bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Remission with Inotuzumab Ozogamicin as Fourth-Line Salvage Therapy in a Child with Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Tragiannidis Athanasios , Antari Vassiliki , Tsotridou Eleni , Sidiropoulos Theodoros , Kaisari Aikaterini , Palabougiouki Maria , Vyzantiadis Timoleon-Achilleas , Hatzipantelis Emmanuel , Galli-Tsinopoulou Assimina , Goussetis Evgenios
Published: September 2024

Background: Despite the progress achieved regarding survival rates in childhood acute lymphoblastic leukemia (ALL), relapsed or refractory disease still poses a therapeutic challenge. Inotuzumab ozogamicin is a CD22-directed monoclonal antibody conjugated to calicheamicin, which has been approved by the Food and Drug Administration for adults and pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia. Case presentation: Herein, we present the case of a 23-month-old girl with high-risk B-ALL who experienced very early isolated medullary relapse; following the failure of conventional chemotherapy according to the ALL-IC REL 2016 protocol, she went on to receive the bispecific T-cell engager (BiTE) blinatumomab and subsequently, due to refractory disease, the combination of fludarabine, cytarabine, and the proteasome inhibitor bortezomib without achieving remission. Given the high CD22 expression by the lymphoblasts, off-label use of inotuzumab ozogamicin (InO) was chosen and administrated in a 28-day cycle as a salvage treatment. The minimal residual disease (MRD) was 0.08% on day 28, and InO was continued, thus achieving MRD negativity; the patient successfully underwent an allogeneic stem cell transplantation from a matched family donor. Conclusions: Our case highlights the efficacy and safety of InO as a salvage treatment in the setting of relapsed B-ALL refractory not only to conventional chemotherapy but also to novel treatments, such as blinatumomab and bortezomib.
Integrated Phenotypic Physiology and Transcriptome Analysis Revealed the Molecular Genetic Basis of Anthocyanin Accumulation in Purple Pak-Choi
Authors: Yang Qinyu , Huang Tao , Zhang Li , Yang Xiao , Zhang Wenqi , Chen Longzheng , Jing Zange , Li Yuejian , Yang Qichang , Xu Hai , Song Bo
Published: September 2024

Purple Pak-choi is rich in anthocyanins, which have both ornamental and edible health functions, and has been used more and more widely in facility cultivation. In order to further clarify the molecular mechanism of purple Pak-choi, two Pak-choi inbred lines (‘PQC’ and ‘HYYTC’) were selected for the determination of pigment content and transcriptome analysis, and the key genes controlling the formation of purple character in leaves of Pak-choi were discovered. The results of pigment determination showed that the anthocyanin content of ‘PQC’ was 0.29 mg/g, which was about 100 times than ‘HYYTC’; The chlorophyll content of ‘HYYTC’ was 2.25 mg/g, while ‘PQC’ only contained 1.05 mg/g. A total of 20 structural genes related to anthocyanin biosynthesis and 28 transcriptional regulatory genes were identified by transcriptome analysis. Weighted gene co-expression network analysis (WGCNA) was used to construct the weight network analysis map of 14 genes. The results showed that the cinnamate hydroxylase gene (BraA04002213, BrC4H3), flavanone-3- hydroxylase (BraA09004531, BrF3H1), and chalcone synthetase (BraA10002265, BrCHS1) were the core genes involved in the anthocyanin synthesis pathway of purple Pak-choi. The results identified the key genes controlling the formation of purple leaf traits, which laid a foundation for further analysis of the molecular mechanism of anthocyanin accumulation in purple Pak-choi and provided a theoretical basis for leaf color regulation.
From Weeds to Feeds: Exploring the Potential of Wild Plants in Horticulture from a Centuries-Long Journey to an AI-Driven Future
Authors: Rivera Diego , Rivera-Obón Diego-José , Palazón José-Antonio , Obón Concepción
Published: September 2024

Given the increasing food needs of humanity and the challenges cultivated species face in adapting to the climatic uncertainties we experience, it is urgent to cultivate new species. A highly relevant repertoire for this purpose is offered by the array of edible wild plants. We analyzed data from Murcia (Spain), involving 61 species and 59 informants, and the Global Database of Wild Food Plants, which includes 15,000 species, 500 localities, and nearly 700 references. Using local consensus, global distribution, and GBIF occurrence data, we built simple unimodal or bimodal models to explore their limitations. Our study highlights that approximately 15,000 wild or feral plant species are consumed as food, underlining the urgent need to support existing crops with new species due to current food crises and climate irregularities. We examined wild plant diversity from a horticultural perspective, considering their relationships with weeds and invasive species. Partial criteria, such as local consensus or global use, were found insufficient for selecting candidate species. We propose developing a specific artificial intelligence to integrate various factors—ecological, nutritional, toxicological, agronomic, biogeographical, ethnobotanical, economic, and physiological—to accurately model a species’ potential for domestication and cultivation. We propose the necessary tools and a protocol for developing this AI-based model.
Influence of Intercropping on Eugenia dysenterica (Mart.) DC. Fruit Quality
Authors: Almeida Micael , Dornelles Paulo , Rezende Thaisa , Silva Ludiele , Silva Fabiano , Duarte Larissa , de Oliveira Filho Josemar , Egea Mariana
Published: September 2024

Intercropping to integrate cover crops with fruit trees in the Brazilian Cerrado is an innovative strategy for creating a more sustainable food system. This agricultural practice contributes to maintaining soil quality and improves fruits’ chemical and technological properties, such as those of Eugenia dysenterica (Mart.) DC. (cagaita). Given the significant fruit production potential of the Brazilian Cerrado, this study aimed to investigate the impact of an intercropping system involving cagaita trees and various cover crops, specifically Calopogonium mucunoides Desv. (CA), Crotalaria juncea (CR), Lablab purpureus (L.) Sweet (LA), brachiaria (Brachiaria decumbens L.) + nitrogen source (urea) (BRN), and brachiaria (Brachiaria decumbens L.) (BR), on the chemical composition, technological properties, and morphological characteristics of cagaita fruits. Treatments involving leguminous cover crops (CA, LA, and CR) significantly increased nitrogen (N) levels in cagaita fruits, comparable to those observed with the BRN treatment. However, the treatment utilizing BR resulted in the highest levels of macrominerals (Ca, Mg, and K), which are essential for meeting the Recommended Dietary Intake (RDI) and demonstrated a notable positive impact on pulp yield (>78%). Additionally, the antioxidant potential and phenolic content were the highest in the BR, CA, and LA treatments, with the lowest levels recorded for the CR treatment. This study underscores the importance of sustainable agricultural practices in the Brazilian Cerrado, demonstrating their potential to enhance the nutritional quality (both micro and macronutrients), technological properties, and overall development of Eugenia dysenterica DC. fruits, thereby adding value to food and contributing to a more resilient and productive food system.
Fragile Egos and Broken Hearts: Narcissistic and Borderline Personality Traits Predict Reactions to Potential Infidelity
Authors: Besser Avi , Zeigler-Hill Virgil
Published: September 2024

We examined the connections that narcissistic and borderline personality traits had with hypothetical responses to romantic infidelity in a sample of Israeli community members (N = 997). We distinguished between four forms of narcissism: extraverted narcissism (characterized by assertive self-enhancement), antagonistic narcissism (characterized by defensiveness and hostility), neurotic narcissism (characterized by emotional distress), and communal narcissism (characterized by attempts to emphasize superiority over others by exaggerating communal characteristics such as being extraordinarily helpful). We also measured levels of borderline personality traits. Results showed that neurotic narcissism was strongly associated with heightened negative emotional responses, particularly in high-threat infidelity scenarios, aligning with predictions regarding emotional volatility. Antagonistic and communal narcissism showed detrimental effects on relationship evaluations primarily under low-threat conditions, indicating distinct patterns of defensiveness and vulnerability. Extraverted narcissism showed no significant association with emotional responses. Borderline traits were linked to intense emotional reactions across conditions, emphasizing their broad impact on perceived relational threats. These findings suggest that while some personality traits exacerbate reactions in less severe conditions, infidelity trauma can overwhelm these differences, underscoring the potential need for personalized therapeutic approaches. Discussion is focused on the implications for understanding personality traits in relational contexts and future research directions exploring varied threat manipulations.
To See and Be Seen: A Swedish Register Study on Children Who Witness Family Violence
Authors: Trygged Sven , Bylund Grenklo Tove , Marttila Anneli , Halin Niklas
Published: September 2024

Authorities and civilians can make a report-of-concern to Social Services if they suspect a child is experiencing or witnessing violence. In 2021, Sweden implemented new legislation that considers children as victims of crime not only when abused but also when witnessing family violence, i.e., Barnfridsbrott. This study aimed to describe and analyze reports-of-concern regarding children witnessing family violence. Are there any changes in number of reports over the years? Who is reporting? And what interventions are most frequent? This is a register-based study of reports-of-concern in Gävle municipality in Sweden for the years 2018–2022. This unique register makes it possible to identify and follow up reported cases as long as they are active by Social Services. Results show there was already a major increase in the number of reports-of-concern in 2020. Most reports are made by Social Services and the police. Of all reports related to family violence, an increasing number lead to further investigations. In most of those cases, the children stay with their families, and Social Services offer counselling. Conclusion: there was a distinct increase in reports related to children witnessing family violence already starting in 2020 in the studied municipality, before the new legislation was implemented.
Sex-Based Differences in Pulmonary Function and Cardiopulmonary Response 30 Months Post-COVID-19: A Brazilian Multicentric Study
Authors: Goulart Cássia da Luz , Arêas Guilherme Peixoto Tinoco , Milani Mauricio , Borges Fernanda Facioli dos Reis , Magalhães Juliana Ribeiro , Back Guilherme Dionir , Borghi-Silva Audrey , Oliveira Luciano Fonseca Lemos , de Paula André Ribeiro , Marinho Carolina Coimbra , Prado Déborah Pereira , Almeida Celso Nascimento de , Dias Cristiane Maria Carvalho Costa , Gomes Vinícius Afonso , Ritt Luiz Eduardo Fonteles , Franzoni Leandro Tolfo , Stein Ricardo , Neto Mansueto Gomes , Cipriano Junior Gerson , Almeida-Val Fernando
Published: September 2024

Aim: (I) to verify if there are sex differences in respiratory function, respiratory muscle strength, and effort limitation in individuals recovered from severe acute COVID-19 30 months after the initial infection, and (II) to evaluate the influence of length of stay on cardiorespiratory capacity among men and women. Methods: Cross-sectional observational multicentric study with participants from five Brazilian states (São Paulo, Amazonas, Minas Gerais, Bahia, and Brasília). We assessed lung function and respiratory muscle strength by maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and cardiorespiratory fitness by cardiopulmonary exercise test (CPET). Results: 86 individuals were stratified by sex (48 women and 38 men). Females had significantly longer hospitalization for acute COVID-19 (p < 0.05) and showed a marked reduction in MIP (cmH2O and % predicted). Regarding the CPET, women presented lower V˙O2% predicted, O2 pulse, and oxygen uptake efficiency slope (OUES, % predicted) (p < 0.05). In addition, women also had greater abnormal combinations between RER < 1.10, OUES < 80% predicted, VE/VVM < 15% [3 (6.2%)] and V˙O2% predicted < 80%, V˙E/V˙CO2 slope and V˙O2/workload < 8.4 mL/min/W [8 (17%)]. The regression analysis showed a significant influence of age, length of hospitalization (< and >10 days), and FEV1/FVC (%) on the V˙O2 peak (mL·kg−1·min−1). Secondarily, we found that women hospitalized for more than 10 days had worse O2 pulse (p = 0.03), OUES % predicted (p < 0.001), and worse V˙O2% predicted (p < 0.009). Conclusion: Women exhibited more pronounced impairments in several key indicators of cardiopulmonary function 30 months post-infection.
Navigating the Controversies: Role of TRPM Channels in Pain States
Authors: Gandini Maria A. , Zamponi Gerald W.
Published: September 2024

Chronic pain is a debilitating condition that affects up to 1.5 billion people worldwide and bears a tremendous socioeconomic burden. The success of pain medicine relies on our understanding of the type of pain experienced by patients and the mechanisms that give rise to it. Ion channels are among the key targets for pharmacological intervention in chronic pain conditions. Therefore, it is important to understand how changes in channel properties, trafficking, and molecular interactions contribute to pain sensation. In this review, we discuss studies that have demonstrated the involvement of transient receptor potential M2, M3, and M8 channels in pain generation and transduction, as well as the controversies surrounding these findings.
New Application of an Old Drug: Anti-Diabetic Properties of Phloroglucinol
Authors: Drygalski Krzysztof , Maciejczyk Mateusz , Miksza Urszula , Ustymowicz Andrzej , Godzień Joanna , Buczyńska Angelika , Chomentowski Andrzej , Walczak Iga , Pietrowska Karolina , Siemińska Julia , Pawlukianiec Cezary , Czajkowski Przemysław , Fiedorczuk Joanna , Moroz Monika , Modzelewska Beata , Zalewska Anna , Kutryb-Zając Barbara , Kleszczewski Tomasz , Ciborowski Michał , Hady Hady Razak , Foretz Marc , Adamska-Patruno Edyta
Published: September 2024

Phloroglucinol (PHG), an analgesic and spasmolytic drug, shows promise in preventing high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. In Wistar rats, 10 weeks of PHG treatment did not prevent HFD-induced weight gain but significantly mitigated fasting hyperglycemia, impaired insulin responses, and liver steatosis. This protective effect was not linked to hepatic lipogenesis or AMP-activated protein kinase (AMPK) activation. Instead, PHG improved mitochondrial function by reducing oxidative stress, enhancing ATP production, and increasing anti-oxidant enzyme activity. PHG also relaxed gastric smooth muscles via potassium channel activation and nitric oxide (NO) signaling, potentially delaying gastric emptying. A pilot intervention in pre-diabetic men confirmed PHG’s efficacy in improving postprandial glycemic control and altering lipid metabolism. These findings suggest PHG as a potential therapeutic for NAFLD and insulin resistance, acting through mechanisms involving mitochondrial protection, anti-oxidant activity, and gastric motility modulation. Further clinical evaluation is warranted to explore PHG’s full therapeutic potential.
Melatonin Supplementation Alleviates Impaired Spatial Memory by Influencing Aβ1-42 Metabolism via γ-Secretase in the icvAβ1-42 Rat Model with Pinealectomy
Authors: Georgieva Irina , Tchekalarova Jana , Nenchovska Zlatina , Kortenska Lidia , Tzoneva Rumiana
Published: September 2024

In the search for Alzheimer’s disease (AD) therapies, most animal models focus on familial AD, which accounts for a small fraction of cases. The majority of AD cases arise from stress factors, such as oxidative stress, leading to neurological changes (sporadic AD). Early in AD progression, dysfunction in γ-secretase causes the formation of insoluble Aβ1-42 peptides, which aggregate into senile plaques, triggering neurodegeneration, cognitive decline, and circadian rhythm disturbances. To better model sporadic AD, we used a new AD rat model induced by intracerebroventricular administration of Aβ1-42 oligomers (icvAβ1-42) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ1-42 + pin model experienced impaired spatial memory and increased Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ1-42 or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ1-42 and γ-secretase levels in both structures. Our findings suggest that our icvAβ1-42 + pin model is extremely valuable for future AD research.
Betaine Induces Apoptosis and Inhibits Invasion in OSCC Cell Lines
Authors: Kulthanaamondhita Promphakkon , Kornsuthisopon Chatvadee , Chansaenroj Ajjima , Phattarataratip Ekarat , Sappayatosok Kraisorn , Samaranayake Lakshman , Osathanon Thanaphum
Published: September 2024

Betaine, known as trimethylglycine, is a non-toxic natural substance reported to affect cancer cell responses. This study delves into the impact of betaine on the survival, proliferation, and invasion of oral squamous cell carcinoma (OSCC) cells in vitro. Human OSCC cells (HSC-4 and HSC-7) were subjected to varying concentrations of betaine, and their viability and proliferation were assessed through colourimetric MTT and colony-forming unit assays. Cell cycle progression and cell apoptosis were also investigated using flow cytometry, while cell migration and invasion were examined using a transwell migration assay, and the mRNA expression was evaluated by a quantitative polymerase chain reaction. Finally, proteomic analysis was conducted through liquid chromatography-tandem mass spectrometry on the extracted protein component of the cells. Results indicate that betaine effectively suppressed OSCC proliferation and colony formation. It triggered early apoptosis without disrupting cell cycle progression, reduced cell migration, and inhibited invasion. Betaine exposure led to significantly decreased mRNA levels of MMP1, MMP2, and MMP9 while downregulating FN1, a gene linked to epithelial-to-mesenchymal transition. Proteomic analysis revealed 9240 differentially expressed up/downregulated proteins in cells treated with betaine. The significantly upregulated proteins were associated with ATP-binding cassette (ABC) transporters, while the down-regulated proteins were associated with G protein-coupled receptors (GPCR) ligand binding. In conclusion, betaine exhibits potent anti-cancer properties by attenuating OSCC cell proliferation and mitigating invasion. Exploring this natural product as an adjunct for managing oral squamous cell carcinoma shows promise, although further investigations are needed to fully elucidate its functionality.
Bacteria and Allergic Diseases
Authors: Guryanova Svetlana V.
Published: September 2024

Microorganisms colonize all barrier tissues and are present on the skin and all mucous membranes from birth. Bacteria have many ways of influencing the host organism, including activation of innate immunity receptors by pathogen-associated molecular patterns and synthesis of various chemical compounds, such as vitamins, short-chain fatty acids, bacteriocins, toxins. Bacteria, using extracellular vesicles, can also introduce high-molecular compounds, such as proteins and nucleic acids, into the cell, regulating the metabolic pathways of the host cells. Epithelial cells and immune cells recognize bacterial bioregulators and, depending on the microenvironment and context, determine the direction and intensity of the immune response. A large number of factors influence the maintenance of symbiotic microflora, the diversity of which protects hosts against pathogen colonization. Reduced bacterial diversity is associated with pathogen dominance and allergic diseases of the skin, gastrointestinal tract, and upper and lower respiratory tract, as seen in atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, and asthma. Understanding the multifactorial influence of microflora on maintaining health and disease determines the effectiveness of therapy and disease prevention and changes our food preferences and lifestyle to maintain health and active longevity.
Cross-Species Studies Reveal That Dysregulated Mitochondrial Gene Expression and Electron Transport Complex I Activity Are Crucial for Sarcopenia
Authors: Lee Ji-Yoon , Shin Su-Kyung , Han Ji-Won , Kwon Eun-Young , Bae Heekyong R.
Published: September 2024

The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia by conducting a comparative analysis of skeletal muscle gene expression in sarcopenia phenotypes from rats, mice, and humans. Our findings reveal a common mechanistic link across species, particularly highlighting the correlation between the suppression of complex I of ETC activity and dysregulated mitochondrial transcription and translation in sarcopenia phenotypes. Additionally, we observed macrophage dysfunction alongside abnormal metabolic processes within skeletal muscle tissues across all species, implicating their pathogenic role in the onset of sarcopenia. These discoveries underscore the importance of understanding the shared mechanisms associated with complex I of ETC in sarcopenia development. The identified correlations provide valuable insights into potential targets for therapeutic interventions aimed at mitigating the impact of sarcopenia, a condition with substantial implications for aging populations.
Transition Period and Young Adulthood in Patients with Childhood Onset Growth Hormone Deficiency (COGHD): Impact of Growth Hormone Replacement on Bone Mass and Body Composition
Authors: Doknic Mirjana , Stojanovic Marko , Markovic Aleksandra
Published: September 2024

The aim of this review article is to highlight the consequences of COGHD after the end of linear growth on bone mass and body composition and the opposing beneficial effects of continuing GH replacement in the transition period and young adults. The role of growth hormone in the period of late adolescence and young adulthood is well established, mainly in achieving peak bone mass and a favorable body composition, characterized by muscle mass increase and fat mass reduction. Patients with childhood onset growth hormone deficiency (COGHD), after reaching the adult height, have a reduced bone mineral density and muscle mass with increased fat mass compared to healthy controls. Inadequate body composition is a predictor for cardiovascular risk, while low bone mass in early youth hallmarks the risk of osteoporosis and bone fractures in later life. Cessation of growth hormone replacement (GHr) after completion of growth will lead to delayed peak bone mass and unbalanced body composition with increased abdominal fat deposits. According to numerous clinical studies monitoring the effects of GH treatment on the physical and psychological status of patients with persistent GHD after completion of growth, we suggest continuing this treatment between 16 and 25 years of age. It is advised that GHr in the transition period be administered in intermediate doses between those for the pediatric population and those for the adult population. Usual daily GHr doses are between 0.3 and 0.5 mg but need to be individually optimized, with the aim of maintaining IGF-I in the age-specific normal range.
Silicon Nanomaterials Enhance Seedling Growth and Plant Adaptation to Acidic Soil by Promoting Photosynthesis and Antioxidant Activity in Mustard (Brassica campestris L.)
Authors: Hasan Md. Kamrul , Shopan Jannat , Jahan Israt , Suravi Tonima Islam
Published: September 2024

Soil acidity is a divesting factor that restricts crop growth and productivity. Conversely, silicon nanomaterials (Si-NMs) have been praised as a blessing of modern agricultural intensification by overcoming the ecological barrier. Here, we performed a sequential study from seed germination to the yield performance of mustard (Brassica campestris) crops under acid-stressed conditions. The results showed that Si-NMs significantly improved seed germination and seedling growth under acid stress situations. These might be associated with increased antioxidant activity and the preserve ratio of GSH/GSSG and AsA/DHA, which is restricted by soil acidity. Moreover, Si-NMs in field regimes significantly diminished the acid-stress-induced growth inhibitions, as evidenced by increased net photosynthesis and biomass accumulations. Again, Si-NMs triggered all the critical metrics of crop productivity, including the seed oil content. Additionally, Si-NMs, upon dolomite supplementation, further triggered all the metrics of yields related to farming resilience. Therefore, the present study highlighted the crucial roles of Si-NMs in sustainable agricultural expansion and cropping intensification, especially in areas affected by soil acidity.
Stilbene Treatment Reduces Stemness Features in Human Lung Adenocarcinoma Model
Authors: Livraghi Vittoria , Grossi Alice , Scopelliti Anna , Senise Giorgia , Gamboa Luciano Augusto , Solito Samantha , Stivala Lucia Anna , Sottile Virginie , Savio Monica
Published: September 2024

Lung cancer is among the most clinically challenging tumors because of its aggressive proliferation, metastasis, and the presence of cancer stem cells (CSCs). Natural bioactive substances have been used for cancer prevention, and, in particular, resveratrol (RSV), a stilbene-based compound with wide biological properties, has been proposed for chemoprevention. Its lesser-known analogue 4,4’-dihydroxy-trans-stilbene (DHS) has demonstrated superior activity both in cell-based assays and in mouse and zebrafish in vivo models. The present study analyzed the effects of DHS and RSV on A549 lung cancer cells, with a particular focus on stemness features and CSCs, isolated by sorting of the side population (SP). The results show that both stilbenes, especially DHS, strongly inhibited cell cycle progression. A reduction in the S phase was induced by DHS, whereas an increase in this phase was obtained with RSV. In addition, 50% reductions in the clonogenicity and soft agar colony formation were observed with the DHS treatment only. Finally, both stilbenes, especially DHS, reduced stemness marker expression in A549 cells and their sorted SP fraction. Spheroid formation, higher in SP cells than in the main population (MP), was significantly reduced after pretreatment with DHS, which was found to decrease SOX2 levels more than RSV. These findings indicate that stilbenes, and particularly DHS, affect stemness features of A549 cells and the SP fraction, suggesting their potential utility as anticancer agents, either alone or combined with chemotherapeutic drugs.
Optical Nanoscopy of Cytokine-Induced Structural Alterations of the Endoplasmic Reticulum and Golgi Apparatus in Insulin-Secreting Cells
Authors: Pugliese Licia Anna , De Lorenzi Valentina , Tesi Marta , Marchetti Piero , Cardarelli Francesco
Published: September 2024

Pro-inflammatory cytokines play a role in the failure of β cells in type 1 and type 2 diabetes. While existing data from ‘omics’ experiments allow for some understanding of the molecular mechanisms behind cytokine-induced dysfunction in β cells, no report thus far has provided information on the direct imaging of the β cell landscape with nanoscale resolution following cytokine exposure. In this study, we use Airyscan-based optical super-resolution microscopy of Insulinoma 1E (INS-1E) cells to investigate the structural properties of two subcellular membranous compartments involved in the production, maturation and secretion of insulin-containing granules, the endoplasmic reticulum (ER) and the Golgi apparatus (GA). Our findings reveal that exposure of INS-1E cells to IL-1β and IFN-γ for 24 h leads to significant structural alterations of both compartments. In more detail, both the ER and the GA fragment and give rise to vesicle-like structures with markedly reduced characteristic area and perimeter and increased circularity with respect to the original structures. These findings complement the molecular data collected thus far on these compartments and their role in β cell dysfunction and lay the groundwork for future optical microscopy-based ex vivo and in vivo investigations.
Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model
Authors: Du Xiaoyu , Dong Quanxiu , Zhu Jie , Li Lingjie , Yu Xiaolin , Liu Ruitian
Published: September 2024

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin’s multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.
Low-Molecular-Weight Compounds Produced by the Intestinal Microbiota and Cardiovascular Disease
Authors: Cuervo Lorena , McAlpine Patrick L. , Olano Carlos , Fernández Javier , Lombó Felipe
Published: September 2024

Cardiovascular disease is the main cause of mortality in industrialized countries, with over 500 million people affected worldwide. In this work, the roles of low-molecular-weight metabolites originating from the gut microbiome, such as short-chain fatty acids, hydrogen sulfide, trimethylamine, phenylacetic acid, secondary bile acids, indoles, different gases, neurotransmitters, vitamins, and complex lipids, are discussed in relation to their CVD-promoting or preventing activities. Molecules of mixed microbial and human hepatic origin, such as trimethylamine N-oxide and phenylacetylglutamine, are also presented. Finally, dietary agents with cardioprotective effects, such as probiotics, prebiotics, mono- and poly-unsaturated fatty acids, carotenoids, and polyphenols, are also discussed. A special emphasis is given to their gut microbiota-modulating properties.
Metabolome and Transcriptome Joint Analysis Reveals That Different Sucrose Levels Regulate the Production of Flavonoids and Stilbenes in Grape Callus Culture
Authors: Gu Xiaojiao , Fan Zhiyi , Wang Yuan , He Jiajun , Zheng Chuanlin , Ma Huiqin
Published: September 2024

To reveal the effect of sucrose concentration on the production of secondary metabolites, a metabolome and transcriptome joint analysis was carried out using callus induced from grape variety Mio Red cambial meristematic cells. We identified 559 metabolites—mainly flavonoids, phenolic acids, and stilbenoids—as differential content metabolites (fold change ≥2 or ≤0.5) in at least one pairwise comparison of treatments with 7.5, 15, or 30 g/L sucrose in the growing media for 15 or 30 days (d). Resveratrol, viniferin, and amurensin contents were highest at 15 d of subculture; piceid, ampelopsin, and pterostilbene had higher contents at 30 d. A transcriptome analysis identified 1310 and 498 (at 15 d) and 1696 and 2211 (at 30 d) differentially expressed genes (DEGs; log2(fold change) ≥ 1, p < 0.05) in 7.5 vs. 15 g/L and 15 vs. 30 g/L sucrose treatments, respectively. In phenylpropane and isoflavone pathways, DEGs encoding cinnamic acid 4-hydroxylase, chalcone synthase, chalcone isomerase, and flavanone 3-hydroxylase were more highly expressed at 15 d than at 30 d, while other DEGs showed different regulation patterns corresponding to sucrose concentrations and cultivation times. For all three sucrose concentrations, the stilbene synthase (STS) gene exhibited significantly higher expression at 15 vs. 30 d, while two resveratrol O-methyltransferase (ROMT) genes related to pterostilbene synthesis showed significantly higher expression at 30 vs. 15 d. In addition, a total of 481 DEGs were annotated as transcription factors in pairwise comparisons; an integrative analysis suggested MYB59, WRKY20, and MADS8 as potential regulators responding to sucrose levels in flavonoid and stilbene biosynthesis in grape callus. Our results provide valuable information for high-efficiency production of flavonoids and stilbenes using grape callus.
Oral Chronic Graft-Versus-Host Disease: Pathogenesis, Diagnosis, Current Treatment, and Emerging Therapies
Authors: Nguyen Joe T. , Jessri Maryam , Costa-da-Silva Ana C. , Sharma Rubina , Mays Jacqueline W. , Treister Nathaniel S.
Published: September 2024

Chronic graft-versus-host disease (cGvHD) is a multisystem disorder that occurs in recipients of allogeneic hematopoietic (alloHCT) stem cell transplants and is characterized by both inflammatory and fibrotic manifestations. It begins with the recognition of host tissues by the non-self (allogeneic) graft and progresses to tissue inflammation, organ dysfunction and fibrosis throughout the body. Oral cavity manifestations of cGVHD include mucosal features, salivary gland dysfunction and fibrosis. This review synthesizes current knowledge on the pathogenesis, diagnosis and management of oral cGVHD, with a focus on emerging trends and novel therapeutics. Data from various clinical studies and expert consensus are integrated to provide a comprehensive overview.
Hot Spots of Site-Specific Integration into the Sinorhizobium meliloti Chromosome
Authors: Vladimirova Maria E. , Roumiantseva Marina L. , Saksaganskaia Alla S. , Muntyan Victoria S. , Gaponov Sergey P. , Mengoni Alessio
Published: September 2024

The diversity of phage-related sequences (PRSs) and their site-specific integration into the genomes of nonpathogenic, agriculturally valuable, nitrogen-fixing root nodule bacteria, such as Sinorhizobium meliloti, were evaluated in this study. A total of 314 PRSs, ranging in size from 3.24 kb to 88.98 kb, were identified in the genomes of 27 S. meliloti strains. The amount of genetic information foreign to S. meliloti accumulated in all identified PRSs was 6.30 Mb. However, more than 53% of this information was contained in prophages (Phs) and genomic islands (GIs) integrated into genes encoding tRNAs (tRNA genes) located on the chromosomes of the rhizobial strains studied. It was found that phiLM21-like Phs were predominantly abundant in the genomes of S. meliloti strains of distant geographical origin, whereas RR1-A- and 16-3-like Phs were much less common. In addition, GIs predominantly contained fragments of phages infecting bacteria of distant taxa, while rhizobiophage-like sequences were unique. A site-specific integration analysis revealed that not all tRNA genes in S. meliloti are integration sites, but among those in which integration occurred, there were “hot spots” of integration into which either Phs or GIs were predominantly inserted. For the first time, it is shown that at these integration “hot spots”, not only is the homology of attP and attB strictly preserved, but integrases in PRSs similar to those of phages infecting the Proteobacteria genera Azospirillum or Pseudomonas are also present. The data presented greatly expand the understanding of the fate of phage-related sequences in host bacterial genomes and also raise new questions about the role of phages in bacterial–phage coevolution.
Estimation of Chloride Channel Residual Function and Assessment of Targeted Drugs Efficiency in the Presence of a Complex Allele [L467F;F508del] in the CFTR Gene
Authors: Efremova Anna , Melyanovskaya Yuliya , Krasnova Maria , Voronkova Anna , Mokrousova Diana , Zhekaite Elena , Bulatenko Nataliya , Makhnach Oleg , Bukharova Tatiana , Kutsev Sergei , Goldshtein Dmitry , Kondratyeva Elena
Published: September 2024

Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the Russian population of patients with CF is 0.74%, and in patients with the F508del/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele [L467F;F508del] in a cohort of patients with genotypes [L467F;F508del]/class I (c.3532_3535dup, c.1766+2T>C, W1310X, 712-1G>T), and data for a unique patient with the genotype [L467F;F508del]/[L467F;F508del]. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for [L467F;F508del]/class I and [L467F;F508del]/[L467F;F508del] genotypes. In intestinal organoids, it was shown that [L467F;F508del] in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6–12 months.
Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil
Authors: Childers Matthew Carter , Regnier Michael
Published: September 2024

The binding of small molecules to sarcomeric myosin can elicit powerful effects on the chemomechanical cycle, making them effective therapeutics in the clinic and research tools at the benchtop. However, these myotropes can have complex effects that act on different phases of the crossbridge cycle and which depend on structural, dynamic, and environmental variables. While small molecule binding sites have been identified crystallographically and their effects on contraction studied extensively, small molecule-induced dynamic changes that link structure–function are less studied. Here, we use molecular dynamics simulations to explore how omecamtiv mecarbil (OM), a cardiac myosin-specific myotrope, alters the coordinated dynamics of the lever arm and the motor domain in the pre-powerstroke state. We show that the lever arm adopts a range of orientations and find that different lever arm orientations are accompanied by changes in the hydrogen bonding patterns near the converter. We find that the binding of OM to myosin reduces the conformational heterogeneity of the lever arm orientation and also adjusts the average lever arm orientation. Finally, we map out the distinct conformations and ligand–protein interactions adopted by OM. These results uncover some structural factors that govern the motor domain–tail orientations and the mechanisms by which OM primes the pre-powerstroke myosin heads.
Interaction of Tri-Cyclic Nucleobase Analogs with Enzymes of Purine Metabolism: Xanthine Oxidase and Purine Nucleoside Phosphorylase
Authors: Stachelska-Wierzchowska Alicja , Narczyk Marta , Wierzchowski Jacek , Bzowska Agnieszka , Wielgus-Kutrowska Beata
Published: September 2024

Fluorescent markers play important roles in spectroscopic and microscopic research techniques and are broadly used in basic and applied sciences. We have obtained markers with fluorescent properties, two etheno derivatives of 2-aminopurine, as follows: 1,N2-etheno-2-aminopurine (1,N2-ε2APu, I) and N2,3-etheno-2-aminopurine (N2,3-ε2APu, II). In the present paper, we investigate their interaction with two key enzymes of purine metabolism, purine nucleoside phosphorylase (PNP), and xanthine oxidase (XO), using diffraction of X-rays on protein crystals, isothermal titration calorimetry, and fluorescence spectroscopy. Crystals were obtained and structures were solved for WT PNP and D204N-PNP mutant in a complex with N2,3-ε2APu (II). In the case of WT PNP—1,N2-ε2APu (I) complex, the electron density corresponding to the ligand could not be identified in the active site. Small electron density bobbles may indicate that the ligand binds to the active site of a small number of molecules. On the basis of spectroscopic studies in solution, we found that, in contrast to PNP, 1,N2-ε2APu (I) is the ligand with better affinity to XO. Enzymatic oxidation of (I) leads to a marked increase in fluorescence near 400 nm. Hence, we have developed a new method to determine XO activity in biological material, particularly suitable for milk analysis.
Vitamin B6 Pathway Maintains Glioblastoma Cell Survival in 3D Spheroid Cultures
Authors: Moosa Najla Yussuf , Azeem Sara Abdullah , Lodge John K. , Cheung William , Ahmed Shafiq Uddin
Published: September 2024

Glioblastoma (GBM) is a deadly brain cancer. The prognosis of GBM patients has marginally improved over the last three decades. The response of GBMs to initial treatment is inevitably followed by relapse. Thus, there is an urgent need to identify and develop new therapeutics to target this cancer and improve both patient outcomes and long-term survival. Metabolic reprogramming is considered one of the hallmarks of cancers. However, cell-based studies fail to accurately recapitulate the in vivo tumour microenvironment that influences metabolic signalling and rewiring. Against this backdrop, we conducted global, untargeted metabolomics analysis of the G7 and R24 GBM 2D monolayers and 3D spheroid cultures under identical cell culture conditions. Our studies revealed that the levels of multiple metabolites associated with the vitamin B6 pathway were significantly altered in 3D spheroids compared to the 2D monolayer cultures. Importantly, we show that pharmacological intervention with hydralazine, a small molecule that reduces vitamin B6 levels, resulted in the cell death of 3D GBM spheroid cultures. Thus, our study shows that inhibition of the vitamin B6 pathway is a novel therapeutic strategy for the development of targeted therapies in GBMs.
The Intriguing Pattern of Nontuberculous Mycobacteria in Bulgaria and Description of Mycobacterium bulgaricum sp. nov.
Authors: Zimenkov Danila , Atanasova Yuliana , Ushtanit Anastasia , Yordanova Stanislava , Baykova Ana , Filippova Marina , Semenova Uliana , Mokrousov Igor , Bachiyska Elizabeta
Published: September 2024

We investigated the rise of nontuberculous mycobacteria (NTM) infections in Bulgaria, focusing on species identification and distribution from 2018 to 2022. Utilizing advanced diagnostic tools, including the Hain Mycobacterium CM/AS method, Myco-biochip assay, and whole-genome sequencing, the study identifies and characterizes a diverse range of Mycobacterium species from clinical samples. While M. avium, M. gordonae, M. fortuitum, and M. chelonae were dominating, a number of rare species were also found. They include such species as M. marseillense and M. celatum. Moreover, the noticeable prevalence of M. terrae complex species missed by conventional testing was observed. We identified a rare species, highly homologous to previously described strains from Japan; based on genome–genome distance data, we propose its reannotation as a new species. Further, a novel species was identified, which is significantly distinct from its closest neighbor, M. iranicum, with ANI = 87.18%. Based on the SeqCode procedure, we propose to name this new species Mycobacterium bulgaricum sp. nov. Dynamic changes in NTM species prevalence in Bulgaria observed from 2011 to 2022 highlight the emergence of new species and variations tied to environmental and demographic factors. This underscores the importance of accurate species identification and genotyping for understanding NTM epidemiology, informing public health strategies, and enhancing diagnostic accuracy and treatment protocols.
Characterization, Evolution, Expression and Functional Divergence of the DMP Gene Family in Plants
Authors: Ahmad Zeeshan , Tian Dingyan , Li Yan , Aminu Isah Mansur , Tabusam Javaria , Zhang Yongshan , Zhu Shouhong
Published: September 2024

The DMP (DOMAIN OF UNKNOWN FUNCTION 679 membrane protein) domain, containing a family of membrane proteins specific to green plants, is involved in numerous biological functions including physiological processes, reproductive development and senescence in Arabidopsis, but their evolutionary relationship and biological function in most crops remains unknown. In this study, we scrutinized phylogenetic relationships, gene structure, conserved domains and motifs, promoter regions, gene loss/duplication events and expression patterns. Overall, 240 DMPs were identified and analyzed in 24 plant species selected from lower plants to angiosperms. Comprehensive evolutionary analysis revealed that these DMPs underwent purifying selection and could be divided into five groups (I–V). DMP gene structure showed that it may have undergone an intron loss event during evolution. The five DMP groups had the same domains, which were distinct from each other in terms of the number of DMPs; group III was the largest, closely followed by group V. The DMP promotor region with various cis-regulatory elements was predicted to have a potential role in development, hormone induction and abiotic stresses. Based on transcriptomic data, expression profiling revealed that DMPs were primarily expressed in reproductive organs and were moderately expressed in other tissues. Evolutionary analysis suggested that gene loss events occurred more frequently than gene duplication events among all groups. Overall, this genome-wide study elucidates the potential function of the DMP gene family in selected plant species, but further research is needed in many crops to validate their biological roles.
In Silico Analysis of the Molecular Interaction between Anthocyanase, Peroxidase and Polyphenol Oxidase with Anthocyanins Found in Cranberries
Authors: Araya Victoria , Gatica Marcell , Uribe Elena , Román Juan
Published: September 2024

Anthocyanins are bioactive compounds responsible for various physiological processes in plants and provide characteristic colors to fruits and flowers. Their biosynthetic pathway is well understood; however, the enzymatic degradation mechanism is less explored. Anthocyanase (β-glucosidase (BGL)), peroxidase (POD), and polyphenol oxidase (PPO) are enzymes involved in degrading anthocyanins in plants such as petunias, eggplants, and Sicilian oranges. The aim of this work was to investigate the physicochemical interactions between these enzymes and the identified anthocyanins (via UPLC-MS/MS) in cranberry (Vaccinium macrocarpon) through molecular docking to identify the residues likely involved in anthocyanin degradation. Three-dimensional models were constructed using the AlphaFold2 server based on consensus sequences specific to each enzyme. The models with the highest confidence scores (pLDDT) were selected, with BGL, POD, and PPO achieving scores of 87.6, 94.8, and 84.1, respectively. These models were then refined using molecular dynamics for 100 ns. Additionally, UPLC-MS/MS analysis identified various flavonoids in cranberries, including cyanidin, delphinidin, procyanidin B2 and B4, petunidin, pelargonidin, peonidin, and malvidin, providing important experimental data to support the study. Molecular docking simulations revealed the most stable interactions between anthocyanase and the anthocyanins cyanidin 3-arabinoside and cyanidin 3-glucoside, with a favorable ΔG of interaction between −9.3 and −9.2 kcal/mol. This study contributes to proposing a degradation mechanism and seeking inhibitors to prevent fruit discoloration.