Desorption Separation Ionization Mass Spectrometry (DSI-MS) for Rapid Analysis of COVID-19.

During the coronavirus disease 2019 (COVID-19) pandemic, which has witnessed over 772 million confirmed cases and over 6 million deaths globally, the outbreak of COVID-19 has emerged as a significant medical challenge affecting both affluent and impoverished nations. Therefore, there is an urgent need to explore the disease mechanism and to implement rapid detection methods. To address this, we employed the desorption separation ionization (DSI) device in conjunction with a mass spectrometer for the efficient detection and screening of COVID-19 urine samples. The study encompassed patients with COVID-19, healthy controls (HC), and patients with other types of pneumonia (OP) to evaluate their urine metabolomic profiles. Subsequently, we identified the differentially expressed metabolites in the COVID-19 patients and recognized amino acid metabolism as the predominant metabolic pathway involved. Furthermore, multiple established machine learning algorithms validated the exceptional performance of the metabolites in discriminating the COVID-19 group from healthy subjects, with an area under the curve of 0.932 in the blind test set. This study collectively suggests that the small-molecule metabolites detected from urine using the DSI device allow for rapid screening of COVID-19, taking just three minutes per sample. This approach has the potential to expand our understanding of the pathophysiological mechanisms of COVID-19 and offers a way to rapidly screen patients with COVID-19 through the utilization of machine learning algorithms.

Integrative deep learning with prior assisted feature selection.

Integrative analysis has emerged as a prominent tool in biomedical research, offering a solution to the "small n $$ n $$ and large p $$ p $$ " challenge. Leveraging the powerful capabilities of deep learning in extracting complex relationship between genes and diseases, our objective in this study is to incorporate deep learning into the framework of integrative analysis. Recognizing the redundancy within candidate features, we introduce a dedicated feature selection layer in the proposed integrative deep learning method. To further improve the performance of feature selection, the rich previous researches are utilized by an ensemble learning method to identify "prior information". This leads to the proposed prior assisted integrative deep learning (PANDA) method. We demonstrate the superiority of the PANDA method through a series of simulation studies, showing its clear advantages over competing approaches in both feature selection and outcome prediction. Finally, a skin cutaneous melanoma (SKCM) dataset is extensively analyzed by the PANDA method to show its practical application.

BMP6 participates in the pathogenesis of adolescent idiopathic scoliosis by regulating osteopenia.

Adolescent idiopathic scoliosis (AIS) is a complex disease characterized by three-dimensional structural deformities of the spine. Its pathogenesis is associated with osteopenia. Bone-marrow-derived mesenchymal stem cells (BMSCs) play an important role in bone metabolism. We detected 1919 differentially expressed mRNAs and 744 differentially expressed lncRNAs in BMSCs from seven patients with AIS and five patients without AIS via high-throughput sequencing. Multiple analyses identified bone morphogenetic protein-6 (BMP6) as a hub gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS. BMP6 expression was found to be decreased in AIS and its knockdown in human BMSCs significantly altered the degree of osteogenic differentiation. Additionally, CAP1-217 has been shown to be a potential upstream regulatory molecule of BMP6. We showed that CAP1-217 knockdown downregulated the expression of BMP6 and the osteogenic differentiation of BMSCs. Simultaneously, knockout of BMP6 in zebrafish embryos significantly increased the deformity rate. The findings of this study suggest that BMP6 is a key gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS via the CAP1-217/BMP6/RUNX2 axis.

Biofluid Metabolic Profiling for Lung Cancer Screening via Reactive Matrix-Assisted Laser Desorption Ionization Mass Spectrometry.

Lung cancer (LC) has the highest mortality rate among various cancer diseases. Developing an early screening method for LC with high classification accuracy is essential. Herein, 2-hydrazinoquinoline (2-HQ) is utilized as a dual-mode reactive matrix for metabolic fingerprint analysis and LC screening via matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). Metabolites in both positive mode and negative mode can be detected using 2-HQ as the matrix, and derivative analysis of aldehyde and ketone compounds can be achieved simultaneously. Hundreds of serum and urine samples from LC patients and healthy volunteers were analyzed. Combined with machine learning, LC patients and healthy volunteers were successfully distinguished with a high area under the curve value (0.996 for blind serum samples and 0.938 for urine). The MS signal was identified for metabolic profiling, and dysregulated metabolites of the LC group were analyzed. The above results showed that this method has great potential for rapid screening of LC.

Pocket-Size Wireless Nanoelectrospray Ionization Mass Spectrometry for Metabolic Analysis of Salty Biofluids and Single Cells.

Analysis of volume-limited biological samples such as single cells and biofluids not only benefits clinical purposes but also promotes fundamental research in life sciences. Detection of these samples, however, imposes strict requirements on measurement performance because of the minimal volume and concentrated salts of the samples. Herein, we developed a self-cleaning nanoelectrospray ionization device powered by a pocket-size "MasSpec Pointer" (MSP-nanoESI) for metabolic analysis of salty biological samples with limited volume. The self-cleaning effect induced by Maxwell-Wagner electric stress helps with keeping the borosilicate glass capillary tip free from clogging and thus increasing salt tolerance. This device possesses a high sample economy (about 0.1 µL per test) due to its pulsed high voltage supply, sampling method (dipping the nanoESI tip into analyte solution), and contact-free electrospray ionization (ESI) (the electrode does not touch the analyte solution during ESI). High repeatable results could be acquired by the device with a relative standard deviation (RSD) of 1.02% for voltage output and 12.94% for MS signals of caffeine standard. Single MCF-7 cells were metabolically analyzed directly from phosphate buffered saline, and two types of untreated cerebrospinal fluid from hydrocephalus patients were distinguished with 84% accuracy. MSP-nanoESI gets rid of the bulky apparatus and could be held in hand or put into one's pocket for transportation, and it could operate for more than 4 h without recharge. We believe this device will boost scientific research and clinical usage of volume-limited biological samples with high-concentration salts in a low-cost, convenient, and rapid manner.

ASARA, a prediction model based on Child-Pugh class in hepatocellular carcinoma patients undergoing transarterial chemoembolization.

BACKGROUND: Due to the high heterogeneity among hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE), the prognosis of patients varies significantly. The decision-making on the initiation and/or repetition of TACE under different liver functions is a matter of concern in clinical practice. Thus, we aimed to develop a prediction model for TACE candidates using risk stratification based on varied liver function. METHODS: A total of 222 unresectable HCC patients who underwent TACE as their only treatment were included in this study. Cox proportional hazards regression was performed to select the independent risk factors and establish a predictive model for the overall survival (OS). The model was validated in patients with different Child-Pugh class and compared to previous TACE scoring systems. RESULTS: The five independent risk factors, including alpha-fetoprotein (AFP) level, maximal tumor size, the increase of albumin-bilirubin (ALBI) grade score, tumor response, and the increase of aspartate aminotransferase (AST), were used to build a prognostic model (ASARA). In the training and validation cohorts, the OS of patients with ASARA score ≤ 2 was significantly higher than that of patients with ASARA score > 2 (P < 0.001, P = 0.006, respectively). The ASARA model and its modified version "AS(ARA)" can effectively distinguish the OS (P < 0.001, P = 0.004) between patients with Child-Pugh class A and B, and the C-index was 0.687 and 0.706, respectively. For repeated TACE, the ASARA model was superior to Assessment for Retreatment with TACE (ART) and ALBI grade, maximal tumor size, AFP, and tumor response (ASAR) among Child-Pugh class A patients. For the first TACE, the performance of AS(ARA) was better than that of modified hepatoma arterial-embolization prognostic (mHAP), mHAP3, and ASA(R) models among Child-Pugh class B patients. CONCLUSIONS: The ASARA scoring system is valuable in the decision-making of TACE repetition for HCC patients, especially Child-Pugh class A patients. The modified AS(ARA) can be used to screen the ideal candidate for TACE initiation in Child-Pugh class B patients with poor liver function.

Perceptual Learning beyond Perception: Mnemonic Representation in Early Visual Cortex and Intraparietal Sulcus.

The ability to discriminate between stimuli relies on a chain of neural operations associated with perception, memory and decision-making. Accumulating studies show learning-dependent plasticity in perception or decision-making, yet whether perceptual learning modifies mnemonic processing remains unclear. Here, we trained human participants of both sexes in an orientation discrimination task, while using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to separately examine training-induced changes in working memory (WM) representation. fMRI decoding revealed orientation-specific neural patterns during the delay period in primary visual cortex (V1) before, but not after, training, whereas neurodisruption of V1 during the delay period led to behavioral deficits in both phases. In contrast, both fMRI decoding and disruptive effect of TMS showed that intraparietal sulcus (IPS) represented WM content after, but not before, training. These results suggest that training does not affect the necessity of sensory area in representing WM information, consistent with the sensory recruitment hypothesis in WM, but likely alters the coding format of the stored stimulus in this region. On the other hand, training can render WM content to be maintained in higher-order parietal areas, complementing sensory area to support more robust maintenance of information.SIGNIFICANCE STATEMENT There has been accumulating progresses regarding experience-dependent plasticity in perception or decision-making, yet how perceptual experience moulds mnemonic processing of visual information remains less explored. Here, we provide novel findings that learning-dependent improvement of discriminability accompanies altered WM representation at different cortical levels. Critically, we suggest a role of training in modulating cortical locus of WM representation, providing a plausible explanation to reconcile the discrepant findings between human and animal studies regarding the recruitment of sensory or higher-order areas in WM.

Ultra-High-Field Neuroimaging Reveals Fine-Scale Processing for 3D Perception.

Binocular disparity provides critical information about three-dimensional (3D) structures to support perception and action. In the past decade significant progress has been made in uncovering human brain areas engaged in the processing of binocular disparity signals. Yet, the fine-scale brain processing underlying 3D perception remains unknown. Here, we use ultra-high-field (7T) functional imaging at submillimeter resolution to examine fine-scale BOLD fMRI signals involved in 3D perception. In particular, we sought to interrogate the local circuitry involved in disparity processing by sampling fMRI responses at different positions relative to the cortical surface (i.e., across cortical depths corresponding to layers). We tested for representations related to 3D perception by presenting participants (male and female, N = 8) with stimuli that enable stable stereoscopic perception [i.e., correlated random dot stereograms (RDS)] versus those that do not (i.e., anticorrelated RDS). Using multivoxel pattern analysis (MVPA), we demonstrate cortical depth-specific representations in areas V3A and V7 as indicated by stronger pattern responses for correlated than for anticorrelated stimuli in upper rather than deeper layers. Examining informational connectivity, we find higher feedforward layer-to-layer connectivity for correlated than anticorrelated stimuli between V3A and V7. Further, we observe disparity-specific feedback from V3A to V1 and from V7 to V3A. Our findings provide evidence for the role of V3A as a key nexus for disparity processing, which is implicated in feedforward and feedback signals related to the perceptual estimation of 3D structures.SIGNIFICANCE STATEMENT Binocular vision plays a significant role in supporting our interactions with the surrounding environment. The fine-scale neural mechanisms that underlie the brain's skill in extracting 3D structures from binocular signals are poorly understood. Here, we capitalize on recent advances in ultra-high-field functional imaging to interrogate human brain circuits involved in 3D perception at submillimeter resolution. We provide evidence for the role of area V3A as a key nexus for disparity processing, which is implicated in feedforward and feedback signals related to the perceptual estimation of 3D structures from binocular signals. These fine-scale measurements help bridge the gap between animal neurophysiology and human fMRI studies investigating cross-scale circuits, from micro circuits to global brain networks for 3D perception.

Neurochemical and functional interactions for improved perceptual decisions through training.

Learning and experience are known to improve our ability to make perceptual decisions. Yet, our understanding of the brain mechanisms that support improved perceptual decisions through training remains limited. Here, we test the neurochemical and functional interactions that support learning for perceptual decisions in the context of an orientation identification task. Using magnetic resonance spectroscopy (MRS), we measure neurotransmitters (i.e., glutamate, GABA) that are known to be involved in visual processing and learning in sensory [early visual cortex (EV)] and decision-related [dorsolateral prefrontal cortex (DLPFC)] brain regions. Using resting-state functional magnetic resonance imaging (rs-fMRI), we test for functional interactions between these regions that relate to decision processes. We demonstrate that training improves perceptual judgments (i.e., orientation identification), as indicated by faster rates of evidence accumulation after training. These learning-dependent changes in decision processes relate to lower EV glutamate levels and EV-DLPFC connectivity, suggesting that glutamatergic excitation and functional interactions between visual and dorsolateral prefrontal cortex facilitate perceptual decisions. Further, anodal transcranial direct current stimulation (tDCS) in EV impairs learning, suggesting a direct link between visual cortex excitation and perceptual decisions. Our findings advance our understanding of the role of learning in perceptual decision making, suggesting that glutamatergic excitation for efficient sensory processing and functional interactions between sensory and decision-related regions support improved perceptual decisions.NEW & NOTEWORTHY Combining multimodal brain imaging [magnetic resonance spectroscopy (MRS), functional connectivity] with interventions [transcranial direct current stimulation (tDCS)], we demonstrate that glutamatergic excitation and functional interactions between sensory (visual) and decision-related (dorsolateral prefrontal cortex) areas support our ability to optimize perceptual decisions through training.

Thioredoxin interacting protein drives astrocytic glucose hypometabolism in corticosterone-induced depressive state.

Brain energetics disturbance is a hypothesized cause of depression. Glucose is the predominant fuel of brain energy metabolism; however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remains unclear. In this study, we firstly applied 18 F-FDG PET and observed brain glucose hypometabolism in the prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100 nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be over-expressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP over-expression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression and, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.

Matrix Metalloproteinase 3: a Novel Effective Biomarker for Predicting the Mortality and the Severity of Pneumonia.

BACKGROUND: Matrix metalloproteinase 3 (MMP3) is known as an inflammatory factor; however, the effectiveness of MMP3 for diagnosis of pneumonia and predicting outcomes is unclear. We evaluated the diagnostic and prognostic value of serum MMP3 in patients with pneumonia. METHODS: One hundred and eighty-five patients with pneumonia and 52 healthy controls were enrolled. Serum MMP3, neutrophil gelatinase-associated lipocalin (NGAL), interleukin 6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) concentrations were measured at admission. The patients were followed up for 90 days. RESULTS: Compared with healthy controls, the concentrations of MMP3, NGAL, and IL-6 at admission were significantly higher in patients with pneumonia (p < 0.05). The median concentrations of MMP3, NGAL, and IL-6 were significantly higher in the patients with severe pneumonia than the group of non-severe pneumonia (p < 0.05). Compared with PCT (AUC = 0.778), CRP (AUC = 0.719), and IL-6 (AUC = 0.726), MMP3 (AUC = 0.846) and NGAL (AUC = 0.826) had significantly higher AUC values for distinguishing the severity of pneumonia. The ROC of the combination of MMP3, neutrophil to lymphocyte ratio (NLR), and D-dimer showed the best performance of predicting pneumonia severity, which gave an AUC of 0.956. The AUC of MMP3 (0.950) for predicting mortality was highest, followed by NLR (AUC = 0.945), D-dimer (AUC = 0.938), and NGAL (AUC = 0.913). Multivariable logistic regression analysis showed MMP3, D-dimer, and NLR were the independent predictors of hospital mortality in patients with pneumonia. Patients with MMP3 concentration > 124.3 ng/mL had a significantly higher risk of mortality (p < 0.05). CONCLUSIONS: MMP3 is a valuable biomarker in assessment of the severity and prediction of mortality in patients with pneumonia.

[Mechanism of Panlongqi Tablets intervening in vertebral artery type of cervical spondylosis in rats through PI3K/AKT signaling pathway based on network pharmacology and experimental verification].

This study aimed to further explore the relevant mechanism of action by network pharmacology integrated with animal experimental verification based on previous proven effective treatment of vertebral artery type of cervical spondylosis(CSA) by Panlongqi Tablets. Bionetwork analysis was performed to establish drug-disease interaction network, and it was found that the key candidate targets of Panlongqi Tablets were enriched in multiple signaling pathways related to CSA pathological links, among which phosphatidylinositol 3-kinase(PI3 K)/serine-threonine kinase(AKT/PKB) signaling pathway was the most significant. Further, mixed modeling method was used to build the CSA rat model, and the rats were divided into normal, model, Panlongqi Tablets low-, medium-and high-dose(0.16, 0.32, 0.64 g·kg~(-1)) and Jingfukang Granules(positive drug, 1.35 g·kg~(-1)) groups. After successful modeling, the rats were administered for 8 consecutive weeks. Pathological changes of rat cervical muscle tissues were detected by hematoxylin-eosin(HE) staining, and the content of interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), vascular endothelial cell growth factor(VEGF) and chemokine(C-C motif) ligand 2(CCL2) in rat serum and/or cervical tissues was determined by enzyme-linked immunosorbent assay(ELISA). Western blot was employed to detect the protein expression levels of chemokine(C-C motif) receptor 2(CCR2), PI3 K, AKT, phosphorylated AKT(p-AKT), I-kappa-B-kinase beta(IKK-beta/IKKß), nuclear factor kappa B(NF-κB P65) and phosphorylated nuclear factor kappa B(NF-κB p-P65) in rat cervical tissues, and positive expression of p-NF-κB P65 in rat cervical muscle tissues was detected by immunofluorescence. The results showed that Panlongqi Tablets at different doses improved the degree of muscle fibrosis and inflammation in cervical muscle tissues of CSA rats, and reduced the content of inflammatory factors IL-1ß, TNF-α, VEGF, CCL2 and CCR2 in serum and/or cervical tissues. The protein expression levels of PI3 K, p-AKT, IKKß and p-NF-κB P65 as well as the nuclear entry of p-NF-κB P65 in cervical tissues were down-regulated. These findings suggest that Panlongqi Tablets can significantly inhibit the inflammatory response of CSA rats, and the mechanism of action may be related to the down-regulation of the activation of PI3 K/AKT signaling pathway.

Liver cirrhosis in a patient with hepatic hereditary hemorrhagic telangiectasia and Budd-Chiari syndrome: a case report.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) often involves the liver, and belongs to abnormal blood vessel disease. The etiology of Budd-Chiari syndrome (BCS) is not clear, but congenital vascular dysplasia is considered to be one of the causes. Liver cirrhosis due to hepatic hereditary hemorrhagic telangiectasia concomitant with BCS has not been reported. Here, we report a case of cirrhosis with hepatic hereditary hemorrhagic telangiectasia (HHHT) and BCS. CASE PRESENTATION: A 58-year-old woman with hepatic hereditary hemorrhagic telangiectasia showed decompensated liver cirrhosis, and abdominal imaging revealed Budd-Chiari syndrome. Disease has progressed considerably during 2.5 years after hospital discharge despite subsequent transjugular intrahepatic portosystemic shunting (TIPS). One hypothesis that might explain the coexistence of hepatic hereditary hemorrhagic telangiectasia and Budd-Chiari syndrome in this patient is ischemia and thrombosis of hepatic veins. CONCLUSIONS: Further studies are required to evaluate the relationship between HHHT and BCS. Our observations already challenged the TIPS therapeutic strategy in BCS secondary to HHHT patients.

Author Correction: Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice.

During re-read of our previously article Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of micepublished in Acta Pharmacologica Sinica, we were regretted to point out a mistake shown in Fig. 2a. The representative figure chosen to indicate the inhibitory effect of 4 mg/kg of plumbagin treatment at 1 week against MDA-MB-231SArfp cells localization within bone environment was incorrect due to the mishandling in manuscript preparation. Although this correction does not affect the results and conclusion of the paper, all the authors agree on the correction of our negligence as providing the corrected Fig. 2a presented below. We feel sorry and apologize for all the inconvenience it caused.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[Comparative study on chronic multiple organ injury in normal rats caused by high dose of Tripterygium Glycosides Tablets from 6 different manufacturers].

The aim of this paper was to compare different effects of Tripterygium Glycosides Tablets from 6 different manufacturers on multiple organ injuries in rats and to explore mechanism of hepatotoxicity preliminarily from the perspective of apoptosis and oxidative stress. Rats were randomly divided into the groups normal, Zhejiang, Hunan, Hubei, Shanghai, Jiangsu and Fujian(7 groups with 16 rats in each group, sex in half). Rats were given Tripterygium Glycosides Tablets at 144 mg·kg~(-1)·d~(-1)(16 times the clinical equivalent dose) once a day according to its corresponding group like rats in Zhejiang group was given Tripterygium Glycosides Tablets from Zhejiang manufactures continuously for 20 days with the life and death situation of mice to be observed, then rats were executed to detect various indicators. RESULTS:: showed that 8 female rats in Zhejiang group died after 15 days of administration, the serum NEUT of rats in Hubei, Fujian and Shanghai groups was significantly lower than that of normal rats. The serum AST, ALT and/or TBiL levels were increased in all rats, and serum BUN and/or CRE levels of rats were also increased in Hunan, Hubei, Fujian and Shanghai groups. In dosage groups, testicular and ovarian coefficients of rats were reduced, the number of sperm were significant decreased while the rate of sperm malformation increased and sperm dynamics parameters of normal, especially in Jiangsu and Zhejiang groups. Liver histopathology and apoptosis of liver cells were observed in dosage groups, especially in Jiangsu and Hubei groups. In liver, Nrf2, HO-1 and Bcl-2 were inhibited and the protein expression level of Bax were increased simultaneously in dosage groups. These results showed that all Tripterygium Glycosides Tablets from 6 manufacturers could lead to chronic multiple organ injuries with disparate specialties in rats, and Jiangsu and Zhejiang groups were more toxic. It could be the mechanism promoting mitochondrial mediated Bax/Bcl-2 cell apoptosis signaling pathway and negatively regulating Nrf2/HO-1 oxidative stress signaling pathway that Tripterygium Glycosides Tablets from 6 different manufacturers resulted in chronic liver injury, the results above were for reference only in subsequent study.

[Meta-analysis on safety of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis].

To systematically evaluate the adverse drug reaction(ADR) of Tripterygium Glycosides Tablets(TGT) in the treatment of rheumatoid arthritis(RA). Four Chinese databases(CNKI, VIP, WanFang, SinoMed) and three English databases(Cochrane Library, EMbase, PubMed), from the time of database establishing to August 2019, were systematically retrieved to collect literature on the treatment of all types of RA with TG. Screening literature and extracting data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria, with data being extracted and Meta-analyzed. There were 79 studies included, randomized controlled trials(RCT) containing TGT in the treatment group, non-randomized controlled trials(non-RCT), case series, case reports, and RCT containing TGT only in the control group were covered. There were in the control group; 765 ADR of 2 214 patients in 30 RCT(treatment group given TGT), 11 non-RCT and 7 case reports. The results of Meta-analysis of these 48 literatures showed that the overall incidence of ADRs was 0.23(95%CI[0.22,0.24]); ADR mainly occured in the reproductive, gastrointestinal, skin and accessories, blood, hepatobiliary system damage and the incidence of ADR in systems mentioned about respectively were 0.14(95%CI[0.12,0.17]),0.07(95%CI[0.06,0.08]),0.06(95%CI[0.04,0.07]),0.04(95%CI[0.03,0.05]),0.04(95%CI[0.03,0.05]). Further subgroup analysis results showed that the incidence of total ADR, especially the gastrointestinal, reproductive and cutaneous ADR of patients with treatment alone was higher than that in those paients with MTX or MTX+LEF therapy; The incidence of ADR, especially the gastrointestinal ADR, was also positively correlated with daily dose and course of treatment, while the incidence of different systems ADR was also correlated with different drug manufacturers, for instance, damage on the female reproductive system occurs most frequently in Hunan manufacture TGT administration, same as the damage on skin and accessories induced by TGT from Jiangsu manufacture. Above all, The clinical treatment of TGT for RA will cause multi-system ADR, with the highest incidence in the reproductive system, followed by the gastrointestinal system, which is closely related to the way of medication(monotherapy), daily dose, course of medication and drug manufacturer. Therefore, it is recommended that, in the treatment of RA, using TGT in combination, low dose or short-course medication, take measures to protect the reproductive system, stomach and liver, and paying attention to the drug manufacturer as well response of patients during administration should be valued to avoid ADRs to the maximum possibility.

[Analgesic effect of Fengshi Qutong Capsules on mice with chronic inflammatory pain caused by complete Freund's adjuvant].

The aim was to observe the analgesic effect of Fengshi Qutong Capsules(FSQTC) on chronic inflammatory pain in mice, and investigate its effect on p-ERK/COX-2 signal molecular activity. A model of chronic inflammatory pain was induced in mice by complete Freund's adjuvant(CFA). The mice were divided into normal control group, model group, model+FSQTC 0.3, 0.6 and 1.2 g·kg~(-1 )groups, model+positive control drug ibuprofen(IBP, 0.34 mg·kg~(-1)·d~(-1)) group, and normal control+ FSQTC 1.2 g·kg~(-1)group. FSQTC or IBP was given once a day by oral administration. Standard Von Frey fiber was used to evaluate the mechanical pain threshold, and the acetone stimulation was used to induce inflammatory plantar and observe the cold pain reaction scores. The mechanical pain threshold and cold pain reaction scores were observed before administration and 1, 2, 3, 4, 6 h after administration on the first day, as well as 3 h after administration on the 3 rd to 7 th day. The protein levels of PGE_2, COXs-1,2 and p-ERK in the spinal cord of the inflammatory foot and lumbar 4-5 were detected by enzyme-linked immunosorbent assay, Western blot, immunohistochemistry and immunofluorescence. The results showed that the mechanical pain threshold of the model group decreased and the cold pain reaction score increased as compared with the normal group. FSQTC application could dose-dependently increase the mechanical pain threshold and decrease the cold pain reaction score. The effect lasted for 6 h, most significant at 3 h. The effect of ibuprofen was similar to that of the 0.6 g·kg~(-1) dose group. In addition, FSQTC could reduce the abnormally increased protein content of PGE_2, COX-2 and p-ERK in the inflammatory foot and/or spinal cord of the model group, and the effect was most significant in middle and high dose groups. However, it had no effect on COX-1 in the inflammatory foot and spinal cord of mice. The results suggest that FSQTC has ob-vious analgesic effect on chronic inflammatory pain in mice, which may be related to inhibition of p-ERK/COX-2 signaling pathway.

Cytogenetic and genomic organization analyses of chloroplast DNA invasions in the nuclear genome of Asparagus officinalis L. provides signatures of evolutionary complexity and informativity in sex chromosome evolution.

BACKGROUND: The transfer of chloroplast DNA into nuclear genome is a common process in plants. These transfers form nuclear integrants of plastid DNAs (NUPTs), which are thought to be driving forces in genome evolution, including sex chromosome evolution. In this study, NUPTs in the genome of a dioecious plant Asparagus officinalis L. were systematically analyzed, in order to investigate the characteristics of NUPTs in the nuclear genome and the relationship between NUPTs and sex chromosome evolution in this species. RESULTS: A total of 3155 NUPT insertions were detected, and they represented approximated 0.06% of the nuclear genome. About 45% of the NUPTs were organized in clusters. These clusters were derived from various evolutionary events. The Y chromosome contained the highest number and largest proportion of NUPTs, suggesting more accumulation of NUPTs on sex chromosomes. NUPTs were distributed widely in all of the chromosomes, and some regions preferred these insertions. The highest density of NUPTs was found in a 47 kb region in the Y chromosome; more than 75% of this region was occupied by NUPTs. Further cytogenetic and sequence alignment analysis revealed that this region was likely the centromeric region of the sex chromosomes. On the other hand, the male-specific region of the Y chromosome (MSY) and the adjacent regions did not have NUPT insertions. CONCLUSIONS: These results indicated that NUPTs were involved in shaping the genome of A. officinalis through complicated process. NUPTs may play important roles in the centromere shaping of the sex chromosomes of A. officinalis, but were not implicated in MSY formation.

[Effect of Tripterygium Glycosides Tablets on synovial angiogenesis in rats with type â ¡ collagen induced arthritis].

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 µg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.

[Effects of Tripterygium Glycosides Tablets from 6 different manufacturers on acute liver injury of normal mice].

The aim of this paper was to compare the performance of acute liver injury in mice induced by Tripterygium Glycosides Tablets from 6 different manufacturers,and to explore the toxicity mechanism from the perspective of oxidative stress and apoptosis preliminarily. Male or female mice were randomly divided into normal group,Zhejiang group,Hunan group,Hubei group,Shanghai group,Jiangsu group and Fujian group. Mice in Tripgerygium Glycosides Tablets groups were given 16 times the clinical equivalent dose( 300 mg·kg-1) Tripgerygium Glycosides Tablets by oral administration for one time,mice were executed in 24 h after lavaged.Then the visceral brain coefficient of the organ was calculated. Histopathological changes of liver were observed by hematoxylin-eosin staining. Td T-mediated d UTP nick-end labeling was used to detect the apoptosis of the liver cells and the protein content of oxidative stress related factors in liver homogenate. Nuclear transcription factor E2-related factor( Nrf2) and heme oxygenase-1( HO-1) as well as mitochondrial mediated apoptosis-related protein expression levels of Bax and Bcl-2 in hepatic tissue were measured by Western blot.Within 24 hours of administration,6 male mice in Jiangsu group and 2 female mice in Zhejiang group were dying; compared with normal ones,liver coefficients of mice in Zhejiang,Shanghai,Jiangsu and Hunan groups were significantly increased,thymus coefficients in the first two groups were significantly reduced,as well as the lung coefficients of Fujian group mice,the rest was normal. In addition to Hubei group,serum AST,ALT or ALP levels of mice were increased,while TBi L were not being affected. Histopathological changes and apoptosis of liver cells were observed in all mice,and the degree of severity was ranked as Jiangsu,Zhejiang,Shanghai,Hunan,Hubei and Fujian group. All Tripterygium Glycosides Tablets increased the MDA and reduced the content of T-SOD,CAT or GSH in liver tissue while inhibited Nrf2,HO-1 and Bcl-2,increased the protein expression level of Bax( except Hunan group). Tripgerygium Glycosides Tablets from 6 manufacturers all resulted in liver function damage and liver histopathological changes,especially in Jiangsu,Hubei and Fujian,and the mechanism may related to inhibit Nrf2/HO-1 oxidative stress pathway and activate Bax/Bcl-2 apoptosis pathway to mediate lipid peroxidation and induce liver cell apoptosis. Triptolide A may be one of the main toxic components of Tripgerygium Glycosides Tablets that causing drug-induced liver injury. This study was conducted on normal mice with super dose medication,so the relevant results are for reference only.