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摘要： 鼻眶血管瘤是一种常见的成人良性眶内病变，复发性病例在传统手术治疗后仍面临较高的复发风险及并发症。本报告介绍了一例21岁男性患者，先后接受多次手术治疗后血管瘤复发，且伴随严重鼻出血，手术已无法进一步控制病情。采用抗血管生成药物贝伐单抗进行非手术治疗，显著缩小了肿瘤，并有效控制了症状。经过两年的随访观察，患者肿瘤未出现复发，且无严重不良反应。本案例表明，贝伐单抗可作为复发性鼻眶血管瘤的一种安全且有效的非手术治疗选择，为该类难治性血管瘤的治疗给予了新的方向。

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摘要

背景: 本研究旨在揭示DNA拓扑异构酶IIα（TOP2A）在视网膜母细胞瘤（RB）中的关键作用，重点关注其对上皮-间质转化（EMT）的调控机制，并探讨TOP2A抑制作为潜在治疗策略的临床应用价值。

方法: 顺利获得分析公共基因表达数据库（GSE97508、GSE110811和GSE172170）中的RB组织数据，我们评估了TOP2A的表达水平。随后，在人RB细胞系（Y79和WERI-Rb-1）中，顺利获得敲低或过表达TOP2A进行功能实验，检测其对细胞增殖、迁移、侵袭能力的影响，并利用RT-PCR和Western blot技术分析EMT标志物的表达变化。此外，我们在皮下移植瘤和肝转移小鼠模型中进一步验证了TOP2A调控对肿瘤生长和转移的抑制作用。

结果: RB组织中TOP2A的表达显著上调（p < 0.0001）。体外实验表明，敲低TOP2A可显著抑制RB细胞的增殖、迁移和侵袭能力，并逆转EMT标志物的表达（p < 0.05）；而TOP2A过表达则促进了这些致癌过程。在体内实验中，敲低或抑制TOP2A显著减缓了皮下移植瘤和肝转移模型的肿瘤生长及转移（p < 0.05）。值得注意的是，TOP2A抑制剂与EMT抑制剂的联合治疗表现出协同抗肿瘤效应，显著降低了肿瘤负荷和转移病灶的数量（p < 0.01）。

结论: TOP2A在RB的发病机制和进展中扮演了核心角色，其顺利获得调控EMT促进了肿瘤的恶性表型。抑制TOP2A不仅能够有效抑制RB细胞的增殖和转移，还可逆转EMT过程，从而为RB的治疗给予了新的靶点。本研究为开发靶向TOP2A的治疗策略奠定了重要理论基础，并为后续临床转化研究给予了科学依据。

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Purpose: Chronic suppurative otitis media (CSOM) is a prominent contributor to preventable hearing loss globally. Probiotic therapy has attracted research interest in human infectious and inflammatory disease. As the most prevalent probiotic, the role of Lactobacillus in CSOM remains poorly defined. This study aimed to investigate the antipathogenic effects and underlying mechanism of Lactobacillus on CSOM.

Methods: RNA sequencing of granulation of middle ear cavity from CSOM patients and lavage fluid of middle ear from normal volunteer was conducted. Human middle ear epithelial cells (HMEEC) and rats infected with Bacillus cereus (B. cereus) and Staphylococcus aureus (S. aureus) were used for CSOM constructing. Western blot, qPCR and Vybrant™ Alexa Fluor™ 488 lipid raft labeling were performed to explore the possible molecular mechanism by which lipid raft linker (RFTN1) regulates lipid raft/toll-like receptor 4 (TLR4). ELISA and HE staining was utilized to evaluate the effect of Lactobacillus on the progression of CSOM in vivo.

Results: Based on RNA Sequence analysis, a total of 3646 differentially expressed genes (1620 up-regulated and 2026 down-regulated) were identified in CSOM. RFTN1 was highly expressed in CSOM. Inhibition of RFTN1 not only reduced the inflammatory response of CSOM but also suppressed the formation of lipid rafts. Further investigation revealed that RFTN1 inhibition could reduce the expression of TLR4, which also localizes to the lipid rafts. TLR4 responds to RFTN1-mediated inflammatory responses in CSOM. We treated the CSOM model with Lactobacillus, which has great potential for alleviating the inflammatory response, and found that Lactobacillus attenuated the development of CSOM by reducing RFTN1 and TLR4 expression.

Conclusion: In conclusion, these findings suggest a crucial role for Lactobacillus in alleviating CSOM progression and uncovered the molecular mechanism involving Lactobacillus-regulated inhibition of the RFTN1-lipid raft-TLR4 signaling pathway under CSOM conditions.

Keywords: CSOM, Lactobacillus, RFTN1, TLR4, S. aureus, B. cereus

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Abstract: Aflatoxin contamination poses a significant challenge to global food safety, public health, and agricultural sustainability. Traditional methods for mitigating aflatoxins, such as chemical and physical detoxification techniques, often raise concerns about environmental harm, nutrient loss, and potential toxicity. In contrast, green-synthesized nanomaterials have emerged as an environmentally friendly and effective solution for controlling aflatoxins. This study explores the potential of green-synthesized nanomaterials for aflatoxin mitigation, focusing on their mechanisms of action, effectiveness, and long-term applicability in agricultural and food safety contexts. A comprehensive review of 116 articles on the latest developments in green nanotechnology was used, focusing on the creation, characterization, and application of nanoparticles, including silver, zinc oxide, titanium dioxide, and iron-based nanomaterials. Green nanoparticles reduce aflatoxin load primarily through their antioxidant properties, which neutralize oxidative stress, and their high adsorption capacity, which binds aflatoxins and reduces their bioavailability. Photocatalytic degradation, adsorption, and enzymatic detoxification were also evaluated. The results indicate that green-synthesized nanoparticles exhibit high efficacy, biocompatibility, and minimal environmental impact, especially when compared to traditional detoxification methods. However, challenges such as nanoparticle stability, large-scale production, regulatory issues, and potential long-term toxicity still require further investigation. To advance this field, future studies should focus on refining green synthesis processes, enhancing nanoparticle stability, and exploring the integration of nanotechnology with biosensors and smart packaging for real-time aflatoxin monitoring. By advancing these sustainable technologies, this research aims to contribute to the development of effective and safe methods for aflatoxin mitigation, thereby supporting global food security, public health, and environmental sustainability.

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Abstract: This mini-review paper gives a brief summary of recent works in the development of bimetallic core@shell nanoparticles composed of nickel (as a core) and a silver shell (Ni@Ag NPs). We present the methods of Ni@Ag NPs synthesis, ink preparation, and their coatings formation. We also place emphasis on the selection and optimization of the sintering process of materials based on Ni@Ag NPs. Finally, the challenges in the application of Ni@Ag NPs in printed conductive structures are presented.

Keywords: nickel@silver core@shell nanoparticles, conductive inks, sintering methods, conductive coatings, printed electronics

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Purpose: The study aimed to investigate in vitro anti-aging activities of 29 Dendrobium spp. and develop and characterize microemulsions (MEs) for topical application.

Methods: Antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), H2O2 scavenging, and ferric reducing antioxidant power (FRAP) assays. The anti-collagenase (MMP-1 and MMP-2) and anti-elastase activities were also evaluated. Cytotoxicity and human intracellular reactive oxygen species (ROS) levels were determined using resazurin reduction and 2′,7′-dichlorofluorescin diacetate (DCFDA) assays, respectively. D. kentrophyllum extract-loaded microemulsion (DKME) was then prepared and optimized. The stability of DKME was studied using a heating-cooling cycle.

Results: D. kentrophyllum appeared to be the best candidate anti-aging agent because of its antioxidant, anti-collagenase, and anti-elastase activities. The extract was safe for human skin cells at a concentration of 6.25– 100 μg/mL. It also decreased the intracellular ROS-induced ultraviolet B (UVB) irradiation compared to that in the control. DKME comprising Tween 80:ethanol (5:1), water, and isononyl isononanoate showed a suitable appearance, droplet size, polydisperse index, zeta potential, pH, and viscosity. This formulation demonstrated desirable physical and chemical stability, with non-cytotoxic effects.

Conclusion: DKME is considered a promising anti-aging product. However, an in vivo study of this optimized formulation might be evaluated in further study for anti-aging purposes.

Keywords: reactive oxygen species, anti-aging activities, Dendrobium kentrophyllum, microemulsion

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Background: Conradi–Hünermann–Happle syndrome (CDPX2, OMIM 302960) is an X-linked dominant inherited disorder caused by variants in the EBP gene, which primarily affects the skin, bones, and eyes.

Objective: To describe the clinical manifestations and genetic mutation in a 7-year-old girl presenting with severe scoliosis, hydronephrosis, and other skeletal abnormalities.

Methods: The patient's medical history was collected from birth. Exome sequencing was performed to identify candidate genes, and the detected variant was confirmed by Sanger sequencing.

Results: Exome sequencing revealed a de novo EBP mutation (c.452A>G, p.Gln151Arg) in the patient.

Conclusion: The patient was diagnosed with X-linked chondrodysplasia punctata type 2 (CDPX2). This novel missense mutation expands the mutation spectrum of CDPX2 and underscores the clinical utility of exome sequencing in diagnosing this condition.

Keywords: EBP, c.452A>G, p.Gln151Arg, exome sequencing, CDPX2

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Objective: We evaluate whether next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) improves the cumulative pregnancy outcomes of patients with unexplained recurrent implantation failure (uRIF) as compared to conventional in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI).

Patients and Methods: This was a retrospective cohort study (2015– 2022). A total of 705 couples diagnosed with uRIF were included in the study. 229 women transferred blastocysts based on morphological grading (IVF/ICSI) and 476 couples opted for PGT-A to screen blastocysts by NGS. Women were further stratified according to age at retrieval (< 38 years and ≥ 38 years). The primary outcome was the cumulative live-birth rate after all the embryos were transferred in a single oocyte retrieval or until achieving a live birth. Confounders were adjusted using binary logistic regression models.

Results: Cumulative live-birth rate was similar between the IVF/ICSI group and the PGT-A group after stratified by age: IVF/ICSI vs PGT-A in the < 38 years subgroup (49.7% vs 57.7%, adjusted OR (95% CI) = 1.25 (0.84– 1.84), P = 0.270) and in the ≥ 38 years subgroup (14.0% vs 19.5%, adjusted OR (95% CI) = 1.09 (0.41– 2.92), P = 0.866), respectively. Nonetheless, the PGT group had a lower first-time biochemical pregnancy loss rate (17.0% vs 8.7%, P = 0.034) and a higher cumulative good birth outcome rate (35.2% vs 46.4%, P = 0.014) than the IVF/ICSI group in the < 38 years subgroup. Other pregnancy outcomes after the initial embryo transfer and multiple transfers following a single oocyte retrieval were all similar between groups.

Conclusion: Our results showed no evidence of favorable effects of PGT-A treatment on improving the cumulative live birth rate in uRIF couples regardless of maternal age. Use of PGT-A in the < 38 years uRIF patients would help to decrease the first-time biochemical pregnancy loss and increase the cumulative good birth outcome.

Keywords: preimplantation genetic testing for aneuploidy, unexplained recurrent implantation failure, cumulative live-birth rate, cumulative good birth outcome

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Background: Congenital sucrase isomaltase deficiency (CSID) is in general a very rare disease. However, 2– 3% of the Greenlandic population are homozygous (HO) carriers of an Arctic-specific loss-of-function (LoF) variant in the sucrase-isomaltase (SI) encoding gene, causing CSID. The condition is characterized by gastrointestinal symptoms such as stomachache, diarrhea, and weight loss when consuming sucrose, the most common dietary sugar. However, the awareness of the condition in the population and the healthcare system seems to be limited, potentially leading to a higher healthcare burden. Hence, we aimed to investigate whether HO-carriers visit the healthcare system more with gastrointestinal symptoms compared to the control groups by using registry data.

Methods: We performed a case–control study identifying cases and controls using genotype information from the 1999– 2001 and 2005– 2010 Greenlandic health population cohorts. The cases were defined as HO LoF SI-carriers and controls were defined as non-carriers and were matched (1:1) on sex, age, place of residence, and European genetic admixture. We used electronic medical records to assess the number of electronic medical record contacts (EMRc) related to gastrointestinal symptoms and the number of gastrointestinal-related diagnostic procedures.

Results: A total of 80 HO-carriers and 80 non-carriers were included. The HO-carriers had 19% more EMRc related to gastrointestinal symptoms (IRR, 1.19, 95% CI [1.02;1.40], p=0.02) and had a 41% higher incidence of gastrointestinal related diagnostic procedures compared to controls (IRR, 1.41, 95% CI [1.05– 1.92], p=0.02). Only one HO-carrier was aware of the condition according to the electronic medical records.

Conclusion: HO-carriers of the LoF SI-variant had both significantly more gastrointestinal-related EMRc and significantly more diagnostic procedures conducted due to gastrointestinal symptoms. Only one HO-carrier was aware of the condition. Given the high prevalence of HO-carriers in the Greenlandic population, we anticipate that diagnosing more patients with CSID and providing dietary advice could potentially reduce symptom burden and healthcare visits among HO-carriers.

Keywords: Inuit, genetic metabolism, sucrase-isomaltase, Greenland, congenital sucrase-isomaltase deficiency, loss-of-function variant

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Purpose: This study aimed to screen potential drug candidates from the flavonoids of the genus Erythrina for the Corona Virus Disease 2019 (COVID-19) treatment.

Patients and Methods: A comprehensive screening was conducted on the structures of 473 flavonoids derived from the genus Erythrina, focusing on their potential toxicity and pharmacokinetic profiles. Subsequently, flavonoids that were non-toxic and possessed favorable pharmacokinetic properties underwent further analysis to explore their interactions with the angiotensin-converting enzyme 2 (ACE2) receptor, employing molecular docking and molecular dynamics simulations.

Results: Among 473 flavonoids, 104 were predicted to be safe from being mutagenic, hepatotoxic, and inhibitors of the human ether-a-go-go-related gene (hERG). Among these 104 flavonoids, 18 compounds were predicted not to be substrates of P-glycoprotein (P-gp). Among these 18 flavonoids, gangetinin ( 471) and erybraedin D ( 310) exhibit low binding affinities and root mean square deviation (RMSD) values, indicating stable binding to the ACE2 receptor. The physicochemical attributes of compounds 310 and 471 suggest that they possess drug-like properties.

Conclusion: Gangetinin ( 471) and erybraedin D ( 310) may serve as promising candidates for COVID-19 treatment due to their potential to inhibit the ACE2-RBD interaction. This warrants further investigation into their inhibitory effects on ACE2-RBD binding through in vitro experiments.

Keywords: structure-based virtual screening, Erythrina, flavonoids, angiotensin-converting enzyme 2, corona virus disease 2019

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Introduction: Amorphous drug dispersion is frequently used to enhance the solubility and dissolution of poorly water-soluble drugs, thereby improving their oral bioavailability. The dispersion of these drugs into polymer matrix can inhibit their recrystallization. The inter-molecular interactions between drug and polymer plays a role in the improvement of the dissolution rate, solubility, and physical stability of drug.

Aim: This study aims to investigate the formation and interactions of ritonavir (RTV)/poloxamer (PLX) amorphous formulation using a computational approach via molecular dynamics (MD) simulations, which mimicked solvent evaporation and melt-quenching method.

Methods: TheRoot Mean Square Deviation (RMSD) value, Root Mean Square Fluctuation (RMSF), Radial Distribution Function (RDF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and hydrogen bond interactions were analyzed to determine interaction mechanisms between RTV and PLX in amorphous solid dispersion.

Results: The pi-alkyl bonds between RTV and PLX were formed after simulations of solvent evaporation, while the hydrogen bond interactions of RTV-PLX was observed during melt method simulations. These results indicate the successful formulation of amorphous solid dispersion (ASD) from RTV and PLX. The RMSD values obtained from the solvent evaporation, melt-cooling-A, melt-cooling-B, and melt-cooling-C methods were 3.33 Å, 1.97 Å, 1.30 Å, and 1.29 Å, respectively, while the average RMSF values were 2.65 Å, 1.04 Å, 1.05 Å, and 1.07 Å, respectively. This indicates that the suppression of translational motion of RTV from the melt method can be stronger than solvent evaporation caused by the intermolecular interactions of RTV-PLX.

Conclusion: MD simulations helped in understanding the formation and interaction mechanisms of ASD formulations that were difficult to detect by experimental approaches.

Keywords: amorphous solid dispersion, molecular interaction, molecular dynamics simulations, ritonavir, poloxamer

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Abstract: The mammalian oocyte is pivotal in reproductive biology, acting as a central hub for cellular reprogramming and stemness. It uniquely contributes half of the zygotic nuclear genome and the entirety of the mitochondrial genome, ensuring individual development and health. Oocyte-mediated reprogramming, exemplified by nuclear transfer, resets somatic cell identity to achieve pluripotency and has transformative potential in regenerative medicine. This process is critical for understanding cellular differentiation, improving assisted reproductive technologies, and advancing cloning and stem cell research. During fertilization, the maternal-zygotic transition shifts developmental control from maternal factors to zygotic genome activation, establishing totipotency. Oocytes also harbor reprogramming factors that guide nuclear remodeling, epigenetic modifications, and metabolic reprogramming, enabling early embryogenesis. Structures like mitochondria, lipid droplets, and cytoplasmic lattices contribute to energy production, molecular regulation, and cellular organization. Recent insights into oocyte components, such as ooplasmic nanovesicles and endolysosomal vesicular assemblies (ELVAS), highlight their roles in maintaining cellular homeostasis, protein synthesis, and reprogramming efficiency. By unraveling the reprogramming mechanisms inherent in oocytes, we advance our understanding of cloning, cell differentiation, and stem cell therapy, highlighting their valuable significance in developmental biology and regenerative medicine.

Keywords: reprogramming, oocytes, genome activation, epigenetics

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Objective: Chronic wounds are a common clinical problem that necessitate the exploration of novel regenerative therapies. We report a method to investigate the in vitro wound healing capacity of an innovative biomaterial, which is based on amniotic membrane-derived stem cells (AMSCs) embedded in an alginate hydrogel matrix. The aim of this study was to prepare an sodium alginate-based hydrogel, cross-linked calcium chloride (CaCl2) with the active ingredient AMSC (AMSC/Alg-H) and to evaluate its in vitro effectiveness for wound closure.

Methods: This hydrogel preparation involved combining sterile solutions of AMSC, sodium alginate, and CaCl2, followed by rinsing with serum-free media. The cells were cultured in different 6-well plates, namely sodium alginate, calcium chloride, AMSC, Alg-H, and AMSC/Alg-H, in complete medium with 10% FBS. The hydrogel was successfully formulated, as confirmed by characterization techniques including Scanning Electron Microscopy (SEM), Fourier Transform Infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), Cytotoxicity Studies, TGF-β 1 Level Measurement by ELISA, and Cell Scratch Wound Assay.

Results: Cryo-EM characterization of the Alg-H preparation successfully demonstrated the encapsulation of MSCs. FTIR and DSC analyses indicate that crosslinking transpires in Alg-H encapsulating AMSC. The AMSC/Alg-H preparation showed no significant difference in toxicity compared to HaCaT cells (p < 0.05), indicating it was not toxic to HaCaT cells. Furthermore, in the scratch wound assay test at 24 hours, the AMSC/Alg-H preparation achieved 100% wound closure, outperforming both AMSC and Alg-H alone. In vitro assessment revealed that AMSC/Alg-H significantly enhanced key wound healing processes, including cell proliferation and migration, compared to Alg-H.

Conclusion: Our study demonstrated the promising potential of AMSC/Alg-H as an enhanced regenerative therapy for in vitro wound healing. AMSC/Alg-H was able to maintain the viability of AMSCs and facilitate the formation of tissue-like structures.

Keywords: AMSC, alginate, hydrogel, wound healing

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