Simultaneous determination of unecritinib (TQ-B3101) and its active metabolite crizotinib in rat plasma by LC-MS/MS：An application to pharmacokinetic studies.

Unecritinib (TQ-B3101) is a selective tyrosine kinase receptor inhibitor. In the study, in vitro metabolic experiments revealed that the hydrolysis of TQ-B3101 was mainly catalyzed by carboxylesterase 2 (CES2), followed by CES1. Next, a sensitive and reliable LC-MS/MS method was established for the simultaneous determination of TQ-B3101 and its metabolite crizotinib in rat plasma. To prevent in vitro hydrolysis of TQ-B3101, sodium fluoride, the CESs inhibitor at a concentration of 2 M, was immediately added after whole blood collection. Plasma samples were extracted by acetonitrile-induced protein precipitation method, and chromatographically separated on a Gemini C18 column (50 mm × 2.0 mm i.d., 5 µm) using gradient elution with a mobile phase of 0.1% formic acid and 5 mmol/L ammonium acetate with 0.1% formic acid. The retention times for TQ-B3101 and crizotinib were 2.61 and 2.38 min, respectively. The analytes were detected with tandem mass spectrometer by positive electrospray ionization, using the ion transitions at m/z 492.3 → 302.3 for TQ-B3101, m/z 450.3 → 260.3 for crizotinib, and m/z 494.0 → 394.3 for imatinib (internal standard). Method validation was conducted in the linear range of 1.00-800 ng/mL for the two analytes. The precision, accuracy and stabilities all met the acceptance criteria. The pharmacokinetic study indicated that TQ-B3101 was rapidly hydrolyzed to crizotinib with the elimination half-life of 1.11 h after a single gavage administration of 27 mg/kg to Sprague-Dawley rats, and the plasma exposure of TQ-B3101 was only 2.98% of that of crizotinib.

Research progress on prediction of RNA-protein binding sites in the past five years.

Accurately predicting RNA-protein binding sites is essential to gain a deeper comprehension of the protein-RNA interactions and their regulatory mechanisms, which are fundamental in gene expression and regulation. However, conventional biological approaches to detect these sites are often costly and time-consuming. In contrast, computational methods for predicting RNA protein binding sites are both cost-effective and expeditious. This review synthesizes already existing computational methods, summarizing commonly used databases for predicting RNA protein binding sites. In addition, applications and innovations of computational methods using traditional machine learning and deep learning for RNA protein binding site prediction during 2018-2023 are presented. These methods cover a wide range of aspects such as effective database utilization, feature selection and encoding, innovative classification algorithms, and evaluation strategies. Exploring the limitations of existing computational methods, this paper delves into the potential directions for future development. DeepRKE, RDense, and DeepDW all employ convolutional neural networks and long and short-term memory networks to construct prediction models, yet their algorithm design and feature encoding differ, resulting in diverse prediction performances.

Exploring the effective components of honey-processed licorice (Glycyrrhiza uralensis Fisch.) in attenuating Doxorubicin-induced myocardial cytotoxicity by combining network pharmacology and in vitro experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is widely used clinically as one of the most famous traditional Chinese herbs. Its herb roasted with honey is called honey-processed licorice (HPL). Modern studies have shown that HPL has a stronger cardioprotective ability compared to raw licorice (RL), however the material basis and mechanism of action of the potential cardioprotection have not been fully elucidated. AIM OF THE STUDY: To screen and validate the material basis of cardioprotection exerted by HPL and to preliminarily predict the potential mechanism of action. MATERIALS AND METHODS: UPLC-QTOF-MS/MS was used to analyze HPL samples with different processing levels, and differential compounds were screened out through principal component analysis. Network pharmacology and molecular docking were applied to explore the association between differential compounds and doxorubicin cardiomyopathy and their mechanisms of action were predicted. An in vitro model was established to verify the cardioprotective effects of differential compounds. RESULTS: Six differential compounds were screened as key components of HPL for potential cardioprotection. Based on network pharmacology, 113 potential important targets for the treatment of Dox-induced cardiotoxicity were screened. KEGG enrichment analysis predicted that the PI3K-Akt pathway was closely related to the mechanism of action of active ingredients. Molecular docking results showed that the six differential compounds all had good binding activity with Nrf2 protein. In addition, in vitro experiments had shown that five of the active ingredients (liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, and licochalcone A) can significantly increase Dox-induced H9c2 cell viability, SOD activity, and mitochondrial membrane potential, significantly reduces MDA levels and inhibits ROS generation. CONCLUSION: Liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin and licochalcone A are key components of HPL with potential cardioprotective capabilities. Five active ingredients can alleviate Dox-induced cardiotoxicity by inhibiting oxidative stress and mitochondrial damage.

Overexpression of circulating CD38+ NK cells in colorectal cancer was associated with lymph node metastasis and poor prognosis.

Introduction: Lymph node metastasis (LNM) is a critical prognostic factor for colorectal cancer (CRC). Due to the potential influence of immune system on CRC progression, investigation into lymphocyte subsets as clinical markers has gained attention. The objective of this study was to assess the capability of lymphocyte subsets in evaluating the lymph node status and prognosis of CRC. Methods: Lymphocyte subsets, including T cells (CD3+), natural killer cells (NK, CD3- CD56+), natural killer-like T cells (NK-like T, CD3+ CD56+), CD38+ NK cells (CD3- CD56+ CD38+) and CD38+ NK-like T cells (CD3+ CD56+ CD38+), were detected by flow cytometry. Univariate and multivariate analyses were used to assess the risk factors of LNM. The prognostic role of parameters was evaluated by survival analysis. Results: The proportion of CD38+ NK cells within the NK cell population was significantly higher in LNM-positive patients (p <0.0001). However, no significant differences were observed in the proportions of other lymphocyte subsets. Poorer histologic grade (odds ratio [OR] =4.76, p =0.03), lymphovascular invasion (LVI) (OR =22.38, p <0.01), and CD38+ NK cells (high) (OR =4.54, p <0.01) were identified as independent risk factors for LNM. Furthermore, high proportion of CD38+ NK cells was associated with poor prognosis of CRC patients (HR=2.37, p =0.03). Conclusions: It was demonstrated that the proportion of CD38+ NK cells was a marker overexpressed in LNM-positive patients compared with LNM-negative patients. Moreover, an elevated proportion of CD38+ NK cells is a risk factor for LNM and poor prognosis in CRC.

Changes of serum CA125 and PGE2 before and after high-intensity focused ultrasound combined with GnRH-a in treatment of patients with adenomyosis.

This study aimed to investigate the changes of serum carbohydrate antigen 125 (CA125) and prostaglandin E2 (PGE2) in patients with adenomyosis before and after treatment with high-intensity focused ultrasound (HIFU) combined with gonadotropin-releasing hormone agonist (GnRH-a). One hundred and sixty-five patients with adenomyosis who received HIFU combined with GnRH-a were selected as case group. Sixty-five healthy women who underwent physical examination at the same time were taken as normal control group. At the end of follow-up 6 months after treatment, the case group were divided into effective subgroup and ineffective subgroup according to clinical efficacy. Changes of serum CA125 and PGE2 were analyzed. Serum CA125 and PGE2 levels in the case group were higher than those in the normal control group before treatment (both P < 0.001). Serum CA125 and PGE2 levels in the case group 6 months after treatment were lower than those before treatment (both P < 0.001). There was no difference in serum CA125 and PGE2 levels between effective subgroup and ineffective subgroup before treatment (P = 0.351, 0.284, respectively). Serum CA125 and PGE2 levels in the effective subgroup were lower than those in the ineffective subgroup 6 months after treatment (both P < 0.001). Serum CA125 and PGE2 may be involved in the development of adenomyosis, and their expression levels may be related to the prognosis of patients. Levels of serum CA125 and PGE2 in patients with adenomyosis decrease after treatment with HIFU combined with GnRH-a. The detection of serum CA125 and PGE2 may be used as an index to diagnose adenomyosis and evaluate the therapeutic effect of HIFU combined with GnRH-a.

What happens to regulatory T cells in multiple myeloma.

Abnormal tumor microenvironment and immune escape in multiple myeloma (MM) are associated with regulatory T cells (Tregs), which play an important role in maintaining self-tolerance and regulating the overall immune response to infection or tumor cells. In patients with MM, there are abnormalities in the number, function and distribution of Tregs, and these abnormalities may be related to the disease stage, risk grade and prognosis of patients. During the treatment, Tregs have different responses to various treatment regiments, thus affecting the therapeutic effect of MM. It is also possible to predict the therapeutic response by observing the changes of Tregs. In addition to the above, we reviewed the application of Tregs in the treatment of MM. In conclusion, there is still much room for research on the mechanism and application of Tregs in MM.

A Preliminary Study of Brain Functional Magnetic Resonance Imaging in Text Reading and Comprehension.

BACKGROUND: Few studies have focused on the changes in human brain function activities caused by reading Chinese characters with different intelligibility and whether it can reflect the understanding and cognitive ability of the human brain. OBJECTIVE: Task-fMRI based on Chinese character reading tasks with different intelligibility was used to explore activated brain regions and their cognitive changes. METHODS: Volunteers were randomly recruited using advertisements. Forty volunteers were recruited based on strict inclusion and exclusion criteria, and 40 volunteers were recruited. Brain function data of 40 healthy right-handed volunteers in fuzzy/clear Chinese reading tasks were collected using a Siemens Skyra 3.0T magnetic resonance scanner. Data were preprocessed and statistically analyzed using the statistical software SPM12.0 to observe the activation of the cortex and analyze its characteristics and possible changes in cognitive function. RESULTS: Task-fMRI analysis: (1) The main brain regions activated in fuzzy/clear reading tasks were located in the occipital visual cortex (P < 0.001); (2) a paired sample t-test suggested that there was a significant difference in BOLD signals in the brain regions activated by fuzzy/clear reading tasks (P < 0.001, equiv Z = 4.25). Compared with the fuzzy reading task, the brain regions more strongly activated in the clear reading task were mainly located in the right superior frontal gyrus and the bilateral temporal lobe. Compared with the clear reading task, the brain region that was more strongly activated in the fuzzy reading task was mainly located in the right fusiform gyrus. CONCLUSION: Clear Chinese character information mainly activates the dorsal stream of the visual-spatial network. This reflects the information transmission of the brain after understanding the text content and is responsible for guiding and controlling attention. Fuzzy words that cannot provide clear text content activate the fusiform gyrus of the ventral stream of the visual-spatial network, strengthening the function of orthographic processing.

Application of MFI-5 in severe complications and unfavorable outcomes after radical resection of colorectal cancer.

BACKGROUND: Frailty is considered a characteristic manifestation of physiological decline in multiple organ systems, which significantly increases the vulnerability of elderly individuals with colorectal cancer (CRC) and is associated with a poor prognosis. While studies have demonstrated that the 11-factor Modified Frailty Index (mFI-11) can effectively predict adverse outcomes following radical resection of CRC, there is a lack of research on the applicability of the 5-factor Modified Frailty Index (mFI-5) within this patient population. METHODS: In this retrospective analysis, we examined a cohort of CRC patients aged 65 years and above who had undergone radical resection. For each patient, we calculated their mFI-5 score, considering a score of ≥ 2 as an indication of frailty. We conducted univariate and multivariate analyses to assess the association between the mFI-5 and adverse outcomes as well as postoperative complications. RESULTS: Patients with an mFI-5 score ≥ 2 exhibited a significantly higher incidence of serious postoperative complications (53% vs. 30%; P = 0.001) and experienced a longer hospital stay [19.00 (15.00-24.50) vs. 17.00 (14.00-20.00); P < 0.05]. Notably, an mFI-5 score greater than 2 emerged as an independent risk factor for severe postoperative complications (odds ratio: 2.297; 95% confidence interval: 1.216 to 4.339; P = 0.01). Furthermore, the mFI-5 score displayed predictive capabilities for severe postoperative complications with an area under the receiver operating characteristic (ROC) curve of 0.629 (95% confidence interval: 0.551 to 0.707; P < 0.05). CONCLUSION: The mFI-5 demonstrates a high level of sensitivity in predicting serious complications, prolonged hospital stays, and mortality following radical resection of colorectal carcinoma. As a practical clinical assessment tool, the mFI-5 enables the identification of high-risk patients and facilitates preoperative optimization.

Anti-arrhythmia potential of honey-processed licorice in zebrafish model: Antioxidant, histopathological and tissue distribution.

ETHNOPHARMACOLOGICAL RELEVANCE: Honey-processed licorice (HPL) is the roasted product of licorice. It is recorded in the "Shang Han Lun" that licorice has better protection on heart after honey-processed. However, researches regarding its protective effect on the heart and the distribution of HPL in vivo are still limited. AIM OF THE STUDY: To evaluate the cardio-protection of HPL and explore the law of ten main components distribution in vivo under physiological and pathological conditions for an attempt to clarify the pharmacological substance basis of HPL in treating arrhythmia. MATERIALS AND METHODS: The adult zebrafish arrhythmia model was established by doxorubicin (DOX). Electrocardiogram (ECG) was used to detect the heart rate changes of zebrafish. SOD and MDA assays were used to evaluate oxidative stress levels in the myocardium. HE staining was used to observe the morphological change of myocardial tissues after HPL treatment. The UPLC-MS/MS was adapted to detect the content of ten main components of HPL in heart, liver, intestine, and brain under normal and heart injury conditions. RESULTS: Heart rate of zebrafish was decreased, the SOD activity was attenuated and MDA content was increased in myocardium after administration of DOX. Moreover, tissue vacuolation and inflammatory infiltration were detected in zebrafish myocardium induced by DOX. HPL could ameliorate heart injury and bradycardia induced by DOX to a certain extent by increasing SOD activity and reducing MDA content. In addition, the study of tissue distribution revealed that the content of liquiritin, isoliquiritin, and isoliquiritigenin in the heart was higher in the presence of arrhythmias than those in the normal condition. Under pathological conditions, the heart highly exposed to these three components could elicit anti-arrhythmic effects by regulating immunity and oxidation. CONCLUSION: These findings indicate that the HPL is protective against heart injury induced by DOX, and its effect is associated with the alleviation of oxidative stress and tissue injury. And the cardioprotective effect of HPL under pathological conditions may be related to the high distribution of liquiritin, isoliquiritin, and isoliquiritigenin in heart tissue. This study provides an experimental basis for the cardioprotective effects and tissue distribution of HPL.

Safety and efficacy of PD-1 and PD-L1 inhibitors in relapsed and refractory Hodgkin's lymphoma: a systematic review and meta-analysis of 20 prospective studies.

BACKGROUND: Inhibitors of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have been used in the treatment of relapsed and refractory Hodgkin's lymphoma (R/R HL) recently. To further understand the safety and efficacy of PD-1/PD-L1 inhibitors in R/R HL, we conducted this meta-analysis. METHODS: Databases and the Clinical Registration Platforms have been systematically searched for related studies by March 2022. For safety analysis, the incidence and exhibition of any grade and grade 3 or higher adverse effects (AEs) were evaluated. Besides, severe AEs (SAEs), treatment-related deaths, and AEs leading to treatment discontinuation were summarized. The overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), overall survival (OS), and duration of response (DOR) were calculated for efficacy analysis. All processes were implemented mainly through the package Meta and MetaSurv of software R 4.1.2. RESULTS: Overall 20 studies and 1440 patients were enrolled. The pooled incidence of any grade and grade 3 or higher AEs were 92% and 26%, respectively. The pooled ORR, CR rate and PR rate were 79%, 44% and 34%, respectively. The most common AEs were neuropathy (29%), nausea (27%), pyrexia (26%), and leukopenia (25%), and the most common grade 3 or higher AEs included leukopenia (10%), infusion reaction (8%), weight gain (3%), and neutropenia (2.7%). In survival analysis, pembrolizumab monotherapy appeared to perform better compared to nivolumab monotherapy. CONCLUSIONS: PD-1/PD-L1 inhibitors show promising efficacy and tolerable AEs in the treatment of R/R HL.

Characteristics of Hearing Loss in Patients with Systemic Lupus Erythematosus.

OBJECTIVE: To investigate the clinical characteristics of hearing loss (HL) in patients with systemic lupus erythematosus (SLE) and its related factors. METHODS: Ninety-one hospitalized SLE patients and thirty healthy controls were enrolled. All subjects completed pure tone audiometry (PTA), extended high frequency audiometry (EHFA) and distortion product otoacoustic emission (DPOAE) to assess hearing function. SLE patients were divided into two groups according to the presence or absence of HL, and the risk factors of HL were determined by multivariate logistic regression. RESULTS: The incidence of HL was 27.47% in SLE patients, significantly higher than in the control group (3.3%) and most cases were mild-to-moderate, bilateral and predominantly sensorineural. Compared with the control group, the hearing thresholds of SLE patients increased significantly in the middle and high frequencies starting from 2000 Hz. Even though the PTA test results were normal, the EHFA test results showed significant differences in hearing impairment between SLE patients and normal controls. For patients with abnormal PTA results, the signal-to-noise ratio (SNR) in DPOAE was markedly reduced, and the pass rate was also decreased. The Systemic Lupus International Collaborating Clinics Damage Index (SDI, OR 9.13) and secondary Sjögren's syndrome (sSS, OR 8.20) were identified as independent associated factors for HL, and there was no difference in PTA and EHFA at all frequencies between hydroxychloroquine users and non-users. CONCLUSIONS: HL is not rare in SLE patients, and EHFA can help identify early hearing impairment. Having a high SDI score and secondary Sjögren's syndrome may predict the presence of HL in SLE.

Efficacy and safety of ixazomib maintenance therapy for patients with multiple myeloma: a meta-analysis.

OBJECTIVES: Multiple myeloma(MM) is a malignant plasma cell disease. Maintenance treatment is beneficial to prolong survival time in patients with MM. Ixazomib was approved for the treatment of relapsed or refractory MM in combination with lenalidomide and dexamethasone. Here, we carried out a meta-analysis to determine the efficacy and safety of ixazomib maintenance therapy. METHODS: Several databases were searched including PubMed, Web of Science, Embase, the Cochrane Library, etc. The last search dated back to July, 2020. Three clinical trials with a total of 1440 participants with newly diagnosed MM were included. RESULTS AND CONCLUSION: The pooled HR of progression-free survival (PFS) was 0.69 (95% CI = 0.59-0.79), which suggested ixazomib maintenance therapy could prolong PFS remarkably. In addition, ixazomib was effective in deepening remission (RR = 1.57, 95% CI = 1.26-1.96). But it could not significantly prolong PFS in cytogenetic high-risk patients (HR = 0.74, 95% CI = 0.47-1.00). In terms of adverse reactions, our analysis revealed higher incidences of grade 3-4 thrombocytopenia (RR = 7.47, 95% CI = 2.06-27.06), neuropathy (RR = 1.48, 95% CI = 1.14-1.92), grade 3-4 infections (RR = 1.77, 95% CI = 1.21-2.59) and gastrointestinal disorders (RR = 1.48, 95% CI = 1.32-1.66). There was no significant correlation between the use of ixazomib and grade 3-4 neutropenia (RR = 1.46, 95% CI = 0.77-2.78, p = 0.25) or the occurrence of new primary malignant tumor (RR = 0.88, 95% CI = 0.53-1.46, p = 0.62). Additionally, more RCTs are needed for better choice of treatment regimen.

A Multiparametric MR-Based RadioFusionOmics Model with Robust Capabilities of Differentiating Glioblastoma Multiforme from Solitary Brain Metastasis.

This study aimed to evaluate the diagnostic potential of a novel RFO model in differentiating GBM and SBM with multiparametric MR sequences collected from 244 (131 GBM and 113 SBM) patients. Three basic volume of interests (VOIs) were delineated on the conventional axial MR images (T1WI, T2WI, T2_FLAIR, and CE_T1WI), including volumetric non-enhanced tumor (nET), enhanced tumor (ET), and peritumoral edema (pTE). Using the RFO model, radiomics features extracted from different multiparametric MRI sequence(s) and VOI(s) were fused and the best sequence and VOI, or possible combinations, were determined. A multi-disciplinary team (MDT)-like fusion was performed to integrate predictions from the high-performing models for the final discrimination of GBM vs. SBM. Image features extracted from the volumetric ET (VOIET) had dominant predictive performances over features from other VOI combinations. Fusion of VOIET features from the T1WI and T2_FLAIR sequences via the RFO model achieved a discrimination accuracy of AUC = 0.925, accuracy = 0.855, sensitivity = 0.856, and specificity = 0.853, on the independent testing cohort 1, and AUC = 0.859, accuracy = 0.836, sensitivity = 0.708, and specificity = 0.919 on the independent testing cohort 2, which significantly outperformed three experienced radiologists (p = 0.03, 0.01, 0.02, and 0.01, and p = 0.02, 0.01, 0.45, and 0.02, respectively) and the MDT-decision result of three experienced experts (p = 0.03, 0.02, 0.03, and 0.02, and p = 0.03, 0.02, 0.44, and 0.03, respectively).

[Effects of understory removal on soil microbial community composition in subtropical Phyllostachys edulis plantations]. / 林下植物剔除对毛竹林土壤微生物群落结构的影响.

We investigated the effects of understory removal on soil microbial community and soil physicochemical properties in a field experiment following random block design in subtropical moso bamboo (Phyllostachys edulis) plantations, which were widely contributed in middle subtropical area, aiming to assess the regulation mechanism of understory plants on soil microbial community. The results showed that understory removal significantly increased the contents of soil N, NO3--N, and soil available phosphorus, but decreased soil pH and the contents of soil NH4+-N and soil phosphorus (TP). Moreover, understory removal decreased total and bacterial PLFAs (B) and increasing soil fungal PLFAs (F), resulting in a higher F/B ratio. Redundancy analysis showed that changes in fungal PLFAs caused by understory removal were mainly attributed to soil acidification, while changes in bacterial PLFAs caused by understory removal were mainly due to the decreases in soil TP and pH. Furthermore, i14:0、i15:0 and i16:0 contributed to the decreases in bacterial biomass. Our results suggested that understory removal might not be suitable for the management of subtropical P. edulis plantations, as it would alter microbial community composition. The shift of soil microbial community from bacteria to fungi could inhibit microbial decomposition function.

Probing protein dissociation from gold nanoparticles and the influence of temperature from the protein corona formation mechanism.

Gold nanoparticles (AuNPs) provide a novel approach for protein enrichment and analysis due to their protein adsorption properties, forming a so called protein corona. This corona can significantly influence the protein's structure and characteristics, hindering their identification in situ. Dissociation is an important solution to analyze and identify the composition of protein coronas. However, a comprehensive picture of adsorbed protein dissociation is lacking. In this study, the protein dissociation from the protein corona and influencing factors were investigated on the basis of the formation mechanism and time evolution. Temperature and cysteine are the key factors influencing protein dissociation by altering the protein's binding ability. The results showed that half Au-S formation time is an important time point for thio-protein dissociation by the method of high speed centrifugation. When incubated for longer than that time, the thio-protein located in the hard corona could only be separated by ß-mercaptoethanol replacement under analytical ultracentrifugation. However, Fourier-transform infrared spectroscopy (FTIR) revealed significant changes that occurred in ßlg's secondary structure after ultracentrifugation. The Au-S bond formation time offers the potential to define the protein enrichment time of AuNPs.

Ultrafast Luminescent Light-Up Guest Detection Based on the Lock of the Host Molecular Vibration.

Light-up luminescence sensors have been employed in real-time in situ visual detection of target molecules including volatile organic compounds (VOCs). However, currently employed light-up sensors, which are generally based on the aggregation-induced emission (AIE) or solvent-induced energy transfer effect, exhibit limited sensitivity for light-up detection and poor recycling performances thereby significantly hindering their industrial applications. Inspired by the low-temperature enhanced luminescence phenomenon, we herein propose and show that a guest-lock-induced luminescence enhancement mechanism can be used to realize the ultrafast light-up detection of target VOCs. Through introduction of chlorinated hydrocarbons to lock the molecular vibrations within a designed [Cu4I4]-based metal-organic framework (MOF), luminescence intensity could be enhanced significantly at room temperature. This guest-lock-induced luminescence enhancement is brought about by weak supramolecular interactions between the host framework and the guest molecules, allowing highly sensitive and specific detection of the guest vapor with ultrafast response time (<1 s). Single-crystal X-ray diffraction (SCXRD) analysis of guest molecules-loaded MOFs and density functional theory (DFT) calculations were employed to investigate the host-guest interactions involved in this phenomenon. Moreover, the above MOF sensor successfully achieved real-time detection of a toxic chloroaromatic molecule, chlorobenzene. The guest-lock-induced light-up mechanism opens up a route to discovering high-performance ultrafast light-up luminescent sensors for real-time detection applications.

Activin a promotes myofibroblast differentiation of endometrial mesenchymal stem cells via STAT3-dependent Smad/CTGF pathway.

BACKGROUND: Endometriosis, characterized by the presence of functional endometrial tissues outside the uterus, is one of the most common gynecological disorders. Endometrial mesenchymal stem cells (MSCs) are crucial for the occurrence and development of endometriosis. Ectopic endometrial MSCs exist in the peritoneal cavity. Thus, the bioactive factors in endometriotic peritoneal fluid may regulate the biological behaviors of endometrial MSCs. METHODS: In this study, after assessing the concentration of Activin A in peritoneal fluid using ELISA, we isolated and cultured endometrial MSCs and investigated whether Activin A stimulated endometrial MSCs to differentiate into myofibroblasts and clarified the underlying mechanisms by quantitative real-time PCR, Western blot analysis, immunofluorescent staining, RNA interference and Chromatin immunoprecipitation. We also employed the inhibitors of Activin A to explore the possibility of suppressing the development of fibrosis in endometriosis using primary endometrial MSCs cultures and a mouse model of endometriosis. RESULTS: Here, we revealed that Activin A significantly elevated in endometriotic peritoneal fluid and activin receptor-like kinase (ALK4), the specific receptor for Activin A, obviously enhanced in ectopic endometrial MSCs compared with eutopic endometrial MSCs from women with or without endometriosis. Next, we found that Activin A drived myofibroblast differentiation of endometrial MSCs, with extremely enhanced expression of connective tissue growth factor (CTGF). CTGF was shown to be required for Activin A-induced expression of ACTA2, COL1A1 and FN1 in endometrial MSCs. CTGF induction by Activin A in endometrial MSCs involved the activation of Smad2/3, as evidenced by the phosphorylation and nuclear translocation of Smad2/3 as well as the binding of Smad2/3 to CTGF promoter. Furthermore, Smad/CTGF pathway in endometrial MSCs required activation of STAT3 while independent of PI3K, JNK and p-38 pathways. In addition, we also demonstrated that inhibition of Activin A pathway impeded myofibroblast differentiation of endometrial MSCs and ameliorated fibrosis in endometriosis mice. CONCLUSIONS: Activin A promotes myofibroblast differentiation of endometrial mesenchymal stem cells via STAT3-dependent Smad/CTGF pathway. The results provided the first evidence that STAT3 acted as a crucial Activin A downstream mediator to regulate CTGF production. Our data may supplement the stem cell theory of endometriosis and provide the experimental basis to treat endometriosis-associated fibrosis by manipulating Activin A signaling.

Internalization, distribution, and activity of peptide H2 against the intracellular multidrug-resistant bovine mastitis-causing bacterium Staphylococcus aureus.

Bovine mastitis is mainly caused by Staphylococcus aureus, which is difficult to eliminate, prone to escape from antibacterial agents, and may cause recurring infections due to the intracellular nature of its infection and multidrug resistance. In this study, the intracellular activities of the NZ2114 derivative peptide H18R (H2) against methicillin-resistant S. aureus (MRSA) and multidrug-resistant bovine S. aureus strains were investigated in bovine mammary epithelial MAC-T cells and mouse mammary glands. The minimum inhibitory concentrations of H2 against S. aureus were 0.5‒1 µg/ml; H2 displayed a lower cytotoxicity than its parental peptide NZ2114 (survival rates of MAC-T cells: 100% [H2 treatment] vs 60.7% [NZ2114 (256 µg/ml) treatment]). H2 was internalized into MAC-T cells mainly via clathrin-mediated endocytosis, and distributed in the cytoplasm. The intracellular inhibition rates against MRSA ATCC43300, the mastitis isolates S. aureus CVCC 3051 and E48 were above 99%, 99%, and 94%, respectively; these were higher than those in case of vancomycin (23-47%). In the mouse model of S. aureus E48-induced mastitis, after treatment with 100 µg of H2 and vancomycin, bacterial numbers in each mammary gland were reduced by 3.96- and 1.59-log CFU, respectively. Additionally, similar to NZ2114 and vancomycin, H2 alleviated the histopathological damage of the mammary tissue and polymorphonuclear neutrophil infiltration in the alveoli. These results suggest that H2 can be used as a safe and effective candidate for treating S. aureus-induced mastitis.

[Application Status and Development Trends of Medical Proton and Heavy Ion Accelerators].

Cancer therapy with accelerated proton or heavy ion beam is the most advanced radiotherapy technology, which is recognized by the international community at present. It is of great practical significance to study the medical proton and heavy ion accelerators and the radiotherapy technology, in order to promote the development of the advanced medical radiotherapy equipments and improve the quality of life of cancer patients in China. After a brief overview of cancer therapy with proton and heavy ion beam, this paper summarized and analyzed the application status of medical proton accelerators and medical heavy ion accelerators at home and abroad, and finally put forward the future development trends of medical proton and heavy ion accelerators and the radiotherapy technology, it can provide a reference for the progress and development strategies of the advanced radiotherapy equipments in China.

Neural Induction Potential and MRI of ADSCs Labeled Cationic Superparamagnetic Iron Oxide Nanoparticle In Vitro.

Magnetic resonance imaging (MRI) combined with contrast agents is believed to be useful for stem cell tracking in vivo, and the aim of this research was to investigate the biosafety and neural induction of SD rat-originated adipose derived stem cells (ADSCs) using cationic superparamagnetic iron oxide (SPIO) nanoparticle which was synthesized by the improved polyol method, in order to allow visualization using in vitro MRI. The scan protocols were performed with T2-mapping sequence; meanwhile, the ultrastructure of labeled cells was observed by transmission electron microscopy (TEM) while the iron content was measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES). After neural induction, nestin and NSE (neural markers) were obviously expressed. In vitro MRI showed that the cationic PEG/PEI-modified SPIO nanoparticles could achieve great relaxation performance and favourable longevity. And the ICP-AES quantified the lowest iron content that could be detected by MRI as 1.56~1.8 pg/cell. This study showed that the cationic SPIO could be directly used to label ADSCs, which could then inductively differentiate into nerve and be imaged by in vitro MRI, which would exhibit important guiding significance for the further in vivo MRI towards animal models with neurodegenerative disorders.