bluuebunny/crossref_metadata_2025 huggingface dataset:
The Extremely-Low-Frequency Electromagnetic Field Affects Apoptosis and Oxidative-Stress-Related Genes and Proteins in the Porcine Endometrium—An In Vitro Study
Authors: Wydorski Pawel Jozef , Zmijewska Agata , Franczak Anita
Published: June 2024

Nowadays, the extremely-low-frequency electromagnetic field (ELF-EMF) is recognized as environmental pollution. The data indicate that the ELF-EMF may affect factors related to epigenetic regulation and alter important biological processes in the uterus. The impact of the ELF-EMF on apoptosis and oxidative-stress-related genes has not been documented in porcine endometrium. This raises the question of whether the exposure to the ELF-EMF can induce apoptosis and/or oxidative stress in the endometrium of pigs during the peri-implantation period. Porcine endometrial slices (100 ± 5 mg) collected (n = 5) during the peri-implantation period were treated in vitro with ELF-EMF at a frequency of 50 Hz and flux density of 8 × 104 mG for 2 h. To determine the effect of ELF-EMF on apoptosis and oxidative stress in the endometrium, CASP3, CASP7, CIDEB, GADD45G, NOS1, NOS2, NOS3, and TP53I3 mRNA transcript were analyzed using real-time PCR, and protein abundance of CASP3, CASP7 using Western blot, and eNOS using ELISA were determined. Moreover, CASP3/7 and NOS activity was analyzed using flow cytometry and colorimetry, respectively. The decreased CASP7 and increased NOS3 mRNA transcript and protein abundance in ELF-EMF-treated endometrium were observed. Moreover, CIDEB, GADD45G, and TP53I3 mRNA transcript abundance was increased. Only p ≤ 0.05 was considered a statistically significant difference. The documented alterations indicate the potential of the ELF-EMF to affect apoptosis and generate oxidative stress in the endometrium. The insight into observed consequences documents for the first time the fact that the ELF-EMF may influence endometrial cell proliferation, angiogenesis, and/or tissue receptivity during peri-implantation.
Exploring the Role of Bempedoic Acid in Metabolic Dysfunction Associated Steatotic Liver Disease: Actual Evidence and Future Perspectives
Authors: Butera Elena , Termite Fabrizio , Esposto Giorgio , Galasso Linda , Mignini Irene , Borriello Raffaele , Ainora Maria Elena , Miele Luca , Gasbarrini Antonio , Zocco Maria Assunta
Published: June 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.
Comparison of the Influence of Bisphenol A and Bisphenol S on the Enteric Nervous System of the Mouse Jejunum
Authors: Makowska Krystyna , Gonkowski Sławomir
Published: June 2024

Bisphenols are dangerous endocrine disruptors that pollute the environment. Due to their chemical properties, they are globally used to produce plastics. Structural similarities to oestrogen allow bisphenols to bind to oestrogen receptors and affect internal body systems. Most commonly used in the plastic industry is bisphenol A (BPA), which also has negative effects on the nervous, immune, endocrine, and cardiovascular systems. A popular analogue of BPA-bisphenol S (BPS) also seems to have harmful effects similar to BPA on living organisms. Therefore, with the use of double immunofluorescence labelling, this study aimed to compare the effect of BPA and BPS on the enteric nervous system (ENS) in mouse jejunum. The study showed that both studied toxins impact the number of nerve cells immunoreactive to substance P (SP), galanin (GAL), vasoactive intestinal polypeptide (VIP), the neuronal isoform of nitric oxide synthase (nNOS), and vesicular acetylcholine transporter (VAChT). The observed changes were similar in the case of both tested bisphenols. However, the influence of BPA showed stronger changes in neurochemical coding. The results also showed that long-term exposure to BPS significantly affects the ENS.
Feasibility and Impact of Embedding an Extended DNA and RNA Tissue-Based Sequencing Panel for the Routine Care of Patients with Advanced Melanoma in Spain
Authors: Castrejon Natalia , Martin Roberto , Carrasco Antonio , Castillo Paola , Garcia Adriana , Albero-González Raquel , García Mireia , Marginet Marta , Palau Núria , Hernández Mónica , Montironi Carla , Clot Guillem , Arance Ana , Alos Llucia , Teixido Cristina
Published: June 2024

Targeted NGS allows a fast and efficient multi-gene analysis and the detection of key gene aberrations in melanoma. In this study, we aim to describe the genetic alterations in a series of 87 melanoma cases using the oncomine focus assay (OFA), relate these results with the clinicopathological features of the patients, and compare them with our previous study results in which we used a smaller panel, the oncomine solid tumor (OST) DNA kit. Patients diagnosed with advanced melanoma at our center from 2020 to 2022 were included and DNA and RNA were extracted for sequencing. Common mutated genes were BRAF (29%), NRAS (28%), ALK, KIT, and MAP2K1 (5% each). Co-occurring mutations were detected in 29% of the samples, including BRAF with KIT, CTNNB1, EGFR, ALK, HRAS, or MAP2K1. Amplifications and rearrangements were detected in 5% of cases. Only BRAF mutation showed a significant statistical association with sun exposure. For patients with a given genetic profile, the melanoma survival and recurrence-free survival rates were equivalent, but not for stage and LDH values. This expanded knowledge of molecular alterations has helped to more comprehensively characterize our patients and has provided relevant information for deciding the best treatment strategy.
Repurposing Anticancer Drugs Targeting the MAPK/ERK Signaling Pathway for the Treatment of Respiratory Virus Infections
Authors: Liu Yuchen , Luo Zhijun
Published: June 2024

Respiratory virus infections remain a significant challenge to human health and the social economy. The symptoms range from mild rhinitis and nasal congestion to severe lower respiratory tract dysfunction and even mortality. The efficacy of therapeutic drugs targeting respiratory viruses varies, depending upon infection time and the drug resistance engendered by a high frequency of viral genome mutations, necessitating the development of new strategies. The MAPK/ERK pathway that was well delineated in the 1980s represents a classical signaling cascade, essential for cell proliferation, survival, and differentiation. Since this pathway is constitutively activated in many cancers by oncogenes, several drugs inhibiting Raf/MEK/ERK have been developed and currently used in anticancer treatment. Two decades ago, it was reported that viruses such as HIV and influenza viruses could exploit the host cellular MAPK/ERK pathway for their replication. Thus, it would be feasible to repurpose this category of the pathway inhibitors for the treatment of respiratory viral infections. The advantage is that the host genes are not easy to mutate such that the drug resistance rarely occurs during short-period treatment of viruses. Therefore, in this review we will summarize the research progress on the role of the MAPK/ERK pathway in respiratory virus amplification and discuss the potential of the pathway inhibitors (MEK inhibitors) in the treatment of respiratory viral infections.
The Effects and Mechanism of ATM Kinase Inhibitors in Toxoplasma gondii
Authors: Xue Yangfei , Ying Zhu , Wang Fei , Yin Meng , Pei Yanqun , Liu Jing , Liu Qun
Published: June 2024

Toxoplasma gondii, an important opportunistic pathogen, underscores the necessity of developing novel therapeutic drugs and identifying new drug targets. Our findings indicate that the half-maximal inhibitory concentrations (IC50) of KU60019 and CP466722 (abbreviated as KU and CP) against T. gondii are 0.522 μM and 0.702 μM, respectively, with selection indices (SI) of 68 and 10. Treatment with KU and CP affects the in vitro growth of T. gondii, inducing aberrant division in the daughter parasites. Transmission electron microscopy reveals that KU and CP prompt the anomalous division of T. gondii, accompanied by cellular enlargement, nuclear shrinkage, and an increased dense granule density, suggesting potential damage to parasite vesicle transport. Subsequent investigations unveil their ability to modulate the expression of certain secreted proteins and FAS II (type II fatty acid synthesis) in T. gondii, as well as including the dot-like aggregation of the autophagy-related protein ATG8 (autophagy-related protein 8), thereby expediting programmed death. Leveraging DARTS (drug affinity responsive target stability) in conjunction with 4D-Label-free quantitative proteomics technology, we identified seven target proteins binding to KU, implicated in pivotal biological processes such as the fatty acid metabolism, mitochondrial ATP transmission, microtubule formation, and Golgi proteins transport in T. gondii. Molecular docking predicts their good binding affinity. Furthermore, KU has a slight protective effect on mice infected with T. gondii. Elucidating the function of those target proteins and their mechanism of action with ATM kinase inhibitors may potentially enhance the treatment paradigm for toxoplasmosis.
Candidate Genes and Favorable Haplotypes Associated with Iron Toxicity Tolerance in Rice
Authors: Miao Siyu , Lu Jingbing , Zhang Guogen , Jiang Jing , Li Pingping , Qian Yukang , Wang Wensheng , Xu Jianlong , Zhang Fan , Zhao Xiuqin
Published: June 2024

Iron (Fe) toxicity is a major issue adversely affecting rice production worldwide. Unfortunately, the physiological and genetic mechanisms underlying Fe toxicity tolerance in rice remain relatively unknown. In this study, we conducted a genome–wide association study using a diverse panel consisting of 551 rice accessions to identify genetic mechanisms and candidate genes associated with Fe toxicity tolerance. Of the 29 quantitative trait loci (QTL) for Fe toxicity tolerance detected on chromosomes 1, 2, 5, and 12, five (qSH_Fe5, qSFW_Fe2.3, qRRL5.1, qRSFW1.1, and qRSFW12) were selected to identify candidate genes according to haplotype and bioinformatics analyses. The following five genes were revealed as promising candidates: LOC_Os05g40160, LOC_Os05g40180, LOC_Os12g36890, LOC_Os12g36900, and LOC_Os12g36940. The physiological characteristics of rice accessions with contrasting Fe toxicity tolerance reflected the importance of reactive oxygen species–scavenging antioxidant enzymes and Fe homeostasis for mitigating the negative effects of Fe toxicity on rice. Our findings have clarified the genetic and physiological mechanisms underlying Fe toxicity tolerance in rice. Furthermore, we identified valuable genetic resources for future functional analyses and the development of Fe toxicity–tolerant rice varieties via marker–assisted selection.
Cell Therapies for Acute Radiation Syndrome
Authors: Christy Barbara A. , Herzig Maryanne C. , Wu Xiaowu , Mohammadipoor Arezoo , McDaniel Jennifer S. , Bynum James A.
Published: June 2024

The risks of severe ionizing radiation exposure are increasing due to the involvement of nuclear powers in combat operations, the increasing use of nuclear power, and the existence of terrorist threats. Exposure to a whole-body radiation dose above about 0.7 Gy results in H-ARS (hematopoietic acute radiation syndrome), which is characterized by damage to the hematopoietic system; higher doses result in further damage to the gastrointestinal and nervous systems. Only a few medical countermeasures for ARS are currently available and approved for use, although others are in development. Cell therapies (cells or products produced by cells) are complex therapeutics that show promise for the treatment of radiation injury and have been shown to reduce mortality and morbidity in animal models. Since clinical trials for ARS cannot be ethically conducted, animal testing is extremely important. Here, we describe cell therapies that have been tested in animal models. Both cells and cell products appear to promote survival and lessen tissue damage after whole-body irradiation, although the mechanisms are not clear. Because radiation exposure often occurs in conjunction with other traumatic injuries, animal models of combined injury involving radiation and future countermeasure testing for these complex medical problems are also discussed.
Susceptibility to Pentylenetetrazole-Induced Seizures in Mice with Distinct Activity of the Endogenous Opioid System
Authors: Ruszczak Anna , Poznański Piotr , Leśniak Anna , Łazarczyk Marzena , Skiba Dominik , Nawrocka Agata , Gaweł Kinga , Paszkiewicz Justyna , Mickael Michel-Edwar , Sacharczuk Mariusz
Published: June 2024

Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist—naloxone—and a GABA receptor agonist—diazepam (DZP)—facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.
TLR2 and TLR4 Polymorphisms Are Not Associated with Dental Caries in Polish Children
Authors: Milona Marta , Olszowski Tomasz , Uzar Izabela , Safranow Krzysztof , Janiszewska-Olszowska Joanna , Szmidt-Kądys Monika , Rola Hubert , Sikora Maciej , Chlubek Dariusz , Adler Grażyna
Published: June 2024

The aim of the present study was to analyze the association of the TLR2 (Toll-like receptor 2 gene) 2258G>A (rs5743708), TLR4 (Toll-like receptor 4 gene) 896A>G (rs4986790), and TLR4 1196C>T (rs4986791) polymorphisms with dental caries in Polish children. The participants, 261 15-year-old children, were divided into two groups: 82 cases (i.e., children with DMFT (Decayed, Missing, and Filled Teeth) index >5, having either moderate or high caries experience, assigned as the “higher” caries experience group) and 179 controls (i.e., children with DMFT ≤ 5, having either low or very low caries experience, assigned as the “lower” caries experience group). Genomic DNA was isolated from buccal swabs, and genotyping was determined by means of real-time PCR (polymerase chain reaction). There were no significant differences in the genotype or allele distributions in all tested SNPs (single nucleotide polymorphisms) between children with “higher” caries experience and those with “lower” caries experience. TLR4 haplotype frequencies did not differ significantly between cases and controls. In an additional analysis with another case definition applied (subjects with DMFT ≥ 1 were assigned as “cases”, whereas children with DMFT = 0 were assigned as “controls”), no significant differences in the TLR2 and TLR4 genotype, allele frequencies, and TLR4 haplotype frequencies were found between the case and the control groups. The results of the present study broaden our knowledge on the potential genetic factors that might affect caries risk and suggest that TLR2 rs5743708 and TLR4 rs4986790 and rs4986791 SNPs are not associated with dental caries susceptibility in Polish children.
Proteomics Analyses of Small Extracellular Vesicles of Aqueous Humor: Identification and Validation of GAS6 and SPP1 as Glaucoma Markers
Authors: Rejas-González Raquel , Montero-Calle Ana , Valverde Alejandro , Salvador Natalia Pastora , Carballés María José Crespo , Ausín-González Emma , Sánchez-Naves Juan , Campuzano Susana , Barderas Rodrigo , Guzman-Aranguez Ana
Published: June 2024

Cataracts and glaucoma account for a high percentage of vision loss and blindness worldwide. Small extracellular vesicles (sEVs) are released into different body fluids, including the eye’s aqueous humor. Information about their proteome content and characterization in ocular pathologies is not yet well established. In this study, aqueous humor sEVs from healthy individuals, cataracts, and glaucoma patients were studied, and their specific protein profiles were characterized. Moreover, the potential of identified proteins as diagnostic glaucoma biomarkers was evaluated. The protein content of sEVs from patients’ aqueous humor with cataracts and glaucoma compared to healthy individuals was analyzed by quantitative proteomics. Validation was performed by western blot (WB) and ELISA. A total of 828 peptides and 192 proteins were identified and quantified. After data analysis with the R program, 8 significantly dysregulated proteins from aqueous humor sEVs in cataracts and 16 in glaucoma showed an expression ratio ≥ 1.5. By WB and ELISA using directly aqueous humor samples, the dysregulation of 9 proteins was mostly confirmed. Importantly, GAS6 and SPP1 showed high diagnostic ability of glaucoma, which in combination allowed for discriminating glaucoma patients from control individuals with an area under the curve of 76.1% and a sensitivity of 65.6% and a specificity of 87.7%.
Cellular Therapy in Experimental Autoimmune Encephalomyelitis as an Adjuvant Treatment to Translate for Multiple Sclerosis
Authors: Perussolo Maiara Carolina , Mogharbel Bassam Felipe , Saçaki Cláudia Sayuri , Rosa Nádia Nascimento da , Irioda Ana Carolina , Oliveira Nathalia Barth de , Appel Julia Maurer , Lührs Larissa , Meira Leanderson Franco , Guarita-Souza Luiz Cesar , Nagashima Seigo , Paula Caroline Busatta Vaz de , Noronha Lucia de , Zotarelli-Filho Idiberto José , Abdelwahid Eltyeb , Carvalho Katherine Athayde Teixeira de
Published: June 2024

This study aims to evaluate and compare cellular therapy with human Wharton’s jelly (WJ) mesenchymal stem cells (MSCs) and neural precursors (NPs) in experimental autoimmune encephalomyelitis (EAE), a preclinical model of Multiple Sclerosis. MSCs were isolated from WJ by an explant technique, differentiated to NPs, and characterized by cytometry and immunocytochemistry analysis after ethical approval. Forty-eight rats were EAE-induced by myelin basic protein and Freund’s complete adjuvant. Forty-eight hours later, the animals received intraperitoneal injections of 250 ng/dose of Bordetella pertussis toxin. Fourteen days later, the animals were divided into the following groups: a. non-induced, induced: b. Sham, c. WJ-MSCs, d. NPs, and e. WJ-MSCs plus NPs. 1 × 105. Moreover, the cells were placed in a 10 µL solution and injected via a stereotaxic intracerebral ventricular injection. After ten days, the histopathological analysis for H&E, Luxol, interleukins, and CD4/CD8 was carried out. Statistical analyses demonstrated a higher frequency of clinical manifestation in the Sham group (15.66%) than in the other groups; less demyelination was seen in the treated groups than the Sham group (WJ-MSCs, p = 0.016; NPs, p = 0.010; WJ-MSCs + NPs, p = 0.000), and a lower cellular death rate was seen in the treated groups compared with the Sham group. A CD4/CD8 ratio of <1 showed no association with microglial activation (p = 0.366), astrocytes (p = 0.247), and cell death (p = 0.577) in WJ-MSCs. WJ-MSCs and NPs were immunomodulatory and neuroprotective in cellular therapy, which would be translated as an adjunct in demyelinating diseases.
Inter-Species Pharmacokinetic Modeling and Scaling for Drug Repurposing of Pyronaridine and Artesunate
Authors: Kang Dong Wook , Kim Ju Hee , Kim Kyung Min , Cho Seok-jin , Choi Go-Wun , Cho Hea-Young
Published: June 2024

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.
Iron Metabolism in the Recovery Phase of Critical Illness with a Focus on Sepsis
Authors: Zhang Xiyang , Holbein Bruce , Zhou Juan , Lehmann Christian
Published: June 2024

Iron is an essential nutrient for humans and microbes, such as bacteria. Iron deficiency commonly occurs in critically ill patients, but supplementary iron therapy is not considered during the acute phase of critical illness since it increases iron availability for invading microbes and oxidative stress. However, persistent iron deficiency in the recovery phase is harmful and has potential adverse outcomes such as cognitive dysfunction, fatigue, and cardiopulmonary dysfunction. Therefore, it is important to treat iron deficiency quickly and efficiently. This article reviews current knowledge about iron-related biomarkers in critical illness with a focus on patients with sepsis, and provides possible criteria to guide decision-making for iron supplementation in the recovery phase of those patients.
Metabolic Endotoxemia: From the Gut to Neurodegeneration
Authors: Chmielarz Mateusz , Sobieszczańska Beata , Środa-Pomianek Kamila
Published: June 2024

Metabolic endotoxemia is a severe health problem for residents in developed countries who follow a Western diet, disrupting intestinal microbiota and the whole organism’s homeostasis. Although the effect of endotoxin on the human immune system is well known, its long-term impact on the human body, lasting many months or even years, is unknown. This is due to the difficulty of conducting in vitro and in vivo studies on the prolonged effect of endotoxin on the central nervous system. In this article, based on the available literature, we traced the path of endotoxin from the intestines to the blood through the intestinal epithelium and factors promoting the development of metabolic endotoxemia. The presence of endotoxin in the bloodstream and the inflammation it induces may contribute to lowering the blood–brain barrier, potentially allowing its penetration into the central nervous system; although, the theory is still controversial. Microglia, guarding the central nervous system, are the first line of defense and respond to endotoxin with activation, which may contribute to the development of neurodegenerative diseases. We traced the pro-inflammatory role of endotoxin in neurodegenerative diseases and its impact on the epigenetic regulation of microglial phenotypes.
The Effects of ML385 on Head and Neck Squamous Cell Carcinoma: Implications for NRF2 Inhibition as a Therapeutic Strategy
Authors: Jeong Eun-Jeong , Choi Jong Joong , Lee Sun Young , Kim Yeon Soo
Published: June 2024

Head and neck squamous cell carcinoma (HNSCC) affects squamous cells in the head and neck region and is currently ranked as the sixth most common cancer worldwide. NF-E2-related factor 2 (NRF2) plays a crucial role in cellular protection and defence mechanisms and NRF2 over-expression has been linked to various cancers; however, its role in the response of HNSCC cells remains elusive. We investigated the effects of ML385, a selective NRF2 inhibitor, on HNSCC to understand the underlying molecular mechanisms, and to assess the potential of ML385 as a therapeutic agent. We treated HNSCC cell lines with ML385 and observed a significant reduction in the expression of NRF2 and its downstream target, heme oxygenase-1 (HO-1), using Western blotting. We evaluated its effects on various cellular processes, including cell proliferation, cloning, migration, and wound healing, in HNSCC cell lines. ML385 treatment substantially reduced NRF2 expression, promoting a decrease in the investigated cellular activities. Additionally, we examined changes in the expression of cell-cycle-related proteins and found that ML385 induced cell cycle arrest at the G1/S phase in HNSCC cell lines. Our findings suggest that ML385 can regulate cell cycle progression, inhibit HNSCC growth, and have potential as a therapeutic agent for HNSCC.
Elucidation of the Gemcitabine Transporters of Escherichia coli K-12 and Gamma-Proteobacteria Linked to Gemcitabine-Related Chemoresistance
Authors: Iosifidou Nikoleta , Anagnostopoulou Eleni , Botou Maria , Kalfa Eirini , Tatsaki Ekaterini , Frillingos Stathis
Published: June 2024

Gemcitabine (2′,2′-difluoro-2′-deoxycytidine), a widely used anticancer drug, is considered a gold standard in treating aggressive pancreatic cancers. Gamma-proteobacteria that colonize the pancreatic tumors contribute to chemoresistance against gemcitabine by metabolizing the drug to a less active and deaminated form. The gemcitabine transporters of these bacteria are unknown to date. Furthermore, there is no complete knowledge of the gemcitabine transporters in Escherichia coli or any other related proteobacteria. In this study, we investigate the complement of gemcitabine transporters in E. coli K-12 and two common chemoresistance-related bacteria (Klebsiella pneumoniae and Citrobacter freundii). We found that E. coli K-12 has two high-affinity gemcitabine transporters with distinct specificity properties, namely, NupC and NupG, whereas the gemcitabine transporters of C. freundii and K. pneumoniae include the NupC and NupG orthologs, functionally indistinguishable from their counterparts, and, in K. pneumoniae, one additional NupC variant, designated KpNupC2. All these bacterial transporters have a higher affinity for gemcitabine than their human counterparts. The highest affinity (KM 2.5–3.0 μΜ) is exhibited by NupGs of the bacteria-specific nucleoside-H+ symporter (NHS) family followed by NupCs (KM 10–13 μΜ) of the concentrative nucleoside transporter (CNT) family, 15–100 times higher than the affinities reported for the human gemcitabine transporter hENT1/SLC29A1, which is primarily associated with gemcitabine uptake in the pancreatic adenocarcinoma cells. Our results offer a basis for further insight into the role of specific bacteria in drug availability within tumors and for understanding the structure–function differences of bacterial and human drug transporters.
The Role of Piromelatine on Peripheral and Hippocampal Insulin Resistance in Rat Offspring Exposed to Chronic Maternal Stress
Authors: Ivanova Natasha , Atanasova Milena , Terzieva Dora , Georgieva Katerina , Tchekalarova Jana
Published: June 2024

Prenatal stress (PNS), which alters the hypothalamic-pituitary-adrenal axis function in the offspring, predisposes to insulin resistance (IR) in later life and is associated with numerous disorders, including cognitive and memory impairments. At present, our main goal is to assess the effects of chronic piromelatine (Pir) administration, a melatonin analogue, on PNS-provoked IR in the periphery and the hippocampus in male and female offspring. Pregnant Sprague–Dawley rats were exposed to chronic stress (one short-term stressor on a daily basis and one long-term stressor on a nightly basis) from the first gestation week until birth. Vehicle or Pir 20 mg/kg were administered intraperitoneally for 21 days. Plasma glucose, serum insulin levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) were determined as markers of peripheral IR. For the hippocampal IR assessment, insulin receptors (IRs) and glucose transporter 4 (GLUT4) were examined. Prenatally stressed offspring of both sexes indicated enhanced plasma glucose and serum insulin concentrations, increased HOMA-IR, and decreased hippocampal GLUT4 only in male rats. The PNS-induced changes were corrected by chronic treatment with Pir. The present results suggest that the melatoninergic compound Pir exerts beneficial effects on altered glucose/insulin homeostasis in PNS-exposed offspring.
Effects of the MCF-7 Exhausted Medium on hADSC Behaviour
Authors: Garroni Giuseppe , Cruciani Sara , Serra Diletta , Pala Renzo , Coradduzza Donatella , Cossu Maria Laura , Ginesu Giorgio Carlo , Ventura Carlo , Maioli Margherita
Published: June 2024

Stem cells possess the ability to differentiate into different lineages and the ability to self-renew, thus representing an excellent tool for regenerative medicine. They can be isolated from different tissues, including the adipose tissue. Adipose tissue and human adipose-derived stem cells (hADSCs) are privileged candidates for regenerative medicine procedures or other plastic reconstructive surgeries. The cellular environment is able to influence the fate of stem cells residing in the tissue. In a previous study, we exposed hADSCs to an exhausted medium of a breast cancer cell line (MCF-7) recovered at different days (4, 7, and 10 days). In the same paper, we inferred that the medium was able to influence the behaviour of stem cells. Considering these results, in the present study, we evaluated the expression of the major genes related to adipogenic and osteogenic differentiation. To confirm the gene expression data, oil red and alizarin red colorimetric assays were performed. Lastly, we evaluated the expression of miRNAs influencing the differentiation process and the proliferation rate, maintaining a proliferative state. The data obtained confirmed that cells exposed to the medium maintained a stem and proliferative state that could lead to a risky proliferative phenotype.
Mitochondrial Protein Density, Biomass, and Bioenergetics as Predictors for the Efficacy of Glioma Treatments
Authors: Sharapova Gulnaz , Sabirova Sirina , Gomzikova Marina , Brichkina Anna , Barlev Nick A , Kalacheva Natalia V , Rizvanov Albert , Markov Nikita , Simon Hans-Uwe
Published: June 2024

The metabolism of glioma cells exhibits significant heterogeneity and is partially responsible for treatment outcomes. Given this variability, we hypothesized that the effectiveness of treatments targeting various metabolic pathways depends on the bioenergetic profiles and mitochondrial status of glioma cells. To this end, we analyzed mitochondrial biomass, mitochondrial protein density, oxidative phosphorylation (OXPHOS), and glycolysis in a panel of eight glioma cell lines. Our findings revealed considerable variability: mitochondrial biomass varied by up to 3.2-fold, the density of mitochondrial proteins by up to 2.1-fold, and OXPHOS levels by up to 7.3-fold across the cell lines. Subsequently, we stratified glioma cell lines based on their mitochondrial status, OXPHOS, and bioenergetic fitness. Following this stratification, we utilized 16 compounds targeting key bioenergetic, mitochondrial, and related pathways to analyze the associations between induced changes in cell numbers, proliferation, and apoptosis with respect to their steady-state mitochondrial and bioenergetic metrics. Remarkably, a significant fraction of the treatments showed strong correlations with mitochondrial biomass and the density of mitochondrial proteins, suggesting that mitochondrial status may reflect glioma cell sensitivity to specific treatments. Overall, our results indicate that mitochondrial status and bioenergetics are linked to the efficacy of treatments targeting metabolic pathways in glioma.
Apolipoproteins in Health and Disease
Authors: Ordóñez-Llanos Jordi , Escolà-Gil Joan Carles
Published: June 2024

Although apolipoproteins (apo) were initially acknowledged as major determinants in lipoprotein metabolism and cardiovascular disease, the findings of recent studies have revealed the significance of multiple apolipoprotein classes and subclasses in various biological processes and pathophysiological pathways [...]
Tebuconazole Induces Mouse Fetal Testes Damage via ROS Generation in an Organ Culture Method
Authors: Lee Won-Young , Lee Ran , Park Hyun-Jung
Published: June 2024

The fungicide tebuconazole (TEB) poses risks to human and animal health via various exposure routes. It induces toxicity in multiple organs and disrupts reproductive health by affecting steroid hormone synthesis and fetal development. In this study, we investigated the impact of TEB on fetal testes using in vitro models, focusing on germ, Sertoli, and Leydig cells, and explored the mechanisms underlying cellular damage. The results revealed significant damage to germ cells and disruption of Leydig cell development. TEB exposure led to a decrease in germ cell numbers, as indicated by histological and immunostaining analyses. TEB induced the up- and down-regulation of the expression of fetal and adult Leydig cell markers, respectively. Additionally, TEB-treated fetal testes exhibited increased expression of oxidative-stress-related genes and proteins. However, co-treatment with the antioxidant N-acetylcysteine mitigated TEB-induced germ cell damage and prevented abnormal Leydig cell development. These findings suggest that administration of antioxidants can prevent the intratesticular damage typically caused by TEB exposure.
Therapeutic Approaches for Non-Melanoma Skin Cancer: Standard of Care and Emerging Modalities
Authors: Sol Stefano , Boncimino Fabiana , Todorova Kristina , Waszyn Sarah Elizabeth , Mandinova Anna
Published: June 2024

Skin cancer encompasses a range of cutaneous malignancies, with non-melanoma skin cancers (NMSCs) being the most common neoplasm worldwide. Skin exposure is the leading risk factor for initiating NMSC. Ultraviolet (UV) light induces various genomic aberrations in both tumor-promoting and tumor-suppressing genes in epidermal cells. In conjunction with interactions with a changed stromal microenvironment and local immune suppression, these aberrations contribute to the occurrence and expansion of cancerous lesions. Surgical excision is still the most common treatment for these lesions; however, locally advanced or metastatic disease significantly increases the chances of morbidity or death. In recent years, numerous pharmacological targets were found through extensive research on the pathogenic mechanisms of NMSCs, leading to the development of novel treatments including Hedgehog pathway inhibitors for advanced and metastatic basal cell carcinoma (BCC) and PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC). Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise with long-term treatment. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. This review summarizes the current and emerging therapies used to treat NMSC.
Functional Analysis of Forkhead Transcription Factor Fd59a in the Spermatogenesis of Drosophila melanogaster
Authors: Tang Ting , Pei Mengyuan , Xiao Yanhong , Deng Yingshan , Lu Yuzhen , Yu Xiao-Qiang , Wen Liang , Hu Qihao
Published: June 2024

Spermatogenesis is critical for insect reproduction and is regulated by many different genes. In this study, we found that Forkhead transcription factor Fd59a functions as a key factor in the spermatogenesis of Drosophila melanogaster. Fd59a contains a conversed Forkhead domain, and it is clustered to the FoxD subfamily with other FoxD members from some insect and vertebrate species. Mutations in Fd59a caused swelling in the apical region of the testis. More importantly, fewer mature sperm were present in the seminal vesicle of Fd59a mutant flies compared to the control flies, and the fertility of Fd59a2/2 mutant males was significantly lower than that of the control flies. Immunofluorescence staining showed that the homeostasis of the testis stem cell niche in Fd59a2/2 mutant and Fd59a RNAi flies was disrupted and the apoptosis of sperm bundles was increased. Furthermore, results from RNA sequencing and qRT-PCR suggested that Fd59a can regulate the expression of genes related to reproductive process and cell death. Taken together, our results indicated that Fd59a plays a key role in the spermatogenesis of Drosophila.
Ovicidal Toxicity and Morphological Changes in Housefly Eggs Induced by the Essential Oils of Star Anise and Lemongrass and Their Main Constituents
Authors: Passara Hataichanok , Sittichok Sirawut , Sinthusiri Jirisuda , Moungthipmalai Tanapoom , Puwanard Cheepchanok , Murata Kouhei , Soonwera Mayura
Published: June 2024

This study attempted to evaluate the ovicidal activity of single-component formulations and combination formulations of lemongrass and star anise essential oils (EOs) and their main constituents against housefly eggs. The efficacies of the combinations were compared with those of single-component formulations and α-cypermethrin. Safety bioassays of all treatments and α-cypermethrin on non-target predators—guppy and molly—were conducted. Two combinations: 1% lemongrass EO + 1% trans-anethole and 1% star anise EO + 1% geranial, exhibited a strong ovicidal activity with an inhibition rate of 94.4 to 96.2%. They were 1.1 times as effective as α-cypermethrin. The two combinations also showed high synergistic activity compared to single-component formulations, with a high synergistic index and a high increased inhibition value of 37.4 to 57.7%. All EO treatments were benign for all non-target aquatic species with a high 50% lethal time (LT50) and safety index. In contrast, α-cypermethrin was highly toxic to them with a low LT50. The morphological abnormalities observed in housefly eggs at death were those such as the shrivelling of the eggs, aberrations and damage to the eggshells, hatching lines, aeropyles, plastron, and micropyle. The potential of these two combinations as a cypermethrin replacement is compelling.
Clinical Characteristics of Unilateral Macular Neovascularization Patients with Pachydrusen in the Fellow Eye
Authors: Kamao Hiroyuki , Mitsui Erika , Date Yuto , Goto Katsutoshi , Mizukawa Kenichi , Miki Atsushi
Published: June 2024

Background/Objectives: To approach the clinical properties of pachydrusen that differ from conventional drusen, we investigated the incidence of macular neovascularization (MNV) in fellow eyes and the treatment outcomes of intravitreal aflibercept (IVA) in MNV eyes of unilateral MNV patients with pachydrusen in the fellow eye. Methods: We retrospectively studied 261 consecutive patients with treatment-naïve unilateral MNV. Patients were classified into four groups according to the type of drusen in the fellow eye: the pachydrusen group (n = 49), the soft drusen group (n = 63), the subretinal drusenoid deposit (SDD) group (n = 24), and the no drusen group (n = 125). The development of the MNV in the fellow eye was evaluated for five years, and the retreatment proportion after three monthly aflibercept injections was evaluated for one year. Results: The choroidal thickness in the fellow eyes and MNV eyes was the greatest in the pachydrusen group (all p < 0.001). The 5-year incidence of MNV in the pachydrusen group was similar to that in the soft drusen group and no drusen group. The pachydrusen group had a lower retreatment rate than the other groups did (pachydrusen group: 46.4%; soft drusen group: 78.1%; SDDs: 87.5%; no drusen group: 83.3%). Conclusions: Unilateral MNV patients with pachydrusen in the fellow eye had a lower retreatment rate (46.4%/1 year); therefore, aflibercept monotherapy using the PRN regimen is one of the preferred treatment methods for MNV patients with pachydrusen in the fellow eye.
Perceptions of Skills Needed for STEM Jobs: Links to Academic Self-Concepts, Job Interests, Job Gender Stereotypes, and Spatial Ability in Young Adults
Authors: Signorella Margaret L. , Liben Lynn S.
Published: June 2024

Gender gaps in spatial skills—a domain relevant to STEM jobs—have been hypothesized to contribute to women’s underrepresentation in STEM fields. To study emerging adults’ beliefs about skill sets and jobs, we asked college students (N = 300) about the relevance of spatial, mathematical, science and verbal skills for each of 82 jobs. Analyses of responses revealed four job clusters—quantitative, basic & applied science, spatial, and verbal. Students’ ratings of individual jobs and job clusters were similar to judgments of professional job analysts (O*NET). Both groups connected STEM jobs to science, math, and spatial skills. To investigate whether students’ interests in STEM and other jobs are related to their own self-concepts, beliefs about jobs, and spatial performance, we asked students in another sample (N = 292) to rate their self-concepts in various academic domains, rate personal interest in each of the 82 jobs, judge cultural gender stereotypes of those jobs, and complete a spatial task. Consistent with prior research, jobs judged to draw on math, science, or spatial skills were rated as more strongly culturally stereotyped for men than women; jobs judged to draw on verbal skills were more strongly culturally stereotyped for women than men. Structural equation modeling showed that for both women and men, spatial task scores directly (and indirectly through spatial self-concept) related to greater interest in the job cluster closest to the one O*NET labeled “STEM”. Findings suggest that pre-college interventions that improve spatial skills might be effective for increasing spatial self-concepts and the pursuit of STEM careers among students from traditionally under-represented groups, including women.
Experimental Methodology to Identify Optimal Friction Stir Welding Parameters Based on Temperature Measurement
Authors: Abboud Moura , Dubourg Laurent , Racineux Guillaume , Kerbrat Olivier
Published: June 2024

Friction stir welding (FSW) is a widely employed welding process, in which advancing and rotational speeds consitute critical parameters shaping the welding outcome and affecting the temperature evolution. This work develops an experimental methodology to identify optimal FSW parameters based on real-time temperature measurement via a thermocouple integrated within the tool. Different rotational and welding speeds were tested on AA5083-H111 and AA6082-T6. Our results underscore the importance of attaining a minimum temperature threshold, specifically 0.65 times the solidus temperature, to ensure high-quality welds are reached. The latter are defined by combining temperature measurements with joint quality information obtained from cross-sectional views. Our research contributes to advancing the efficiency and effectiveness of friction stir welding in industrial settings. Furthermore, our findings suggest broad implications for the manufacturing industry, offering practical insights for enhancing weld quality and process optimization.
Mental Health in Healthcare Workers Post-COVID-19: A Latin American Review and Insights into Personalized Management Strategies
Authors: Muñoz-Ortega Sandra , Santamaría-Guayaquil Daniela , Pluas-Borja Jade , Alvarado-Villa Geovanny , Sandoval Verónica , Alvarado Rubén , Cherrez-Ojeda Ivan , Faytong-Haro Marco
Published: June 2024

Over the COVID-19 pandemic, the impact of enduring mental health on healthcare workers has become increasingly evident. This review focuses on post-pandemic mental health challenges faced by healthcare personnel in Latin America. This highlights the persistent burden on healthcare workers, especially women, which is exacerbated by economic disparities, inadequacies in the healthcare system, and ongoing occupational stressors. Our literature review, utilizing databases such as PubMed, Scopus, and Google Scholar, scrutinized the mental health status of healthcare professionals in the region after the pandemic’s peak. The analysis indicated sustained levels of psychological distress, with frontline workers and women continuing to be affected disproportionately. These findings emphasize the urgent need for personalized interventions to effectively address the complex mental health challenges in this context. This review advocates strategic interventions, including tailored psychological support, innovative diagnostics, and technological solutions, integrated into patient-centered care models. Such approaches aim to enhance the mental resilience and overall well-being of healthcare professionals across Latin America in the post-COVID era.
The Path from Personality to Anxiety and Depression Is Mediated by Cognition in Multiple Sclerosis
Authors: Schenk Alina , Popa Cosmin Octavian , Cojocaru Cristiana Manuela , Marian Ștefan , Maier Smaranda , Bălașa Rodica
Published: June 2024

Background: Multiple sclerosis (MS) is a neurodegenerative immunological disease causing significant impairment in all life areas. Therefore, personality changes are observed and associated with higher prevalence of depression and anxiety disorders. Considering this relationship, we hypothesized that clinical symptoms and personality disorders are more prevalent in MS and that dysfunctional psychological mechanisms mediate the path from personality disorders to clinical symptoms. Methods: The study sample consisted of 43 patients with MS (age M = 41.9, SD = 11.5) and 31 controls (age M = 39.8, SD = 10.3). Measures of personality, anxiety, depression, fatigue, health status, and dysfunctional psychological mechanisms were conducted. Results: The prevalence of clinical symptoms was increased in MS patients as compared to controls. Also, dependent and schizoid personality traits (PTs) were observed in the patient sample. Negative automatic thoughts (NATs) were found to mediate the association between dependent PT and clinical symptoms. Along with schizoid PT, all dysfunctional psychological mechanisms impacted clinical symptoms. Discussion: The results of our research are in line with previous studies showing that anxiety, depression, and dysfunctional personality traits are more prevalent in MS as compared to controls. Conclusions: PTs and dysfunctional psychological mechanisms predicted depression, anxiety, fatigue, and health status in MS patients. Cognition acts as a strong mediator between PTs and psychopathology in MS. Hence, integrative personalized psychological treatment is recommended to improve the quality of care in MS.