Targeting BMP2 for therapeutic strategies against hepatocellular carcinoma.

OBJECTIVES: This study aimed to investigate the role of BMP2 in hepatocellular carcinoma (HCC) growth and metastasis using a dual approach combining single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. METHODS: scRNA-seq data from the GEO database and bulk RNA-seq data from the TCGA database were analyzed. Differentially expressed marker genes of endothelial cells were identified and analyzed using enrichment analysis, PPI analysis, correlation analysis, and GSEA. In vitro, experiments were conducted using the Huh-7 HCC cell line, and in vivo, models of HCC growth and metastasis were established by knocking down BMP2. RESULTS: The scRNA-seq analysis identified BMP2 as a key marker gene in endothelial cells of HCC samples. Elevated BMP2 expression correlated with poor prognosis in HCC. In vitro experiments showed that silencing BMP2 inhibited the proliferation, migration, and invasion of liver cancer cells. In vivo studies confirmed increased BMP2 expression in HCC tissues, promoting angiogenesis and HCC growth. CONCLUSION: This study highlights the role of BMP2 in tumor angiogenesis and HCC progression. Targeting BMP2 could be a promising therapeutic strategy against HCC.

Inhibition of vascular calcification by Compound Danshen Dripping Pill through multiple mechanisms.

BACKGROUND: Vascular calcification refers to the abnormal accumulation of calcium in the walls of blood vessels and is a risk factor often overlooked in cardiovascular disease. However, there is currently no specific drug for treating vascular calcification. Compound Danshen Dripping Pill (CDDP) is widely used to treat cardiovascular diseases, but its effect on vascular calcification has not been reported. PURPOSE: We investigated the effects of CDDP on vascular calcification in ApoE-/- mice and in vitro and elucidated its mechanism of action. STUDY DESIGN: Firstly, we found that CDDP has the potential to improve calcification based on network pharmacology analysis. Then, we performed the following experiments: in vivo, ApoE-/- mice were fed a high-fat diet randomly supplemented with CDDP for 16 weeks. Atherosclerosis and vascular calcification were determined. In vitro, human aortic smooth muscle cells (HASMCs), human umbilical vein endothelial cells (HUVECs), and human aortic endothelial cells (HAECs) were used to determine the mechanisms for CDDP-inhibited vascular calcification. RESULTS: In this study, we observed that CDDP reduced intimal calcification in atherosclerotic lesions of ApoE-deficient mice fed a high-fat diet, as well as the calcification in cultured SMCs and ECs. Mechanistically, CDDP inhibited the Wnt/ß-catenin pathway by up-regulating the expression of DKK1 and LRP6, which are upstream inhibitors of Wnt, leading to a reduction in the expression of osteoblastic transition markers (ALP, OPN, BMP2, and RUNX2). Furthermore, CDDP enhanced the secretion of DKK1, which plays a role in mediating EC-SMC crosstalk in calcification. Additionally, VC contributes to vascular aging by inhibiting Sirt1 and increasing senescence parameters (SA-ß-gal, p21, and p16). However, CDDP reversed these changes by activating Sirt1. CDDP also reduced the levels of pro-inflammatory cytokines and the senescence-associated secretory phenotype in vivo and in vitro. CONCLUSIONS: Our study suggests that CDDP reduces vascular calcification by regulating the DKK1/LRP6/ß-catenin signaling pathway in ECs/SMCs and interactions with the crosstalk of ECs and SMCs. It also reduces the senescence of ECs/SMCs, contributing to the Sirt1 activation, indicating CDDP's novel role in ameliorating vascular calcification.

Butyrate alleviates renal fibrosis in CKD by regulating NLRP3-mediated pyroptosis via the STING/NF-κB/p65 pathway.

Chronic kidney disease (CKD) is a serious and irreversible disease primarily characterized by chronic inflammation and renal fibrosis. Recent studies have suggested that gut microbiota-related metabolites, particularly short-chain fatty acids (SCFAs) are significantly associated with kidney diseases. Notably, butyrate, a type of SCFAs, plays a crucial role in this correlation. However, the effect of butyrate on renal fibrosis in patients with CKD and its potential mechanisms remain unclear. In this study, we demonstrated that butyrate levels are reduced as CKD progresses using a CKD C57BL/6 mouse model established by a 0.2% adenine diet. Exogenous supplementation of butyrate effectively alleviated renal fibrosis and repressed the levels of proteins associated with NLRP3-mediated pyroptosis (NLRP3, IL-1ß, caspase-1, and GSDMD). Additionally, we conducted an in vitro experiment using HK-2 cells, which also confirmed that the elevated levels of NLRP3-mediated pyroptosis proteins in TGF-ß1-stimulated HK-2 cells are reversed by butyrate intervention. Further, butyrate mitigated the activity of the STING/NF-κB/p65 pathway, and STING overexpression impaired the protective function of butyrate in CKD. Hence, we suggest that butyrate may have a renoprotective role in CKD, alleviating renal fibrosis possibly by regulating NLRP3-mediated pyroptosis via the STING/NF-κB/p65 pathway.

DCABM-TCM: A Database of Constituents Absorbed into the Blood and Metabolites of Traditional Chinese Medicine.

Traditional Chinese medicine (TCM) not only maintains the health of Asian people but also provides a great resource of active natural products for modern drug development. Herein, we developed a Database of Constituents Absorbed into the Blood and Metabolites of TCM (DCABM-TCM), the first database systematically collecting blood constituents of TCM prescriptions and herbs, including prototypes and metabolites experimentally detected in the blood, together with the corresponding detailed detection conditions through manual literature mining. The DCABM-TCM has collected 1816 blood constituents with chemical structures of 192 prescriptions and 194 herbs and integrated their related annotations, including physicochemical, absorption, distribution, metabolism, excretion, and toxicity properties, and associated targets, pathways, and diseases. Furthermore, the DCABM-TCM supported two blood constituent-based analysis functions, the network pharmacology analysis for TCM molecular mechanism elucidation, and the target/pathway/disease-based screening of candidate blood constituents, herbs, or prescriptions for TCM-based drug discovery. The DCABM-TCM is freely accessible at http://bionet.ncpsb.org.cn/dcabm-tcm/. The DCABM-TCM will contribute to the elucidation of effective constituents and molecular mechanism of TCMs and the discovery of TCM-derived drug-like compounds that are both bioactive and bioavailable.

Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms.

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

An Equivalent Substitute Strategy for Constructing 3D Ordered Porous Carbon Foams and Their Electromagnetic Attenuation Mechanism.

Three-dimensional (3D) ordered porous carbon is generally believed to be a promising electromagnetic wave (EMW) absorbing material. However, most research works targeted performance improvement of 3D ordered porous carbon, and the specific attenuation mechanism is still ambiguous. Therefore, in this work, a novel ultra-light egg-derived porous carbon foam (EDCF) structure has been successfully constructed by a simple carbonization combined with the silica microsphere template-etching process. Based on an equivalent substitute strategy, the influence of pore volume and specific surface area on the electromagnetic parameters and EMW absorption properties of the EDCF products was confirmed respectively by adjusting the addition content and diameter of silica microspheres. As a primary attenuation mode, the dielectric loss originates from the comprehensive effect of conduction loss and polarization loss in S-band and C band, and the value is dominated by polarization loss in X band and Ku band, which is obviously greater than that of conduction loss. Furthermore, in all samples, the largest effective absorption bandwidth of EDCF-3 is 7.12 GHz under the thickness of 2.13 mm with the filling content of approximately 5 wt%, covering the whole Ku band. Meanwhile, the EDCF-7 sample with optimized pore volume and specific surface area achieves minimum reflection loss (RLmin) of - 58.08 dB at 16.86 GHz while the thickness is 1.27 mm. The outstanding research results not only provide a novel insight into enhancement of EMW absorption properties but also clarify the dominant dissipation mechanism for the porous carbon-based absorber from the perspective of objective experiments.

Exploration of Target Spaces in the Human Genome for Protein and Peptide Drugs.

After decades of development, protein and peptide drugs have now grown into a major drug class in the marketplace. Target identification and validation are crucial for the discovery of protein and peptide drugs, and bioinformatics prediction of targets based on the characteristics of known target proteins will help improve the efficiency and success rate of target selection. However, owing to the developmental history in the pharmaceutical industry, previous systematic exploration of the target spaces has mainly focused on traditional small-molecule drugs, while studies related to protein and peptide drugs are lacking. Here, we systematically explore the target spaces in the human genome specifically for protein and peptide drugs. Compared with other proteins, both successful protein and peptide drug targets have many special characteristics, and are also significantly different from those of small-molecule drugs in many aspects. Based on these features, we develop separate effective genome-wide target prediction models for protein and peptide drugs. Finally, a user-friendly web server, Predictor Of Protein and PeptIde drugs' therapeutic Targets (POPPIT) (http://poppit.ncpsb.org.cn/), is established, which provides not only target prediction specifically for protein and peptide drugs but also abundant annotations for predicted targets.

CTR-DB, an omnibus for patient-derived gene expression signatures correlated with cancer drug response.

To date, only some cancer patients can benefit from chemotherapy and targeted therapy. Drug resistance continues to be a major and challenging problem facing current cancer research. Rapidly accumulated patient-derived clinical transcriptomic data with cancer drug response bring opportunities for exploring molecular determinants of drug response, but meanwhile pose challenges for data management, integration, and reuse. Here we present the Cancer Treatment Response gene signature DataBase (CTR-DB, http://ctrdb.ncpsb.org.cn/), a unique database for basic and clinical researchers to access, integrate, and reuse clinical transcriptomes with cancer drug response. CTR-DB has collected and uniformly reprocessed 83 patient-derived pre-treatment transcriptomic source datasets with manually curated cancer drug response information, involving 28 histological cancer types, 123 drugs, and 5139 patient samples. These data are browsable, searchable, and downloadable. Moreover, CTR-DB supports single-dataset exploration (including differential gene expression, receiver operating characteristic curve, functional enrichment, sensitizing drug search, and tumor microenvironment analyses), and multiple-dataset combination and comparison, as well as biomarker validation function, which provide insights into the drug resistance mechanism, predictive biomarker discovery and validation, drug combination, and resistance mechanism heterogeneity.

Evaluation of efficiency omega 3 fatty acid improves the behavioural phenotype and protects against oxidative stress against MPP+ induces Parkinson's disease in mice.

This experiment proposed to study the efficiency omega 3 fatty acid on behavioural phenotype of Parkinson's disease (PD) in mice. Totally 7 groups (each group 6 mice) were used in this assessment, each groups were treated with saline (control), MPP+, L-DOPA, Omega 3 oil, Omega 3 oil (three different concentrations) +MPP+ separately. The behavioral assessments such as bar test, open field test, maze test, hang test were noted on 7th, 14th, 21st and 28th day. After the examination period, the tested animals' midbrains and frontal cortex were dissected to analyze TBARS, GSH, Catalase, Superoxide Dismutase and Glutathione Peroxidase assay. In the bar test, 500mg omega 3 fatty acid administrated mice showed a high cataleptic scores. In open field Test, significant reductions in behavior analysis were observed from the tested mice group. Maze test and hang test doesn't show much difference. In biochemical test, tested groups showed promising results compared to control group. The result strongly proved that the omega 3 fatty acid has remarkable abilities to control the neurodegenerative diseases.

Correction: PPA1 promotes NSCLC progression via a JNK- and TP53-dependent manner.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PPA1 promotes NSCLC progression via a JNK- and TP53-dependent manner.

Inorganic pyrophosphatase (PPA1) promotes tumor progression in several tumor types. However, the underlying mechanism remains elusive. Here, we disclosed that PPA1 expression is markedly upregulated in lung carcinoma tissue versus normal lung tissue. We also found that the non-small cell lung cancer (NSCLC) cell lines show increased PPA1 expression levels versus normal lung cell line control. Moreover, the knockdown of PPA1 promotes cell apoptosis and inhibits cell proliferation. Whereas, the ectopic expression of PPA1 reduces cell apoptosis and enhances cell proliferation. Most interestingly, the expression of mutant PPA1 (D117A) significantly abolishes PPA1-mediated effect on cell apoptosis and proliferation. The underlying mechanism demonstrated that TP53 expression deficiency or JNK inhibitor treatment could abolish PPA1-mediated NSCLC progression. In summary, the aforementioned findings in this study suggest a new pathway the PPA1 mediates NSCLC progression either via TP53 or JNK. Most important, the pyrophosphatase activity is indispensible for PPA1-mediated NSCLC progression. This may provide a promising target for NSCLC therapy.

Association of G-protein coupled purinergic receptor P2Y2 with ischemic stroke in a Han Chinese population of North China.

The G-protein-coupled purinergic receptor P2Y2 (P2RY2) plays an important role in the mechanism of atherosclerosis, which is relevant to ischemic stroke. This retrospective case-control study aimed to assess the relationship between P2RY2 gene polymorphisms and ischemic stroke risk in the northern Han Chinese population. In this study, clinical data and peripheral blood specimens were collected from 378 ischemic stroke patients and 344 controls. The ischemic stroke participants were recruited from the First Affiliated Hospital of China Medical University and the First Affiliated Hospital of Liaoning Medical University. The controls were recruited from the Health Check Center at the First Affiliated Hospital of China Medical University. Ischemic stroke patients were divided into two subgroups according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification: large-artery atherosclerosis (n = 178) and small-artery occlusion (n = 200) strokes. All subjects were genotyped for three single nucleotide polymorphisms (rs4944831, rs1783596, and rs4944832) in the P2RY2 gene using peripheral venous blood samples. The distribution of the dominant rs4944832 phenotype (GG vs. GA+AA) differed significantly between small-artery occlusion patients and control subjects (odds ratio (OR) = 1.720, 95% confidence interval (CI): 1.203-2.458, P < 0.01). Multivariable logistic regression analysis revealed that the GG genotype of rs4944832 was significantly more prevalent in small-artery occlusion patients than in control subjects (OR = 1.807, 95% CI: 1.215-2.687, P < 0.01). The overall distribution of the haplotype established by rs4944831-rs1783596-rs4944832 was significantly different between ischemic stroke patients and controls (P < 0.01). In ischemic stroke patients, the frequency of the G-C-G haplotype was significantly higher than in control subjects (P = 0.028), whereas the frequency of the T-C-A haplotype was lower than in control subjects (P = 0.047). These results indicate that the G-C-G haplotype of P2RY2 is a susceptibility haplotype for ischemic stroke. In addition, the GG genotype of rs4944832 may be associated with the development of small-artery occlusion in the northern Han Chinese population. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of China Medical University on February 20, 2012 (No. 2012-38-1) and the First Affiliated Hospital of Liaoning Medical University, China, on March 1, 2013 (No. 2013-03-1). All participants gave their informed consent. This trial was registered with the ISRCTN Registry (ISRCTN11439124) on October 24, 2018. Protocol version (1.0).

Associations between thromboxane A synthase 1 gene polymorphisms and the risk of ischemic stroke in a Chinese Han population.

Thromboxane A synthase 1 (TBXAS1) catalyses the synthesis of thromboxane A2 (TXA2), which plays an important role in the pathogenesis of ischemic stroke. Thus, the TBXAS1 gene was investigated as a candidate gene involved in the formation of atherosclerosis. This case-control study collected peripheral blood specimens and clinical data of 370 ischemic stroke patients and 340 healthy controls in the Northern Chinese Han population from October 2010 to May 2011. Two TBXAS1 single-nucleotide polymorphisms, rs2267682 and rs10487667, were analyzed using a SNaPshot Multiplex sequencing assay to explore the relationships between the single-nucleotide polymorphisms in TBXAS1 and ischemic stroke. The TT genotype frequency and T allele frequency of rs2267682 in the patients with ischemic stroke were significantly higher than those in the controls (P < 0.01 and P = 0.02). Furthermore, compared with the GG + GT genotype, the TT rs2267682 genotype was associated with increased risk of ischemic stroke (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.16-2.79, P < 0.01). Multivariate logistic analysis with adjustments for confounding factors revealed that rs2267682 was still associated with ischemic stroke (OR = 1.94, 95% CI : 1.13-3.33, P = 0.02). The frequency of the T-G haplotype in the patients was significantly higher than that in the controls according haplotype analysis (OR = 1.49, 95% CI: 1.10-2.00, P < 0.01). These data reveal that the rs2267682 TBXAS1 polymorphism is associated with ischemic stroke. The TT genotype of TBXAS1 and T allele of rs2267682 increase susceptibility to ischemic stroke in this Northern Chinese Han population. The protocol has been registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559).

Clinical significance and functional validation of PPA1 in various tumors.

The aim of the study was to detect PPA1 expression in various tumors and to investigate the relationship between PPA1 expression and clinicopathological parameters to further analyze its clinical significance. Immunohistochemical staining detected PPA1 expression in 305 noncancerous tissues and 675 tumor tissues, which included 12 different tumor types. QPCR and western blot examined PPA1 expression in tumor-derived cell lines including those derived from liver, breast, lung, and ovarian cancers. Cell proliferation and apoptosis assays were used to investigate PPA1-regulated cell growth in tumor cells. Finally, a bioinformatics analysis was used to verify the role of PPA1 in carcinogenesis. Among the 12 types of tumors, PPA1 expression was significantly higher in lung and ovarian cancers (P < 0.001). In lung cancer, PPA1 expression was associated with tumor size, patients' age, and smoking status, whereas in ovarian cancer, PPA1 expression was associated with pathological grade (P < 0.05). Moreover, we found that PPA1 expression was up-regulated in lung and ovarian cancer cell lines compared with nontumor cells. In addition, suppression of PPA1 expression by RNA interference in lung and ovarian cancer cells showed increased cell apoptosis and decreased cell proliferation, which was mediated by TP53 and p21 signaling. Notably, a bioinformatics analysis was used to verify the function of PPA1 in the development and progression of tumors. PPA1 expression is significantly higher in many tumors, especially those of lung and ovarian origin, which suggests that PPA1 plays an important role in carcinogenesis and in the development of some tumors.

Association of AHSG gene polymorphisms with ischemic stroke in a Han Chinese population.

Previous studies have shown associations of fetuin-A (alpha2-Heremans-Schmid glycoprotein, AHSG) with various disorders, including insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and atherosclerosis. In this study, genotype and allele frequencies of the rs4918 SNP in the AHSG gene were examined in 380 patients with ischemic stroke and 350 healthy controls from a Northern Han Chinese population via the PCR-RFLP technique. Frequencies of the GG genotype and the G allele in AHSG (rs4918) were significantly higher in patients with ischemic stroke or atherosclerotic cerebral infarction than those in the control group (P < 0.05). Logistic regression analysis demonstrated the significance of rs4918 in these patients, after adjustment for confounding factors (P < 0.05). These findings suggest that rs4918 SNPs of the AHSG gene are associated with a risk for ischemic stroke in a Northern Han Chinese population.

Spinocerebellar ataxia type 31 exists in northeast China.

Spinocerebellar ataxia type 31 (SCA31), is a recently defined subtype of autosomal dominant cerebellar ataxia (ADCA) characterized by late-onset pure cerebellar ataxia. SCA31 is common in Japan but whether or not it exists in other countries is still unclear. In this study, the authors describe a sporadic Chinese patient with SCA31. Although the cardinal clinical features, i.e., late-onset cerebellar ataxia and hearing impairment in our sporadic patient were similar to those described previously in Japan, mild axonal sensorimotor neuropathy was identified in our SCA31 patient, which is somewhat distinct from most prior reports of the disease. This is the first report of SCA31 in China; thus, extending the ethnic association beyond families of Japanese origin. In addition, our study suggests that the clinical features of SCA31 might be broader than previously thought.

The RANTES gene promoter polymorphisms are associated with the risk of atherothrombotic cerebral infarction in Northern Han Chinese.

BACKGROUND: Regulated upon activation, normal T-cell expressed and secreted (RANTES) plays an important role in the inflammatory process. This study is aimed at evaluating the potential association of the -403G/A (rs2107538) and -28C/G (rs2280788) polymorphisms of the RANTES gene promoter with the risk of atherothrombotic cerebral infarction (ACI) in Northern Han Chinese. METHOD: A total of 314 patients with ACI and 389 unrelated aged-matched healthy controls were recruited. Their genotypes of the RANTES gene promoter -403G/A (rs2107538) and -28C/G (rs2280788) were analyzed by multiplex polymerase chain reaction (multiplex PCR) and multiplex SNaPshot analysis. The potential association of genotyping and allele frequencies with ACI in this population was assessed statistically. RESULTS: The frequencies of -403AA genotype and A allele in ACI male patients were significantly higher than that in healthy controls (P=0.007, P=0.009, respectively). Female patients were not different. Multiple logistic regression analysis revealed that the -403AA genotype in males was significantly associated with an increased risk of ACI, even after adjusting for confounding factors (OR=4.344; 95% CI=1.969-9.582; P<0.001). Although there was no significant association of the -28C/G polymorphism with ACI, the A-(403)C-(28) haplotype was significantly associated with an increased risk of ACI in Han Chinese [OR=1.56, 95% CI=1.23-1.98, P<0.001]. CONCLUSIONS: Our data suggest that the -403AA genotype and A allele of the RANTES promoter were associated with increased risk for the development of ACI in male Northern Han Chinese.