bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of TERT suppressed proliferation and induced apoptosis in chronic myeloid leukemia cells
Authors: Liu Wen , Deng Fang , Wang Teng 
Published: January 2025

Abstract

Purpose
The targeting of telomerase in cancer therapy elicits significant attention due to recent findings indicating a correlation between high telomerase activity and adverse cancer outcomes, as well as disease resistance. The precise role of telomerase and its catalytic subunit, human telomerase reverse transcriptase (hTERT), in chronic myeloid leukemia (CML) has not been thoroughly elucidated. However, telomerase activity is recognized as a mechanism underlying resistance to imatinib (IM), a tyrosine kinase inhibitor. The loss of telomerase activity in CML has also been associated with acquiring infinite proliferative potential, which is closely linked to maintenance through telomerase reactivation.
Methods
K562 cells, along with their IM-resistant derivatives (K562R), were subjected to si-RNA targeting hTERT or a combination treatment involving IM and the hTERT inhibitor BIBR1532. To evaluate the role of hTERT in drug resistance, cell viability following exposure to si-hTERT, IM, and the combination of IM and BIBR1532 was evaluated using the Cell Counting Kit-8 (CCK-8) assay and colony-formation assays. The percentage of apoptosis was quantified using the Annexin V assay. Additionally, the transcriptional and protein expression levels of p73, p21, FOXO3a, c-Myc, hTERT, and other apoptosis-related target genes were analyzed through quantitative polymerase chain reaction (qPCR) and Western blotting (WB).
Results
In K562R and K562 cell lines, telomerase activity was significantly reduced following the pharmacological inhibition of telomerase using the inhibitor BIBR1532, as well as through the knockdown of hTERT. Flow cytometry analysis revealed that the knockdown of hTERT induced apoptosis in chronic myeloid leukemia (CML) cells and results in cell-cycle arrest at the G2 phase. Furthermore, the inhibition of hTERT was found to suppress the transcriptional activity of c-Myc while concurrently reactivating the transcription factors p73, p21, and Foxo3a. The combination of BIBR1532 with imatinib exhibited a synergistic anticancer effect on CML cells.
Conclusions
Overall, the combination of BIBR1532 is a novel therapeutic strategy for CML that may soon be clinically accessible.
Long-term survival outcome of portal vein embolization in patients with perihilar cholangiocarcinoma
Authors: Lee Min Woo , Paik Woo Hyun , Huh Gunn , Lee Dong Ho , Bae Jae Seok , Kwon Woo Il , Jang Jin Young , Cho In Rae , Ryu Ji Kon , Lee Sang Hyub 
Published: January 2025

Abstract

Background
Portal vein embolization (PVE) is often recommended to avoid postoperative liver failure and subsequent mortality after surgical resection of perihilar cholangiocarcinoma (CCA). However, evidence of its effect on surgical outcomes and long-term survival is limited.
Methods
We retrospectively reviewed the data of 137 patients diagnosed with Bismuth type III–IV perihilar CCA between April 2011 and August 2021. Among 137 patients, 88 were included in the analyses and divided into three groups: resection without PVE (A); resection after PVE (B); and no resection after PVE (C). We analyzed the outcomes using inverse probability treatment weighting (IPTW). Factors associated with overall survival were analyzed using Cox regression analysis stratified by surgical resection.
Results
There was no significant difference in median overall survival (OS) and recurrence-free survival (RFS) between groups A and B (mOS 19.6 vs. 26.6 months; P = 0.382; mRFS 11.9 vs. 18.1 months, P = 0.099). However, a significant difference was found in median OS between groups B and C (26.6 vs 10.5 months; P = 0.004). In the stratified Cox regression analysis with IPTW, age (adjusted hazard ratio [aHR] 1.364ㅡ10.97), CA19-9 level (aHR 1.181ㅡ4.147), and percentage of future liver remnant after PVE (post-PVE %FLR; aHR 0.180ㅡ0.815) were associated with OS.
Conclusions
There was no difference in OS and RFS based on whether PVE was performed before surgical resection. Post PVE %FLR was associated with OS irrespective of subsequent surgical resection.
Morphological segmentation with tiling light sheet microscopy to quantitatively analyze the three-dimensional structures of spinal motoneurons
Authors: Hu Huijie , Wang Dongyue , Chen Yanlu , Gao Liang 
Published: January 2025

Abstract

Spinal motoneurons control muscle fibers contraction and drive all motor behaviors in vertebrates. Although spinal motoneurons share the fundamental role of innervating muscle fibers, they exhibit remarkable diversity that reflects their specific identities. Defining the morphological changes during postnatal development is critical for elucidating this diversity. However, our understanding of the three-dimensional (3D) morphology of spinal motoneurons at these stages remains limited, largely due to the lack of high-throughput imaging tools. Using tiling light sheet microscopy combined with tissue clearing methods, we imaged motoneurons of the lateral and median motor column in the cervical and lumbar cord during postnatal development. By analyzing their soma size, we found that motoneurons innervating the upper limbs differentiate into two subpopulations with distinct soma size by postnatal day 14 (P14), while differentiation of motoneurons innervating the lower limbs is delayed. Furthermore, coupling adenovirus labeling with 3D volumetric reconstruction, we traced and measured the number and lengths of dendrites of flexor and extensor motoneurons in the lumbar cord, finding that the number of dendrites initially increases and subsequently declines as dendritic order rises. Together, these findings provide a quantitative analysis of the 3D morphological changes underlying spinal motoneuron diversity.
Metode Gamifikasi untuk Pembelajaran Menulis Cerpen Siswa Kelas XI SMK Islam Darussalam
Authors: Ramadhani Abd Wafir , Wachidah Liana Rochmatul 
Published: January 2025

This article analyzes the application of gamification methods that are used as an effort to improve the short story writing skills of class XI students of SMK Islam Darussalam. Gamification is a learning method that involves game elements such as leaderboards, points, challenges, and prizes in learning, which are proven to be able to create interesting and interactive learning. This study uses a qualitative method with a case study approach. This approach is used because it allows researchers to gain a deep understanding of the phenomenon being studied in a real context. This study shows that the gamification method can improve students' writing skills, because its application can create active and enjoyable learning. The thing that must be considered in implementing this method is the right strategy, because with the right strategy gamification has the potential to create dynamic and student-centered learning, thus helping students improve their skills, especially short story writing skills.
Desenvolvimento e Validação de Produto Educacional sobre Primeiros Socorros voltados a Recém-Nascidos:Estudo Metodológico
Authors: Zuccon e Silva Fernando , Nunes Guedes de Oliveira Rebeca 
Published: January 2025

RESUMO: A morte de recém-nascidos ocasionada por engasgamento, aspiração de corpo estranho e morte súbita ainda representa elevada magnitude em diversos cenários. Em junho de 2022, a Secretaria Municipal da Casa Civil de São Paulo publicou a Lei no 17.811, que dispõe sobre a obrigatoriedade de os hospitais e maternidades capacitarem os pais ou responsáveis de recém-nascidos para realizarem atendimento de primeiros socorros para os casos de engasgamento, aspiração de corpo estranho e prevenção de morte súbita. O estudo aborda o processo de desenvolvimento de estratégia educativa voltada à prevenção deste problema em um serviço público de saúde. O objetivo foi elaborar e validar um vídeo educativo para os pais ou responsáveis de recém-nascidas sobre como realizar manobras de primeiros socorros para os casos de engasgamento, aspiração de corpo estranho e prevenção de morte súbita. Trata-se de um estudo metodológico que foi constituído pelas fases de concepção, desenvolvimento e validação, pelo público-alvo, de um produto educacional. Os conteúdos do vídeo foram definidos a partir de levantamento bibliográfico, realizado nas bases de dados PubMed; LILACS; Google scholar, respectivamente, usando os descritores “Morte Súbita do Lactente”; “Engasgo”; “aspiração de corpo estranho”; e “primeiros socorros”. O produto educacional foi desenvolvido no formato de vídeo educativo. Para a validação do vídeo junto ao público-alvo, foi aplicado questionário após a exposição do vídeo a puérperas e aos respectivos responsáveis legais dos recém-nascidos na Maternidade do Conjunto Hospitalar do Mandaqui. Após a apresentação do vídeo e aplicação do questionário junto ao público-alvo, foi aplicado o Índice de Validação de Conteúdo, avaliado quanto ao, objetivos, organização, estilo do vídeo, aparência e motivação, seguindo, de forma adaptada, o questionário publicado por Dantas et al. (2022). Foi obtida a validação do produto com um IVC total de 0,99. Como produto de pesquisa foi desenvolvido foi um vídeo educativo validado, vislumbrando a sua implementação no cenário do estudo, com possibilidade de ampliação a partir de ampla divulgação do material para toda a rede de saúde.

Palavras-chave: atenção à saúde; garantia da qualidade dos cuidados de saúde; morte súbita do lactente; engasgo; primeiros socorros.
Virtual Screening Identifies Inhibitors of SARS-CoV-2 Main Protease through
Pharmacophore and Similarity Approaches
Authors: Khanfar Mohammad A. , Saleh Mohammad 
Published: January 2025

Introduction:
The emergence of SARS-CoV-2 and the COVID-19 pandemic highlighted the urgent
need for novel antiviral therapies. The main protease (Mpro) of SARS-CoV-2 is a key enzyme in viral replication and a promising therapeutic target.

Methods:
This study employed virtual screening approaches to identify potential Mpro inhibitors, leveraging
both structure- and ligand-based methods.

Results:
Two optimum pharmacophore models were built from hundreds of crystallographic structures of Mpro
,
validated through ROC curve analysis and Dynophores dynamic simulations. These models captured ≈ 60K
hits from six diverse compound libraries made of more than 3 million compounds. Additionally, a ligandbased similarity search using ROCS software identified 1024 potential hits based on shape and atom-based
comparisons with co-crystallized ligands. Subsequent molecular docking and filtering based on physicochemical properties and structural diversity yielded 16 and 6 hits from structure- and ligand-based screening, respectively. Molecular dynamics simulations were conducted on the top-scoring hits to assess their binding stability
within the Mpro active site. SCR00943 demonstrated stable binding, interacting favorably with key residues, including the catalytic dyad, resulting in a binding affinity of -61.2 kcal/mol

Conclusion:
This virtual screening campaign identified promising Mpro inhibitors, showcasing the potential of
computational approaches to accelerate drug discovery efforts against COVID-19.
Unveiling the Interplay between Dopamine-like Molecules and Β-Amyloid Peptide: A Combined Molecular Dynamic and DFT Approach
Authors: Zand Mohammad Erfan , Bozorgmehr Mohammad Reza , Heravi Mohammad Momen , Beyramabadi S. Ali 
Published: January 2025

Aims:
This study aims explore the impact of catechol, dopamine, and L-DOPA on the
stability and toxicity of β-amyloid peptides, which play a key role in the neurodegenerative process
of Alzheimer's disease, to assess their potential as therapeutic agents.

Background:
Alzheimer's disease is marked by the aggregation of β-amyloid peptides, which
contribute to neurodegeneration. Exploring how various compounds interact with β-amyloid
peptides can offer valuable insights into potential therapeutic strategies.

Objective:
The objective of this research is to explore the interaction mechanisms of catechol,
dopamine, and L-DOPA with β-amyloid peptides and assess their impact on peptide stability and
aggregation.

Method:
This study employs molecular dynamics simulations combined with density functional
theory to investigate the interactions between β-amyloid and the three compounds. It evaluates
changes in peptide stability and salt bridge lengths and performs electronic structure analyses using
the Electron Localization Function (ELF) and Harmonic Oscillator Model of Aromaticity
(HOMA).

Results:
The findings reveal that β-amyloid stability decreases significantly when interacting
with dopamine and L-DOPA compared to catechol. All three compounds inhibit β-amyloid, with
dopamine and L-DOPA showing stronger effects. Catechol primarily interacts through hydrophobic
interactions, while dopamine and L-DOPA also form hydrogen bonds with β-amyloid.
Electronic structure analysis shows catechol has higher electron localization and anti-aromatic
character, affecting its interactions differently than dopamine and L-DOPA. A decrease in the
HOMO-LUMO gap from catechol to L-DOPA to dopamine indicates increasing reactivity towards
β-amyloid.

Conclusion:
Dopamine and L-DOPA more effectively disrupt β-amyloid aggregation than catechol,
likely due to additional hydrogen bonding and increased electronic reactivity. These insights
are crucial for developing therapeutic strategies targeting β-amyloid aggregation in Alzheimer's
disease, emphasizing the importance of molecular interactions in modulating peptide
stability and toxicity.
The study also provides a comparative analysis of the electronic properties and interaction dynamics
of the compounds, which can guide future research in the design of β-amyloid inhibitors.
The utilization of advanced simulation techniques underscores the potential for computational
methods in understanding complex biological interactions and developing novel therapeutic
agents. Furthermore, the insights into the differential effects of hydrophobic interactions versus
hydrogen bonding offer valuable information for the synthesis of new compounds aimed at mitigating
β-amyloid toxicity.
Verification of Qianlong Shutong Formula in the Treatment of Benign
Prostatic Hyperplasia
Authors: Zhang Ze-chao , Zhu Min , Huang Shu-ping , Wei Zhi-feng , Chen Yu , Shang Chang-jie 
Published: January 2025

Aims:
To investigate the mechanisms through which Qianlong Shutong Formula
(QLSTF) exerts its effects on the management of benign prostatic hyperplasia (BPH).

Background:
BPH is a prevalent condition among older men and poses significant management challenges due to the limited effectiveness and potential side effects associated with current treatment options. QLSTF, a traditional Chinese medicine, has been utilized in the treatment of BPH; however, its mechanism of action remains inadequately understood.

Objective:
This study aimed to identify potential therapeutic targets of QLSTF for the management of BPH through the application of network pharmacology and subsequent experimental
validation.

Methods:
QLSTF compounds were identified utilizing liquid chromatography-mass spectrometry (LC-MS). Potential targets of QLSTF, as well as BPH-related targets, were retrieved from
public databases. Crucial bioactive ingredients, potential targets, and signaling pathways were
acquired through bioinformatics analysis, including protein-protein interaction (PPI), as well as
the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.
Subsequently, molecular docking was carried out to predict the combination of active compounds with core targets. Lastly, in vitro and in vivo experiments were conducted to further verify the findings.

Results:
A total of 52 bioactive ingredients of QLSTF and 760 QLSTF-BPH-related targets
were screened. Bioinformatics analysis revealed that Afzelin, Ononin, Glycitin, Emodin and
Erythritol may be potential candidate agents. AKT1, SRC, STAT3, GRB2, HRAS, MAPK3,
PIK3CA, PIK3R1, HSP90AA1, and EP300 could become potential therapeutic targets. PI3KAKT signaling pathway might play an important role in QLSTF against BPH. Moreover, molecular docking suggested that Afzelin, Ononin, Glycitin, Emodin, and Erythritol combined well
with AKT1, SRC, STAT3, HRAS, MAPK3, PIK3CA, and PIK3R1, respectively. In vitro and in
vivo experiments showed that QLSTF could inhibit the proliferation of cells, as well as the
PI3K-Akt signaling pathway, which further confirmed the prediction by network pharmacology
strategy and molecular docking.

Conclusions:
QLSTF may exert its therapeutic effects on BPH by modulating the PI3K/AKT
signaling pathway and inhibiting glandular hyperplasia. This study offers valuable insights into
the therapeutic targets of QLSTF in the management of BPH.
Bioinformatics Analysis of Lactylation-Related Biomarkers and Potential Pathogenesis Mechanisms in Age-Related Macular Degeneration
Authors: Gui Chenwei , Gao Yan , Zhang Rong , Zhou Guohong 
Published: January 2025

Background:
Lactylation is increasingly recognized to play a crucial role in human
health and diseases. However, its involvement in age-related macular degeneration (AMD) remains
largely unclear.

Objective:
The aim of this study was to identify and characterize the pivotal lactylation-related
genes and explore their underlying mechanism in AMD.

Methods:
Gene expression profiles of AMD patients and control individuals were obtained and integrated
from the GSE29801 and GSE50195 datasets. Differentially expressed genes (DEGs)
were screened and intersected with lactylation-related genes for lactylation-related DEGs. Machine
learning algorithms were used to identify hub genes associated with AMD. Subsequently,
the selected hub genes were subject to correlation analysis, and reverse transcription quantitative
real-time PCR (RT-qPCR) was used to detect the expression of hub genes in AMD patients and
healthy control individuals.

Results:
A total of 68 lactylation-related DEGs in AMD were identified, and seven genes, including
HMGN2, TOP2B, HNRNPH1, SF3A1, SRRM2, HIST1H1C, and HIST1H2BD were selected as
key genes. RT-qPCR analysis validated that all 7 key genes were down-regulated in AMD patients.

Conclusion:
We identified seven lactylation-related key genes potentially associated with the progression
of AMD, which might deepen our understanding of the underlying mechanisms involved
in AMD and provide clues for the targeted therapy.
The Role of Lactate in Ischemic Stroke: As an Energy Source and Signaling Molecule
Authors: Zhang Rui , Li Xintong , Liu Kemeng , Yang Meng , Dong Peiliang , Han Hua 
Published: January 2025

Abstract:
Stroke is an acute cerebrovascular disease that causes brain tissue damage due to sudden
blockage or rupture of blood vessels in the brain. According to the latest data from the Global
Burden of Disease Study, the number of stroke patients worldwide is estimated to exceed 100 million,
and more than 80% of patients suffer from stroke. Ischemic stroke is a type of stroke due to
which two-thirds of the patients are disabled or even die, seriously affecting the patient's quality
of life. Lactate is an indispensable substance in various physiological and pathological cells and
plays a regulatory role in different aspects of energy metabolism and signal transduction. Studies
have found that during cerebral ischemia and hypoxia, lactate concentration increases significantly,
improving the energy supply to the ischemic area. Based on the scientific concept of lactate
travelling through the brain, this article focuses on the important role of lactate as an energy
source after ischemic stroke and analyzes the relationship between lactate as a signaling molecule
and neuroprotection, angiogenesis, and anti-inflammatory effects. The aim of this study is to outline
the molecular mechanisms by which lactate exerts its different effects in ischemic stroke.
Some references are provided in this study for the research on lactate therapy for ischemic stroke.
Protein Misfolding and Aggregation of Pathological Igg Light Chains in Oncohematological Dyscrasias: From Molecular Pathways to Clinical
Implications
Authors: Guman Tomáš , Sýkora Ján , Demčáková Veronika , Žoldák Gabriel 
Published: January 2025

Abstract:
Neoplastic transformation of B cells of the post-germinative center can lead to oncohematological
dyscrasias, which often results in an abnormal production of monoclonal immunoglobulin
light chains. The non-physiological production of large amounts of IgG light chains leads to
the formation of extracellular deposits called 'aggregomas' and rare conditions such as light chain
crystal deposition disease. Kidney manifestations and heavy-chain deposition disease can also occur
in plasma cell dyscrasias, emphasizing the role of IgG misfolding and aggregation. This
minireview describes molecular mechanisms of IgG light-chain aggregation, as well as the consequences
and therapeutic implications of IgG light chain misfolding in these disorders. By elucidating
the mechanisms of IgG light chain misfolding and aggregation, researchers can identify specific
molecular and cellular pathways. This knowledge opens the door to novel therapeutic targets, offering
the potential for interventions that can either prevent the initial misfolding events, promote
the proper folding and processing of immunoglobulins, or enhance the clearance of misfolded proteins
and aggregates. These protein folding-related issues persist even after the successful elimination
of the malignant B cells. Such targeted protein-folding therapies could significantly improve
patients' quality of life and contribute to their recovery. Thus, a deep understanding of IgG light
chain misfolding and its consequences not only sheds light on the complex biology of oncohematological
dyscrasias but also opens the way for innovative treatment strategies that could transform
patient care in these conditions, instilling hope and motivation in the healthcare professionals and
researchers in this field.
Benzopyrene Aggravates Nonalcoholic Liver Fatty Diseases in Female Mice Via the AHR/ERα Axis
Authors: Wu Yongkang , Xie Jing , Tao Qing , Tan Lina , Zhu Xiangyu , Yong Jin 
Published: January 2025

Objective:
Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver
condition worldwide, and the statistics show that men have a higher incidence and
prevalence than women, but its toxicological mechanism is not completely clear. This
research is intended to explore the role of BaP in NAFLD and to study how the
environmental pollutant BaP influences the AHR/ERα axis to mediate the progression
of NAFLD.

Methods:
In this study, we established NAFLD models in vivo and in vitro by treating
HepG2 cells with a high-fat diet and Oleic acid (OA) in C57BL/6J mice. Liver injury
indexes ALT, AST, and lipid metabolism indexes TG and TC were evaluated to verify
the success of modeling. Then, the model was treated with BaP, and the mRNA and
protein expressions of CYP1A1, ERα, and SREBP-1c were evaluated by RT-PCR and
WB, and the changes of liver fat were evaluated by HE and oil red O staining. Next,
BaP was added into the cells treated with or without estradiol (E2), and the lipid
metabolism in the cells was evaluated by oil red O staining, and whether the above
levels of CYP1A1, ERα and SREBP-1c were changed.

Results:
Our results show that after exposure to BaP, ERα protein levels in mice and
cells are inhibited, mRNA and protein levels of SREBP-1c are reduced, and lipid
metabolism processes are obstructed. The addition of E2 can reduce the increase of
SREBP-1c mRNA and protein expression induced by OA, and reduce the deposition of
lipids in cells. However, BaP treatment can weaken the action of E2 and destroy the
protection of E2 in cells.

Conclusion:
The results showed that E2 could reduce SREBP-1c mRNA and protein
levels. BaP can stimulate AHR, leading to the degradation of ERα protein, reducing the
binding of E2 to ERα, and aggravating the progression of NAFLD. This reveals the
toxicological mechanism by which environmental pollutant BaP influences E2 to
mediate NAFLD, and provides strong evidence for differences in NAFLD between the
sexes.