bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-target protective effect of Danggui-Shaoyao-San on the vascular endothelium of atherosclerotic mice
Authors: Sun Yuemeng , Gao Yushan , Zhou Lu , Lu Yixing , Zong Yulin , Zhu Haoyu , Tang Yang , Zheng Fengjie , Sun Yan , Li Yuhang 
Published: February 2023

Abstract
Background
Atherosclerosis (AS) is a chronic disease characterized by abnormal blood lipid metabolism, inflammation and vascular endothelial injury. Vascular endothelial injury is the initial stage during the occurrence of AS. However, the function and mechanism of anti-AS are not well characterized. Danggui-Shaoyao-San (DGSY) is a classic Traditional Chinese Medicine (TCM) prescription for the treatment of gynecological diseases, and has been widely used in the treatment of AS in recent years.

Methods
ApoE−/− atherosclerosis male mice were established by feeding with high-fat diet, and then randomly divided into three groups: Atherosclerosis group (AS), Danggui-Shaoyao-San group (DGSY), and Atorvastatin calcium group (X). The mice were administered with the drugs for 16 weeks. Pathological changes in aortic vessels were examined by staining with Oil red O, Masson and hematoxylin–eosin. In addition, blood lipids were analyzed. The level of IL-6 and IL-8 in aortic vessels were detected by ELISA and the expression of ICAM-1 and VCAM-1 in the aortic vascular endothelium were measured by Immunohistochemical. The mRNA expression of interα5β1/c-Abl/YAP in the aortic vessels were measured by Real-time quantitative PCR and location of expression was assessed by immunofluorescence.

Results
DGSY can significantly reduce the content of TC,TG and LDL-C and increase the level of HDL-C in the serum, reduce the plaque area and inhibit the concentration of IL-6 and IL-8, down-regulate the expression of IVAM-1,VCAM-1 and interα5β1/ c-Abl/YAP in the aortic vessels.

Conclusions
Collectively, DGSY can alleviate vascular endothelium damage and delay the occurrence of AS, and the underlying mechanism may be related to the multi-target protective of DGSY.
Angiotensin converting enzyme (ACE) inhibitors activity from purified compounds Fructus Phaleria macrocarpa (Scheff) Boerl
Authors: Eff Aprilita Rina Yanti , Huri Hasniza Zaman , Radji Maksum , Mun’im Abdul , Suyatna F. D. , Eden Yonatan 
Published: February 2023

Abstract
Background
Mahkota Dewa [Phaleria macrocarpa (Scheff) Boerl.] fruit in vitro and in- vivo can decrease and prevent elevation of the blood pressure, lower plasma glucose levels, possess an antioxidant effect, and recover liver and kidney damage in rats. This study aimed to determine the structure and inhibitory activity of angiotensin-converting enzyme inhibitors (ACE) from the Mahkota Dewa fruit.

Methods
The fruit powder was macerated using methanol and then partitioned by hexane, ethyl acetate, n-butanol, and water. The fractions were chromatographed on the column chromatography and incorporated with TLC and recrystallization to give pure compounds. The structures of isolated compounds were determined by UV-Visible, FT-IR, MS, proton (1H-NMR), carbon (13C-NMR), and 2D-NMR techniques encompassing HMQC and HMBC spectra. The compounds were evaluated for their ACE inhibitory activity, and the strongest compound was determined by the kinetics enzyme inhibition.

Results
Based on the spectral data, the isolated compounds were determined as 6,4-dihydroxy-4-methoxybenzophenone–2-O-β-D-glucopyranoside (1), 4,4′-dihydroxy-6-methoxybenzophenone-2-O-β-D-glucopyranoside (2) and mangiferin (3). IC50 values of the isolated compounds 1, 2 and 3 were 0.055, 0.07, and 0.025 mM, respectively.

Conclusion
The three compounds have ACE inhibitor and mangiferin demonstrated the best ACE inhibitory activity with competitive inhibition on ACE with the type of inhibition kinetics is competitive inhibition.
Predictis: an IoT and machine learning-based system to predict risk level of cardio-vascular diseases
Authors: Islam Muhammad Nazrul , Raiyan Kazi Rafid , Mitra Shutonu , Mannan M. M. Rushadul , Tasnim Tasfia , Putul Asima Oshin , Mandol Angshu Bikash 
Published: February 2023

Abstract
Background
Despite technological advancement in the field of healthcare, the worldwide burden of illness caused by cardio-vascular diseases (CVDs) is rising, owing mostly to a sharp increase in developing nations that are undergoing fast health transitions. People have been experimenting with techniques to extend their lives since ancient times. Despite this, technology is still a long way from attaining the aim of lowering mortality rates.

Methods
From methodological perspective, a design Science Research (DSR) approach is adopted in this research. As such, to investigate the current healthcare and interaction systems created for predicting cardiac disease for patients, we first analyzed the body of existing literature. After that, a conceptual framework of the system was designed using the gathered requirements. Based on the conceptual framework, the development of different components of the system was completed. Finally, the evaluation study procedure was developed taking into account the effectiveness, usability and efficiency of the developed system.

Results
To attain the objectives, we proposed a system consisting of a wearable device and mobile application, which allows the users to know their risk levels of having CVDs in the future. The Internet of Things (IoT) and Machine Learning (ML) techniques were adopted to develop the system that can classify its users into three risk levels (high, moderate and low risk of having CVD) with an F1 score of 80.4% and two risk levels (high and low risk of having CVD) with an F1 score of 91%. The stacking classifier incorporating best-performing ML algorithms was used for predicting the risk levels of the end-users utilizing the UCI Repository dataset.

Conclusion
The resultant system allows the users to check and monitor their possibility of having CVD in near future using real-time data. Also, the system was evaluated from the Human-Computer Interaction (HCI) point of view. Thus, the created system offers a promising resolution to the current biomedical sector.

Trial Registration
Not Applicable.
Targeting the gut-lung axis by synbiotic feeding to infants in a randomized controlled trial
Authors: Sjödin Kotryna Simonyté , Sjödin Andreas , Ruszczyński Marek , Kristensen Mette Bach , Hernell Olle , Szajewska Hania , West Christina E. 
Published: February 2023

Abstract
Background
Formula-fed infants are at increased risk of infections. Due to the cross-talk between the mucosal systems of the gastrointestinal and respiratory tracts, adding synbiotics (prebiotics and probiotics) to infant formula may prevent infections even at distant sites. Infants that were born full term and weaned from breast milk were randomized to prebiotic formula (fructo- and galactooligosaccharides) or the same prebiotic formula with Lactobacillus paracasei ssp. paracasei F19 (synbiotics) from 1 to 6 months of age. The objective was to examine the synbiotic effects on gut microbiota development.

Results
Fecal samples collected at ages 1, 4, 6, and 12 months were analyzed using 16S rRNA gene sequencing and a combination of untargeted gas chromatography-mass spectrometry/liquid chromatography-mass spectrometry. These analyses revealed that the synbiotic group had a lower abundance of Klebsiella, a higher abundance of Bifidobacterium breve compared to the prebiotic group, and increases in the anti-microbial metabolite d-3-phenyllactic acid. We also analyzed the fecal metagenome and antibiotic resistome in the 11 infants that had been diagnosed with lower respiratory tract infection (cases) and 11 matched controls using deep metagenomic sequencing. Cases with lower respiratory tract infection had a higher abundance of Klebsiella species and antimicrobial resistance genes related to Klebsiella pneumoniae, compared to controls. The results obtained using 16S rRNA gene amplicon and metagenomic sequencing were confirmed in silico by successful recovery of the metagenome-assembled genomes of the bacteria of interest.

Conclusions
This study demonstrates the additional benefit of feeding specific synbiotics to formula-fed infants over prebiotics only. Synbiotic feeding led to the underrepresentation of Klebsiella, enrichment of bifidobacteria, and increases in microbial degradation metabolites implicated in immune signaling and in the gut-lung and gut-skin axes. Our findings support future clinical evaluation of synbiotic formula in the prevention of infections and associated antibiotic treatment as a primary outcome when breastfeeding is not feasible.

Trial registration
ClinicalTrials.gov NCT01625273. Retrospectively registered on 21 June 2012.
Osteosarcoma transcriptome data exploration reveals STC2 as a novel risk indicator in disease progression
Authors: Wang Ziyue , Zeng Zixin , Gao Feng , Gui Ziwei , Du Juan , Shen Ningning , Shang Yangwei , Yang Zhiqing , Shang Lifang , Wei Rong , Ma Wenxia , Wang Chen 
Published: February 2023

Abstract
Background
Osteosarcoma has been the most common primary bone malignant tumor in children and adolescents. Despite the considerable improvement in the understanding of genetic events attributing to the rapid development of molecular pathology, the current information is still lacking, partly due to the comprehensive and highly heterogeneous nature of osteosarcoma. The study is to identify more potential responsible genes during the development of osteosarcoma, thus identifying promising gene indicators and aiding more precise interpretation of the disease.

Methods
Firstly, from GEO database, osteosarcoma transcriptome microarrays were used to screen the differential expression genes (DEGS) in cancer comparing to normal bone samples, followed by GO/KEGG interpretation, risk score assessment and survival analysis of the genes, for the purpose of selecting a credible key gene. Further, the basic physicochemical properties, predicted cellular location, gene expression in human cancers, the association with clinical pathological features and potential signaling pathways involved in the key gene’s regulation on osteosarcoma development were in succession explored.

Results
Based on the selected GEO osteosarcoma expression profiles, we identified the differential expression genes in osteosarcoma versus normal bone samples, and the genes were classified into four groups based on the difference level, further genes interpretation indicated that the high differently level (> 8 fold) genes were mainly located extracellular and related to matrix structural constituent regulation. Meanwhile, module function analysis of the 67 high differential level (> 8 fold) DEGS revealed a 22-gene containing extracellular matrix regulation associated hub gene cluster. Further survival analysis of the 22 genes revealed that STC2 was an independent prognosis indicator in osteosarcoma. Moreover, after validating the differential expression of STC2 in cancer vs. normal tissues using local hospital osteosarcoma samples by IHC and qRT-PCR experiment, the gene’s physicochemical property revealed STC2 as a cellular stable and hydrophilic protein, and the gene’s association with osteosarcoma clinical pathological parameters, expression in pan-cancers and the probable biological functions and signaling pathways it involved were explored.

Conclusion
Using multiple bioinformatic analysis and local hospital samples validation, we revealed the gain of expression of STC2 in osteosarcoma, which associated statistical significantly with patients survival, and the gene’s clinical features and potential biological functions were also explored. Although the results shall provide inspiring insights into further understanding of the disease, further experiments and detailed rigorous clinical trials are needed to reveal its potential drug-target role in clinical medical use.
A novel DNA damage repair gene-related prognostic model for evaluating the prognosis and tumor microenvironment infiltration of esophageal squamous cell carcinoma
Authors: Guo Dong , Zhang Xueyuan , Du Xingyu , Yao Weinan , Shen Wenbin , Zhu Shuchai 
Published: February 2023

Abstract
Background
This study aimed to investigate the potential prognostic value of DNA damage repair genes (DDRGs) in esophageal squamous cell carcinoma (ESCC) and their relationship with immune-related characteristics.

Methods
We analyzed DDRGs of the Gene Expression Omnibus database (GSE53625). Subsequently, the GSE53625 cohort was used to construct a prognostic model based on least absolute shrinkage and selection operator regression, and Cox regression analysis was used to construct a nomogram. The immunological analysis algorithms explored the differences between the potential mechanism, tumor immune activity, and immunosuppressive genes in the high- and low-risk groups. Of the prognosis model-related DDRGs, we selected PPP2R2A for further investigation. Functional experiments were conducted to evaluate the effect on ESCC cells in vitro.

Results
A 5-DDRG (ERCC5, POLK, PPP2R2A, TNP1 and ZNF350) prediction signature was established for ESCC, stratifying patients into two risk groups. Multivariate Cox regression analysis showed that the 5-DDRG signature was an independent predictor of overall survival. Immune cells such as CD4 T cells and monocytes displayed lower infiltration levels in the high-risk group. Additionally, the immune, ESTIMATE, and stromal scores in the high-risk group were all considerably higher than those in the low-risk group. Functionally, knockdown of PPP2R2A significantly suppressed cell proliferation, migration and invasion in two ESCC cell lines (ECA109 and TE1).

Conclusion
The clustered subtypes and prognostic model of DDRGs could effectively predict the prognosis and immune activity of ESCC patients.
The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy
Authors: Sanganalmath Santosh K , Dubey Shubham , Veeranki Sudhakar , Narisetty Keerthy , Krishnamurthy Prasanna 
Published: February 2023

AbstractDiabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.
MMP2 is a immunotherapy related biomarker and correlated with cancer-associated fibroblasts infiltrate in melanoma
Authors: Peng Kunwei , Zhang Yanyan , Liu Deyi , Chen Jingqi 
Published: February 2023

Abstract
Background
Mounting evidence supports that matrix metalloproteinase (MMPs) are highly associated with tumor progression and that targeting MMPs may overcome the barrier of immune suppression. Among these, whether MMP2 functions as an immunosuppressive role in melanoma, remains unclear.

Methods
The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the prognosis of MMP2 in melanoma, after which Tumor immune estimation resource (TIMER) was used to explore the relationship between MMP2 expression and cancer associated fibroblasts (CAFs) infiltration. Finally, we evaluated the efficacy of MMP2 inhibitor on CAFs infiltration and immunotherapy using a mouse melanoma model.

Results
In general, the expression of MMP2, MMP13, MMP16, MMP17 and MMP25 were significantly associated with skin cutaneous melanoma (SKCM) patients prognosis, among which MMP2 low expression benefited patients the most. Especially, the overall survival (OS) of BRAF mutation patients with high MMP2 expression was significantly lower than the MMP2 low expression group, but there was no significant difference in BRAF wild-type patients. KEGG and GO enrichment analysis indicated that MMP2 related genes were mostly associated with extracellular structure organization, collagen-containing extracellular matrix and extracellular matrix structural constituent. Furthermore, in almost all cancers, MMP2 expression was positively correlated with CAFs infiltration. MMP2 inhibitor works synergistically with PD-1 antibody and induces tumor regression in a mouse melanoma model, which is dependent on decreased CAFs infiltration.

Conclusions
This suggests that MMP2 plays a vital role in the regulation of CAFs infiltration, potentially participating in immunotherapy response, and thus representing a valuable target of immunotherapy in melanoma.
Metabolic responses in blood-stage malaria parasites associated with increased and decreased sensitivity to PfATP4 inhibitors
Authors: Tewari Shivendra G. , Elahi Rubayet , Kwan Bobby , Rajaram Krithika , Bhatnagar Suyash , Reifman Jaques , Prigge Sean T. , Vaidya Akhil B. , Wallqvist Anders 
Published: February 2023

Abstract
Background
Spiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intracellular Na+ homeostasis. Recently, a PfATP4 mutation was discovered that confers resistance to a pyrazoleamide while increasing sensitivity to a spiroindolone. Transcriptomic and metabolic adaptations that underlie this seemingly contradictory response of P. falciparum to sublethal concentrations of each compound were examined to understand the different cellular accommodation to PfATP4 disruptions.

Methods
A genetically engineered P. falciparum Dd2 strain (Dd2A211V) carrying an Ala211Val (A211V) mutation in PfATP4 was used to identify metabolic adaptations associated with the mutation that results in decreased sensitivity to PA21A092 (a pyrazoleamide) and increased sensitivity to KAE609 (a spiroindolone). First, sublethal doses of PA21A092 and KAE609 causing substantial reduction (30–70%) in Dd2A211V parasite replication were identified. Then, at this sublethal dose of PA21A092 (or KAE609), metabolomic and transcriptomic data were collected during the first intraerythrocytic developmental cycle. Finally, the time-resolved data were integrated with a whole-genome metabolic network model of P. falciparum to characterize antimalarial-induced physiological adaptations.

Results
Sublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts, whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, a substantial alteration (≥ fourfold) in the abundances of carbohydrate metabolites in the presence of either compound was found. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol.

Conclusion
The results of this study suggest that malaria parasites activate protein kinases via phospholipid-dependent signalling in response to the ionic perturbation induced by the Na+ homeostasis disruptor PA21A092. Therefore, targeted disruption of phospholipid signalling in PA21A092-resistant parasites could be a means to block the emergence of resistance to PA21A092.
Fusion plasmid enhanced the endemic extensively drug resistant Klebsiella pneumoniae clone ST147 harbored blaOXA-48 to acquire the hypervirulence and cause fatal infection
Authors: Liu Chao , Du Pengcheng , Yang Ping , Lu Ming , Shen Ning 
Published: February 2023

Abstract
Background
Klebsiella Pneumoniae (Kp) sequence type (ST) 147 has emerged globally and spread rapidly, particularly the extensively drug resistant (XDR) isolates. However, the infections caused by this subtype is rare reported in China for now. The clinical, microbiological and genomic characteristics are unclear.

Methods
A systemic retrospective study was conducted in a Chinese tertiary hospital. Clinical information of the infection cases was collected, and whole-genome sequencing and phenotypic experiments were performed on the ST147 isolates. The resistance and virulence genes were identified, and the plasmids harboring these genes were further studied.

Results
Six ST147 isolates from six patients among 720 available clincial Kp isolates were detected. Notably, two isolates, PEKP4035 and PEKP4265, represented both XDR and hypervirulence by acquiring blaOXA-48, blaCTX-M-15 and key virulence genes, iucA + rmpA2, representing no fitness cost and resulting fatal infection. Four of the six ST147 isolates presented with more nucleotide differences, whereas the PEKP4035 and PEKP4265 both isolated from the intensive care unit possessed 20 single nucleotide polymorphisms among one year, indicating the prolonged survive and transmission. Interestingly, the two isolates harbored the same fused plasmid composed of sul2 and iucA + rmpA2, which might be generated by recombination of a plasmid like KpvST101_OXA-48 with the pLVPK plasmid via IS26. Besides, two ~ 70 kb plasmids conferring multiple-drug resistance were also identified among the two isolates, which presented resistance genes including blaOXA-48, blaCTX-M-16, strA and strB. Interestingly, we reported that blaCTX-M-15, a common resistance gene within ST147, has successfully transferred into the chromosome by ISEcp1.

Conclusions
XDR hypervirulent ST147 Kp is emerging, suggesting enhanced surveillance is essential.