Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.

Nucleotide metabolism is the ultimate and most critical link in the self-replication process of tumors, including gastric cancer (GC). However, in clinical treatment, classic anti-tumor drugs such as 5-fluorouracil (5-FU) are mostly metabolic analogues of purines or pyrimidines, which lack specificity for tumor cells and therefore have significant side effects. It is unclear whether there are other drugs that can target nucleotide metabolism, except for nucleic acid analogues. Here, we found that a natural compound, dehydroabietylamine (DHAA), significantly reduced the viability and proliferation of GC cells and organoids. DHAA disrupts purine and pyrimidine metabolism of GC cells, causing DNA damage and further inducing apoptosis. DHAA treatment decreased transcription and protein levels of key enzymes involved in nucleotide metabolism pathway, with significant reductions in the expression of pyrimidine metabolism key enzymes CAD, DHODH, and purine metabolism key enzymes PAICS. We also found that DHAA directly binds to and reduces the expression of Forkhead box K2 (FOXK2), a common transcription factor for these metabolic enzymes. Ultimately, DHAA was shown to delay tumorigenesis in K19-Wnt1/C2mE transgenic mice model and reduce levels of CAD, DHODH, and PAICS in vivo. We demonstrate that DHAA exerts an anticancer effect on GC by targeting transcription factor FOXK2, reducing transcription of key genes for nucleotide metabolism and impairing nucleotide biosynthesis, thus DHAA is a promising candidate for GC therapy.

Traditional chinese medicine injections with activating blood circulation, equivalent effect of anticoagulation or antiplatelet, for acute myocardial infarction: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Traditional Chinese medicine injection for Activating Blood Circulation (TCMi-ABC), which exhibits comparable anticoagulant and antiplatelet effects, is commonly used as an adjuvant treatment for acute myocardial infarction (AMI) in China. OBJECTIVE: The aim of this study was to conduct a meta-analysis to assess the efficacy and safety of TCMi-ABC in combination with conventional western medicine in reducing mortality associated with AMI. METHODS: We conducted a comprehensive search of PubMed, Cochrane Library, EMBASE, Web of Science, CBM, WanFang Data, and CNKI databases. Randomized controlled trials (RCTs) investigating the use of TCMi-ABC (including Danhong injection, sodium tanshinone IIA sulfonate injection, salvia miltiorrhiza ligupyrazine injection, and puerarin injection) for the treatment of AMI were included. The search included studies published from the inception of the databases up to December 2022. Two authors independently screened RCTs, extracted data, and assessed the risk of bias. Meta-analysis was performed using RevMan 5.3 and Stata 17.0. The quality of evidence was evaluated using the GRADE approach. RESULTS: A total of 52 RCTs involving 5363 patients were included in the analysis, none of which described independent testing of the purity or potency of the TCMi-ABC product used. 19/52 reported random sequence generation. All RCTs lack adequate description of allocation concealment. 51/52 failed to assess blinding. The meta-analysis results demonstrated that the combined application of TCMi-ABC, compared with conventional western medicine treatment alone, significantly reduced in-hospital mortality in AMI patients [RR= 0.41, 95% CI (0.29, 0.59), P < 0.05], decreased the incidence of malignant arrhythmia [RR= 0.40, 95% CI (0.26, 0.61), P < 0.05], and increased left ventricular ejection fraction (LVEF) [MD= 5.53, 95% CI (3.81, 7.26), P < 0.05]. There was no significant difference in the incidence of adverse events between the two groups (P > 0.05). The GRADE evidence quality classification indicated that the evidence for in-hospital mortality, malignant arrhythmia, and adverse events was of moderate quality, while the evidence for LVEF was of low quality. CONCLUSION: TCMi-ABC demonstrates additional clinical value in reducing mortality and the risk of malignant arrhythmia in patients with AMI. However, further validation of these findings is warranted through high-quality clinical trials due to methodological weaknesses in randomization, blinding, allocation concealment, and insufficient assessing for the purity/potency of herbs and the gram amount of active constituents. SYSTEMATIC REVIEW REGISTRATION: [INPLASY], identifier [INPLASY202170082].

Unique Electron-Transfer-Mediated Electrochemiluminescence of AuPt Bimetallic Nanoclusters and the Application in Cancer Immunoassay.

Noble Metal nanoclusters (NCs) are promising electrochemiluminescence (ECL) emitters due to their amazing optical properties and excellent biocompatibility. They have been widely used in the detection of ions, pollutant molecules, biomolecules, etc. Herein, we found that glutathione-capped AuPt bimetallic NCs (GSH-AuPt NCs) emitted strong anodic ECL signals with triethylamine as co-reactants which had no fluorescence (FL) response. Due to the synergistic effect of bimetallic structures, the ECL signals of AuPt NCs were 6.8 and 94 times higher than those of monometallic Au and Pt NCs, respectively. The electric and optical properties of GSH-AuPt NCs differed from those of Au and Pt NCs completely. An electron-transfer mediated ECL mechanism was proposed. The excited electrons may be neutralized by Pt(II) in GSH-Pt and GSH-AuPt NCs, resulting in the vanished FL. Furthermore, abundant TEA radicals formed on the anode contributed electrons to the highest unoccupied molecular orbital of GSH-Au2.5Pt NCs and Pt(II), booming intense ECL signals. Because of the ligand effect and ensemble effect, bimetallic AuPt NCs exhibited much stronger ECL than GSH-Au NCs. A sandwich-type immunoassay for alpha fetoprotein (AFP) cancer biomarkers was fabricated with GSH-AuPt NCs as signal tags, which displayed a wide linear range from 0.01 to 1000 ng·mL-1 and a limit of detection (LOD) down to 1.0 pg·mL-1 at 3S/N. Compared to previous ECL AFP immunoassays, this method not only had a wider linear range but also a lower LOD. The recoveries of AFP in human serum were around 108%, providing a wonderful strategy for fast, sensitive, and accurate cancer diagnosis.

Traditional Chinese medicine injections with activating blood circulation, equivalent effect of anticoagulation or antiplatelet, for acute myocardial infarction: A protocol for the systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: In spite of a growing number in the use of percutaneous coronary intervention (PCI) in China, the mortality of acute myocardial infarction (AMI) has not decreased. Traditional Chinese medicine injections for Activating Blood Circulation (TCMi-ABC), equivalent effect of anticoagulation or antiplatelet, are widely used in China; however, the improvement of fatality towards AMI is unclear. Therefore, we intend to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of TCMi-ABC in treatment with AMI. METHODS: Based on the "National Medical Products Administration of China," TCMi-ABC with AMI treatment indication will be selected, including Danhong injection, Sodium Tanshinone IIA Sulfonate injection, Danshen Chuanxiongqin injection, and Puerarin injection. Randomized controlled studies will be searched from as follows: PubMed, Embase, the CENTRAL in Cochrane Library, Chinese Biomedical Literature Database (SinoMed), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang Data Knowledge Service Platform. Two researchers will work independently on literature selection, data extraction, and quality assessment. The outcomes focus on the effects of TCMi-ABC on fatality of patients with AMI in hospitalization and in the long term, the incidence of malignant arrhythmia, left ventricular ejection fraction, and adverse events. RevMan 5.4.1 software was used for mate analysis. RESULTS: This study will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the efficacy and safety of TCMi-ABC for AMI. CONCLUSION: This study will provide high-quality evidence for treatment of AMI with TCMi-ABC in terms of efficacy and safety, which may help clinicians make a better complementary treatment schedule of patients with AMI.

Integration of GWAS and transcriptome analyses to identify SNPs and candidate genes for aluminum tolerance in rapeseed (Brassica napus L.).

BACKGROUND: The exchangeable aluminum (Al), released from the acid soils, is another addition to the environmental stress factors in the form of Al toxicity stress. Al stress affects the normal crop development and reduces the overall yield of rapeseed (Brassica napus L.). The response mechanism of plants to Al toxicity is complicated and difficult to understand with few QTL related studies in rapeseed under Al toxicity stress. RESULT: Using 200,510 SNPs developed by SLAF-seq (specific-locus amplified fragment sequencing) technology, we carried out the genome-wide association analysis (GWAS) in a population of 254 inbred lines of B. napus with large genetic variation and Al-tolerance differences. There were 43 SNPs significantly associated with eight Al-tolerance traits in the seedling stage were detected on 14 chromosomes, and 777 candidate genes were screened at the flanking 100 kb region of these SNPs. Moreover, RNA-seq detected 8291 and 5341 DEGs (the differentially expressed gene) in the Al -tolerant line (ATL) and -sensitive line (ASL), respectively. Based on integration of GWAS and RNA-seq analysis, 64 candidate genes from GWAS analysis differentially expressed at least once in 6 h vs 0 h or 24 h vs 0 h conditions in ATL or ASL. Moreover, four out of sixty-four candidate genes (BnaA03g30320D, BnaA10g11500D, BnaC03g38360D and BnaC06g30030D) were differentially expressed in both 6 h and 24 h compared to 0 h (control) conditions in both lines. The proposed model based on the candidate genes excavated in this study highlighted that Al stress disturb the oxidation-redox balance, causing abnormal synthesis and repair of cell wall and ABA signal transduction, ultimately resulting in inhibition of root elongation. CONCLUSIONS: The integration of GWAS and transcriptome analysis provide an effective strategy to explore the SNPs and candidate genes, which has a potential to develop molecular markers for breeding Al tolerant rapeseed varieties along with theoretical basis of molecular mechanisms for Al toxicity response of Brassica napus plants.

Identification of crucial genes of pyrimidine metabolism as biomarkers for gastric cancer prognosis.

BACKGROUND: Metabolic reprogramming has been reported in various kinds of cancers and is related to clinical prognosis, but the prognostic role of pyrimidine metabolism in gastric cancer (GC) remains unclear. METHODS: Here, we employed DEG analysis to detect the differentially expressed genes (DEGs) in pyrimidine metabolic signaling pathway and used univariate Cox analysis, Lasso-penalizes Cox regression analysis, Kaplan-Meier survival analysis, univariate and multivariate Cox regression analysis to explore their prognostic roles in GC. The DEGs were experimentally validated in GC cells and clinical samples by quantitative real-time PCR. RESULTS: Through DEG analysis, we found NT5E, DPYS and UPP1 these three genes are highly expressed in GC. This conclusion has also been verified in GC cells and clinical samples. A prognostic risk model was established according to these three DEGs by Univariate Cox analysis and Lasso-penalizes Cox regression analysis. Kaplan-Meier survival analysis suggested that patient cohorts with high risk score undertook a lower overall survival rate than those with low risk score. Stratified survival analysis, Univariate and multivariate Cox regression analysis of this model confirmed that it is a reliable and independent clinical factor. Therefore, we made nomograms to visually depict the survival rate of GC patients according to some important clinical factors including our risk model. CONCLUSION: In a word, our research found that pyrimidine metabolism is dysregulated in GC and established a prognostic model of GC based on genes differentially expressed in pyrimidine metabolism.

The effects of different repair methods for a posterior root tear of the lateral meniscus on the biomechanics of the knee: a finite element analysis.

PURPOSE: To explore the impact of different repair methods for a lateral meniscus posterior root tear on the biomechanics of the knee joint using finite element analysis. METHODS: Finite element models of a healthy knee were established on the basis of MRI data from a volunteer using Mimics software, and the validity of the models was tested. The changes in the contact mechanics and kinematics of these finite element models under different repair approaches were then analyzed and compared. RESULTS: The normal meniscus had the maximum joint contact area, the minimum contact pressure, and the minimum contact stress. When total meniscectomy of the lateral meniscus was performed, the lateral compartment had the minimum joint contact area, the maximum contact pressure and the maximum contact stress. When complete avulsions of the posterior root of the lateral meniscus occurred, the maximum values of contact pressure and contact stress were between those of an intact meniscus and those of a meniscus treated with total meniscectomy. Lateral meniscal root attachment reconstruction by the single-stitch and double-stitch techniques resulted in a significant decrease in joint contact pressure and contact stress, leading to values comparable to those of a normal knee joint, and the double-stitch technique performed better than the single-stitch technique. CONCLUSIONS: Repair surgery for lateral meniscal posterior root avulsions can effectively restore the contact mechanics and kinematics of the knee joint, and the double-stitch technique can result in better clinical outcomes than the single-stitch technique.

Repurposing Protein Degradation for Optogenetic Modulation of Protein Activities.

Non-neuronal optogenetic approaches empower precise regulation of protein dynamics in live cells but often require target-specific protein engineering. To address this challenge, we developed a generalizable light-modulated protein stabilization system (GLIMPSe) to control the intracellular protein level independent of its functionality. We applied GLIMPSe to control two distinct classes of proteins: mitogen-activated protein kinase phosphatase 3 (MKP3), a negative regulator of the extracellular signal-regulated kinase (ERK) pathway, and a constitutively active form of MEK (CA MEK), a positive regulator of the same pathway. Kinetics study showed that light-induced protein stabilization could be achieved within 30 min of blue light stimulation. GLIMPSe enables target-independent optogenetic control of protein activities and therefore minimizes the systematic variation embedded within different photoactivatable proteins. Overall, GLIMPSe promises to achieve light-mediated post-translational stabilization of a wide array of target proteins in live cells.

Genome-Wide Analysis of the DREB Subfamily in Saccharum spontaneum Reveals Their Functional Divergence During Cold and Drought Stresses.

Drought and cold stresses are the main environmental factors that affect the yield of sugarcane, and DREB genes play very important roles in tolerance to drought, cold, and other environmental stresses. In this study, bioinformatics analysis was performed to characterize Saccharum spontaneum SsDREB genes. RNA sequencing (RNA-seq) was used to detect the expression profiles of SsDREBs induced by cold and drought stresses. According to our results, there are 110 SsDREB subfamily proteins in S. spontaneum, which can be classified into six groups; 106 of these genes are distributed among 29 chromosomes. Inter- and intraspecies synteny analyses suggested that all DREB groups have undergone gene duplication, highlighting the polyploid events that played an important role in the expansion of the DREB subfamily. Furthermore, RNA-seq results showed that 45 SsDREBs were up- or downregulated under cold stress; 35 of them were found to be involved in responding to drought stress. According to protein-protein interaction analysis, SsDREB100, SsDREB102, and SsDREB105 play key roles during the response to cold stress. These results reveal that functional divergence exists between collinear homologous genes or among common origin genes in the DREB subfamily of S. spontaneum. This study presents a comprehensive analysis and systematic understanding of the precise mechanism of SsDREBs in response to abiotic stress and will lead to improvements in sugarcane.

Comparison of leaf transcriptomes of cassava "Xinxuan 048" diploid and autotetraploid plants.

Polyploidy breeding of cassava has been used to improve cassava traits over the past years. We previously reported in vitro induction of tetraploids in the cassava variety "Xinxuan 048" using colchicine. Significant differences in morphology and anatomy were found between the diploid and tetraploid plants. However, very little is known about the transcriptome difference between them. In this study, morphological and physiological characteristics including leaf thickness, plant height, internode length, chlorophyll content, and photosynthetic capacity were measured. Further, we investigated and validated the difference in gene expression patterns between cassava "Xinxuan 048" tetraploid genotype and its diploid plants using RNA sequencing (RNAseq) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Significant differences in morphology and physiology were observed during tetraploidization. A comparison revealed that tetraploidy induced very limited changes in the leaf transcriptomes of cassava "Xinxuan 048" diploid and autotetraploid plants. However, the differentially expressed genes (DEGs) between 2× and 4× plants, especially those upregulated in 4× plants, were strongly associated with hormonal and stress responses. Large changes in morphology and physiology between the diploid cassava "Xinxuan 048" and its autotetraploid were not associated with large changes in their leaf transcriptomes. Moreover, the differently expressed genes related to the regulation of gibberellin and brassinosteroids potentially explained why the plant height and internode length of 4× plants became shorter. Collectively, our results suggest that 4× cassava is potentially valuable for breeding strains with improved stress resistance.