bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates
Authors: Muema Jackson M. , Mutunga James M. , Obonyo Meshack A. , Getahun Merid N. , Mwakubambanya Ramadhan S. , Akala Hoseah M. , Cheruiyot Agnes C. , Yeda Redemptah A. , Juma Dennis W. , Andagalu Ben , Johnson Jaree L. , Roth Amanda L. , Bargul Joel L. 
Published: May 2023

Abstract
Background
The unmet demand for effective malaria transmission-blocking agents targeting the transmissible stages of Plasmodium necessitates intensive discovery efforts. In this study, a bioactive bisbenzylisoquinoline (BBIQ), isoliensinine, from Cissampelos pariera (Menispermaceae) rhizomes was identified and characterized for its anti-malarial activity.

Methods
Malaria SYBR Green I fluorescence assay was performed to evaluate the in vitro antimalarial activity against D6, Dd2, and F32-ART5 clones, and immediate ex vivo (IEV) susceptibility for 10 freshly collected P. falciparum isolates. To determine the speed- and stage-of-action of isoliensinine, an IC50 speed assay and morphological analyses were performed using synchronized Dd2 asexuals. Gametocytocidal activity against two culture-adapted gametocyte-producing clinical isolates was determined using microscopy readouts, with possible molecular targets and their binding affinities deduced in silico.

Results
Isoliensinine displayed a potent in vitro gametocytocidal activity at mean IC50gam values ranging between 0.41 and 0.69 µM for Plasmodium falciparum clinical isolates. The BBIQ compound also inhibited asexual replication at mean IC50Asexual of 2.17 µM, 2.22 µM, and 2.39 µM for D6, Dd2 and F32-ART5 respectively, targeting the late-trophozoite to schizont transition. Further characterization demonstrated a considerable immediate ex vivo potency against human clinical isolates at a geometric mean IC50IEV = 1.433 µM (95% CI 0.917–2.242). In silico analyses postulated a probable anti-malarial mechanism of action by high binding affinities for four mitotic division protein kinases; Pfnek1, Pfmap2, Pfclk1, and Pfclk4. Additionally, isoliensinine was predicted to possess an optimal pharmacokinetics profile and drug-likeness properties.

Conclusion
These findings highlight considerable grounds for further exploration of isoliensinine as an amenable scaffold for malaria transmission-blocking chemistry and target validation.
EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer
Authors: Chen Jianfeng , Hong Jing Han , Huang Yulin , Liu Shini , Yin Jiaxin , Deng Peng , Sun Yichen , Yu Zhaoliang , Zeng Xian , Xiao Rong , Chan Jason Yongsheng , Guan Peiyong , Wang Yali , Wang Peili , Liu Lizhen , Wen Shijun , Yu Qiang , Ong Choon Kiat , Teh Bin-Tean , Xiong Ying , Tan Jing 
Published: May 2023

Abstract
Background
Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and plays an oncogenic role in various cancers through catalysis-dependent or catalysis-independent pathways. However, the related mechanisms contributing to ovarian cancer (OC) are not well understood.

Methods
The levels of EZH2 and H3K27me3 were evaluated in 105 OC patients by immunohistochemistry (IHC) staining, and these patients were stratified based on these levels. Canonical and noncanonical binding sites of EZH2 were defined by chromatin immunoprecipitation sequencing (ChIP-Seq). The EZH2 solo targets were obtained by integrative analysis of ChIP-Seq and RNA sequencing data. In vitro and in vivo experiments were performed to determine the role of EZH2 in OC growth.

Results
We showed that a subgroup of OC patients with high EZH2 expression but low H3K27me3 exhibited the worst prognosis, with limited therapeutic options. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked OC cell proliferation and tumorigenicity in vitro and in vivo. Integrative analysis of genome-wide chromatin and transcriptome profiles revealed extensive EZH2 occupancy not only at genomic loci marked by H3K27me3 but also at promoters independent of PRC2, indicating a noncanonical role of EZH2 in OC. Mechanistically, EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing tricarboxylic acid cycle (TCA cycle) activity, which contributed to the growth of OC.

Conclusions
These data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.
Novel plant-derived exosome-like nanovesicles from Catharanthus roseus: preparation, characterization, and immunostimulatory effect via TNF-α/NF-κB/PU.1 axis
Authors: Ou Xiaozheng , Wang Haoran , Tie Huilin , Liao Jiapei , Luo Yuanyuan , Huang Weijuan , Yu Rongmin , Song Liyan , Zhu Jianhua 
Published: May 2023

Abstract
Background
Plant-derived exosomes-like nanovesicles (PDENs) have been found to be advantageous in disease treatment and drug delivery, but research on their biogenesis, compositional analysis, and key marker proteins is still in its infancy, which limits the standardized production of PDENs. Efficient preparation of PDENs continues to be a major challenge.

Results
Novel PDENs-based chemotherapeutic immune modulators, Catharanthus roseus (L.) Don leaves-derived exosome-like nanovesicles (CLDENs) were isolated from apoplastic fluid. CLDENs were membrane structured vesicles with a particle size of 75.51 ± 10.19 nm and a surface charge of −21.8 mV. CLDENs exhibited excellent stability, tolerating multiple enzymatic digestions, resisting extreme pH environments, and remaining stable in the gastrointestinal simulating fluid. Biodistribution experiments showed that CLDENs could be internalized by immune cells, and targeted at immune organs after intraperitoneal injection. The lipidomic analysis revealed CLDENs’ special lipid composition, which contained 36.5% ether-phospholipids. Differential proteomics supported the origin of CLDENs in multivesicular bodies, and six marker proteins of CLDENs were identified for the first time. 60 ~ 240 μg/ml of CLDENs promoted the polarization and phagocytosis of macrophages as well as lymphocyte proliferation in vitro. Administration of 20 mg/kg and 60 mg/kg of CLDENs alleviated white blood cell reduction and bone marrow cell cycle arrest in immunosuppressive mice induced by cyclophosphamide. CLDENs strongly stimulated the secretion of TNF-α, activated NF-κB signal pathway and increased the expression of the hematopoietic function-related transcription factor PU.1 both in vitro and in vivo. To ensure a steady supply of CLDENs, plant cell culture systems of C. roseus were established to provide CLDENs-like nanovesicles which had similar physical properties and biological activities. Gram-level nanovesicles were successfully obtained from the culture medium, and the yield was three times as high as the original.

Conclusions
Our research supports the use of CLDENs as a nano-biomaterial with excellent stability and biocompatibility, and for post-chemotherapy immune adjuvant therapy applications.

Graphical Abstract
Intracorporeal versus extracorporeal anastomosis in laparoscopic right colectomy: a retrospective study
Authors: Chen Fangqian , Lv Zeping , Feng Wenqing , Xu Zhuoqing , Miao Yiming , Xu Zifeng , Zhang Yuchen , Gao Han , Zheng Minhua , Zong Yaping , Zhao Jingkun , Lu Aiguo 
Published: May 2023

Abstract

Background
The surgical procedure for laparoscopic right colectomy (LRC) is not standardized. Some published studies show the superiority of ileocolic anastomosis (IIA), but the evidence so far is insufficient. This study aimed to investigate the potential advantages in postoperative recovery and safety of IIA in LRC.

Methods
A total of 114 patients who underwent LRC with IIA (n = 58) or extracorporeal ileocolic anastomosis (EIA, n = 56) between January 2019 and September 2021 were enrolled. We collected certain factors as clinical features, intraoperative characteristics, oncological outcomes, postoperative recovery, and short-term outcomes. Our primary outcome was time to gastrointestinal (GI) function recovery. Secondary outcomes were postoperative complications within 30 days, postoperative pain, and length of hospital stay.

Results
Faster GI recovery and less postoperative pain were observed in patients with IIA compared to EIA [time to first flatus: (2.4 ± 0.7) vs (2.8 ± 1.0) days, p < 0.01; time to liquid intake: (3.5 ± 0.7) vs (4.0 ± 1.1) days, p = 0.01; postoperative visual analogue scale score: (3.9 ± 1.0) vs (4.3 ± 0.6), p = 0.02]. No significant differences were detected in oncological outcomes or postoperative complications. IIA, rather than EIA, tended to be performed in patients with higher body mass index [(23.93 ± 3.52) vs (22.36 ± 2.87) kg/m2, p = 0.01].

Conclusions
IIA is associated with faster GI function recovery and less postoperative pain and may be more favorable for obese patients.
CEBPG suppresses ferroptosis through transcriptional control of SLC7A11 in ovarian cancer
Authors: Zhang Xiaoqian , Zheng Xiaocui , Ying Xiang , Xie Weiwei , Yin Yujia , Wang Xipeng 
Published: May 2023

Abstract
Background
Ovarian cancer (OC) has high mortality and poor prognosis for lacking of specific biomarkers and typical clinical symptoms in the early stage. CEBPG is an important regulator in tumor development, yet it is unclear exactly how it contributes to the progression of OC.

Methods
TCGA and tissue microarrays with immunohistochemical staining (IHC) were used to examine CEBPG expression in OC. A variety of in vitro assays were conducted, including colony formation, proliferation, migration, and invasion. The orthotopic OC mouse model was established for in vivo studies. Ferroptosis was detected by observing mitochondrial changes with electron microscopy, detecting ROS expression, and detecting cell sensitivity to drugs by CCK8 assay. The interaction between CEBPG and SLC7A11 was confirmed by CUT&Tag and dual luciferase reporter assays.

Results
A significantly higher expression level of CEBPG in OC when compared with benign tissues of ovary, and that high CEBPG expression level was also tightly associated with poor prognosis of patients diagnosed with OC, as determined by analysis of datasets and patient samples. Conversely, knockdown of CEBPG inhibited OC progression using experiments of OC cell lines and in vivo orthotopic OC-bearing mouse model. Importantly, CEBPG was identified as a new participator mediating ferroptosis evasion in OC cells using RNA-sequencing, which could contribute to OC progression. The CUT&Tag and dua luciferase reporter assays further revealed the inner mechanism that CEBPG regulated OC cell ferroptosis through transcriptional control of SLC7A11.

Conclusions
Our findings established CEBPG as a novel transcriptional regulator of OC ferroptosis, with potential value in predicting clinical outcomes and as a therapeutic candidate.
Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer’s disease patients
Authors: Bayraktar Abdulahad , Li Xiangyu , Kim Woonghee , Zhang Cheng , Turkez Hasan , Shoaie Saeed , Mardinoglu Adil 
Published: May 2023

Abstract
Background
Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer’s patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer’s studies.

Methods
Here, we investigated central co-expressed genes upregulated in Alzheimer’s disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene’s estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved.

Results
We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood–brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool.

Conclusions
This study method effectively identified an Alzheimer’s disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer’s disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer’s patients.
Pathological hemodynamic changes and leukocyte transmigration disrupt the blood–spinal cord barrier after spinal cord injury
Authors: Zhou Rubing , Li Junzhao , Chen Zhengyang , Wang Ruideng , Shen Yin , Zhang Rong , Zhou Fang , Zhang Yong 
Published: May 2023

Abstract
Background
Blood–spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking.

Methods
A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption.

Results
Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration.

Conclusions
Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI.
A qualitative investigation into pregnancy experiences and maternal healthcare utilisation among adolescent mothers in Nigeria
Authors: Alex-Ojei Christiana A. , Odimegwu Clifford O. , Ntoimo Lorretta F. C. 
Published: May 2023

Abstract
Background
Adolescent maternal healthcare utilisation is low in Nigeria, and little is understood about the pregnancy experiences and drivers of maternal healthcare utilisation among of adolescent girls. This study investigated the pregnancy experiences and maternal healthcare utilisation among adolescent mothers across Nigeria.

Methods
The study used the qualitative design. Urban and rural communities in Ondo, Imo and Katsina states were selected as research sites. Fifty-five in-depth interviews were conducted with adolescent girls who were currently pregnant or had given birth to a child recently, and nineteen in-depth interviews were conducted with older women who were either mothers or guardians of adolescent mothers. Additionally, key informant interviews were conducted with five female community leaders and six senior health workers. The interviews were transcribed, and resulting textual data were analysed via framework thematic analysis using a semantic and deductive approach, with the aid of NVivo software.

Results
The findings showed that the majority of unmarried participants had unintended pregnancies and stigma against pregnant adolescents was common. Social and financial support from family members, maternal support and influence, as well as healthcare preferences shaped by cultural and religious norms were the major drivers of maternal healthcare use among adolescent mothers, and the choice of their healthcare providers.

Conclusions
Interventions to support adolescent mothers and increase maternal healthcare utilisation among them must focus on ensuring the provision of social and financial support for adolescent mothers, and should be culturally sensitive.
Eggsplorer: a rapid plant–insect resistance determination tool using an automated whitefly egg quantification algorithm
Authors: Devi Micha Gracianna , Rustia Dan Jeric Arcega , Braat Lize , Swinkels Kas , Espinosa Federico Fornaguera , van Marrewijk Bart M. , Hemming Jochen , Caarls Lotte 
Published: May 2023

Abstract
Background
A well-known method for evaluating plant resistance to insects is by measuring insect reproduction or oviposition. Whiteflies are vectors of economically important viral diseases and are, therefore, widely studied. In a common experiment, whiteflies are placed on plants using clip-on-cages, where they can lay hundreds of eggs on susceptible plants in a few days. When quantifying whitefly eggs, most researchers perform manual eye measurements using a stereomicroscope. Compared to other insect eggs, whitefly eggs are many and very tiny, usually 0.2 mm in length and 0.08 mm in width; therefore, this process takes a lot of time and effort with and without prior expert knowledge. Plant insect resistance experiments require multiple replicates from different plant accessions; therefore, an automated and rapid method for quantifying insect eggs can save time and human resources.

Results
In this work, a novel automated tool for fast quantification of whitefly eggs is presented to accelerate the determination of plant insect resistance and susceptibility. Leaf images with whitefly eggs were collected from a commercial microscope and a custom-built imaging system. A deep learning-based object detection model was trained using the collected images. The model was incorporated into an automated whitefly egg quantification algorithm, deployed in a web-based application called Eggsplorer. Upon evaluation on a testing dataset, the algorithm was able to achieve a counting accuracy as high as 0.94, r2 of 0.99, and a counting error of ± 3 eggs relative to the actual number of eggs counted by eye. The automatically collected counting results were used to determine the resistance and susceptibility of several plant accessions and were found to yield significantly comparable results as when using the manually collected counts for analysis.

Conclusion
This is the first work that presents a comprehensive step-by-step method for fast determination of plant insect resistance and susceptibility with the assistance of an automated quantification tool.
Chronic psychological stress promotes breast cancer pre-metastatic niche formation by mobilizing splenic MDSCs via TAM/CXCL1 signaling
Authors: Zheng Yifeng , Wang Neng , Wang Shengqi , Zhang Juping , Yang Bowen , Wang Zhiyu 
Published: May 2023

Abstract
Background

Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown.

Methods
The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8+ T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2+/+ MDSCs facilitating PMN formation under CUMS.

Results
CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8+ T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2−/−MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis.

Conclusion
Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2.

Graphical Abstract