our group, compound 14 was obtained to dose-dependently inhibit the calcification of vascular smooth muscle cells without affecting the normal proliferation of cells, decreasing the intracellular calcium concentration, inhibiting the activity of ALP enzyme. In conclusion, the calcium lowering effect of compound 14 is a potential candidate for drugs for the treatment of vascular calcification. This work aims to screen drugs for preventing and treating vascular calcification. Method: We screened a series of 3-arylcoumarins for the detection of vascular calcification-associated factors using human aortic vascular smooth muscle cells. We found that compounds 14 and 32 significantly inhibited alkaline phosphatase (ALP) activity similar to aminoguanidine hydrochloride (AGH) in a cellular model of AGEs-induced calcification. We also found that compounds 14 and 32 could significantly decrease the levels of factors such as AGEs, intracellular calcium ions, and total ROS in the calcified cell model. Further study indicates that compound 14 could significantly inhibit the expression of P-ERK1/2, PKC, NF-κB, RAGE and OPN proteins and increased the expression of SM22-α and PPAR-γ proteins in the calcified cells. We speculate that compound 14 inhibits vascular calcification by inhibiting oxidative stress and inhibiting AGEs production, suggesting that 3-arylcoumarin derivatives are potential candidates for the treatment of vascular calcification.

Introduction: Mori Cortex has been used in traditional Chinese Medicine as an antidiabetic agent. The aim of this study was to establish a UPLC-MS/MS method for simultaneous determination of morin, morusin, umbelliferone and mulberroside A in rat plasma and investigate the pharmacokinetics differences between normal and diabetic rats following oral administration of Mori Cortex total flavonoid extract. Methods: Samples were pre-treated by protein precipitation and genkwanin was used as internal standard. Chromatographic separation was performed using a Hypersil GOLD C 18 column (50 mm × 2.1 mm, 3 μm). The mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) in gradient mode at a flow rate of 0.5 ml/min. The transitions of m/z 300.9→107.1, m/z 419.3→297.1, m/z 160.9→77.0, m/z 567.1→243.2 and m/z 283.1→268.2 were selected for morin, morusin, umbelliferone, mulberroside A and internal standard, respectively. Results: The intra- and inter-day precision for analytes were less than 12.5% and the accuracy ranged from −8.1% to 3.5%. The extraction recovery was >88.5% and no obvious matrix effect was observed. The AUC (0-t) and C max of morin were 501.3 ± 115.5 ng/mL*h and 127.8 ± 56.0 ng/mL in normal rats and 717.3 ± 117.4 ng/ml*h and 218.6 ± 33.5 ng/ml in diabetic rats. Meanwhile, the AUC (0-t) and C max of morusin were 116.4 ± 38.2 ng/ml*h and 16.8 ± 10.1 ng/mL in normal rats and 325.0 ± 87.6 ng/mL*h and 39.2 ± 5.9 ng/ml in diabetic rats. For umbelliferone and mulberroside A, the AUC (0-t) and C max also increased significantly in diabetic rats ( p < 0.05). Discussion: The validated method was successfully applied to the pharmacokinetic study in normal and diabetic rats.

Nuclear decoupling and softening are the main cellular mechanisms to resist mechanical stress-induced nuclear/DNA damage, however, its molecular mechanisms remain much unknown. Our recent study of Hutchinson-Gilford progeria syndrome (HGPS) disease revealed the role of nuclear membrane protein Sun2 in mediating nuclear damages and cellular senescence in progeria cells. However, the potential role of Sun2 in mechanical stress-induced nuclear damage and its correlation with nuclear decoupling and softening is still not clear. By applying cyclic mechanical stretch to mesenchymal stromal cells (MSCs) of WT and Zmpset24 −/− mice (Z24 −/− , a model for HGPS), we observed much increased nuclear damage in Z24 −/− MSCs, which also featured elevated Sun2 expression, RhoA activation, F-actin polymerization and nuclear stiffness, indicating the compromised nuclear decoupling capacity. Suppression of Sun2 with siRNA effectively reduced nuclear/DNA damages caused by mechanical stretch, which was mediated by increased nuclear decoupling and softening, and consequently improved nuclear deformability. Our results reveal that Sun2 is greatly involved in mediating mechanical stress-induced nuclear damage by regulating nuclear mechanical properties, and Sun2 suppression can be a novel therapeutic target for treating progeria aging or aging-related diseases.