bluuebunny/crossref_metadata_2025 huggingface dataset:
Tribbles Genes in Gastric Cancer: A Tumor-Suppressive Role for TRIB2
Authors: Foscarini Alessia , Tricarico Rossella , Gentile Federica , Satam Swapna , Mohr Hermine , Kiss-Toth Endre , Ranzani Guglielmina Nadia , Pellegata Natalia Simona
Published: December 2023

Tribbles pseudokinases (TRIB1-3) are important signaling modulators involved in several cancers. However, their function in gastric cancer (GC) remains undefined. GC is still a deadly disease since the lack of sensitive and specific biomarkers for early diagnosis and therapy response prediction negatively affects patients’ outcome. The identification of novel molecular players may lead to more effective diagnostic and therapeutic avenues. Therefore, we investigated the role of TRIB genes in gastric tumorigenesis. Data mining of the TCGA dataset revealed that chromosomal instability (CIN) tumors have lower TRIB2 and higher TRIB3 expression versus microsatellite instability (MSI)-high tumors, while TRIB1 levels are similar in both tumor types. Moreover, in CIN tumors, low TRIB2 expression is significantly associated with aggressive stage IV disease. As no studies on TRIB2 in GC are available, we focused on this gene for further in vitro analyses. We checked the effect of TRIB2 overexpression (OE) on MKN45 and NCI-N87 CIN GC cell lines. In MKN45 cells, TRIB2 OE reduced proliferation and colony formation ability and induced G2/M arrest, while it decreased the proliferation and cell motility of NCI-N87 cells. These effects were not mediated by the MAPK pathway. Our results suggest a tumor-suppressive function of TRIB2 in GC with a CIN phenotype.
A Novel Homozygous Loss-of-Function Variant in SPRED2 Causes Autosomal Recessive Noonan-like Syndrome
Authors: Onore Maria Elena , Caiazza Martina , Farina Antonella , Scarano Gioacchino , Budillon Alberto , Borrelli Rossella Nicoletta , Limongelli Giuseppe , Nigro Vincenzo , Piluso Giulio
Published: December 2023

Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, PTPN11 was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (KRAS, SOS1, RAF1, MAP2K1, BRAF, NRAS, RIT1, and LZTR1) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway. Recently, SPRED2 was recognized as a novel Noonan syndrome gene with autosomal recessive inheritance, and only four families have been described to date. Here, we report the first Italian case, a one-year-old child with left ventricular hypertrophy, moderate pulmonary valve stenosis, and atrial septal defect, with a clinical suspicion of RASopathy supported by the presence of typical Noonan-like facial features and short stature. Exome sequencing identified a novel homozygous loss-of-function variant in the exon 3 of SPRED2 (NM_181784.3:c.325del; p.Arg109Glufs*7), likely causing nonsense-mediated decay. Our results and the presented clinical data may help us to further understand and dissect the genetic heterogeneity of Noonan syndrome.
The Phytochemical Profile and Antioxidant Activity of Thermally Processed Colorful Sweet Potatoes
Authors: Basílio Letícia Silva Pereira , Nunes Aline , Minatel Igor Otavio , Diamante Marla Sílvia , Di Lázaro Carla Beatriz , Silva Anna Carolina Abreu Francisco e , Vargas Pablo Forlan , Vianello Fabio , Maraschin Marcelo , Lima Giuseppina Pace Pereira
Published: December 2023

The effects of home cooking methods (e.g., boiling, steaming, oven, and microwave) on the contents phenolic compounds, biogenic amines, and precursor amino acids in colored-fleshed sweet potatoes were investigated in this study. Sixteen genotypes of colored sweet potatoes (cream/white, yellow, orange, and purple pulp) were analyzed using spectrophotometry for their total phenolic compounds, total flavonoids, antioxidant capacity (DPPH and MDA) and pigments. Of these, five genotypes with orange and purple pulps were investigated using HPLC-DAD for their polyphenols, biogenic amines and precursor amino acids. The results revealed that orange-fleshed sweet potatoes contain higher amounts of phenolic compounds, carotenoids, amino acids, and beneficial amines, especially when cooked in a microwave or in an oven, wrapped in aluminum foil. For the purple sweet potatoes, superior quantities of bioactive were found after cooking with steam, microwave, and in the oven with aluminum foil protection. In general, the colored genotypes showed a superior phytochemical profile than the traditionally commercialized ones before and after heat treatments, characterizing them as richer sources of the bioactive compounds of interest for producers, consumers, and industry.
Why Do Physicians in Japan Use e-Cigarettes and/or Heated Tobacco Products? A Cross-Sectional Survey
Authors: Otsuka Yuichiro , Kaneita Yoshitaka , Itani Osamu , Matsumoto Yuuki
Published: December 2023

Background: The tobacco industry has actively advocated for electronic cigarettes (e-cigarettes) and heated tobacco products (HTPs) as harm-reduction alternatives to traditional cigarettes. Around 40% of smoking physicians have adopted HTPs. This study aimed to uncover the motivations behind Japanese physicians’ e-cigarette and HTP use while analyzing the associations between product use, physician demographics, lifestyles, and smoking preferences. Methods: A mail-based survey was conducted in 2020, targeting 6000 male and 1500 female physicians. From the 5492 survey participants, 346 physicians aged 28 to 98 who were current smokers were selected. The survey assessed their usage of e-cigarettes and HTPs and explored the reasons for initial adoption. A multivariate logistic regression analysis examined the relationships between product use, physician characteristics, and behaviors. Results: Approximately 33.8% of smoking physicians had experimented with e-cigarettes and HTPs. E-cigarette and HTP use correlated with youthfulness, nicotine addiction, and a history of medical treatment. The primary drivers for adopting e-cigarettes and HTPs were reduced odor (74.4%), perceived harm reduction (48.7%), and decreased exposure to secondhand smoke (29.1%). Conclusions: Physicians, when transitioning from conventional cigarettes to HTPs or e-cigarettes, are primarily motivated by a desire to reduce the odor of conventional cigarettes rather than health-related concerns.
The Role of Trust in Disaster Risk Reduction: A Critical Review
Authors: Bonfanti Rubinia Celeste , Oberti Benedetta , Ravazzoli Elisa , Rinaldi Anna , Ruggieri Stefano , Schimmenti Adriano
Published: December 2023

In recent years, there has been a growing interest in the concept of trust within the domain of natural disaster management. Trust can be defined as a state of vulnerability where one party relies on another party with the expectation that the latter will carry out entrusted responsibilities without exploiting this inherent vulnerability. This comprehensive literature review is dedicated to the examination of research concerning community and institutional trust in the field of disaster risk reduction (DRR). Particular emphasis is placed on elucidating the influence of trust throughout the distinct phases of natural disaster management, namely prevention, preparedness, response, and recovery. The critical examination of the pertinent body of the literature demonstrates that trust plays a central role across the different phases of DRR, being positively associated with effective community responses and resilience. Hence, it becomes imperative to actively foster the development of trust at both institutional and community levels within the realm of DRR. This endeavor is essential for adequately preparing communities to confront natural disasters, crafting effective protocols to enhance community responsiveness and mitigate adverse consequences, and advancing strategies for successful reconstruction and recovery.
Qualification of the Microsatellite Instability Analysis (MSA) for Bladder Cancer Detection: The Technical Challenges of Concordance Analysis
Authors: Reynolds Thomas , Bertsche Katie , Moon David , Moon Chulso
Published: December 2023

Bladder cancer (here we refer to transitional carcinoma of bladder) is a major cause of morbidity and mortality in the Western world, and recent understanding of its etiology, the molecular characteristics associated with its progression, renders bladder cancer an ideal candidate for screening. Cystoscopy is invasive and sometimes carries unwanted complications, but it is the gold standard for the detection of bladder cancer. Urine cytology, while the most commonly used test as an initial screening tool, is of limited value due to its low sensitivity, particularly for low-grade tumors. Several new “molecular assays” for the diagnosis of urothelial cancer have been developed over the last two decades. Here, we have established our new bladder cancer test based on an assay established for the Early Detection Research Network (EDRN) study. As a part of the study, a quality control CLIA/College of American Pathology (CAP) accredited laboratory, (QA Lab), University of Maryland Baltimore Biomarker Reference Laboratory (UMB-BRL), performed quality assurance analysis. Quality assurance measures included a concordance study between the testing laboratory (AIBioTech), also CLIA/CAP accredited, and the QA lab to ensure that the assay was performed and the results were analyzed in a consistent manner. Therefore, following the technical transfer and training of the microsatellite analysis assay to the UMB-BRL and prior to the initiation of analysis of the clinical samples by the testing lab, a series of qualification studies were performed. This report details the steps taken to ensure qualification of the assay and illustrates the technical challenges facing biomarker validation of this kind.
Development of Recombinant Oncolytic rVSV-mIL12-mGMCSF for Cancer Immunotherapy
Authors: Ryapolova Anastasia , Minskaia Ekaterina , Gasanov Nizami , Moroz Vasiliy , Krapivin Bogdan , Egorov Alexander D. , Laktyushkin Victor , Zhuravleva Sofia , Nagornych Maksim , Subcheva Elena , Malogolovkin Alexander , Ivanov Roman , Karabelsky Alexander
Published: December 2023

Anti-cancer therapy based on oncolytic viruses (OVs) is a targeted approach that takes advantage of OVs’ ability to selectively infect and replicate in tumor cells, activate the host immune response, and destroy malignant cells over healthy ones. Vesicular stomatitis virus (VSV) is known for its wide range of advantages: a lack of pre-existing immunity, a genome that is easily amenable to manipulation, and rapid growth to high titers in a broad range of cell lines, to name a few. VSV-induced tumor immunity can be enhanced by the delivery of immunostimulatory cytokines. The targeted cytokine delivery to tumors avoids the significant toxicity associated with systemic delivery while also boosting the immune response. To demonstrate this enhanced effect on both tumor growth and survival, a novel recombinant VSV (rVSV)-mIL12-mGMCSF, co-expressing mouse IL-12 (interleukin-12) and GM-CSF (granulocyte-macrophage colony-stimulating factor), was tested alongside rVSV-dM51-GFP (rVSV-GFP) that was injected intratumorally in a syngeneic in vivo C57BL/6 mouse model infused subcutaneously with B16-F10 melanoma cells. The pilot study tested the effect of two viral injections 4 days apart and demonstrated that treatment with the two rVSVs resulted in partial inhibition of tumor growth (TGII of around 40%) and an increased survival rate in animals from the treatment groups. The effect of the two VSVs on immune cell populations will be investigated in future in vivo studies with an optimized experimental design with multiple higher viral doses, as a lack of this information presents a limitation of this study.
Therapeutic Efficacy of YM155 to Regulate an Epigenetic Enzyme in Major Subtypes of RCC
Authors: Hong Seong Hwi , Lee Young Ju , Jang Eun Bi , Hwang Hyun Ji , Kim Eun Song , Son Da Hyeon , Park Sung Yul , Moon Hong Sang , Yoon Young Eun
Published: December 2023

Renal cell carcinoma (RCC) is the most common type of kidney cancer and includes more than 10 subtypes. Compared to the intensively investigated clear cell RCC (ccRCC), the underlying mechanisms and treatment options of other subtypes, including papillary RCC (pRCC) and chromogenic RCC (chRCC), are limited. In this study, we analyzed the public databases for ccRCC, pRCC, and chRCC and found that BIRC5 was commonly overexpressed in a large cohort of pRCC and chRCC patients as well as ccRCC and was closely related to the progression of RCCs. We investigated the potential of BIRC5 as a therapeutic target for these three types of RCCs. Loss and gain of function studies showed the critical role of BIRC5 in cancer growth. YM155, a BIRC5 inhibitor, induced a potent tumor-suppressive effect in the three types of RCC cells and xenograft models. To determine the mechanism underlying the anti-tumor effects of YM155, we examined epigenetic modifications in the BIRC5 promoter and found that histone H3 lysine 27 acetylation (H3K27Ac) was highly enriched on the promoter region of BIRC5. Chromatin-immunoprecipitation analysis revealed that H3K27Ac enrichment was significantly decreased by YM155. Immunohistochemistry of xenografted tissue showed that overexpression of BIRC5 plays an important role in malignancy in RCC. Furthermore, high expression of P300 was significantly associated with the progression of RCC. Our findings demonstrate the P300-H3K27Ac-BIRC5 cascade in three types of RCC and provide a therapeutic path for future research on RCC.
Wnt3a Facilitates SARS-CoV-2 Pseudovirus Entry into Cells
Authors: Melano Ivonne , Chen Hui-Jye , Ngwira Loveness , Hsu Pang-Hung , Kuo Li-Lan , Noriega Lloyd , Su Wen-Chi
Published: December 2023

How ACE2 functions as the major host receptor of SARS-CoV-2 despite having low expression in the lungs is still unknown. To facilitate the development of therapeutic strategies against coronaviruses, gaining a deeper comprehension of the molecular mechanism of SARS-CoV-2 infection is imperative. In our previous study, we identified several potential host factors of SARS-CoV-2 using an shRNA arrayed screen, one of which was Wnt3a. Here, we validated the significance of Wnt3a, a potent activator of the Wnt/β-catenin signaling pathway, for SARS-CoV-2 entry into cells by evaluating the effects of its knockdown and overexpression on SARS-CoV-2 pseudotyped virus entry. Further analysis revealed that SARS-CoV-2 pseudotyped virus infection activates the canonical Wnt/β-catenin signaling pathway, which we found could subsequently stimulate ACE2 transcription. Collectively, our study identified Wnt3a as an important host factor that facilitates ACE2-mediated virus infection. Insight into the virus entry mechanism is impactful as it will aid in developing novel therapeutic strategies against current and future coronavirus pandemics.
The Discovery of the Fucoidan-Active Endo-1→4-α-L-Fucanase of the GH168 Family, Which Produces Fucoidan Derivatives with Regular Sulfation and Anticoagulant Activity
Authors: Silchenko Artem S. , Taran Ilya V. , Usoltseva Roza V. , Zvyagintsev Nikolay V. , Zueva Anastasiya O. , Rubtsov Nikita K. , Lembikova Dana E. , Nedashkovskaya Olga I. , Kusaykin Mikhail I. , Isaeva Marina P. , Ermakova Svetlana P.
Published: December 2023

Sulfated polysaccharides of brown algae, fucoidans, are known for their anticoagulant properties, similar to animal heparin. Their complex and irregular structure is the main bottleneck in standardization and in defining the relationship between their structure and bioactivity. Fucoidan-active enzymes can be effective tools to overcome these problems. In the present work, we identified the gene fwf5 encoding the fucoidan-active endo-fucanase of the GH168 family in the marine bacterium Wenyingzhuangia fucanilytica CZ1127T. The biochemical characteristics of the recombinant fucanase FWf5 were investigated. Fucanase FWf5 was shown to catalyze the endo-type cleavage of the 1→4-O-glycosidic linkages between 2-O-sulfated α-L-fucose residues in fucoidans composed of the alternating 1→3- and 1→4-linked residues of sulfated α-L-fucose. This is the first report on the endo-1→4-α-L-fucanases (EC 3.2.1.212) of the GH168 family. The endo-fucanase FWf5 was used to selectively produce high- and low-molecular-weight fucoidan derivatives containing either regular alternating 2-O- and 2,4-di-O-sulfation or regular 2-O-sulfation. The polymeric 2,4-di-O-sulfated fucoidan derivative was shown to have significantly greater in vitro anticoagulant properties than 2-O-sulfated derivatives. The results have demonstrated a new type specificity among fucanases of the GH168 family and the prospects of using such enzymes to obtain standard fucoidan preparations with regular sulfation and high anticoagulant properties.
Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts
Authors: Um Jee-Hyun , Lee Kang-Min , Kim Young-Yeon , Lee Da-Ye , Kim Eunmi , Kim Dong-Hyun , Yun Jeanho
Published: December 2023

Mitophagy stimulation has been shown to have a therapeutic effect on various neurodegenerative diseases. However, nontoxic mitophagy inducers are still very limited. In this study, we found that the natural alkaloid berberine exhibited mitophagy stimulation activity in various human cells. Berberine did not interfere with mitochondrial function, unlike the well-known mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and subsequently induced mitochondrial biogenesis. Berberine treatment induced the activation of adenosine monophosphate-activated protein kinase (AMPK), and the AMPK inhibitor compound C abolished berberine-induced mitophagy, suggesting that AMPK activation is essential for berberine-induced mitophagy. Notably, berberine treatment reversed mitochondrial dysfunction in PINK1 knockout mouse embryonic fibroblasts. Our results suggest that berberine is a mitophagy-specific inducer and can be used as a therapeutic treatment for neurodegenerative diseases, including Parkinson’s disease, and that natural alkaloids are potential sources of mitophagy inducers.
Identification of 2,4-Di-tert-butylphenol as a Novel Agonist for Insect Odorant Receptors
Authors: Lee Shinhui , Eom Sanung , Pyeon Minsu , Moon Myungmi , Yun Jihwon , Lee Jaehyeong , Choi Yong-Seok , Lee Junho H.
Published: December 2023

Odorant molecules interact with odorant receptors (ORs) lining the pores on the surface of the sensilla on an insect’s antennae and maxillary palps. This interaction triggers an electrical signal that is transmitted to the insect’s nervous system, thereby influencing its behavior. Orco, an OR coreceptor, is crucial for olfactory transduction, as it possesses a conserved sequence across the insect lineage. In this study, we focused on 2,4-di-tert-butylphenol (DTBP), a single substance present in acetic acid bacteria culture media. We applied DTBP to oocytes expressing various Drosophila melanogaster odor receptors and performed electrophysiology experiments. After confirming the activation of DTBP on the receptor, the binding site was confirmed through point mutations. Our findings confirmed that DTBP interacts with the insect Orco subunit. The 2-heptanone, octanol, and 2-hexanol were not activated for the Orco homomeric channel, but DTBP was activated, and the EC50 value was 13.4 ± 3.0 μM. Point mutations were performed and among them, when the W146 residue changed to alanine, the Emax value was changed from 1.0 ± 0 in the wild type to 0.0 ± 0 in the mutant type, and all activity was decreased. Specifically, DTBP interacted with the W146 residue of the Orco subunit, and the activation manner was concentration-dependent and voltage-independent. This molecular-level analysis provides the basis for novel strategies to minimize pest damage. DTBP, with its specific binding to the Orco subunit, shows promise as a potential pest controller that can exclusively target insects.
MNX1 Promotes Anti-HER2 Therapy Sensitivity via Transcriptional Regulation of CD-M6PR in HER2-Positive Breast Cancer
Authors: Chi Weiru , Xiu Bingqiu , Xiong Min , Wang Xuliren , Li Pei , Zhang Qi , Hou Jianjing , Sang Yuting , Zhou Xujie , Chen Ming , Zheng Shuyue , Zhang Liyi , Xue Jingyan , Chi Yayun , Wu Jiong
Published: December 2023

Although targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer has significantly prolonged survival time and improved patients’ quality of life, drug resistance has gradually emerged. This study explored the mechanisms underlying the effect of the motor neuron and pancreatic homeobox 1 (MNX1) genes on drug sensitivity in HER2-positive breast cancer. From July 2017 to 2018, core needle biopsies of HER2-positive breast cancer were collected from patients who received paclitaxel, carboplatin, and trastuzumab neoadjuvant therapy at our center. Based on treatment efficacy, 81 patients were divided into pathological complete response (pCR) and non-pCR groups. High-throughput RNA sequencing results were analyzed along with the GSE181574 dataset. MNX1 was significantly upregulated in the pCR group compared with the non-pCR group in both sequencing datasets, suggesting that MNX1 might be correlated with drug sensitivity in HER2-positive breast cancer. Meanwhile, tissue array results revealed that high MNX1 expression corresponded to a good prognosis. In vitro functional tests showed that upregulation of MNX1 significantly increased the sensitivity of HER2-positive breast cancer cells to lapatinib and pyrotinib. In conclusion, MNX1 may serve as a prognostic marker for patients with HER2-positive breast cancer, and its expression may facilitate clinical screening of patients sensitive to anti-HER2-targeted therapy.
Downregulation of Salt-Inducible Kinase 3 Enhances CCL24 Activation in the Placental Environment with Preeclampsia
Authors: Tsai Hsing-Fen , Tseng Ching-Fen , Liang Yu-Ling , Wu Pei-Ying , Huang Lan-Yin , Lin Yu-Han , Lin Li-Hsuan , Lin Chang-Ni , Hsu Keng-Fu
Published: December 2023

Preeclampsia (PE) remains one of the leading causes of maternal and perinatal morbidity and mortality. However, the exact pathophysiology of PE is still unclear. The recent widely accepted notion that successful pregnancy relies on maternal immunological adaptation is of utmost importance. Moreover, salt-inducible kinase 3 (SIK3) is an AMP-activated protein kinase-related kinase, and it has reported a novel regulator of energy and inflammation, and its expression related with some diseases. To explore whether SIK3 expression correlated with PE, we analyzed SIK3 gene expression and its association with PE through GEO datasets. We identified that SIK3 was significantly downregulated in PE across four datasets (p < 0.05), suggesting that SIK3 participated in the pathogenesis of PE. We initially demonstrated the significant downregulation of SIK3 in trophoblast cells of PE. SIK3 downregulation was positively correlated with the increased number of CD204(+) cells in in vivo and in vitro experiments. The increased number of CD204(+) cells could inhibit the migration and invasion of trophoblast cells. We then clarified the potential mechanism of PE with SIK3 downregulation: M2 skewing was triggered by trophoblast cells derived via the CCL24/CCR3 axis, leading to an increase in CD204(+) cells, a decrease in phagocytosis, and the production of IL-10 at the maternal–fetal interface of the placenta with PE. IL-10 further contributed to a reduction in the migration and invasion of trophoblast cells. It also established a feedback loop wherein trophoblast cells increased CCL24 production to maintain M2 dominance in the placental environments of PE.
Intratumoral Influenza Vaccine Administration Attenuates Breast Cancer Growth and Restructures the Tumor Microenvironment through Sialic Acid Binding of Vaccine Hemagglutinin
Authors: Daniels Preston , Cassoday Stefanie , Gupta Kajal , Giurini Eileena , Leifheit Malia E. , Zloza Andrew , Marzo Amanda L.
Published: December 2023

Breast cancer continues to have a high disease burden worldwide and presents an urgent need for novel therapeutic strategies to improve outcomes. The influenza vaccine offers a unique approach to enhance the anti-tumor immune response in patients with breast cancer. Our study explores the intratumoral use of the influenza vaccine in a triple-negative 4T1 mouse model of breast cancer. We show that the influenza vaccine attenuated tumor growth using a three-dose intratumoral regimen. More importantly, prior vaccination did not alter this improved anti-tumor response. Furthermore, we characterized the effect that the influenza vaccine has on the tumor microenvironment and the underlying mechanisms of action. We established that the vaccine facilitated favorable shifts in restructuring the tumor microenvironment. Additionally, we show that the vaccine’s ability to bind sialic acid residues, which have been implicated in having oncogenic functions, emerged as a key mechanism of action. Influenza hemagglutinin demonstrated binding ability to breast cancer cells through sialic acid expression. When administered intratumorally, the influenza vaccine offers a promising therapeutic strategy for breast cancer patients by reshaping the tumor microenvironment and modestly suppressing tumor growth. Its interaction with sialic acids has implications for effective therapeutic application and future research.
The Metabolically Obese, Normal-Weight Phenotype in Young Rats Is Associated with Cognitive Impairment and Partially Preventable with Leptin Intake during Lactation
Authors: Cifre Margalida , Palou Andreu , Oliver Paula
Published: December 2023

The intake of high-fat diets (HFDs) and obesity are linked to cognitive impairment. Here, we aimed to investigate whether an early metabolically obese, normal-weight (MONW) phenotype, induced with an HFD in young rats, also leads to cognitive dysfunction and to evaluate the potential cognitive benefits of neonatal intake of leptin. To achieve this, Wistar rats orally received physiological doses of leptin or its vehicle during lactation, followed by 11 weeks of pair-feeding with an HFD or control diet post-weaning. Working memory was assessed using a T-maze, and gene expression in the hippocampus and peripheral blood mononuclear cells (PBMCs) was assessed with real-time RT-qPCR to identify cognition biomarkers. Young MONW-like rats showed hippocampal gene expression changes and decreased working memory. Animals receiving leptin during lactation presented similar gene expression changes but preserved working memory despite HFD intake, partly due to improved insulin sensitivity. Notably, PBMC Syn1 expression appears as an accessible biomarker of cognitive health, reflecting both the detrimental effect of HFD intake at early ages despite the absence of obesity and the positive effects of neonatal leptin treatment on cognition. Thus, the MONW phenotype developed at a young age is linked to cognitive dysfunction, which is reflected at the transcriptomic level in PBMCs. Neonatal leptin intake can partly counteract this impaired cognition resulting from early HFD consumption.
microRNA-Based Cancer Diagnosis and Therapy
Authors: Chen Hexin
Published: December 2023

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally by impeding mRNA translation or stability [...]
Molecular Dynamics Investigations of Human DNA-Topoisomerase I Interacting with Novel Dewar Valence Photo-Adducts: Insights into Inhibitory Activity
Authors: Di Martino Jessica , Arcieri Manuel , Madeddu Francesco , Pieroni Michele , Carotenuto Giovanni , Bottoni Paolo , Botta Lorenzo , Castrignanò Tiziana , Gabellone Sofia , Saladino Raffaele
Published: December 2023

Chronic exposure to ultraviolet (UV) radiation is known to induce the formation of DNA photo-adducts, including cyclobutane pyrimidine dimers (CPDs) and Dewar valence derivatives (DVs). While CPDs usually occur at higher frequency than DVs, recent studies have shown that the latter display superior selectivity and significant stability in interaction with the human DNA/topoisomerase 1 complex (TOP1). With the aim to deeply investigate the mechanism of interaction of DVs with TOP1, we report here four all-atom molecular dynamic simulations spanning one microsecond. These simulations are focused on the stability and conformational changes of two DNA/TOP1-DV complexes in solution, the data being compared with the biomimetic thymine dimer counterparts. Results from root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses unequivocally confirmed increased stability of the DNA/TOP1-DV complexes throughout the simulation duration. Detailed interaction analyses, uncovering the presence of salt bridges, hydrogen bonds, water-mediated interactions, and hydrophobic interactions, as well as pinpointing the non-covalent interactions within the complexes, enabled the identification of specific TOP1 residues involved in the interactions over time and suggested a potential TOP1 inhibition mechanism in action.
Key Factors in the Complex and Coordinated Network of Skin Keratinization: Their Significance and Involvement in Common Skin Conditions
Authors: Pondeljak Nives , Lugović-Mihić Liborija , Tomić Lucija , Parać Ena , Pedić Lovre , Lazić-Mosler Elvira
Published: December 2023

The epidermis serves many vital roles, including protecting the body from external influences and healing eventual injuries. It is maintained by an incredibly complex and perfectly coordinated keratinization process. In this process, desquamation is essential for the differentiation of epidermal basal progenitor cells into enucleated corneocytes, which subsequently desquamate through programmed death. Numerous factors control keratinocyte differentiation: epidermal growth factor, transforming growth factor-α, keratinocyte growth factor, interleukins IL-1-β and IL-6, elevated vitamin A levels, and changes in Ca2+ concentration. The backbone of the keratinocyte transformation process from mitotically active basal cells into fully differentiated, enucleated corneocytes is the expression of specific proteins and the creation of a Ca2+ and pH gradient at precise locations within the epidermis. Skin keratinization disorders (histologically characterized predominantly by dyskeratosis, parakeratosis, and hyperkeratosis) may be categorized into three groups: defects in the α-helical rod pattern, defects outside the α-helical rod domain, and disorders of keratin-associated proteins. Understanding the process of keratinization is essential for the pathogenesis of many dermatological diseases because improper desquamation and epidermopoiesis/keratinization (due to genetic mutations of factors or due to immune pathological processes) can lead to various conditions (ichthyoses, palmoplantar keratodermas, psoriasis, pityriasis rubra pilaris, epidermolytic hyperkeratosis, and others).
Cannabinoids, Endocannabinoids, and Synthetic Cannabimimetic Molecules in Neuromuscular Disorders
Authors: Iannotti Fabio Arturo
Published: December 2023

Neuromuscular disorders (NMDs) encompass a large heterogeneous group of hereditary and acquired diseases primarily affecting motor neurons, peripheral nerves, and the skeletal muscle system. The symptoms of NMDs may vary depending on the specific condition, but some of the most common ones include muscle weakness, pain, paresthesias, and hyporeflexia, as well as difficulties with swallowing and breathing. NMDs are currently untreatable. Therapeutic options include symptomatic and experimental medications aimed at delaying and alleviating symptoms, in some cases supplemented by surgical and physical interventions. To address this unmet medical need, ongoing research is being conducted on new treatments, including studies on medical cannabis, endocannabinoids, and related molecules with cannabimimetic properties. In this context, a significant amount of knowledge about the safety and effectiveness of cannabinoids in NMDs has been obtained from studies involving patients with multiple sclerosis experiencing pain and spasticity. In recent decades, numerous other preclinical and clinical studies have been conducted to determine the potential benefits of cannabinoids in NMDs. This review article aims to summarize and provide an unbiased point of view on the current knowledge about the use of cannabinoids, endocannabinoids, and synthetic analogs in NMDs, drawing from an array of compelling studies.
Elevated Expression of HSP72 in the Prefrontal Cortex and Hippocampus of Rats Subjected to Chronic Mild Stress and Treated with Imipramine
Authors: Bielawski Adam , Zelek-Molik Agnieszka , Rafa-Zabłocka Katarzyna , Kowalska Marta , Gruca Piotr , Papp Mariusz , Nalepa Irena
Published: December 2023

The HSP70 and HSP90 family members belong to molecular chaperones that exhibit protective functions during the cellular response to stressful agents. We investigated whether the exposure of rats to chronic mild stress (CMS), a validated model of depression, affects the expression of HSP70 and HSP90 in the prefrontal cortex (PFC), hippocampus (HIP) and thalamus (Thal). Male Wistar rats were exposed to CMS for 3 or 8 weeks. The antidepressant imipramine (IMI, 10 mg/kg, i.p., daily) was introduced in the last five weeks of the long-term CMS procedure. Depressive-like behavior was verified by the sucrose consumption test. The expression of mRNA and protein was quantified by real-time PCR and Western blot, respectively. In the 8-week CMS model, stress alone elevated HSP72 and HSP90B mRNA expression in the HIP. HSP72 mRNA was increased in the PFC and HIP of rats not responding to IMI treatment vs. IMI responders. The CMS exposure increased HSP72 protein expression in the cytosolic fraction of the PFC and HIP, and this effect was diminished by IMI treatment. Our results suggest that elevated levels of HSP72 may serve as an important indicator of neuronal stress reactions accompanying depression pathology and could be a potential target for antidepressant strategy.
Developmental and Nutritional Dynamics of Malpighian Tubule Autofluorescence in the Asian Tiger Mosquito Aedes albopictus
Authors: Croce Anna Cleta , Garbelli Anna , Moyano Andrea , Soldano Sara , Tejeda-Guzmán Carlos , Missirlis Fanis , Scolari Francesca
Published: December 2023

Malpighian tubules (MTs) are arthropod excretory organs crucial for the osmoregulation, detoxification and excretion of xenobiotics and metabolic wastes, which include tryptophan degradation products along the kynurenine (KYN) pathway. Specifically, the toxic intermediate 3-hydroxy kynurenine (3-HK) is metabolized through transamination to xanthurenic acid or in the synthesis of ommochrome pigments. Early investigations in Drosophila larval fat bodies revealed an intracellular autofluorescence (AF) that depended on tryptophan administration. Subsequent observations documented AF changes in the MTs of Drosophila eye-color mutants genetically affecting the conversion of tryptophan to KYN or 3-HK and the intracellular availability of zinc ions. In the present study, the AF properties of the MTs in the Asian tiger mosquito, Aedes albopictus, were characterized in different stages of the insect’s life cycle, tryptophan-administered larvae and blood-fed adult females. Confocal imaging and microspectroscopy showed AF changes in the distribution of intracellular, brilliant granules and in the emission spectral shape and amplitude between the proximal and distal segments of MTs across the different samples. The findings suggest AF can serve as a promising marker for investigating the functional status of MTs in response to metabolic alterations, contributing to the use of MTs as a potential research model in biomedicine.
Silver/Graphene Oxide Nanostructured Coatings for Modulating the Microbial Susceptibility of Fixation Devices Used in Knee Surgery
Authors: Constantinescu Sorin , Niculescu Adelina-Gabriela , Hudiță Ariana , Grumezescu Valentina , Rădulescu Dragoș , Bîrcă Alexandra Cătălina , Irimiciuc Stefan Andrei , Gherasim Oana , Holban Alina Maria , Gălățeanu Bianca , Oprea Ovidiu Cristian , Ficai Anton , Vasile Bogdan Ștefan , Grumezescu Alexandru Mihai , Bolocan Alexandra , Rădulescu Radu
Published: December 2023

Exploring silver-based and carbon-based nanomaterials’ excellent intrinsic antipathogenic effects represents an attractive alternative for fabricating anti-infective formulations. Using chemical synthesis protocols, stearate-conjugated silver (Ag@C18) nanoparticles and graphene oxide nanosheets (nGOs) were herein obtained and investigated in terms of composition and microstructure. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) characterizations revealed the formation of nanomaterials with desirable physical properties, while X-ray diffraction (XRD) analyses confirmed the high purity of synthesized nanomaterials. Further, laser-processed Ag@C18-nGO coatings were developed, optimized, and evaluated in terms of biological and microbiological outcomes. The highly biocompatible Ag@C18-nGO nanostructured coatings proved suitable candidates for the local modulation of biofilm-associated periprosthetic infections.
Comparative Physiological and Transcriptome Analyses of Tolerant and Susceptible Cultivars Reveal the Molecular Mechanism of Cold Tolerance in Anthurium andraeanum
Authors: Dou Na , Li Li , Fang Yifu , Fan Shoujin , Wu Chunxia
Published: December 2023

Anthurium andraeanum is a tropical ornamental flower. The cost of Anthurium production is higher under low temperature (non-freezing) conditions; therefore, it is important to increase its cold tolerance. However, the molecular mechanisms underlying the response of Anthurium to cold stress remain elusive. In this study, comparative physiological and transcriptome sequencing analyses of two cultivars with contrasting cold tolerances were conducted to evaluate the cold stress response at the flowering stage. The activities of superoxide dismutase and peroxidase and the contents of proline, soluble sugar, and malondialdehyde increased under cold stress in the leaves of the cold tolerant cultivar Elegang (E) and cold susceptible cultivar Menghuang (MH), while the soluble protein content decreased in MH and increased in E. Using RNA sequencing, 24,695 differentially expressed genes (DEGs) were identified from comparisons between cultivars under the same conditions or between the treatment and control groups of a single cultivar, 9132 of which were common cold-responsive DEGs. Heat-shock proteins and pectinesterases were upregulated in E and downregulated in MH, indicating that these proteins are essential for Anthurium cold tolerance. Furthermore, four modules related to cold treatment were obtained by weighted gene co-expression network analysis. The expression of the top 20 hub genes in these modules was induced by cold stress in E or MH, suggesting they might be crucial contributors to cold tolerance. DEGs were significantly enriched in plant hormone signal transduction pathways, trehalose metabolism, and ribosomal proteins, suggesting these processes play important roles in Anthurium’s cold stress response. This study provides a basis for elucidating the mechanism of cold tolerance in A. andraeanum and potential targets for molecular breeding.
Activity of Colocasia esculenta (Taro) Corms against Gastric Adenocarcinoma Cells: Chemical Study and Molecular Characterization
Authors: Esposito Tiziana , Pisanti Simona , Mauro Luciano , Mencherini Teresa , Martinelli Rosanna , Aquino Rita Patrizia
Published: December 2023

Colocasia esculenta (L.) Schott is a tuberous plant, also known as taro, employed as food worldwide for its renowned nutritional properties but also traditionally used in several countries for medical purposes. In this study, methanolic extracts were prepared from the corms and leaves of Colocasia, subsequently fractionated via molecular exclusion chromatography (RP-HPLC) and their anti-tumor activity assessed in an in vitro model of gastric adenocarcinoma (AGS cells). Vorm extract and isolated fractions II and III affected AGS cell vitality in a dose-dependent manner through the modulation of key proteins involved in cell proliferation, apoptosis, and cell cycle processes, such as caspase 3, cyclin A, cdk2, IkBα, and ERK. To identify bioactive molecules responsible for anti-tumoral activity fractions II and III were further purified via RP-HPLC and characterized via nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ESI-MS) techniques. The procedure enabled the identification of ten compounds including lignans and neolignans, some isolated for the first time in taro, uncommon megastigmane derivatives, and a gallic acid derivative. However, none of the isolated constituents showed efficacy equivalent to that of the fractions and total extract. This suggests that the whole Colocasia phytocomplex has intriguing anti-tumor activity against gastric cancer.
Palmitate Stimulates Expression of the von Willebrand Factor and Modulates Toll-like Receptors Level and Activity in Human Umbilical Vein Endothelial Cells (HUVECs)
Authors: Seliga Agnieszka K. , Zabłocki Krzysztof , Bandorowicz-Pikuła Joanna
Published: December 2023

An increased concentration of palmitate in circulation is one of the most harmful factors in obesity. The von Willebrand factor (vWF), a protein involved in haemostasis, is produced and secreted by the vascular endothelium. An increased level of vWF in obese patients is associated with thrombosis and cardiovascular disease. The aim of this study was to investigate a palmitate effect on vWF in endothelial cells and understand the mechanisms of palmitate-activated signalling. Human umbilical vein endothelial cells (HUVECs) incubated in the presence of palmitate, exhibited an increased VWF gene expression, vWF protein maturation, and stimulated vWF secretion. Cardamonin, a Nuclear Factor kappa B (NF-κB) inhibitor, abolished the palmitate effect on VWF expression. The inhibition of Toll-like receptor (TLR) 2 with C29 resulted in the TLR4 overactivation in palmitate-treated cells. Palmitate, in the presence of TLR4 inhibitor TAK-242, leads to a higher expression of TLR6, CD36, and TIRAP. The silencing of TLR4 resulted in an increase in TLR2 level and vice versa. The obtained results indicate a potential mechanism of obesity-induced thrombotic complication caused by fatty acid activation of NF-κB signalling and vWF upregulation and help to identify various compensatory mechanisms related to TLR4 signal transduction.
The Regulation of Exosome Generation and Function in Physiological and Pathological Processes
Authors: Wang Ying , Xiao Tong , Zhao Chaoran , Li Guiying
Published: December 2023

Exosomes, a type of extracellular vesicle with a diameter of approximately 100 nm that is secreted by all cells, regulate the phenotype and function of recipient cells by carrying molecules such as proteins, nucleic acids, and lipids and are important mediators of intercellular communication. Exosomes are involved in various physiological and pathological processes such as immunomodulation, angiogenesis, tumorigenesis, metastasis, and chemoresistance. Due to their excellent properties, exosomes have shown their potential application in the clinical diagnosis and treatment of disease. The functions of exosomes depend on their biogenesis, uptake, and composition. Thus, a deeper understanding of these processes and regulatory mechanisms can help to find new targets for disease diagnosis and therapy. Therefore, this review summarizes and integrates the recent advances in the regulatory mechanisms of the entire biological process of exosomes, starting from the formation of early-sorting endosomes (ESCs) by plasma membrane invagination to the release of exosomes by fusion of multivesicular bodies (MVBs) with the plasma membrane, as well as the regulatory process of the interactions between exosomes and recipient cells. We also describe and discuss the regulatory mechanisms of exosome production in tumor cells and the potential of exosomes used in cancer diagnosis and therapy.
Glucans with Different Degrees of Polymerization from Leuconostoc mesenteroides CICC6055: Analysis of Physicochemical Properties and Intestinal Prebiotic Function
Authors: Gu Jiabao , Jiao Ziyan , Wang Tao , Zhang Bolin , Zhao Hongfei
Published: December 2023

This study explored the physicochemical properties and prebiotic activities of glucans and oligoglucans. Oligoglucans were obtained through the fermentation of Leuconostoc mesenteroides CICC6055 and the glucansucrase of strain CICC6055, while glucans were obtained only through fermentation. Thin-layer chromatography and high-performance liquid chromatography identified enzymatically synthesized oligoglucans with a higher yield. Differential scanning calorimetry and derivative thermogravimetry analyses revealed the heat resistance of the glucans and oligoglucans at 280–300 °C. Fourier transform-infrared spectroscopy and nuclear magnetic resonance analyses demonstrated that their main chains were linked with α-1,6-glycosidic bonds accompanied by glucose residue branching. In vitro fermentation experiments demonstrated that they not only improved the contents of short-chain fatty acids but also raised the abundance of predominant flora, such as Bacteroides, Firmicutes, Verrucomicrobia, and Proteobacteria. These results implicate glucansucrase as an efficacious tool for the enzyme synthesis of oligoglucans. Furthermore, both polysaccharides with different degrees of polymerization may be beneficial in maintaining a healthy human gut.
Antioxidant Systems and Quality in Sweet Cherries Are Improved by Preharvest GABA Treatments Leading to Delay Postharvest Senescence
Authors: Carrión-Antolí Alberto , Badiche-El Hilali Fátima , Lorente-Mento José M. , Díaz-Mula Huertas M. , Serrano María , Valero Daniel
Published: December 2023

γ-Aminobutyric acid (GABA) plays important roles in plant development, including the maintenance of fruit quality when applied as postharvest treatment. However, little information is available about the effects of preharvest GABA treatments. Thus, GABA (10, 50 and 100 mM) was applied as foliar spray at key points of fruit development in three sweet cherry cultivars and over two years. The results show that quality parameters, such as total soluble solid content, titratable acidity and firmness were higher in the fruit from GABA-treated trees than in the controls, either at harvest or during four weeks of cold storage. In addition, the total phenolic and total and individual anthocyanin concentrations were also enhanced by GABA treatments and the fruit color was improved. The activities of the antioxidant enzymes catalase, ascorbate peroxidase and peroxidase were also enhanced by the GABA treatments. The most effective concentration was 50 mM, which led to extending the storage period of sweet cherries with high quality traits to up to four weeks, while for the controls this was two weeks. Thus, GABA treatment had a clear effect on delaying the postharvest ripening and senescence processes in sweet cherries, with an additional effect on enhancing the content of bioactive compounds, such as phenolics and anthocyanins, with antioxidant properties and health benefits.