bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic Resonance Enterography Reinvented: Exploring the Potential of a New Natural Beverage as an Alternative to Polyethylene Glycol Solution
Authors: Renzulli Matteo , Cocozza Maria Adriana , Biselli Maurizio , Cattabriga Arrigo , Brandi Nicolò , Giannone Ferdinando Antonino , Storchi Marco , Gionchetti Paolo , Poggioli Gilberto , Laureti Silvio , Golfieri Rita , Cappelli Alberta
Published: August 2023

The aim of the present study was to test a new oral contrast medium composed of natural components for the magnetic resonance (MR) imaging of small bowel diseases. Between January 2018 and June 2019, 35 patients affected by ileocolic Crohn’s disease (CD) were enrolled in the present study. Each patient underwent two sequential MR enterographies, first with the standard polyethylene glycol (PEG) water solution and, after 3 weeks, with the new natural beverage designed by our team. At the end of the administration of each oral contrast, a satisfaction survey was given to the patients to assess the palatability of both beverages. The intestinal distention and the quality of images were evaluated by two expert radiologists for both studies and the interreader agreement was calculated. According to the satisfaction questionnaire, 97.1% of patients expressed positive judgments regarding the natural beverage (71.4% very good and 25.7% good) whereas only 8.6% of them appreciated the PEG water solution (8.6% good) (p = 0.0001). The degree of intestinal distention was excellent and good in 97.1% of patients after the administration of PEG and in 94.3% of the patients after the administration of the natural beverage, without significant differences between the two products and with almost perfect (k = 0.821) and substantial (k = 0.754) inter-observer variability, respectively. No statistical differences were observed between the two expert radiologists regarding the evaluation of the imaging quality; in particular, they were considered good and excellent in 100% of patients after the administration of PEG water solution and in 97.2% of those who took the natural beverage, with substantial (k = 0.618) and almost perfect (k = 0.858) inter-observer variability, respectively. The new natural beverage demonstrated the same intestinal distension and excellent image quality compared to the synthetic standard oral contrast administered during MRE for small bowel diseases, proving to be a valid alternative with better palatability.
Genetic Association between Inflammatory-Related Polymorphism in STAT3, IL-1β, IL-6, TNF-α and Idiopathic Recurrent Implantation Failure
Authors: Kwon Min Jung , Kim Ji Hyang , Kim Kyu Jae , Ko Eun Ju , Lee Jeong Yong , Ryu Chang Su , Ha Yong Hyun , Kim Young Ran , Kim Nam Keun
Published: August 2023

Recurrent implantation failure (RIF) is defined as a failure to achieve pregnancy after multiple embryo transfers. Implantation is closely related to inflammatory gradients, and interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) play a key role in maternal and trophoblast inflammation during implantation. Signal transducer and activator of transcription 3 (STAT3) interacts with cytokines and plays a critical role in implantation through involvement in the inflammation of the embryo and placenta. Therefore, we investigated 151 RIF patients and 321 healthy controls in Korea and analyzed the association between the polymorphisms (STAT3 rs1053004, IL-1β rs16944, IL-6 rs1800796, and TNF-α rs1800629, 1800630) and RIF prevalence. In this paper, we identified that STAT3 rs1053004 (AG, adjusted odds rate [AOR] = 0.623; p = 0.027; GG, AOR = 0.513; p = 0.043; Dominant, AOR = 0.601, p = 0.011), IL-6 rs1800796 (GG, AOR = 2.472; p = 0.032; Recessive, AOR = 2.374, p = 0.037), and TNF-α rs1800629 (GA, AOR = 2.127, p = 0.010, Dominant, AOR = 2.198, p = 0.007) have a significant association with RIF prevalence. This study is the first to investigate the association of each polymorphism with RIF prevalence in Korea and to compare their effect based on their function on inflammation.
Preserving Colour Fidelity in Photogrammetry—An Empirically Grounded Study and Workflow for Cultural Heritage Preservation
Authors: Barbero-Álvarez Miguel Antonio , Brenner Simon , Sablatnig Robert , Menéndez José Manuel
Published: August 2023

In this paper, a study is performed in order to achieve a process that successfully respects the colour integrity of photogrammetry models of cultural heritage pieces. As a crucial characteristic of cultural heritage documentation, the colour of the pieces—as a valuable source of information—needs to be properly handled and preserved, since digital tools may induce variations in its values, or lose them to a degree. Different conditions for image acquisition schemes, RGB value calculation, calibration and photogrammetry have been combined and the results measured, so the adequate procedure is found. Control over all colour transformations is enforced, with blending operations during the texture generation process being the only unpredictable step in the pipeline. It is demonstrated that an excellent degree of colour information preservation can be achieved when applying said control on the factors of acquisition and colour digitalization, inclusive deciding their parameters. This paper aims to serve as guidelines of a correct handling of colour information and workflow so cultural heritage documentation can be performed with the highest degree of colour fidelity, covering the gap of non-existing standard procedure or conditions to perform an optimum digital cultural heritage colour modelling.
Proteomics Research Reveals the Molecular Mechanism by Which Grape Seed Oil Inhibits Tuber Sprouting in Potato
Authors: Lyu Chengcheng , Zhang Xing , Li Xiang , Lu Yifei , Yuan Jichao , Lu Liming , Wang Qiang , Wang Xiyao , Li Liqin
Published: August 2023

Potato tubers are rich in starch, vitamins, protein, minerals, and other nutrients. However, tuber sprouting produces solanine and reduces the commodity value of potatoes during storage. At present, it is known that some plant essential oils can inhibit tuber sprouting. It has been reported that grape seed oil (GSO) has antioxidant, anti-inflammatory, and anticancer characteristics, reducing blood lipids and delaying aging. In this study, we found for the first time that GSO delayed tuber sprouting, and the soluble sugar content and peroxidase activity changed after 60 days of GSO treatment. Furthermore, a comparative proteomic analysis of tuber bud eyes showed that after 30 days of GSO treatment, there were 206 and 129 differentially abundant proteins (DAPs) with increased and decreased abundance levels, respectively. After analysis, we found that 15 ROS-related proteins and 14 proteins involved in energy metabolism were DAPs. Among them, gamma aminobutyrate transaminase 1 had decreased abundance after GSO treatment. Meanwhile, the transcription level of genes related to GABA synthesis increased significantly according to qRT-PCR analysis. Our results provide new approaches to the proteomic mechanism of potato sprouting after GSO treatment and provide a theoretical basis for the application of GSO in inhibiting potato seed sprouts.
The Relationship between Socio-Demographic Factors, Preventive Health Behaviors and Acceptance of COVID-19 Vaccine among Israeli Pregnant Women during the Coronavirus Pandemic
Authors: Nahum Shir , Kushnir Talma
Published: August 2023

Background: The outbreak of the Coronavirus disease led the World Health Organization to publish recommendations regarding preventive health behaviors (PHB). Pregnant women are at a higher risk of severe COVID-19 infection and adherence to these recommendations is critical. There are little data regarding PHB among pregnant women. The current study aims to evaluate the contribution of socio-demographic factors and COVID-19 vaccinations in predicting PHB among pregnant women. Method: 202 pregnant Israeli women (mean age = 30.8 years) participated in an online survey in 2021. Results: 88% of the women were vaccinated and few had been infected. Of the women, 75.2% reported wearing face masks in closed spaces, while 12.4% reported wearing masks outdoors; 63.9% of the women did not travel abroad for fear of infection by the virus and 51% avoided crowded events. A simultaneous regression analysis to predict PHB indicated that pregnancy week and Coronavirus vaccination significantly and positively predicted PHB, but religious status was a negative predictor. Age, number of children, and level of education were not associated with PHB. Conclusions: These findings can be helpful as a preliminary evidence base for policy-making at present and for future epidemics regarding guidelines on PHB adjusted for pregnant women.
Italian Validation of the Delaying Gratification Inventory in Adolescents
Authors: Liang Ziqin , Delvecchio Elisa , Lis Adriana , Mazzeschi Claudia
Published: August 2023

The delay of gratification (DoG) is defined as the willingness to forego immediate satisfaction to achieve greater long-term gratification. This ability is essential in adolescence, as its development is crucial against desirable versus undesirable behaviors. This study investigated the psychometric proprieties of the Delaying Gratification Inventory (DGI) in Italian adolescents. A total of 621 Italian adolescents, ranging from 14 to 17 years old (M = 15.92, SD = 1.05; 47.7% boys), participated in the study. Confirmatory factor analysis identified a four-factor structure (delay of gratification concerning Food, Social Interaction, Money, and Achievement). The reliability of the Italian DGI was acceptable. Measurement invariance across gender was supported. Boys reached a higher DoG score in the Food subscale and a lower score in the Social Interaction and Achievement subscales than girls. Moreover, the Italian DGI dimensions were all positively correlated with self-control and prosocial behavior. Except for the Social Interaction subscale, positive correlations were found between the Food, Money, and Achievement subscales and self-esteem. The present findings suggest that the Italian DGI could be used for assessing DoG ability, a key regulatory ability that promotes healthy behaviors in adolescence.
Implementation of the World Health Organization Age-Friendly Principles: A Case Study from Portugal
Authors: Tavares Jéssica , Santinha Gonçalo , Rocha Nelson Pacheco
Published: August 2023

Demographic ageing has emphasized the need to adapt current healthcare systems to the comorbidity profile of older adults. In 2004, the World Health Organization (WHO) developed the Age-Friendly Principles, but the approach to their implementation in the health systems still remains uncertain. This article intends to address this gap by assessing how the Principles are perceived and implemented in the Portuguese National Health Service (NHS), where this topic has recently been placed on the political agenda. A questionnaire survey was administered to primary care directors and hospital administrators, covering a total of 173 health units. Findings show that most respondents are unaware of the WHO Principles (71%) and do not identify the current organizational structure of care as a problem for the provision of care (80%). However, the implementation of the WHO Principles is lower than desired, especially regarding professional training and the management system (50% and 28% of the criteria are implemented, respectively). These criteria defined by the WHO are implemented in a reduced number of health units, as opposed to the physical environment where implementation is more widespread (64%). Accordingly, further dissemination and implementation support in the national territory are needed in order to improve the health outcomes of older adults and increase the performance of health units.
Site Selection Prediction for Coffee Shops Based on Multi-Source Space Data Using Machine Learning Techniques
Authors: Zhao Jiaqi , Zong Baiyi , Wu Ling
Published: August 2023

Based on a study of the spatial distribution of coffee shops in the main urban area of Beijing, the main influencing factors were selected based on the multi-source space data. Subsequently, three regression models were compared, and the best site selection model was found. A comparison was performed between the prediction model functioning with a buffer and without one, and the accuracy of the location model was verified by comparing the actual change trend and the predicted trend in two years. The following conclusions were obtained: (1) coffee shops in the main urban area of Beijing are clustered in an area within 12 km of the main urban center, and also around the core commercial agglomeration area; (2) the random forest (RF) model is the best model in this study, and the accuracy values before and after buffer analysis were 0.915 and 0.929, respectively; and (3) after verifying the accuracy of the model through two years of data, we recommend the establishment of a main road buffer zone for site selection, and the success rate of site selection was found to reach 72.97%. This study provides crucial insight for coffee shop prediction model selection and potential store location selection, which is significant to improving the layout of leisure spaces and promoting economic development.
Honey Bee Larval Hemolymph as a Source of Key Nutrients and Proteins Offers a Promising Medium for Varroa destructor Artificial Rearing
Authors: Piou Vincent , Vilarem Caroline , Blanchard Solène , Strub Jean-Marc , Bertile Fabrice , Bocquet Michel , Arafah Karim , Bulet Philippe , Vétillard Angélique
Published: August 2023

Varroa destructor, a major ectoparasite of the Western honey bee Apis mellifera, is a widespread pest that damages colonies in the Northern Hemisphere. Throughout their lifecycle, V. destructor females feed on almost every developmental stage of their host, from the last larval instar to the adult. The parasite is thought to feed on hemolymph and fat body, although its exact diet and nutritional requirements are poorly known. Using artificial Parafilm™ dummies, we explored the nutrition of V. destructor females and assessed their survival when fed on hemolymph from bee larvae, pupae, or adults. We compared the results with mites fed on synthetic solutions or filtered larval hemolymph. The results showed that the parasites could survive for several days or weeks on different diets. Bee larval hemolymph yielded the highest survival rates, and filtered larval plasma was sufficient to maintain the mites for 14 days or more. This cell-free solution therefore theoretically contains all the necessary nutrients for mite survival. Because some bee proteins are known to be hijacked without being digested by the parasite, we decided to run a proteomic analysis of larval honey bee plasma to highlight the most common proteins in our samples. A list of 54 proteins was compiled, including several energy metabolism proteins such as Vitellogenin, Hexamerin, or Transferrins. These molecules represent key nutrient candidates that could be crucial for V. destructor survival.
Arabidopsis NF–YC7 Interacts with CRY2 and PIF4/5 to Repress Blue Light-Inhibited Hypocotyl Elongation
Authors: Wang Wei , Gao Lin , Zhao Tianliang , Chen Jiamei , Chen Ting , Lin Wenxiong
Published: August 2023

Light is an important environmental factor. Plants adapt to their light environment by developing the optimal phenotypes. Light-mediated hypocotyl growth is an ideal phenotype for studying how plants respond to light. Thus far, many signaling components in light-mediated hypocotyl growth have been reported. Here, we focused on identifying the transcription factors (TFs) involved in blue light-mediated hypocotyl growth. We analyzed the blue-light-mediated hypocotyl lengths of Arabidopsis TF–overexpressing lines and identified three NF–YC proteins, NF–YC7, NF–YC5, and NF–YC8 (NF–YCs being the short name), as the negative regulators in blue light-inhibited hypocotyl elongation. NF–YC–overexpressing lines developed longer hypocotyls than those of the wild type under blue light, while the deficient mutants nf–yc5nf–yc7 and nf–yc7nf–yc8 failed to exhibit hypocotyl elongation under blue light. NF–YCs physically interacted with CRY2 (cryptochrome 2) and PIF4/5 (phytochrome interacting factor 4 or 5), while the NF–YCs–PIF4/5 interactions were repressed by CRY2. Moreover, the overexpression of CRY2 or deficiency of PIF4/5 repressed NF–YC7–induced hypocotyl elongation under blue light. Further investigation revealed that NF–YC7 may increase CRY2 degradation and regulate PIF4/5 activities under blue light. Taken together, this study will provide new insight into the mechanism of how blue light inhibits hypocotyl elongation.
Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis
Authors: Wu Yunchen , He Yudan , Liu Chen , Ehle Charlotte , Iyer-Bierhoff Aishwarya , Liu Bing , Heinzel Thorsten , Xing Shaojun
Published: August 2023

Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose significant challenges in sepsis treatment. Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been proposed as potent anti-inflammatory agents for treating inflammatory diseases. However, the underlying mechanisms of sepsis treatment remain poorly understood. In this study, we investigated the effects of SAHA treatment in the lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the early stages of the systemic inflammation of sepsis. Our results demonstrate a reduced inflammatory mediator secretion and improved survival rates in mice. Using quantitative acetylomics, we found that SAHA administration increases the acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages (BMDMs) show that SAHA administration reduced oxidative stress and extracellular ATP concentrations, ultimately blunting inflammasome activation. Overall, our study provides insights into the mechanism underlying SAHA’s therapeutic effects in sepsis treatment and highlights LDHA as a potential target for developing novel sepsis treatment.
Connection between Radiation-Regulating Functions of Natural Products and miRNAs Targeting Radiomodulation and Exosome Biogenesis
Authors: Tang Jen-Yang , Chuang Ya-Ting , Shiau Jun-Ping , Yen Ching-Yu , Chang Fang-Rong , Tsai Yi-Hong , Farooqi Ammad Ahmad , Chang Hsueh-Wei
Published: August 2023

Exosomes are cell-derived membranous structures primarily involved in the delivery of the payload to the recipient cells, and they play central roles in carcinogenesis and metastasis. Radiotherapy is a common cancer treatment that occasionally generates exosomal miRNA-associated modulation to regulate the therapeutic anticancer function and side effects. Combining radiotherapy and natural products may modulate the radioprotective and radiosensitizing responses of non-cancer and cancer cells, but there is a knowledge gap regarding the connection of this combined treatment with exosomal miRNAs and their downstream targets for radiation and exosome biogenesis. This review focuses on radioprotective natural products in terms of their impacts on exosomal miRNAs to target radiation-modulating and exosome biogenesis (secretion and assembly) genes. Several natural products have individually demonstrated radioprotective and miRNA-modulating effects. However, the impact of natural-product-modulated miRNAs on radiation response and exosome biogenesis remains unclear. In this review, by searching through PubMed/Google Scholar, available reports on potential functions that show radioprotection for non-cancer tissues and radiosensitization for cancer among these natural-product-modulated miRNAs were assessed. Next, by accessing the miRNA database (miRDB), the predicted targets of the radiation- and exosome biogenesis-modulating genes from the Gene Ontology database (MGI) were retrieved bioinformatically based on these miRNAs. Moreover, the target-centric analysis showed that several natural products share the same miRNAs and targets to regulate radiation response and exosome biogenesis. As a result, the miRNA–radiomodulation (radioprotection and radiosensitization)–exosome biogenesis axis in regard to natural-product-mediated radiotherapeutic effects is well organized. This review focuses on natural products and their regulating effects on miRNAs to assess the potential impacts of radiomodulation and exosome biogenesis for both the radiosensitization of cancer cells and the radioprotection of non-cancer cells.
Combination of Pinocembrin and Epidermal Growth Factor Enhances the Proliferation and Survival of Human Keratinocytes
Authors: Ruttanapattanakul Jirapak , Wikan Nitwara , Potikanond Saranyapin , Nimlamool Wutigri
Published: August 2023

Re-epithelialization is delayed in aged skin due to a slow rate of keratinocyte proliferation, and this may cause complications. Thus, there has been development of new therapies that increase treatment efficacy for skin wounds. Epidermal growth factor (EGF) has been clinically used, but this agent is expensive, and its activity is less stable. Therefore, a stable compound possessing EGF-like properties may be an effective therapy, especially when combined with EGF. The current study discovered that pinocembrin (PC) effectively synergized with EGF in increasing keratinocyte viability. The combination of PC and EGF significantly enhanced the proliferation and wound closure rate of the keratinocyte monolayer through activating the phosphorylation of ERK and Akt. Although these effects of PC were like those of EGF, we clearly proved that PC did not transactivate EGFR. Recent data from a previous study revealed that PC activates G-protein-coupled receptor 120 which further activates ERK1/2 and Akt phosphorylation. Therefore, this clearly indicates that PC possesses a unique property to stimulate the growth and survival of keratinocytes through activating a different receptor, which subsequently conveys the signal to cross-talk with the effector kinases downstream of the EGFR, suggesting that PC is a potential compound to be combined with EGF.
Ceramide Risk Score in the Evaluation of Metabolic Syndrome: An Additional or Substitutive Biochemical Marker in the Clinical Practice?
Authors: Rigamonti Antonello E. , Dei Cas Michele , Caroli Diana , Bondesan Adele , Cella Silvano G. , Paroni Rita , Sartorio Alessandro
Published: August 2023

Ceramide risk score (CERT1, ceramide test 1), based on specific ceramides (Cers) and their corresponding ratios in the plasma, has been reported as a promising biochemical marker for primary and secondary prediction of cardiovascular disease (CVD) risk in different populations of patients. Thus far, limited attention has been paid to metabolic syndrome, a condition considered at high CVD risk. The aim of the present study was to evaluate CERT1 in a group of obese subjects without (OB-MetS−) and with (OB-MetS+) metabolic syndrome (according to the International Diabetes Federation (IDF) diagnostic criteria), compared to an age- and sex-matched normal-weight (NW) group. In all participants, plasma levels of Cer 16:0, Cer 18:0, Cer 24:1, and Cer 24:0 were measured, and the corresponding ratios Cer 16:0/24:0, Cer 18:0/24:0, and Cer 24:1/24:0 were calculated together with CERT1. Subjects with obesity showed higher CERT1 values than the NW group (p < 0.05), with no difference between OB-MetS− and OB-MetS+ groups. Waist circumference (WC), homeostatic model assessment of insulin-resistance (HOMA-IR) (surrogates of IDF diagnostic criteria for metabolic syndrome), and C reactive protein (CRP) (a marker of inflammation) were predictors of CERT1 (p < 0.05), with the contribution of the other IDF criteria such as arterial hypertension and dyslipidemia being negligible. Adjustment for WC resulted in a loss of the difference in CERT1 between OB-MetS− and NW subjects, with the combination of WC and HOMA-IR or CRP as covariates being necessary to yield the same effect for the difference in CERT1 between OB-MetS+ and NW subjects. Importantly, an association was found between CERT1 and vascular age (VA) (p < 0.05). Proportions of NW, OB-MetS− and OB-MetS+ subjects appeared to be distributed according to the CERT1-based risk groups (i.e., low, moderate, increased, and high risk; p < 0.05), with some OB-MetS− subjects included in the increased/high-risk group and some OB-MetS+ in the low/moderate-risk one. In conclusion, the clinical diagnosis of metabolic syndrome seems to be inaccurate to assess CVD risk in the obese population; however, further studies are needed before considering CERT1 as an additional or substitutive biochemical marker in clinical practice.
TET Family Members Are Integral to Porcine Oocyte Maturation and Parthenogenetic Pre-Implantation Embryogenesis
Authors: Chen Fan , Li Ming-Guo , Hua Zai-Dong , Ren Hong-Yan , Gu Hao , Luo An-Feng , Zhou Chang-Fan , Zhu Zhe , Huang Tao , Bi Yan-Zhen
Published: August 2023

The ten-eleven translocation (TET) enzyme family, which includes TET1/2/3, participates in active DNA demethylation in the eukaryotic genome; moreover, TET1/2/3 are functionally redundant in mice embryos. However, the combined effect of TET1/2/3 triple-gene knockdown or knockout on the porcine oocytes or embryos is still unclear. In this study, using Bobcat339, a specific small-molecule inhibitor of the TET family, we explored the effects of TET enzymes on oocyte maturation and early embryogenesis in pigs. Our results revealed that Bobcat339 treatment blocked porcine oocyte maturation and triggered early apoptosis. Furthermore, in the Bobcat339-treated oocytes, spindle architecture and chromosome alignment were disrupted, probably due to the huge loss of 5-hydroxymethylcytosine (5hmC)and concurrent increase in 5-methylcytosine (5mC). After Bobcat339 treatment, early parthenogenetic embryos exhibited abnormal 5mC and 5hmC levels, which resulted in compromised cleavage and blastocyst rate. The mRNA levels of EIF1A and DPPA2 (ZGA marker genes) were significantly decreased, which may explain why the embryos were arrested at the 4-cell stage after Bobcat339 treatment. In addition, the mRNA levels of pluripotency-related genes OCT4 and NANOG were declined after Bobcat339 treatment. RNA sequencing analysis revealed differentially expressed genes in Bobcat339-treated embryos at the 4-cell stage, which were significantly enriched in cell proliferation, cell component related to mitochondrion, and cell adhesion molecule binding. Our results indicated that TET proteins are essential for porcine oocyte maturation and early embryogenesis, and they act by mediating 5mC/5hmC levels and gene transcription.
Exploring the Role of Hsp60 in Alzheimer’s Disease and Type 2 Diabetes: Suggestion for Common Drug Targeting
Authors: Zimbone Stefania , Di Rosa Maria Carmela , Chiechio Santina , Giuffrida Maria Laura
Published: August 2023

Heat shock protein 60 (Hsp60) is a member of the chaperonin family of heat shock proteins (HSPs), primarily found in the mitochondrial matrix. As a molecular chaperone, Hsp60 plays an essential role in mediating protein folding and assembly, and together with the co-chaperon Hsp10, it is thought to maintain protein homeostasis. Recently, it has been found to localize in non-canonical, extra-mitochondrial sites such as cell membranes or extracellular fluids, particularly in pathological conditions. Starting from its biological function, this review aims to provide a comprehensive understanding of the potential involvement of Hsp60 in Alzheimer’s disease (AD) and Type II Diabetes Mellitus (T2DM), which are known to share impaired key pathways and molecular dysfunctions. Fragmentary data reported in the literature reveal interesting links between the altered expression level or localization of this chaperonin and several disease conditions. The present work offers an overview of the past and more recent knowledge about Hsp60 and its role in the most important cellular processes to shed light on neuronal Hsp60 as a potential common target for both pathologies. The absence of any effective cure for AD patients makes the identification of a new molecular target a promising path by which to move forward in the development of new drugs and/or repositioning of therapies already used for T2DM.
Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis
Authors: Song Xiaoyu , Wu Wanfu , Dai Yubing , Warner Margaret , Nalvarte Ivan , Antonson Per , Varshney Mukesh , Gustafsson Jan-Åke
Published: August 2023

Liver X receptors (LXRα and LXRβ) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXRαβ-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXRα and LXRβ are expressed in the colonic epithelium and that in aging LXRαβ−/− mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor β (ERβ) levels. The cytoplasmic compartment of the surface epithelial cells was markedly reduced and there was a massive invasion of macrophages in the lamina propria. The expression and localization of β-catenin, α-catenin, and E-cadherin were not changed, but the shrinkage of the cytoplasm led to an appearance of an increase in staining. In the colonic epithelium there was a reduction in the expression of plectin, a hemidesmosome protein whose loss in mice leads to spontaneous colitis, ELOVL1, a fatty acid elongase protein coding gene whose overexpression is found in colorectal cancer, and non-neuronal choline acetyltransferase (ChAT) involved in the regulation of epithelial cell adhesion. We conclude that in aging LXRαβ−/− mice, the phenotype in the colon is due to loss of ERβ expression.
Decoding the Gene Regulatory Network of Muscle Stem Cells in Mouse Duchenne Muscular Dystrophy: Revelations from Single-Nuclei RNA Sequencing Analysis
Authors: Shen Yan , Kim Il-Man , Tang Yaoliang
Published: August 2023

The gene dystrophin is responsible for Duchenne muscular dystrophy (DMD), a grave X-linked recessive ailment that results in respiratory and cardiac failure. As the expression of dystrophin in muscle stem cells (MuSCs) is a topic of debate, there exists a limited understanding of its influence on the gene network of MuSCs. This study was conducted with the objective of investigating the effects of dystrophin on the regulatory network of genes in MuSCs. To comprehend the function of dystrophin in MuSCs from DMD, this investigation employed single-nuclei RNA sequencing (snRNA-seq) to appraise the transcriptomic profile of MuSCs obtained from the skeletal muscles of dystrophin mutant mice (DMDmut) and wild-type control mice. The study revealed that the dystrophin mutation caused the disruption of several long non-coding RNAs (lncRNAs), leading to the inhibition of MEG3 and NEAT1 and the upregulation of GM48099, GM19951, and GM15564. The Gene Ontology (GO) enrichment analysis of biological processes (BP) indicated that the dystrophin mutation activated the cell adhesion pathway in MuSCs, inhibited the circulatory system process, and affected the regulation of binding. The study also revealed that the metabolic pathway activity of MuSCs was altered. The metabolic activities of oxidative phosphorylation (OXPHOS) and glycolysis were elevated in MuSCs from DMDmut. In summary, this research offers novel insights into the disrupted gene regulatory program in MuSCs due to dystrophin mutation at the single-cell level.
Metabolic Pathway Reconstruction Indicates the Presence of Important Medicinal Compounds in Coffea Such as L-DOPA
Authors: Cherubino Ribeiro Thales Henrique , de Oliveira Raphael Ricon , das Neves Taís Teixeira , Santiago Wilder Douglas , Mansur Bethania Leite , Saczk Adelir Aparecida , Vilela de Resende Mario Lucio , Chalfun-Junior Antonio
Published: August 2023

The use of transcriptomic data to make inferences about plant metabolomes is a useful tool to help the discovery of important compounds in the available biodiversity. To unveil previously undiscovered metabolites of Coffea, of phytotherapeutic and economic value, we employed 24 RNAseq libraries. These libraries were sequenced from leaves exposed to a diverse range of environmental conditions. Subsequently, the data were meticulously processed to create models of putative metabolic networks, which shed light on the production of potential natural compounds of significant interest. Then, we selected one of the predicted compounds, the L-3,4-dihydroxyphenylalanine (L-DOPA), to be analyzed by LC–MS/MS using three biological replicates of flowers, leaves, and fruits from Coffea arabica and Coffea canephora. We were able to identify metabolic pathways responsible for producing several compounds of economic importance. One of the identified pathways involved in isoquinoline alkaloid biosynthesis was found to be active and producing L-DOPA, which is a common product of POLYPHENOL OXIDASES (PPOs, EC 1.14.18.1 and EC 1.10.3.1). We show that coffee plants are a natural source of L-DOPA, a widely used medicine for treatment of the human neurodegenerative condition called Parkinson’s disease. In addition, dozens of other compounds with medicinal significance were predicted as potential natural coffee products. By further refining analytical chemistry techniques, it will be possible to enhance the characterization of coffee metabolites, enabling a deeper understanding of their properties and potential applications in medicine.
Metabolomics of Type 2 Diabetes Mellitus in Sprague Dawley Rats—In Search of Potential Metabolic Biomarkers
Authors: Ndlovu Innocent Siyanda , Tshilwane Selaelo Ivy , Vosloo Andre , Chaisi Mamohale , Mukaratirwa Samson
Published: August 2023

Type 2 diabetes mellitus (T2DM) is an expanding global health concern, closely associated with the epidemic of obesity. Individuals with diabetes are at high risk for microvascular and macrovascular complications, which include retinopathy, neuropathy, and cardiovascular comorbidities. Despite the availability of diagnostic tools for T2DM, approximately 30–60% of people with T2DM in developed countries are never diagnosed or detected. Therefore, there is a strong need for a simpler and more reliable technique for the early detection of T2DM. This study aimed to use a non-targeted metabolomic approach to systematically identify novel biomarkers from the serum samples of T2DM-induced Sprague Dawley (SD) rats using a comprehensive two-dimensional gas chromatography coupled with a time-of-flight mass spectrometry (GCxGC-TOF/MS). Fifty-four male Sprague Dawley rats weighing between 160–180 g were randomly assigned into two experimental groups, namely the type 2 diabetes mellitus group (T2DM) (n = 36) and the non-diabetic control group (n = 18). Results from this study showed that the metabolite signature of the diabetic rats was different from that of the non-diabetic control group. The most significantly upregulated metabolic pathway was aminoacyl-t-RNA biosynthesis. Metabolite changes observed between the diabetic and non-diabetic control group was attributed to the increase in amino acids, such as glycine, L-asparagine, and L-serine. Aromatic amino acids, including L-tyrosine, were associated with the risk of future hyperglycemia and overt diabetes. The identified potential biomarkers depicted a good predictive value of more than 0.8. It was concluded from the results that amino acids that were associated with impaired insulin secretion were prospectively related to an increase in glucose levels. Moreover, amino acids that were associated with impaired insulin secretion were prospectively related to an increase in glucose levels.
Drug Development from Natural Products Based on the Pathogenic Mechanism of Asthma
Authors: Kim Min-Hee , Bae Chun-Sik , Bok So-Hyeon , Choi Hyo-Seung , Ahn Taeho , Cho Seung-Sik , Park Dae-Hun
Published: August 2023

Asthma is a chronic inflammatory disease of the pulmonary system associated with many wheeze-to-sleep apnea complications that may lead to death. In 2019, approximately 262 million patients suffered from asthma, and 455 thousand died from the disease worldwide. It is a more severe health problem in children and older adults, and as the aging of society intensifies, the problem will continue to worsen. Asthma inducers can be classified as indoor and outdoor allergens and can cause asthma due to their repeated invasion. There are several theories about asthma occurrence, such as the imbalance between Th1 and Th2, inflammation in the pulmonary system, and the abnormal apoptosis/cell proliferation of cells related to asthma. Although there are many medications for asthma, as it is an incurable disease, the purpose of the drugs is only to suppress the symptoms. The current drugs can be divided into relievers and controllers; however, as they have many adverse effects, such as immune suppression, growth retardation, promotion of cataracts, hyperactivity, and convulsions, developing new asthma drugs is necessary. Although natural products can have adverse effects, the development of asthma drugs from natural products may be beneficial, as some have anti-asthmatic effects such as immune modulation, anti-inflammation, and/or apoptosis modulation.
Role of microRNAs in Chronic Lymphocytic Leukemia
Authors: Autore Francesco , Ramassone Alice , Stirparo Luca , Pagotto Sara , Fresa Alberto , Innocenti Idanna , Visone Rosa , Laurenti Luca
Published: August 2023

Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia in adults, with a highly variable clinical course. Improvement in the knowledge of the molecular pathways behind this disease has led to the development of increasingly specific therapies, such as BCR signaling inhibitors and BCL-2 inhibitors. In this context, the emerging role of microRNAs (miRNAs) in CLL pathophysiology and their possible application in therapy is worth noting. MiRNAs are one of the most important regulatory molecules of gene expression. In CLL, they can act both as oncogenes and tumor suppressor genes, and the deregulation of specific miRNAs has been associated with prognosis, progression, and drug resistance. In this review, we describe the role of the miRNAs that primarily impact the disease, and how these miRNAs could be used as therapeutic tools. Certainly, the use of miRNAs in clinical practice is still limited in CLL. Many issues still need to be solved, particularly regarding their biological and safety profile, even if several studies have suggested their efficacy on the disease, alone or in combination with other drugs.
Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin
Authors: Pérez-Luz Sara , Lalchandani Jaanam , Matamala Nerea , Barrero Maria Jose , Gil-Martín Sara , Saz Sheila Ramos-Del , Varona Sarai , Monzón Sara , Cuesta Isabel , Justo Iago , Marcacuzco Alberto , Hierro Loreto , Garfia Cristina , Gomez-Mariano Gema , Janciauskiene Sabina , Martínez-Delgado Beatriz
Published: August 2023

Different mutations in the SERPINA1 gene result in alpha-1 antitrypsin (AAT) deficiency and in an increased risk for the development of liver diseases. More than 90% of severe deficiency patients are homozygous for Z (Glu342Lys) mutation. This mutation causes Z-AAT polymerization and intrahepatic accumulation which can result in hepatic alterations leading to steatosis, fibrosis, cirrhosis, and/or hepatocarcinoma. We aimed to investigate lipid status in hepatocytes carrying Z and normal M alleles of the SERPINA1 gene. Hepatic organoids were developed to investigate lipid alterations. Lipid accumulation in HepG2 cells overexpressing Z-AAT, as well as in patient-derived hepatic organoids from Pi*MZ and Pi*ZZ individuals, was evaluated by Oil-Red staining in comparison to HepG2 cells expressing M-AAT and liver organoids from Pi*MM controls. Furthermore, mass spectrometry-based lipidomics analysis and transcriptomic profiling were assessed in Pi*MZ and Pi*ZZ organoids. HepG2 cells expressing Z-AAT and liver organoids from Pi*MZ and Pi*ZZ patients showed intracellular accumulation of AAT and high numbers of lipid droplets. These latter paralleled with augmented intrahepatic lipids, and in particular altered proportion of triglycerides, cholesterol esters, and cardiolipins. According to transcriptomic analysis, Pi*ZZ organoids possess many alterations in genes and cellular processes of lipid metabolism with a specific impact on the endoplasmic reticulum, mitochondria, and peroxisome dysfunction. Our data reveal a relationship between intrahepatic accumulation of Z-AAT and alterations in lipid homeostasis, which implies that liver organoids provide an excellent model to study liver diseases related to the mutation of the SERPINA1 gene.
New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients
Authors: Merlini Luciano , Sabatelli Patrizia , Gualandi Francesca , Redivo Edoardo , Di Martino Alberto , Faldini Cesare
Published: August 2023

Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials.
Cytokine-Induced Killer Cells in Combination with Heat Shock Protein 90 Inhibitors Functioning via the Fas/FasL Axis Provides Rationale for a Potential Clinical Benefit in Burkitt’s lymphoma
Authors: Ge Fangfang , Wang Yulu , Sharma Amit , Yang Yu , Liu Hongde , Essler Markus , Jaehde Ulrich , Schmidt-Wolf Ingo G. H.
Published: August 2023

Constant efforts are being made to develop methods for improving cancer immunotherapy, including cytokine-induced killer (CIK) cell therapy. Numerous heat shock protein (HSP) 90 inhibitors have been assessed for antitumor efficacy in preclinical and clinical trials, highlighting their individual prospects for targeted cancer therapy. Therefore, we tested the compatibility of CIK cells with HSP90 inhibitors using Burkitt’s lymphoma (BL) cells. Our analysis revealed that CIK cytotoxicity in BL cells was augmented in combination with independent HSP90 inhibitors 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) and ganetespib. Interestingly, CIK cell cytotoxicity did not diminish after blocking with NKG2D (natural killer group 2, member D), which is a prerequisite for their activation. Subsequent analyses revealed that the increased expression of Fas on the surface of BL cells, which induces caspase 3/7-dependent apoptosis, may account for this effect. Thus, we provide evidence that CIK cells, either alone or in combination with HSP90 inhibitors, target BL cells via the Fas–FasL axis rather than the NKG2D pathway. In the context of clinical relevance, we also found that high expression of HSP90 family genes (HSP90AA1, HSP90AB1, and HSP90B1) was significantly associated with the reduced overall survival of BL patients. In addition to HSP90, genes belonging to the Hsp40, Hsp70, and Hsp110 families have also been found to be clinically significant for BL survival. Taken together, the combinatorial therapy of CIK cells with HSP90 inhibitors has the potential to provide clinical benefits to patients with BL.
The Effect of Adjuvant Therapy with Molecular Hydrogen on Endogenous Coenzyme Q10 Levels and Platelet Mitochondrial Bioenergetics in Patients with Non-Alcoholic Fatty Liver Disease
Authors: Sumbalová Zuzana , Kucharská Jarmila , Rausová Zuzana , Gvozdjáková Anna , Szántová Mária , Kura Branislav , Mojto Viliam , Slezák Ján
Published: August 2023

Molecular hydrogen (H2) has been recognized as a novel medical gas with antioxidant and anti-inflammatory effects. Non-alcoholic fatty liver disease (NAFLD) is a liver pathology with increased fat accumulation in liver tissue caused by factors other than alcohol consumption. Platelet mitochondrial function is considered to reflect systemic mitochondrial health. We studied the effect of adjuvant therapy with hydrogen-rich water (HRW) on coenzyme Q10 (CoQ10) content and platelet mitochondrial bioenergetics in patients with NAFLD. A total of 30 patients with NAFLD and 15 healthy volunteers were included in this clinical trial. A total of 17 patients (H2 group) drank water three × 330 mL/day with tablets producing HRW (>4 mg/L H2) for 8 weeks, and 13 patients (P group) drank water with placebo tablets producing CO2. The concentration of CoQ10-TOTAL was determined by the HPLC method, the parameter of oxidative stress, thiobarbituric acid reactive substances (TBARS), by the spectrophotometric method, and mitochondrial bioenergetics in platelets isolated from whole blood by high-resolution respirometry. The patients with NAFLD had lower concentrations of CoQ10-TOTAL in the blood, plasma, and platelets vs. the control group. Mitochondrial CI-linked LEAK respiration was higher, and CI-linked oxidative phosphorylation (OXPHOS) and CII-linked electron transfer (ET) capacities were lower vs. the control group. Plasma TBARS concentrations were higher in the H2 group. After 8 weeks of adjuvant therapy with HRW, the concentration of CoQ10 in platelets increased, plasma TBARS decreased, and the efficiency of OXPHOS improved, while in the P group, the changes were non-significant. Long-term supplementation with HRW could be a promising strategy for the acceleration of health recovery in patients with NAFLD. The application of H2 appears to be a new treatment strategy for targeted therapy of mitochondrial disorders. Additional and longer-term studies are needed to confirm and elucidate the exact mechanisms of the mitochondria-targeted effects of H2 therapy in patients with NAFLD.