bluuebunny/crossref_metadata_2025 huggingface dataset:
Occupation-Induced Fatigue and Impacts on Emergency First Responders: A Systematic Review
Authors: Marvin Graham , Schram Ben , Orr Robin , Canetti Elisa F. D.
Published: November 2023

Fatigue in emergency first responders (EFRs) is known to affect performance abilities and safety outcomes for both patients and EFRs. The primary aim of this review was to determine the main contributors to occupation-induced fatigue in EFRs and its subsequent impacts. Following the PRIMSA checklist, academic databases (Medline, Embase, CINAHL, and SPORTDiscus) were searched using key terms with results subjected to inclusion and exclusion criteria. Populations of interest were firefighters, paramedics, or emergency call centre personnel. Of the 5633 records identified, 43 studies, which reported on 186 unique measures from a total population of 6373 participants, informed the review. Synthesis revealed fatigue was caused by lack of sleep during the shift and consistent poor sleep quality which negatively impacted cognitive function, alertness, and physical and mental health while increasing safety-compromising behaviours and injuries. Both subjective and objective assessments of fatigue are necessary for effective risk management in EFRs. EFRs that are consistently fatigued are at a greater risk of poor physical and mental health, reduced cognitive function, and increased injuries. No studies reported on fatigue in emergency call centre personnel, highlighting a literature gap. Funding was provided by the Australian Capital Territory Emergency Services Agency. Preregistration was filed in OSF: osf.io/26f3s.
Health and Psychological Concerns of Communities Affected by Per- and Poly-Fluoroalkyl Substances: The Case of Residents Living in the Orange Area of the Veneto Region
Authors: Menegatto Marialuisa , Zamperini Adriano
Published: November 2023

Residents of an extensive area of the Veneto Region (Italy) face one of the largest technological disasters due to per- and polyfluoroalkyl substances (PFAS). On the basis of a risk gradient of contamination, the affected territories were divided into 4 areas: Red (of maximum exposure, where a human biomonitoring programme (HBM) was activated), Orange, Yellow, and Green. This article presents a case study of residents who live in the Orange Area, the second area in terms of contamination, excluded from the HBM. Semi-structured interviews were conducted with 17 residents engaged in promoting a legal procedure to exercise their right to know. Grounded theory and a thematic analysis method were used. Overall, the findings revealed that experiencing contamination causes a negative psychosocial impact on the residents’ lives; difficulty accessing information; living with uncertainty, caused by the lack of institutional and health support and medical consultation; a sense of abandonment; difficulty managing preventive and protective actions; and the deterioration of relationships, on the basis of the social comparison with residents of the Red Area, to whom HBM was granted and where the concept of health ostracism has emerged. This study demonstrated that biomonitoring may help reduce discomfort in the case of contamination by informing people of their chemical exposure.
Risk Factors for the Impairment of Ambulation in Older People Hospitalized with COVID-19: A Retrospective Cohort Study
Authors: Silva Erika Christina Gouveia e , Schmitt Ana Carolina Basso , de Godoy Caroline Gil , de Oliveira Danielle Brancolini , Tanaka Clarice , Toufen Carlos , de Carvalho Carlos Roberto Ribeiro , Carvalho Celso R. F. , Fu Carolina , Hill Keith D. , Pompeu José Eduardo
Published: November 2023

(1) Background: Some older people hospitalized with COVID-19 have experienced reduced ambulation capacity. However, the prevalence of the impairment of ambulation capacity still needs to be established. Objective: To estimate the prevalence of, and identify the risk factors associated with, the impairment of ambulation capacity at the point of hospital discharge for older people with COVID-19. (2) Methods: A retrospective cohort study. Included are those with an age > 60 years, of either sex, hospitalized due to COVID-19. Clinical data was collected from patients’ medical records. Ambulation capacity prior to COVID-19 infection was assessed through the patients’ reports from their relatives. Multiple logistic regressions were performed to identify the risk factors associated with the impairment of ambulation at hospital discharge. (3) Results: Data for 429 older people hospitalized with COVID-19 were randomly collected from the medical records. Among the 56.4% who were discharged, 57.9% had reduced ambulation capacity. Factors associated with reduced ambulation capacity at discharge were a hospital stay longer than 20 days (Odds Ratio (OR): 3.5) and dependent ambulation capacity prior to COVID-19 (Odds Ratio (OR): 11.3). (4) Conclusion: More than half of the older people who survived following hospitalization due to COVID-19 had reduced ambulation capacity at hospital discharge. Impaired ambulation prior to the infection and a longer hospital stay were risks factors for reduced ambulation capacity.
Effect of Vitamin D in Long COVID Patients
Authors: Hikmet Ramsen Ghasan , Wejse Christian , Agergaard Jane
Published: November 2023

Vitamin D deficiency has been studied in the context of acute coronavirus disease 2019 (COVID-19), revealing associations with increased severity and mortality. Yet, the influence of vitamin D on long COVID symptoms remains unknown. The purpose of this study is to examine the effect of vitamin D on long COVID symptoms. Over the study period, 50,432 individuals within the catchment area of the outpatient COVID-19 clinic tested positive for SARS-CoV-2 via PCR, with 547 patients subsequently referred to a specialized Post-COVID Clinic, and 447 of them enrolled in the study. Patient-reported symptoms and paraclinical measures including vitamin D were evaluated in 442 patients. The majority of participants were female (72%, n = 320/442). The consumption of alcohol and number of current smokers were low. Low vitamin D was observed in 26% (n = 115/442) of the patients, most commonly in male participants (odds ratio (OR) = 1.77, 95% confidence interval (CI) (1.12, 2.79), p = 0.014). Additionally, low vitamin D was correlated with a younger mean age of 41 years (standard deviation (SD) = 12) as opposed to 48 years (SD = 13) in patients with normal vitamin D levels (OR = 0.96, 95% CI (0.94, 0.97), p < 0.001). While our study population indicated a potentially higher prevalence of vitamin D insufficiency in this population compared to the general population, no significant differences in prevalence of symptom or symptom severity scores were observed between the low and normal vitamin D groups. In patients in a Post-COVID Clinic, we found no association between vitamin D levels and long COVID symptoms.
Evaluation and Spatiotemporal Differentiation of Cultural Tourism Development Potential: The Case of the Middle and Lower Reaches of the Yellow River
Authors: Chen Yuying , Li Yajie , Gu Xiangfeng , Yuan Qing , Chen Nan , Jin Qi
Published: November 2023

Cultural tourism development potential (CTDP) is the future value and supporting force of the environmental value, economic and social efficiency, innovation ability and supporting system of cultural tourism. At present, there are few relevant studies on CTDP, but the research results on the tourism development potential of cultural heritage are relatively rich, and the existing evaluation methods lack comprehensiveness, dynamics and visualization. Based on systems theory and sustainable development theory, this article attempts to innovate and collect time series data through the entropy method, multi-index comprehensive evaluation method, spatial kernel density estimation method, and centroid transferring model. The temporal and spatial evolution characteristics and the CTDP of 43 cities in the middle and lower reaches of the Yellow River are examined and analyzed. It is found that the CTDP in the middle and lower reaches of the Yellow River is divided into five levels; the overall potential intensity of the research area is small and has significant spatial differences; influenced by the time factor, the interaction and spatial correlation of within the research area are significant; the development of regional cultural tourism has strong regional dependence in the short range. The center of potential gradually moves to the geometric center. This study is significant for promoting the sustainable development of economic tourism in cradles of world civilization.
Role and Regulation of Transcription Factors in Osteoclastogenesis
Authors: Jiang Tao , Xia Tianshuang , Qiao Fangliang , Wang Nani , Jiang Yiping , Xin Hailiang
Published: November 2023

Bones serve mechanical and defensive functions, as well as regulating the balance of calcium ions and housing bone marrow.. The qualities of bones do not remain constant. Instead, they fluctuate throughout life, with functions increasing in some situations while deteriorating in others. The synchronization of osteoblast-mediated bone formation and osteoclast-mediated bone resorption is critical for maintaining bone mass and microstructure integrity in a steady state. This equilibrium, however, can be disrupted by a variety of bone pathologies. Excessive osteoclast differentiation can result in osteoporosis, Paget’s disease, osteolytic bone metastases, and rheumatoid arthritis, all of which can adversely affect people’s health. Osteoclast differentiation is regulated by transcription factors NFATc1, MITF, C/EBPα, PU.1, NF-κB, and c-Fos. The transcriptional activity of osteoclasts is largely influenced by developmental and environmental signals with the involvement of co-factors, RNAs, epigenetics, systemic factors, and the microenvironment. In this paper, we review these themes in regard to transcriptional regulation in osteoclastogenesis.
Bone Allograft Acid Lysates Change the Genetic Signature of Gingival Fibroblasts
Authors: Panahipour Layla , Abbasabadi Azarakhsh Oladzad , Wagner Anja , Kratochwill Klaus , Pichler Monika , Gruber Reinhard
Published: November 2023

Bone allografts are widely used as osteoconductive support to guide bone regrowth. Bone allografts are more than a scaffold for the immigrating cells as they maintain some bioactivity of the original bone matrix. Yet, it remains unclear how immigrating cells respond to bone allografts. To this end, we have evaluated the response of mesenchymal cells exposed to acid lysates of bone allografts (ALBA). RNAseq revealed that ALBA has a strong impact on the genetic signature of gingival fibroblasts, indicated by the increased expression of IL11, AREG, C11orf96, STC1, and GK—as confirmed by RT-PCR, and for IL11 and STC1 by immunoassays. Considering that transforming growth factor-β (TGF-β) is stored in the bone matrix and may have caused the expression changes, we performed a proteomics analysis, TGF-β immunoassay, and smad2/3 nuclear translocation. ALBA neither showed detectable TGF-β nor was the lysate able to induce smad2/3 translocation. Nevertheless, the TGF-β receptor type I kinase inhibitor SB431542 significantly decreased the expression of IL11, AREG, and C11orf96, suggesting that other agonists than TGF-β are responsible for the robust cell response. The findings suggest that IL11, AREG, and C11orf96 expression in mesenchymal cells can serve as a bioassay reflecting the bioactivity of the bone allografts.
Endotoxic Septic Shock: Diagnosis and Treatment
Authors: Foster Debra M. , Kellum John A.
Published: November 2023

Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term endotoxic septic shock has been used for patients who have a clinical phenotype that is characterized by high endotoxin activity in addition to a high burden of organ failure; especially a pattern of organ failure including hepatic dysfunction, acute kidney injury, and various forms of endothelial dysfunction. Endotoxic septic shock has been a target for drug therapy for decades with no success. A likely barrier to their success was the inability to quantify endotoxin in the bloodstream. The Endotoxin Activity Assay (EAA) is positioned to change this landscape. In addition, medical devices using adsorptive technology in an extra-corporeal circulation has been shown to remove large quantities of endotoxin from the bloodstream. Focusing on the use of EAA to determine high concentrations of endotoxin will allow patients with endotoxic septic shock to be identified quickly and these patients may benefit most from removal of endotoxin using extracorporeal methods.
Structural and pKa Estimation of the Amphipathic HR1 in SARS-CoV-2: Insights from Constant pH MD, Linear vs. Nonlinear Normal Mode Analysis
Authors: Yánez Arcos Dayanara Lissette , Thirumuruganandham Saravana Prakash
Published: November 2023

A comprehensive understanding of molecular interactions and functions is imperative for unraveling the intricacies of viral protein behavior and conformational dynamics during cellular entry. Focusing on the SARS-CoV-2 spike protein (SARS-CoV-2 sp), a Principal Component Analysis (PCA) on a subset comprising 131 A-chain structures in presence of various inhibitors was conducted. Our analyses unveiled a compelling correlation between PCA modes and Anisotropic Network Model (ANM) modes, underscoring the reliability and functional significance of low-frequency modes in adapting to diverse inhibitor binding scenarios. The role of HR1 in viral processing, both linear Normal Mode Analysis (NMA) and Nonlinear NMA were implemented. Linear NMA exhibited substantial inter-structure variability, as evident from a higher Root Mean Square Deviation (RMSD) range (7.30 Å), nonlinear NMA show stability throughout the simulations (RMSD 4.85 Å). Frequency analysis further emphasized that the energy requirements for conformational changes in nonlinear modes are notably lower compared to their linear counterparts. Using simulations of molecular dynamics at constant pH (cpH-MD), we successfully predicted the pKa order of the interconnected residues within the HR1 mutations at lower pH values, suggesting a transition to a post-fusion structure. The pKa determination study illustrates the profound effects of pH variations on protein structure. Key results include pKa values of 9.5179 for lys-921 in the D936H mutant, 9.50 for the D950N mutant, and a slightly higher value of 10.49 for the D936Y variant. To further understand the behavior and physicochemical characteristics of the protein in a biologically relevant setting, we also examine hydrophobic regions in the prefused states of the HR1 protein mutants D950N, D936Y, and D936H in our study. This analysis was conducted to ascertain the hydrophobic moment of the protein within a lipid environment, shedding light on its behavior and physicochemical properties in a biologically relevant context.
Computational Insight into the Nature and Strength of the π-Hole Type Chalcogen∙∙∙Chalcogen Interactions in the XO2∙∙∙CH3YCH3 Complexes (X = S, Se, Te; Y = O, S, Se, Te)
Authors: Lei Fengying , Liu Qingyu , Zhong Yeshuang , Cui Xinai , Yu Jie , Hu Zuquan , Feng Gang , Zeng Zhu , Lu Tao
Published: November 2023

In recent years, the non-covalent interactions between chalcogen centers have aroused substantial research interest because of their potential applications in organocatalysis, materials science, drug design, biological systems, crystal engineering, and molecular recognition. However, studies on π-hole-type chalcogen∙∙∙chalcogen interactions are scarcely reported in the literature. Herein, the π-hole-type intermolecular chalcogen∙∙∙chalcogen interactions in the model complexes formed between XO2 (X = S, Se, Te) and CH3YCH3 (Y = O, S, Se, Te) were systematically studied by using quantum chemical computations. The model complexes are stabilized via one primary X∙∙∙Y chalcogen bond (ChB) and the secondary C−H∙∙∙O hydrogen bonds. The binding energies of the studied complexes are in the range of −21.6~−60.4 kJ/mol. The X∙∙∙Y distances are significantly smaller than the sum of the van der Waals radii of the corresponding two atoms. The X∙∙∙Y ChBs in all the studied complexes except for the SO2∙∙∙CH3OCH3 complex are strong in strength and display a partial covalent character revealed by conducting the quantum theory of atoms in molecules (QTAIM), a non-covalent interaction plot (NCIplot), and natural bond orbital (NBO) analyses. The symmetry-adapted perturbation theory (SAPT) analysis discloses that the X∙∙∙Y ChBs are primarily dominated by the electrostatic component.
Global Analysis of Lysine Lactylation of Germinated Seeds in Wheat
Authors: Zhu Junke , Guo Weiwei , Lan Yubin
Published: November 2023

Protein lactylation is a newly discovered posttranslational modification (PTM) and is involved in multiple biological processes, both in mammalian cells and rice grains. However, the function of lysine lactylation remains unexplored in wheat. In this study, we performed the first comparative proteomes and lysine lactylomes during seed germination of wheat. In total, 8000 proteins and 927 lactylated sites in 394 proteins were identified at 0 and 12 h after imbibition (HAI). Functional enrichment analysis showed that glycolysis- and TCA-cycle-related proteins were significantly enriched, and more differentially lactylated proteins were enriched in up-regulated lactylated proteins at 12 HAI vs. 0 HAI through the KEGG pathway and protein domain enrichment analysis compared to down-regulated lactylated proteins. Meanwhile, ten particularly preferred amino acids near lactylation sites were found in the embryos of germinated seeds: AA*KlaT, A***KlaD********A, KlaA**T****K, K******A*Kla, K*Kla********K, KlaA******A, Kla*A, KD****Kla, K********Kla and KlaG. These results supplied a comprehensive profile of lysine lactylation of wheat and indicated that protein lysine lactylation played important functions in several biological processes.
Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches
Authors: Raheem Farah , Karikalan Suganya Arunachalam , Batalini Felipe , El Masry Aya , Mina Lida
Published: November 2023

Endocrine therapy is the main treatment for hormone receptor-positive (HR+) breast cancer. However, advanced tumors develop resistance to endocrine therapy, rendering it ineffective as the disease progresses. There are several molecular mechanisms of primary and secondary endocrine resistance. Resistance can develop due to either alteration of the estrogen receptor pathway (e.g., ESR1 mutations) or upstream growth factors signaling pathways (e.g., PI3K/Akt/mTOR pathway). Despite progress in the development of molecularly targeted anticancer therapies, the emergence of resistance remains a major limitation and an area of unmet need. In this article, we review the mechanisms of acquired endocrine resistance in HR+ advanced breast cancer and discuss current and future investigational therapeutic approaches.
BR55 Ultrasound Molecular Imaging of Clear Cell Renal Cell Carcinoma Reflects Tumor Vascular Expression of VEGFR-2 in a Patient-Derived Xenograft Model
Authors: Courcier Jean , Leguerney Ingrid , Benatsou Baya , Pochon Sibylle , Tardy Isabelle , Albiges Laurence , Cournède Paul-Henry , De La Taille Alexandre , Lassau Nathalie , Ingels Alexandre
Published: November 2023

Standard imaging cannot reliably predict the nature of renal tumors. Among malignant renal tumors, clear cell renal cell carcinoma (ccRCC) is the most common histological subtype, in which the vascular endothelial growth factor 2 (VEGFR-2) is highly expressed in the vascular endothelium. BR55, a contrast agent for ultrasound imaging, consists of gas-core lipid microbubbles that specifically target and bind to the extracellular portion of the VEGFR-2. The specific information provided by ultrasound molecular imaging (USMI) using BR55 was compared with the vascular tumor expression of the VEGFR-2 by immunohistochemical (IHC) staining in a preclinical model of ccRCC. Patients’ ccRCCs were orthotopically grafted onto Nod-Scid-Gamma (NSG) mice to generate patient-derived xenografts (PdX). Mice were divided into four groups to receive either vehicle or axitinib an amount of 2, 7.5 or 15 mg/kg twice daily. Perfusion parameters and the BR55 ultrasound contrast signal on PdX renal tumors were analyzed at D0, D1, D3, D7 and D11, and compared with IHC staining for the VEGFR-2 and CD34. Significant Pearson correlation coefficients were observed between the area under the curve (AUC) and the CD34 (0.84, p < 10−4), and between the VEGFR-2-specific signal obtained by USMI and IHC (0.72, p < 10−4). USMI with BR55 could provide instant, quantitative information on tumor VEGFR-2 expression to characterize renal masses non-invasively.
Bisphenol AF Induces Prostatic Dorsal Lobe Hyperplasia in Rats through Activation of the NF-κB Signaling Pathway
Authors: Huang Sisi , Wang Kaiyue , Huang Dongyan , Su Xin , Yang Rongfu , Shao Congcong , Jiang Juan , Wu Jianhui
Published: November 2023

Bisphenol AF (BPAF) represents a common environmental estrogenic compound renowned for its capacity to induce endocrine disruptions. Notably, BPAF exhibits an enhanced binding affinity to estrogen receptors, which may have more potent estrogenic activity compared with its precursor bisphenol A (BPA). Notwithstanding, the existing studies on BPAF-induced prostate toxicity remain limited, with related toxicological research residing in the preliminary stage. Our previous studies have confirmed the role of BPAF in the induction of ventral prostatic hyperplasia, but its role in the dorsal lobe is not clear. In this study, BPAF (10, 90 μg/kg) and the inhibitor of nuclear transcription factor-κB (NF-κB), pyrrolidinedithiocarbamate (PDTC, 100 mg/kg), were administered intragastrically in rats for four weeks. Through comprehensive anatomical and pathological observations, as well as the assessment of PCNA over-expression, we asserted that BPAF at lower doses may foster dorsal prostatic hyperplasia in rats. The results of IHC and ELISA indicated that BPAF induced hyperplastic responses in the dorsal lobe of the prostate by interfering with a series of biomarkers in NF-κB signaling pathways, containing NF-κB p65, COX-2, TNF-α, and EGFR. These findings confirm the toxic effect of BPAF on prostate health and emphasize the potential corresponding mechanisms.
Plant Life with and without Oxygen: A Metabolomics Approach
Authors: Yemelyanov Vladislav V. , Puzanskiy Roman K. , Shishova Maria F.
Published: November 2023

Oxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses worldwide. The capacity to exist in the conditions of deficiency or the complete lack of oxygen depends on a number of anatomic, developmental and molecular adaptations. The lack of molecular oxygen leads to an inhibition of aerobic respiration, which causes energy starvation and the acceleration of glycolysis passing into fermentations. We focus on systemic metabolic alterations revealed with the different approaches of metabolomics. Oxygen deprivation stimulates the accumulation of glucose, pyruvate and lactate, indicating the acceleration of the sugar metabolism, glycolysis and lactic fermentation, respectively. Among the Krebs-cycle metabolites, only the succinate level increases. Amino acids related to glycolysis, including the phosphoglycerate family (Ser and Gly), shikimate family (Phe, Tyr and Trp) and pyruvate family (Ala, Leu and Val), are greatly elevated. Members of the Asp family (Asn, Lys, Met, Thr and Ile), as well as the Glu family (Glu, Pro, Arg and GABA), accumulate as well. These metabolites are important members of the metabolic signature of oxygen deficiency in plants, linking glycolysis with an altered Krebs cycle and allowing alternative pathways of NAD(P)H reoxidation to avoid the excessive accumulation of toxic fermentation products (lactate, acetaldehyde, ethanol). Reoxygenation induces the downregulation of the levels of major anaerobically induced metabolites, including lactate, succinate and amino acids, especially members of the pyruvate family (Ala, Leu and Val), Tyr and Glu family (GABA and Glu) and Asp family (Asn, Met, Thr and Ile). The metabolic profiles during native and environmental hypoxia are rather similar, consisting in the accumulation of fermentation products, succinate, fumarate and amino acids, particularly Ala, Gly and GABA. The most intriguing fact is that metabolic alterations during oxidative stress are very much similar, with plant response to oxygen deprivation but not to reoxygenation.
Sulfated Polysaccharides as a Fighter with Protein Non-Physiological Aggregation: The Role of Polysaccharide Flexibility and Charge Density
Authors: Makshakova Olga N. , Bogdanova Liliya R. , Faizullin Dzhigangir A. , Ermakova Elena A. , Zuev Yuriy F.
Published: November 2023

Proteins can lose native functionality due to non-physiological aggregation. In this work, we have shown the power of sulfated polysaccharides as a natural assistant to restore damaged protein structures. Protein aggregates enriched by cross-β structures are a characteristic of amyloid fibrils related to different health disorders. Our recent studies demonstrated that model fibrils of hen egg white lysozyme (HEWL) can be disaggregated and renatured by some negatively charged polysaccharides. In the current work, using the same model protein system and FTIR spectroscopy, we studied the role of conformation and charge distribution along the polysaccharide chain in the protein secondary structure conversion. The effects of three carrageenans (κ, ι, and λ) possessing from one to three sulfate groups per disaccharide unit were shown to be different. κ-Carrageenan was able to fully eliminate cross-β structures and complete the renaturation process. ι-Carrageenan only initiated the formation of native-like β-structures in HEWL, retaining most of the cross-β structures. In contrast, λ-carrageenan even increased the content of amyloid cross-β structures. Furthermore, κ-carrageenan in rigid helical conformation loses its capability to restore protein native structures, largely increasing the amount of amyloid cross-β structures. Our findings create a platform for the design of novel natural chaperons to counteract protein unfolding.
Biophysical Insights into the Antitumoral Activity of Crotalicidin against Breast Cancer Model Membranes
Authors: Klaiss-Luna Maria C. , Giraldo-Lorza Juan M. , Jemioła-Rzemińska Małgorzata , Strzałka Kazimierz , Manrique-Moreno Marcela
Published: November 2023

Bioactive peptides have emerged as promising therapeutic agents with antimicrobial, antifungal, antiparasitic, and, recently, antitumoral properties with a mechanism of action based on membrane destabilization and cell death, often involving a conformational change in the peptide. This biophysical study aims to provide preliminary insights into the membrane-level antitumoral mode of action of crotalicidin, a cationic host defense peptide from rattlesnake venom, toward breast cancer cell lines. The lipid composition of breast cancer cell lines was obtained after lipid extraction and quantification to prepare representative cell membrane models. Membrane–peptide interaction studies were performed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. The outcome evidences the potential antitumoral activity and selectivity of crotalicidin toward breast cancer cell lines and suggests a mechanism initiated by the electrostatic interaction of the peptide with the lipid bilayer surface and posterior conformation change with membrane intercalation between the acyl chains in negatively charged lipid systems. This research provides valuable information that clears up the antitumoral mode of action of crotalicidin.
Relevance of Phytochemical Taste for Anti-Cancer Activity: A Statistical Inquiry
Authors: Grădinaru Teodora-Cristiana , Gilca Marilena , Vlad Adelina , Dragoș Dorin
Published: November 2023

Targeting inflammation and the pathways linking inflammation with cancer is an innovative therapeutic strategy. Tastants are potential candidates for this approach, since taste receptors display various biological functions, including anti-inflammatory activity (AIA). The present study aims to explore the power different tastes have to predict a phytochemical’s anti-cancer properties. It also investigates whether anti-inflammatory phytocompounds also have anti-cancer effects, and whether there are tastes that can better predict a phytochemical’s bivalent biological activity. Data from the PlantMolecularTasteDB, containing a total of 1527 phytochemicals, were used. Out of these, only 624 phytocompounds met the inclusion criterion of having 40 hits in a PubMed search, using the name of the phytochemical as the keyword. Among them, 461 phytochemicals were found to possess anti-cancer activity (ACA). The AIA and ACA of phytochemicals were strongly correlated, irrespective of taste/orosensation or chemical class. Bitter taste was positively correlated with ACA, while sweet taste was negatively correlated. Among chemical classes, only flavonoids (which are most frequently bitter) had a positive association with both AIA and ACA, a finding confirming that taste has predictive primacy over chemical class. Therefore, bitter taste receptor agonists and sweet taste receptor antagonists may have a beneficial effect in slowing down the progression of inflammation to cancer.
Drought Stress Alleviator Melatonin Reconfigures Water-Stressed Barley (Hordeum vulgare L.) Plants’ Photosynthetic Efficiency, Antioxidant Capacity, and Endogenous Phytohormone Profile
Authors: Talaat Neveen B.
Published: November 2023

The production of crops is severely limited by water scarcity. We still do not fully understand the underlying mechanism of exogenous melatonin (MT)-mediated water stress tolerance in barley. This study is the first of its kind to show how MT can potentially mitigate changes in barley’s physio-biochemical parameters caused by water deficiency. Barley was grown under three irrigation levels (100%, 70%, and 30% of field capacity) and was foliar sprayed with 70 μM MT. The results showed that exogenously applied MT protected the photosynthetic apparatus by improving photosynthetic pigment content, photochemical reactions of photosynthesis, Calvin cycle enzyme activity, gas exchange capacity, chlorophyll fluorescence system, and membrane stability index. Furthermore, the increased levels of salicylic acid, gibberellins, cytokinins, melatonin, and indole-3-acetic acid, as well as a decrease in abscisic acid, indicated that foliar-applied MT greatly improved barley water stress tolerance. Additionally, by increasing the activity of antioxidant enzymes such as superoxide dismutase, catalase, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase and decreasing hydrogen peroxide content, lipid peroxidation, and electrolyte leakage, MT application lessened water stress-induced oxidative stress. According to the newly discovered data, MT application improves barley water stress tolerance by reprogramming endogenous plant hormone production and antioxidant activity, which enhances membrane stability and photosynthesis. This study unraveled MT’s crucial role in water deficiency mitigation, which can thus be applied to water stress management.
Major Contribution of c.[1622T>C;3113C>T] Complex Allele and c.5882G>A Variant in ABCA4-Related Retinal Dystrophy in an Eastern European Population
Authors: Kadyshev Vitaly V. , Alekseeva Ekaterina A. , Strelnikov Vladimir V. , Stepanova Anna A. , Polyakov Alexander V. , Marakhonov Andrey V. , Kutsev Sergey I. , Zinchenko Rena A.
Published: November 2023

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4-related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p.Gly1961Glu or G1961E) emerged as primary contributors to this ocular pathology within this population. Additionally, we elucidated distinct disease progression characteristics associated with the G1961E variant. Furthermore, our investigation revealed that patients with loss-of-function variants in ABCA4 were more inclined to develop phenotypes distinct from Stargardt disease. These findings provide crucial insights into the genetic and clinical landscape of ABCA4-related retinal dystrophies in this specific population.
Anti-Adhesive Resorbable Indomethacin/Bupivacaine-Eluting Nanofibers for Tendon Rupture Repair: In Vitro and In Vivo Studies
Authors: Yu Yi-Hsun , Lee Chen-Hung , Hsu Yung-Heng , Chou Ying-Chao , Yu Ping-Chun , Huang Chao-Tsai , Liu Shih-Jung
Published: November 2023

The treatment and surgical repair of torn Achilles tendons seldom return the wounded tendon to its original elasticity and stiffness. This study explored the in vitro and in vivo simultaneous release of indomethacin and bupivacaine from electrospun polylactide–polyglycolide composite membranes for their capacity to repair torn Achilles tendons. These membranes were fabricated by mixing polylactide–polyglycolide/indomethacin, polylactide–polyglycolide/collagen, and polylactide–polyglycolide/bupivacaine with 1,1,1,3,3,3-hexafluoro-2-propanol into sandwich-structured composites. Subsequently, the in vitro pharmaceutic release rates over 30 days were determined, and the in vivo release behavior and effectiveness of the loaded drugs were assessed using an animal surgical model. High concentrations of indomethacin and bupivacaine were released for over four weeks. The released pharmaceutics resulted in complete recovery of rat tendons, and the nanofibrous composite membranes exhibited exceptional mechanical strength. Additionally, the anti-adhesion capacity of the developed membrane was confirmed. Using the electrospinning technique developed in this study, we plan on manufacturing degradable composite membranes for tendon healing, which can deliver sustained pharmaceutical release and provide a collagenous habitat.
GSK2656157, a PERK Inhibitor, Alleviates Pyroptosis of Macrophages Induced by Mycobacterium Bacillus Calmette–Guerin Infection
Authors: Ma Boli , Nie Xueyi , Liu Lei , Li Mengyuan , Chen Qi , Liu Yueyang , Hou Yuxin , Yang Yi , Xu Jinrui
Published: November 2023

Tuberculosis (TB) is the leading cause of human death worldwide due to Mycobacterium tuberculosis (Mtb) infection. Mtb infection can cause macrophage pyroptosis. PERK, as a signaling pathway protein on the endoplasmic reticulum, plays an important role in infectious diseases. It is not clear whether PERK is involved in the regulation of pyroptosis of macrophages during Mtb infection. In this study, Bacillus Calmette–Guerin (BCG) infection resulted in high expression of pro-caspase-1, caspase-1 p20, GSDMD-N, and p-PERK in the THP-1 macrophage, being downregulated with the pre-treatment of GSK2656157, a PERK inhibitor. In addition, GSK2656157 inhibited the secretion of IL-1β and IL-18, cell content release, and cell membrane rupture, as well as the decline in cell viability induced by BCG infection. Similarly, GSK2656157 treatment downregulated the expressions of pro-caspase-1, caspase-1 p20, caspase-11, IL-1β p17, IL-18 p22, GSDMD, GSDMD-N, and p-PERK, as well as reducing fibrous tissue hyperplasia, inflammatory infiltration, and the bacterial load in the lung tissue of C57BL/6J mice infected with BCG. In conclusion, the inhibition of PERK alleviated pyroptosis induced by BCG infection, which has an effect of resisting infection.
Influence of Microbiota-Related Metabolites Associated with Inflammation and Sepsis on the Peroxidase Activity of Cyclooxygenase in Healthy Human Monocytes and Acute Monocytic Leukemia Cells
Authors: Beloborodova Natalia , Fadeev Roman , Fedotcheva Nadezhda
Published: November 2023

The human microbiota produces metabolites that can enter the bloodstream and exert systemic effects on various functions in both healthy and pathological states. We have studied the participation of microbiota-related metabolites in bacterial infection by examining their influence on the activity of cyclooxygenase (COX) as a key enzyme of inflammation. The influence of aromatic microbial metabolites, derivatives of phenylalanine (phenylpropionic acid, PPA), tyrosine (4-hydroxyphenyllactic acid, HPLA), and tryptophan (indolacetic acids, IAA), the concentrations of which in the blood change notably during sepsis, was evaluated. Also, the effect of itaconic acid (ITA) was studied, which is formed in macrophages under the action of bacterial lipopolysaccharides (LPS) and appears in the blood in the early stages of infection. Metabiotic acetyl phosphate (AcP) as a strong acetylating agent was also tested. The activity of COX was measured via the TMPD oxidation colorimetric assay using the commercial pure enzyme, cultured healthy monocytes, and the human acute monocytic leukemia cell line THP-1. All metabolites in the concentration range of 100–500 μM lowered the activity of COX. The most pronounced inhibition was observed on the commercial pure enzyme, reaching up to 40% in the presence of AcP and 20–30% in the presence of the other metabolites. On cell lysates, the effect of metabolites was preserved, although it significantly decreased, probably due to their interaction with other targets subject to redox-dependent and acetylation processes. The possible contribution of the redox-dependent action of microbial metabolites was confirmed by assessing the activity of the enzyme in the presence of thiol reagents and in model conditions, when the COX-formed peroxy intermediate was replaced with tert-butyl hydroperoxide (TBH). The data show the involvement of the microbial metabolites in the regulation of COX activity, probably due to their influence on the peroxidase activity of the enzyme.
scAAV2-Mediated Expression of Thioredoxin 2 and C3 Transferase Prevents Retinal Ganglion Cell Death and Lowers Intraocular Pressure in a Mouse Model of Glaucoma
Authors: Kim Hee Jong , Cha Seho , Choi Jun-Sub , Lee Joo Yong , Kim Ko Eun , Kim Jin Kwon , Kim Jin , Moon Seo Yun , Lee Steven Hyun Seung , Park Keerang , Won So-Yoon
Published: November 2023

Elevated intraocular pressure (IOP) in glaucoma causes retinal ganglion cell (RGC) loss and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. In this paper, we aimed to develop a novel gene therapy for glaucoma using an AAV2-based thioredoxin 2 (Trx2)-exoenzyme C3 transferase (C3) fusion protein expression vector (scAAV2-Trx2-C3). We evaluated the therapeutic effects of this vector in vitro and in vivo using dexamethasone (DEX)-induced glaucoma models. We found that scAAV2-Trx2-C3-treated HeLa cells had significantly reduced GTP-bound active RhoA and increased phosphor-cofilin Ser3 protein expression levels. scAAV2-Trx2-C3 was also shown to inhibit oxidative stress, fibronectin expression, and alpha-SMA expression in DEX-treated HeLa cells. NeuN immunostaining and TUNEL assay in mouse retinal tissues was performed to evaluate its neuroprotective effect upon RGCs, whereas changes in mouse IOP were monitored via rebound tonometer. The present study showed that scAAV2-Trx2-C3 can protect RGCs from degeneration and reduce IOP in a DEX-induced mouse model of glaucoma, while immunohistochemistry revealed that the expression of fibronectin and alpha-SMA was decreased after the transduction of scAAV2-Trx2-C3 in murine eye tissues. Our results suggest that AAV2-Trx2-C3 modulates the outflow resistance of the trabecular meshwork, protects retinal and other ocular tissues from oxidative damage, and may lead to the development of a gene therapeutic for glaucoma.
An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release
Authors: Fleisher-Berkovich Sigal , Battaglia Veronica , Baratta Francesca , Brusa Paola , Ventura Yvonne , Sharon Nitzan , Dahan Arik , Collino Massimo , Ben-Shabat Shimon
Published: November 2023

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects. Angiotensin II activates the angiotensin 1 receptor and regulates neuroinflammation and cognition. Angiotensin receptor 1 blockers (ARBs) were shown to be neuroprotective and prevent cognitive decline. The present study aimed to elucidate the combined role of CBD and ARBs in the modulation of lipopolysaccharide (LPS)-induced glial inflammation. While LPS significantly enhanced nitric oxide synthesis vs. the control, telmisartan and CBD, when administered alone, attenuated this effect by 60% and 36%, respectively. Exposure of LPS-stimulated cells to both compounds resulted in the 95% inhibition of glial nitric oxide release (additive effect). A synergistic inhibitory effect on nitric oxide release was observed when cells were co-treated with losartan (5 μM) and CBD (5 μM) (by 80%) compared to exposure to each compound alone (by 22% and 26%, respectively). Telmisartan and CBD given alone increased TNFα levels by 60% and 40%, respectively. CBD and telmisartan, when given together, attenuated the LPS-induced increase in TNFα levels without statistical significance. LPS-induced IL-17 release was attenuated by CBD with or without telmisartan (by 75%) or telmisartan alone (by 60%). LPS-induced Interferon-γ release was attenuated by 80% when telmisartan was administered in the absence or presence of CBD. Anti-inflammatory effects were recorded when CBD was combined with the known anti-inflammatory agent dimethyl fumarate (DMF)/monomethyl fumarate (MMF). A synergistic inhibitory effect of CBD and MMF on glial release of nitric oxide (by 77%) was observed compared to cells exposed to MMF (by 35%) or CBD (by 12%) alone. Overall, this study highlights the potential of new combinations of CBD (5 μM) with losartan (5 μM) or MMF (1 μM) to synergistically attenuate glial NO synthesis. Additive effects on NO production were observed when telmisartan (5 μM) and CBD (5 μM) were administered together to glial cells.
Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions
Authors: Nguyen Thi Ha , Nguyen Tuan Minh , Ngoc Dinh Thi Minh , You Taesik , Park Mi Kyung , Lee Chang Hoon
Published: November 2023

This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk
Authors: Furutani Kazuharu
Published: November 2023

Modulation of the human Ether-à-go-go-Related Gene (hERG) channel, a crucial voltage-gated potassium channel in the repolarization of action potentials in ventricular myocytes of the heart, has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. For example, hERG channel blockade is a leading cause of long QT syndrome and potentially life-threatening arrhythmias, such as torsades de pointes. Conversely, hERG channel blockade is the mechanism of action of Class III antiarrhythmic agents in terminating ventricular tachycardia and fibrillation. In recent years, it has been recognized that less proarrhythmic hERG blockers with clinical potential or Class III antiarrhythmic agents exhibit, in addition to their hERG-blocking activity, a second action that facilitates the voltage-dependent activation of the hERG channel. This facilitation is believed to reduce the proarrhythmic potential by supporting the final repolarizing of action potentials. This review covers the pharmacological characteristics of hERG blockers/facilitators, the molecular mechanisms underlying facilitation, and their clinical significance, as well as unresolved issues and requirements for research in the fields of ion channel pharmacology and drug-induced arrhythmias.
Menadione Contribution to the In Vitro Radical Scavenging Potential of Phytochemicals Naringenin and Lignin
Authors: Yaneva Zvezdelina , Ivanova Donika , Toneva Monika , Tzanova Milena , Marutsova Vanya , Grozeva Neli
Published: November 2023

Vitamin K3 (menadione), classified as a pro-vitamin, is a synthetic form of the fat-soluble family of vitamin K compounds. The combination of the vitamin with other molecules sharing structural and/or functional similarities, such as naturally occurring polyphenols, vitamins, or biopolymers, could potentiate mutual improvement of their antioxidant activity. The aim of the present study was to evaluate the role and contribution of vitamin K3 to the in vitro radical scavenging capacity of double and triple combinations with the phytochemicals naringenin and lignin, as well as assess possible intermolecular interactions between the bioactive compounds. Comparative analyses of the DPPH and ABTS radical scavenging activity of the pure substances vitamin K3, naringenin, and lignin; the two-component systems lignin/vitamin K3 and vitamin K3/naringenin; and the triple combination vitamin K3/flavonoid/lignin were carried out. The experimental results demonstrated increased DPPH and ABTS activities of the vitamin in combination with lignin compared to those of the two pure substances, i.e., a synergistic effect was observed. The registered significant increases in the radical scavenging activity of the triple combination determined via both methods are indicative of a remarkable potentiation effect, i.e., higher antioxidant potential exceeding the additive activity of the three pure substances.