bluuebunny/crossref_metadata_2025 huggingface dataset:
The Combined Power of Double Mass Curves and Bias Correction for the Maximisation of the Accuracy of an Ensemble Satellite-Based Precipitation Estimate Product
Authors: Sriwongsitanon Nutchanart , Kaprom Chanphit , Tantisuvanichkul Kamonpat , Prasertthonggorn Nattakorn , Suiadee Watchara , Bastiaanssen Wim G. M. , Williams James Alexander
Published: July 2023

Precise estimation of the spatial and temporal characteristics of rainfall is essential for producing the reliable catchment response needed for proper management of water resources. However, in most parts of the world, gauged rainfall stations are sparsely distributed and fail to properly capture the spatial variability of rainfall. Furthermore, the gauged rainfall data can sometimes be of short length or require validation. Following this, we present a procedure that enhances the trustworthiness of gauged rainfall data and the accuracy of the rainfall estimations of five satellite-based precipitation estimate (SPE) products by validating them using the 1779 gauged rainfall stations across Thailand. The five SPE products considered include CMORPH-BLD; TRMM-3B42; CHIRPS; CHIRPS-PL; and TRMM-3B42RT. Prior to validation, the gauged rainfall dataset was verified using double mass curve (DMC) analysis to eliminate questionable and inconsistent readings. This led to the improvement of the Nash–Sutcliffe Efficiency (NSE) between the station of interest and its surroundings by 13.9% (0.758–0.863), together with an average 11.8% increase with SPE products, whilst dropping only 7% of questionable dataset. Three different bias correction (BC) procedures were applied to correct SPE products using gauge-based gridded rainfall (GGR). Once DMC and BC procedures were implemented together, the performance of the SPE products was found to increase significantly. Finally, the application of the ensemble weighted average of the three best-performing bias-corrected SPE products (Bias-CMORPH-BLD, Bias-TRMM-3B42, and Bias-CHIRPS) further enhanced the NSE to 0.907 and 0.880 in calibration and validation time periods, respectively. The proposed DMC-based correction SPE and the weighting procedure of multiple SPE products allows for an easy means of obtaining daily rainfall in remote locations with sufficient accuracy.
Examining the Psychoactive Differences between Kratom Strains
Authors: Huisman Guido , Menke Maximilian , Grundmann Oliver , Schreiber Rudy , Mason Natasha
Published: July 2023

Kratom (Mitragyna speciosa) is a Southeast Asian plant containing various alkaloids that induce pharmacological effects in humans. In Western countries, online vendors sell a variety of different kratom strains which are marketed to have distinct effect profiles. However, as of yet such marketing claims are unsubstantiated, and therefore the current study investigated whether differently colored kratom products can induce distinct effects, as self-reported by users. Six hundred forty-four current kratom users were anonymously surveyed to compare the self-reported effects of and motivations for using kratom products sold as red, green, and white strains. Most of the survey respondents were customers of the same kratom vendor, the products of which had been analyzed for their alkaloid content by an independent laboratory. The survey respondents reported distinct subjective experiences for different kratom strains, in a manner congruent with common marketing descriptions. However, the product analyses revealed no significant cross-strain differences in alkaloid content, suggesting that the reported effect differences might be disproportionally influenced by marketing narratives and anecdotal reports. Future studies should engage a more diverse population and include kratom strains from various vendors. Controlled, blinded experiments could assess whether the reported effect differences stem from a placebo effect or from alternative factors, e.g., minor alkaloids and terpenes.
The Relationships between Compulsive Internet Use, Alexithymia, and Dissociation: Gender Differences among Italian Adolescents
Authors: Germani Alessandro , Lopez Antonella , Martini Elvira , Cicchella Sara , De Fortuna Angelo Maria , Dragone Mirella , Pizzini Barbara , Troisi Gina , De Luca Picione Raffaele
Published: July 2023

Internet Gaming Disorder, Internet Addiction, Problematic Internet Use and Compulsive Internet Use cause distress and significant impairment in important areas of a person’s functioning, in particular among young people. The literature has indicated that males show higher levels of problematic internet use than females. People can use the internet to avoid or alleviate negative affects; in fact, problematic internet use is associated with alexithymia and dissociation. Few studies have focused on the different stages of adolescence, gender differences, and the relationships between the aforementioned variables. This research aims to fill this gap. Five hundred and ninety-four adolescents aged between 13 and 19 filled in the Compulsive Internet Use Scale, the Toronto Alexithymia Scale, the Adolescents Dissociative Experiences Scale, and other ad hoc measures. Surprisingly, females reported higher compulsive internet use compared with males. Moreover, they referred more difficulties/symptoms and greater levels of alexithymia than males. No differences across the stages of adolescence were found. Different strengths in the relationships between variables were found according to gender. Moderated mediation analyses indicated that dissociation is an important mediator in the relation between alexithymia and Compulsive Internet Use only among females. This study shed new light on gender differences around problematic internet use and some related risk factors, in order to identify and develop prevention and treatment programs to face this topical and relevant issue.
Engagement with Nature and the Home Environment: Wellbeing and Proenvironmental Behavior among Irish and Italian University Students during the COVID-19 Emergency
Authors: Tzankova Iana Ivanova , O’Sullivan Catherine , Facciuto Alessandra Iva , Sacchetti Luciana , Fini Fabiana , Cicognani Elvira , Setti Annalisa
Published: July 2023

Growing evidence shows that exposure to nature and psychological engagement with nature improve health and wellbeing and promote greater proenvironmental engagement. The unprecedented situation created by COVID-related lockdowns seems to have brought both potential distress with household confinements and greater research on experiences in nature. University students may have been particularly impacted as the quality of their home arrangements can vary substantially. The aim of the study was to examine how psychological engagement with nature (nature connectedness and noticing nature), time spent in nature, and household conditions relate to psychological wellbeing and proenvironmental behavior among university students. An online survey was administered to a sample of 566 university students from Italy and Ireland. Hierarchical multiple regressions were performed to investigate the relationships between variables. The results indicate that time spent in nature and psychological engagement with nature in terms of nature connectedness and noticing nature were associated with increased wellbeing and pro-nature-conservation behavior, controlling for demographic covariates. Moreover, the perception of chaos in one’s household was related to decreased wellbeing during the prolonged COVID-19 emergency. The findings highlight the need to invest in accessible natural places for students and to focus campus sustainability practices on encouraging nature connectedness to promote wellbeing and proenvironmental engagement.
Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development
Authors: Furukawa Tatsuhiko , Mimami Kentaro , Nagata Toshiyuki , Yamamoto Masatasu , Sato Masami , Tanimoto Akihide
Published: July 2023

The circadian rhythm-related genes BHLHE40/DEC1 and BHLHE41/DEC2 have various functions under different cell and tissue conditions. BHLHE41/DEC2 has been reported to be both a cancer-suppressive and an oncogenic gene during cancer development. The effects of BHLHE41/DEC2 on differentiation have been examined using Bhlhe41/Dec2 knockout mice and/or in vitro differentiation models, and research has been conducted using genetic analysis of tumor cells, in vitro analysis of cancer cell lines, and immunohistochemical studies of the clinical samples. We summarize some of these studies, detail several problems, and consider possible reasons for contradictory results and the needs for further research.
TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma
Authors: Amin Niranjana , Wang Herui , Song Qi , Bhaskar Manju , Yadav Sharda Prasad , Gilbert Mark R. , Pant Harish , Tabouret Emeline , Zhuang Zhengping
Published: July 2023

Colorectal carcinoma (CRC) is a prevalent cancer worldwide with a high mortality rate. Evidence suggests that increased expression of Cyclin-dependent kinase 5 (CDK5) contributes to cancer progression, making it a promising target for treatment. This study examined the efficacy of selectively inhibiting CDK5 in colorectal carcinoma using TP5, a small peptide that selectively inhibits the aberrant and hyperactive CDK5/p25 complex while preserving physiological CDK5/p35 functions. We analyzed TP5’s impact on CDK5 activity, cell survival, apoptosis, the cell cycle, DNA damage, ATM phosphorylation, and reactive oxygen species (ROS) signaling in mitochondria, in CRC cell lines, both alone and in combination with chemotherapy. We also assessed TP5’s efficacy on a xenograft mouse model with HCT116 cells. Our results showed that TP5 decreased CDK5 activity, impaired cell viability and colony formation, induced apoptosis, increased DNA damage, and led to the G1 phase arrest of cell cycle progression. In combination with irinotecan, TP5 demonstrated a synergy by leading to the accumulation of DNA damage, increasing the γH2A.X foci number, and inhibiting G2/M arrest induced by Sn38 treatment. TP5 alone or in combination with irinotecan increased mitochondrial ROS levels and inhibited tumor growth, prolonging mouse survival in the CRC xenograft animal model. These results suggest that TP5, either alone or in combination with irinotecan, is a promising therapeutic option for colorectal carcinoma.
Recruitment of Corticotropin-Releasing Hormone (CRH) Neurons in Categorically Distinct Stress Reactions in the Mouse Brain
Authors: Horváth Krisztina , Juhász Balázs , Kuti Dániel , Ferenczi Szilamér , Kovács Krisztina J.
Published: July 2023

Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (PVH) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however its involvement in the organization of the stress response is not fully understood. In these experiments, we took advantage of recently available Crh-IRES-Cre;Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. A total of 95 brain regions in the adult male mouse brain have been identified as containing putative CRH neurons with significant expression of tdTomato marker gene. With comparison of CRH mRNA and tdTomato distribution, we found match and mismatch areas. Reporter mice were then exposed to restraint, ether, high salt, lipopolysaccharide and predator odor stress and neuronal activation was revealed by FOS immunocytochemistry. In addition to a core stress system, stressor-specific areas have been revealed to display activity marker FOS. Finally, activation of CRH neurons was detected by colocalization of FOS in tdTomato expressing cells. All stressors resulted in profound activation of CRH neurons in the hypothalamic paraventricular nucleus; however, a differential activation of pattern was observed in CRH neurons in extrahypothalamic regions. This comprehensive description of stress-related CRH neurons in the mouse brain provides a starting point for a systematic functional analysis of the brain stress system and its relation to stress-induced psychopathologies.
Modulation of the Proliferative Pathway, Neuroinflammation and Pain in Endometriosis
Authors: Interdonato Livia , Marino Ylenia , D’Amico Ramona , Cordaro Marika , Siracusa Rosalba , Impellizzeri Daniela , Macrì Francesco , Fusco Roberta , Cuzzocrea Salvatore , Di Paola Rosanna
Published: July 2023

Endometriosis is a chronic disease characterized by pelvic inflammation. This study aimed at investigating the molecular mechanisms underlying the pathology and how they can be modulated by the administration of a natural compound, Actaea racemosa (AR). We employed an in vivo model of endometriosis in which rats were intraperitoneally injected with uterine fragments from donor animals. During the experiment, rats were monitored by abdominal high-frequency ultrasound analysis. AR was able to reduce the lesion’s size and histological morphology. From a molecular point of view, AR reduced hyperproliferation, as shown by Ki-67 and PCNA expression and MAPK phosphorylation. The impaired apoptosis pathway was also restored, as shown by the TUNEL assay and RT-PCR for Bax, Bcl-2, and Caspase levels. AR also has important antioxidant (reduced Nox expression, restored SOD activity and GSH levels, and reduced MPO activity and MDA levels) and anti-inflammatory (reduced cytokine levels) properties. Moreover, AR demonstrated its ability to reduce the pain-like behaviors associated with the pathology, the neuro-sensitizing mediators (c-FOS and NGF) expression, and the related central astrogliosis (GFAP expression in the spinal cord, brain cortex, and hippocampus). Overall, our data showed that AR was able to manage several pathways involved in endometriosis suppression.
New Trends in Pathology: From Cell Morphology to Molecular Medicine
Authors: Bonifacio Maria Addolorata , Mariggiò Maria Addolorata
Published: July 2023

After Rudolf Virchow’s pioneering works, technological advances boosted the scientific interest in this research field, which nowadays is still far from extinguished [...]
NanoLC-EI-MS: Perspectives in Biochemical Analysis
Authors: Pereira dos Santos Natalia Gabrielly , Maciel Edvaldo Vasconcelos Soares , Vargas Medina Deyber Arley , Lanças Fernando Mauro
Published: July 2023

Although LC-MS with atmospheric pressure ionization (API) sources is the primary technique used in modern bioanalytical studies, electron ionization mass spectrometry (EI-MS) can provide some substantial advantages over it. EI-MS is a matrix effect-free technique that provides reproducible and comparable mass spectra, serving as a compound fingerprint for easy identification through automated comparison with spectral libraries. Leveraging EI-MS in biochemical studies can yield critical analytical benefits for targeted and untargeted analyses. However, to fully utilize EI-MS for heavy and non-volatile molecules, a new technology that enables the coupling of liquid chromatography with EI-MS is needed. Recent advancements in nanoLC have addressed the compatibility issues between LC and EI-MS, and innovative interfacing strategies such as Direct-EI, liquid electron ionization (LEI), and Cold-EI have extended the application of EI-MS beyond the determination of volatile organic molecules. This review provides an overview of the latest developments in nanoLC-EI-MS interfacing technologies, discussing their scope and limitations. Additionally, selected examples of nanoLC-EI-MS applications in the field of biochemical analysis are presented, highlighting the potential prospects and benefits that the establishment of this technique can bring to this field.
Consensus Gene Network Analysis Identifies the Key Similarities and Differences in Endothelial and Epithelial Cell Dynamics after Candida albicans Infection
Authors: Naik Surabhi , Mohammed Akram
Published: July 2023

Endothelial and epithelial cells are morphologically different and play a critical role in host defense during Candida albicans infection. Both cells respond to C. albicans infection by activating various signaling pathways and gene expression patterns. Their interactions with these pathogens can have beneficial and detrimental effects, and a better understanding of these interactions can help guide the development of new therapies for C. albicans infection. To identify the differences and similarities between human endothelial and oral epithelial cell transcriptomics during C. albicans infection, we performed consensus WGCNA on 32 RNA-seq samples by relating the consensus modules to endothelial-specific modules and analyzing the genes connected. This analysis resulted in the identification of 14 distinct modules. We demonstrated that the magenta module correlates significantly with C. albicans infection in each dataset. In addition, we found that the blue and cyan modules in the two datasets had opposite correlation coefficients with a C. albicans infection. However, the correlation coefficients and p-values between the two datasets were slightly different. Functional analyses of the hub of genes from endothelial cells elucidated the enrichment in TNF, AGE-RAGE, MAPK, and NF-κB signaling. On the other hand, glycolysis, pyruvate metabolism, amino acid, fructose, mannose, and vitamin B6 metabolism were enriched in epithelial cells. However, mitophagy, necroptosis, apoptotic processes, and hypoxia were enriched in both endothelial and epithelial cells. Protein–protein interaction analysis using STRING and CytoHubba revealed STAT3, SNRPE, BIRC2, and NFKB2 as endothelial hub genes, while RRS1, SURF6, HK2, and LDHA genes were identified in epithelial cells. Understanding these similarities and differences may provide new insights into the pathogenesis of C. albicans infections and the development of new therapeutic targets and interventional strategies.
Exploring the Potential of a Genome-Reduced Escherichia coli Strain for Plasmid DNA Production
Authors: Nguyen Thi Thuy , Bui Le Minh , Byun Ji-Young , Cho Byung-Kwan , Kim Sun Chang
Published: July 2023

The global demand for nucleic acid-based vaccines, including plasmid DNA (pDNA) and mRNA vaccines, needs efficient production platforms. However, conventional hosts for plasmid production have encountered challenges related to sequence integrity due to the presence of insertion sequences (ISs). In this study, we explored the potential of a genome-reduced Escherichia coli as a host for pDNA production. This strain had been constructed by removing approximately 23% of the genome which were unessential genes, including the genomic unstable elements. Moreover, the strain exhibits an elevated level of NADPH, a coenzyme known to increase plasmid production according to a mathematical model. We hypothesized that the combination of genome reduction and the abundance of NADPH would significantly enhance pDNA production capabilities. Remarkably, our results confirmed a three-fold increase in pDNA production compared to the widely employed DH5α strain. Furthermore, the genome-reduced strain exhibited heightened sensitivity to various antibiotics, bolstering its potential for large scale industrial pDNA production. These findings suggest the genome-reduced E. coli as an exciting candidate for revolutionizing the pDNA industry, offering unprecedented efficiency and productivity.
Revealing the Beauty Potential of Grape Stems: Harnessing Phenolic Compounds for Cosmetics
Authors: Serra Mónica , Casas Ana , Teixeira José António , Barros Ana Novo
Published: July 2023

Grape stems have emerged as a promising natural ingredient in the cosmetics industry due to their abundance of phenolic compounds, known for their antioxidant and anti-inflammatory properties. These compounds have shown great potential in promoting skin health, fighting signs of aging, and shielding against environmental stressors. With high concentrations of resveratrol, flavonoids, and tannins, grape stems have garnered attention from cosmetic scientists. Research has indicated that phenolic compounds extracted from grape stems possess potent antioxidant abilities, effectively combating free radicals that accelerate aging. Moreover, these compounds have demonstrated the capacity to shield the skin from UV damage, boost collagen production, and enhance skin elasticity. Cosmetic formulations incorporating grape stem extracts have displayed promising results in addressing various skin concerns, including reducing wrinkles, fine lines, and age spots, leading to a more youthful appearance. Additionally, grape stem extracts have exhibited anti-inflammatory properties, soothing irritated skin and diminishing redness. Exploring the potential of grape stem phenolic compounds for cosmetics paves the way for sustainable and natural beauty products. By harnessing the beauty benefits of grape stems, the cosmetics industry can provide effective and eco-friendly solutions for consumers seeking natural alternatives. Ongoing research holds the promise of innovative grape stem-based formulations that could revolutionize the cosmetics market, fully unlocking the potential of these extraordinary botanical treasures.
Amoebiasis: Advances in Diagnosis, Treatment, Immunology Features and the Interaction with the Intestinal Ecosystem
Authors: Morán Patricia , Serrano-Vázquez Angélica , Rojas-Velázquez Liliana , González Enrique , Pérez-Juárez Horacio , Hernández Eric G. , Padilla Maria de los Angeles , Zaragoza Martha E. , Portillo-Bobadilla Tobías , Ramiro Manuel , Ximénez Cecilia
Published: July 2023

This review of human amoebiasis is based on the most current knowledge of pathogenesis, diagnosis, treatment, and Entamoeba/microbiota interactions. The most relevant findings during this last decade about the Entamoeba parasite and the disease are related to the possibility of culturing trophozoites of different isolates from infected individuals that allowed the characterization of the multiple pathogenic mechanisms of the parasite and the understanding of the host–parasite relationship in the human. Second, the considerable advances in molecular biology and genetics help us to analyze the genome of Entamoeba, their genetic diversity, and the association of specific genotypes with the different amoebic forms of human amoebiasis. Based on this knowledge, culture and/or molecular diagnostic strategies are now available to determine the Entamoeba species and genotype responsible for invasive intestinal or extraintestinal amoebiasis cases. Likewise, the extensive knowledge of the immune response in amoebiasis with the appearance of new technologies made it possible to design diagnostic tools now available worldwide. Finally, the understanding of the interaction between the Entamoeba species and the intestinal microbiota aids the understanding of the ecology of this parasite in the human environment. These relevant findings will be discussed in this review.
Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
Authors: Semenova Natalia , Kamenets Elena , Annenkova Eleonora , Marakhonov Andrey , Gusarova Elena , Demina Nina , Guseva Daria , Anisimova Inga , Degtyareva Anna , Taran Natalia , Strokova Tatiana , Zakharova Ekaterina
Published: July 2023

Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the JAG1 or NOTCH2 gene. The variable expressivity of the clinical phenotype and the lack of genotype–phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the JAG1 and NOTCH2 genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases—one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the JAG1 gene—eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with NOTCH2 variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.
From Teeth to Therapy: A Review of Therapeutic Potential within the Secretome of Stem Cells from Human Exfoliated Deciduous Teeth
Authors: Mohd Nor Nurul Hafizah , Mansor Nur Izzati , Mohd Kashim Mohd Izhar Ariff , Mokhtar Mohd Helmy , Mohd Hatta Farah Ayuni
Published: July 2023

Stem cells derived from human exfoliated deciduous teeth (SHED) have emerged as an alternative stem cell source for cell therapy and regenerative medicine because they are readily available, pose fewer ethical concerns, and have low immunogenicity and tumourigenicity. SHED offer a number of advantages over other dental stem cells, including a high proliferation rate with the potential to differentiate into multiple developmental lineages. The therapeutic effects of SHED are mediated by multiple mechanisms, including immunomodulation, angiogenesis, neurogenesis, osteogenesis, and adipogenesis. In recent years, there is ample evidence that the mechanism of action of SHED is mainly due to its paracrine action, releasing a wide range of soluble factors such as cytokines, chemokines, and trophic factors (also known as ‘secretome’) into the local tissue microenvironment to promote tissue survival and recovery. This review provides an overview of the secretome derived from SHED and highlights the bioactive molecules involved in tissue regeneration and their potential applications in regenerative medicine.
Paeonia peregrina Mill Petals as a New Source of Biologically Active Compounds: Chemical Characterization and Skin Regeneration Effects of the Extracts
Authors: Marković Tatjana , Čutović Natalija , Carević Tamara , Gašić Uroš , Stojković Dejan , Xue Jingqi , Jovanović Aleksandra
Published: July 2023

Paeonia peregrina Mill. is a perennial herbaceous plant species, known for the medicinal value of all of its plant parts, although the chemical composition of the petals is unknown. This study aimed to determine the chemical fingerprint of the petals and also establish the optimal extraction parameters, extraction medium, and extraction method for petals collected from different localities in Serbia. The optimization was performed in order to acquire extracts that are rich in the contents of total polyphenol content (TPC) and total flavonoid content (TFC), and also exhibit strong antioxidant activity. In addition, the influence of the extracts on several human skin pathogens was evaluated, as well as their ability to aid wound closure and act as anti-inflammatory agents. Both the extraction medium and the applied technique significantly influenced the skin-beneficial biological activities, while methanol proved to be a more favorable extraction medium. In conclusion, the extraction conditions that yielded the extract with the richest phenolic content with satisfactory biological potential varied between the assays, while the most promising locality in Serbia for the collection of P. peregrina petals was Pančevo (South Banat).
Trapa bispinosa Roxb. Pericarp Extract Exerts 5α-Reductase Inhibitory Activity in Castrated Benign Prostatic Hyperplasia Model Mice
Authors: Fujita Takashi , Aoyama Tomoko , Uemura Tomohiro , Takeshita Shouko , Yamasaki Takuto , Heijou Hiroko , Morimoto Koji
Published: July 2023

Trapa bispinosa Roxb. pericarp extract (TBE) has a polyphenol-rich composition and exhibits potent antioxidant and anti-glycation activities in vitro. In the present study, we investigated the inhibitory effects of TBE on 5α-reductase in vitro using LNCaP cells and in vivo using a mouse model of castrated benign prostatic hyperplasia. TBE showed concentration-dependent inhibitory effects in the 5α-reductase (5αR) activity assay. In a reporter assay using AR-Luc/LNCaP cells, TBE inhibited the activity induced by testosterone, but not that induced by dihydrotestosterone. TBE also suppressed prostate cell proliferation, prostate-specific antigens, and transmembrane protease serine 2 expression in a castrated benign prostatic hyperplasia mouse model. In addition, ellagic acid, but not gallic acid, decreased 5αR and AR-Luc activities. Together, these results suggest a potential role for TBE in benign prostatic hyperplasia through inhibition of 5αR.
Esaxerenone Inhibits Renal Angiogenesis and Endothelial-Mesenchymal Transition via the VEGFA and TGF-β1 Pathways in Aldosterone-Infused Mice
Authors: Gao Xiaomeng , Chang Jingyue , Chang Yi , Fan Lili , Liu Ziqian , Zhang Cuijuan , Shimosawa Tatsuo , Yang Fan , Xu Qingyou
Published: July 2023

Renal fibrosis is an inevitable process in the progression of chronic kidney disease (CKD). Angiogenesis plays an important role in this process. Vascular endothelial cells are involved in renal fibrosis by phenotypic transformation and secretion of extracellular matrix. Aldosterone stimulates mineralocorticoid receptor (MR) activation and induces inflammation, which is important for angiogenesis. Clinically, MR blockers (MRBs) have a protective effect on damaged kidneys, which may be associated with inhibition of angiogenesis. In this study, we used aldosterone-infused mice and found that aldosterone induced angiogenesis and that endothelial-mesenchymal transition (EndMT) in neovascular endothelial cells was involved in renal fibrosis. Notably, aldosterone induced inflammation and stimulated macrophages to secrete vascular endothelial growth factor (VEGF) A to regulate angiogenesis by activating MR, whereas EndMT occurred in response to transforming growth factor-β1 (TGF-β1) induction and participated in renal fibrosis. These effects were antagonized by the MRB esaxerenone. These findings suggest that reducing angiogenesis may be an effective strategy for treating renal fibrosis.
Comparison of Immunohistochemical Markers in Oral Submucous Fibrosis and Oral Submucous Fibrosis Transformed to Oral Squamous Cell Carcinoma—A Systematic Review and Meta-Analysis
Authors: Mohapatra Diksha , Panda Swagatika , Mohanty Neeta , Panda Saurav , Lewkowicz Natalia , Lapinska Barbara
Published: July 2023

The objective of the study was to compare the expression of immunohistochemical (IHC) markers of oral submucous fibrosis (OSMF) (non-transformed group) to those of oral squamous cell carcinoma (OSCC) transformed from OSMF (transformed group). The search for comparative cross-sectional studies was carried out in PubMed and Scopus abiding to the PICO criteria, where expression of IHC markers in OSMF were compared with that of OSCC transformed from OSMF. The cellular distribution, number of positive cases, staining intensity, and mean immunoreactive score (IRS) of each IHC marker were evaluated in both groups. A total of 14 studies were included in the systematic review, in which immunoexpression of 15 epithelial and 4 connective tissue biomarkers were evaluated. Expression of β1-integrin, OCT-3, CD1a, CD207, survivin, Dickkopf-1, COX-2, hTERT, CTGF, MDM2, Ki-67, and α-SMA were increased during transformation of OSMF to OSCC. Conversely, expression of PTEN and lysyl oxidase decreased during transformation of OSMF to OSCC. Expression of a group of epithelial markers, such as COX2, hTERT, CTGF, survivin, MDM2, and p53, was 38 times lower in the non-transformed group cases compared to transformed group cases (95% CI: 58% to 10%; p = 0.01; and I2 = 90%). Meta-analysis of all markers involved in cell metabolism/apoptosis, which included β1-integrin along with the above markers also suggested 42 times lower expression in the non-transformed group as compared to the transformed group (95% CI: 58% to 10%; p = 0.01; and I2 = 90%). Sub-group analyses on cytoplasmic and nuclear epithelial markers were inconclusive. Meta-analysis of connective tissue markers was also inconclusive. No publication bias was found. Instead of delving into numerous markers without a strong basis for their use, it is advisable to further study the markers identified in this study to explore their clinical utility.
Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age
Authors: Nakamura Aurélie , Broséus Lucile , Tost Jörg , Vaiman Daniel , Martins Silvia , Keyes Katherine , Bonello Kim , Fekom Mathilde , Strandberg-Larsen Katrine , Sutter-Dallay Anne-Laure , Heude Barbara , Melchior Maria , Lepeule Johanna
Published: July 2023

The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother–child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.
Sugar Starvation Disrupts Lipid Breakdown by Inducing Autophagy in Embryonic Axes of Lupin (Lupinus spp.) Germinating Seeds
Authors: Borek Sławomir , Stefaniak Szymon , Nuc Katarzyna , Wojtyla Łukasz , Ratajczak Ewelina , Sitkiewicz Ewa , Malinowska Agata , Świderska Bianka , Wleklik Karolina , Pietrowska-Borek Małgorzata
Published: July 2023

Under nutrient deficiency or starvation conditions, the mobilization of storage compounds during seed germination is enhanced to primarily supply respiratory substrates and hence increase the potential of cell survival. Nevertheless, we found that, under sugar starvation conditions in isolated embryonic axes of white lupin (Lupinus albus L.) and Andean lupin (Lupinus mutabilis Sweet) cultured in vitro for 96 h, the disruption of lipid breakdown occurs, as was reflected in the higher lipid content in the sugar-starved (-S) than in the sucrose-fed (+S) axes. We postulate that pexophagy (autophagic degradation of the peroxisome—a key organelle in lipid catabolism) is one of the reasons for the disruption in lipid breakdown under starvation conditions. Evidence of pexophagy can be: (i) the higher transcript level of genes encoding proteins of pexophagy machinery, and (ii) the lower content of the peroxisome marker Pex14p and its increase caused by an autophagy inhibitor (concanamycin A) in -S axes in comparison to the +S axes. Additionally, based on ultrastructure observation, we documented that, under sugar starvation conditions lipophagy (autophagic degradation of whole lipid droplets) may also occur but this type of selective autophagy seems to be restricted under starvation conditions. Our results also show that autophagy occurs at the very early stages of plant growth and development, including the cells of embryonic seed organs, and allows cell survival under starvation conditions.
Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia
Authors: Gao Daniel , Zhou Zhou , Ma Ruidong , Wu Huaizhu , Nguyen Trung , Liu Li , Dong Jingfei
Published: July 2023

When stimulated by proinflammatory mediators, endothelial cells release ultra-large von Willebrand factor (ULVWF) multimers that are hyperactive in activating and aggregating platelets. These ULVWF multimers can accumulate in the circulation and on the inflamed endothelium because they are insufficiently cleaved by the metalloprotease ADAMTS-13, which becomes moderately deficient under conditions of systemic inflammation. This moderate ADAMTS-13 deficiency may lead to thrombotic complications that contribute to ischemic tissue injury and organ failure that are associated with severe infections. To test this hypothesis, we investigated whether recombinant ADAMTS-13 improves the pathological course of endotoxemia in lipopolysaccharide (LPS)-treated mice. C57BL/J6 mice received a bolus infusion of either 5 µg/mouse of ADAMTS-13 or vehicle control 30 min after LPS challenge and were monitored for seven-day survival. During the monitoring period, platelet counts, VWF antigen, and ADAMTS-13 activity were measured. Thrombosis was also examined by the immunohistochemistry in the liver. We found that ADAMTS-13 reduced mortality from 66% to 34.9%. The improved survival was associated with a greater recovery from thrombocytopenia, higher plasma ADAMTS-13 activity, and less thrombotic vascular occlusion. These results suggest that systemic inflammation could result in deficient ULVWF proteolysis by ADAMTS-13 and that ADAMTS-13 improves the outcomes of endotoxemia-induced inflammation.
Genome-Wide Analyses of SlFWL Family Genes and Their Expression Profiles under Cold, Heat, Salt and Drought Stress in Tomato
Authors: Ran Chunxia , Zhang Yingying , Chang Feifei , Yang Xuedong , Liu Yahui , Wang Quanhua , Zhu Weimin
Published: July 2023

PLAC8 is a cysteine-rich protein that serves as a central mediator of tumor evolution in mammals. PLAC8 motif-containing proteins widely distribute in fungi, algae, higher plants and animals that have been described to be implicated in fruit size, cell number and the transport of heavy metals such as cadmium or zinc. In tomatoes, FW2.2 is a PLAC8 motif-containing gene that negatively controls fruit size by regulating cell division and expansion in the carpel ovary during fruit development. However, despite FW2.2, other FWL (FW2.2-Like) genes in tomatoes have not been investigated. In this study, we identified the 21 SlFWL genes, including FW2.2, examined their expression profiles under various abiotic adversity-related conditions. The SlFWL gene structures and motif compositions are conserved, indicating that tomato SlFWL genes may have similar roles. Cis-acting element analysis revealed that the SlFWL genes may participate in light and abiotic stress responses, and they also interacted with a variety of phytohormone-responsive proteins and plant development elements. Phylogenetic analyses were performed on five additional plant species, including Arabidopsis, pepper, soybean, rice and maize, these genes were classified into five subfamilies. Based on the results of collinearity analyses, the SlFWL genes have a tighter homologous evolutionary relationship with soybean, and these orthologous FWL gene pairs might have the common ancestor. Expression profiling of SlFWL genes show that they were all responsive to abiotic stresses, each subgroup of genes exhibited a different expression trend. Our findings provide a strong foundation for investigating the function and abiotic stress responses of the SlFWL family genes.
α5-GABAA Receptor Modulation Reverses Behavioral and Neurophysiological Correlates of Psychosis in Rats with Ventral Hippocampal Alzheimer’s Disease-like Pathology
Authors: Eassa Nicole E. , Perez Stephanie M. , Boley Angela M. , Elam Hannah B. , Sharmin Dishary , Cook James M. , Lodge Daniel J.
Published: July 2023

Of the 35 million people in the world suffering from Alzheimer’s Disease (AD), up to half experience comorbid psychosis. Antipsychotics, used to treat psychosis, are contraindicated in elderly patients because they increase the risk of premature death. Reports indicate that the hippocampus is hyperactive in patients with psychosis and those with AD. Preclinical studies have demonstrated that the ventral hippocampus (vHipp) can regulate dopamine system function, which is thought to underlie symptoms of psychosis. A viral-mediated approach was used to express mutated human genes known to contribute to AD pathology: the Swedish (K670N, M671L), Florida (I716V), and London (V717I) mutations of amyloid precursor protein and two mutations (M146L and L286V) of presenilin 1 specifically in the vHipp, to investigate the selective contribution of AD-like pathology in this region. We observed a significant increase in dopamine neuron population activity and behavioral deficits in this AD-AAV model that mimics observations in rodent models with psychosis-like symptomatologies. Further, systemic administration of MP-III-022 (α5-GABAA receptor selective positive allosteric modulator) was able to reverse aberrant dopamine system function in AD-AAV rats. This study provides evidence for the development of drugs that target α5-GABAA receptors for patients with AD and comorbid psychosis.
Transcriptome and Small RNA Sequencing Reveals the Basis of Response to Salinity, Alkalinity and Hypertonia in Quinoa (Chenopodium quinoa Willd.)
Authors: Han Huanan , Qu Yusen , Wang Yingcan , Zhang Zaijie , Geng Yuhu , Li Yuanyuan , Shao Qun , Zhang Hui , Ma Changle
Published: July 2023

Quinoa (Chenopodium quinoa Willd.) is a dicotyledonous cereal that is rich in nutrients. This important crop has been shown to have significant tolerance to abiotic stresses such as salinization and drought. Understanding the underlying mechanism of stress response in quinoa would be a significant advantage for breeding crops with stress tolerance. Here, we treated the low-altitude quinoa cultivar CM499 with either NaCl (200 mM), Na2CO3/NaHCO3 (100 mM, pH 9.0) or PEG6000 (10%) to induce salinity, alkalinity and hypertonia, respectively, and analyzed the subsequent expression of genes and small RNAs via high-throughput sequencing. A list of known/novel genes were identified in quinoa, and the ones responding to different stresses were selected. The known/novel quinoa miRNAs were also identified, and the target genes of the stress response ones were predicted. Both the differently expressed genes and the targets of differently expressed miRNAs were found to be enriched for reactive oxygen species homeostasis, hormone signaling, cell wall synthesis, transcription factors and some other factors. Furthermore, we detected changes in reactive oxygen species accumulation, hormone (auxin and ethylene) responses and hemicellulose synthesis in quinoa seedlings treated with stresses, indicating their important roles in the response to saline, alkaline or hyperosmotic stresses in quinoa. Thus, our work provides useful information for understanding the mechanism of abiotic stress responses in quinoa, which would provide clues for improving breeding for quinoa and other crops.
Epithelial-to-Mesenchymal Transition Gene Signature in Circulating Melanoma Cells: Biological and Clinical Relevance
Authors: Rapanotti Maria Cristina , Cugini Elisa , Campione Elena , Di Raimondo Cosimo , Costanza Gaetana , Rossi Piero , Ferlosio Amedeo , Bernardini Sergio , Orlandi Augusto , De Luca Anastasia , Bianchi Luca
Published: July 2023

The most promising method for monitoring patients with minimal morbidity is the detection of circulating melanoma cells (CMCs). We have shown that CD45−CD146+ABCB5+ CMCs identify a rare primitive stem/mesenchymal CMCs population associated with disease progression. The epithelial-to-mesenchymal transition (EMT) confers cancer cells a hybrid epithelial/mesenchymal phenotype promoting metastatization. Thus, we investigated the potential clinical value of the EMT gene signature of these primitive CMCs. A reliable quantitative real-time polymerase chain reaction (qRT-PCR) protocol was settled up using tumor cell lines RNA dilutions. Afterwards, immune-magnetically isolated CMCs from advanced melanoma patients, at onset and at the first checkpoint (following immune or targeted therapy), were tested for the level of EMT hallmarks and EMT transcription factor genes. Despite the small cohort of patients, we obtained promising results. Indeed, we observed a deep gene rewiring of the EMT investigated genes: in particular we found that the EMT gene signature of isolated CMCs correlated with patients’ clinical outcomes. In conclusion, We established a reliable qRT-PCR protocol with high sensitivity and specificity to characterize the gene expression of isolated CMCs. To our knowledge, this is the first evidence demonstrating the impact of immune or targeted therapies on EMT hallmark gene expressions in CMCs from advanced melanoma patients.
Building Up a Piperazine Ring from a Primary Amino Group via Catalytic Reductive Cyclization of Dioximes
Authors: Pospelov Evgeny V. , Sukhorukov Alexey Yu.
Published: July 2023

Piperazine is one of the most frequently found scaffolds in small-molecule FDA-approved drugs. In this study, a general approach to the synthesis of piperazines bearing substituents at carbon and nitrogen atoms utilizing primary amines and nitrosoalkenes as synthons was developed. The method relies on sequential double Michael addition of nitrosoalkenes to amines to give bis(oximinoalkyl)amines, followed by stereoselective catalytic reductive cyclization of the oxime groups. The method that we developed allows a straightforward structural modification of bioactive molecules (e.g., α-amino acids) by the conversion of a primary amino group into a piperazine ring.
Antioxidant Chimeric Molecules: Are Chemical Motifs Additive? The Case of a Selenium-Based Ligand
Authors: Zeppilli Davide , Aldinio-Colbachini Anna , Ribaudo Giovanni , Tubaro Cristina , Dalla Tiezza Marco , Bortoli Marco , Zagotto Giuseppe , Orian Laura
Published: July 2023

We set up an in silico experiment and designed a chimeric compound integrating molecular features from different efficient ROS (Reactive Oxygen Species) scavengers, with the purpose of investigating potential relationships between molecular structure and antioxidant activity. Furthermore, a selenium centre was inserted due to its known capacity to reduce hydroperoxides, acting as a molecular mimic of glutathione peroxidase; finally, since this organoselenide is a precursor of a N-heterocyclic carbene ligand, its Au(I) carbene complex was designed and examined. A validated protocol based on DFT (Density Functional Theory) was employed to investigate the radical scavenging activity of available sites on the organoselenide precursor ((SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)), as well as on the organometallic complex ((SMD)-M06-2X/SDD (Au), 6-311+G(d,p)//ZORA-BLYP-D3(BJ)/TZ2P), considering HAT (Hydrogen Atom Transfer) and RAF (Radical Adduct Formation) regarding five different radicals. The results of this case study suggest that the antioxidant potential of chemical motifs should not be considered as an additive property when designing a chimeric compound, but rather that the relevance of a molecular topology is derived from a chemical motif combined with an opportune chemical space of the molecule. Thus, the direct contributions of single functional groups which are generally thought of as antioxidants per se do not guarantee the efficient radical scavenging potential of a molecular species.