bluuebunny/crossref_metadata_2025 huggingface dataset:
Informing ASR Treatment Practices in a Florida Aquifer through a Human Health Risk Approach
Authors: Gitter Anna , Mena Kristina D. , Lisle John T.
Published: September 2023

Aquifer storage and recovery (ASR) can augment water supplies and hydrologic flows under varying climatic conditions. However, imposing drinking water regulations on ASR practices, including pre-treatment before injection into the aquifer, remains arguable. Microbial inactivation data—Escherichia coli, Pseudomonas aeruginosa, poliovirus type 1 and Cryptosporidium parvum—were used in a human health risk assessment to identify how the storage time of recharged water in the Floridan Aquifer enhances pathogen inactivation, thereby mitigating the human health risks associated with ingestion. We used a quantitative microbial risk assessment to evaluate the risks for a gastrointestinal infection (GI) and the associated disability-adjusted life years (DALYs) per person per year. The risk of developing a GI infection for drinking water no longer exceeded the suggested annual risk threshold (1 × 10−4) by days 31, 1, 52 and 80 for each pathogen, respectively. DALYs per person per year no longer exceeded the World Health Organization threshold (1 × 10−6) by days 27, <1, 43 and 72. In summary, storage time in the aquifer yields a significant reduction in health risk. The findings emphasize that considering microbial inactivation, caused by storage time and geochemical conditions within ASR storage zones, is critical for recharge water treatment processes.
Growth Simulations of Urban Underground Space with Ecological Constraints Using a Patch-Based Cellular Automaton
Authors: Wei Lingxiang , Guo Dongjun , Chen Zhilong , Hu Yingying , Wu Yanhua , Ji Junyuan
Published: September 2023

The growth simulation of urban underground space (UUS) under the consideration of ecological constraints can effectively reveal the characteristics and trends of UUS changes, and provide a basis for planning the construction of sustainable and livable ecological cities. Therefore, this study considers urban ecological space as a constraint mechanism for UUS development and conducts a simulation study of the dynamic and complex UUS growth process, with a view toward guiding UUS planning under a long-term overall vision. In this study, a patch-based cellular automaton (CA) model is constructed to simulate the dynamic and complex growth process of UUS, subject to the ecological constraints generated by the agent-based land allocation optimization model. The spatial drivers of UUS growth simulation are determined based on the Random Forest (RF) algorithm. The results of the research case in Tianfu New District, Chengdu City, demonstrate that UUS expansion with ecological constraints exhibits sustainable characteristics. However, the growth rate of the UUS development scale is significantly lower when ecological constraints are present compared to when they are not. This study’s results contribute to urban management by finding a balance between UUS development and ecological space conservation, and providing theoretical support for rational UUS planning and decision making in the construction of low-carbon cities.
Current Challenges and Opportunities for Improved Cannabidiol Solubility
Authors: Hossain Khondker Rufaka , Alghalayini Amani , Valenzuela Stella M.
Published: September 2023

Cannabidiol (CBD), derived from the cannabis plant, has gained significant attention due to its potential therapeutic benefits. However, one of the challenges associated with CBD administration is its low bioavailability, which refers to the fraction of an administered dose that reaches systemic circulation. This limitation necessitates the exploration of various approaches to enhance the bioavailability of CBD, thus helping to maximize its therapeutic potential. A variety of approaches are now emerging, including nanoemulsion-based systems, lipid-based formulations, prodrugs, nanocarriers, and alternative routes of administration, which hold promise for improving the bioavailability of CBD and pave the way for novel formulations that maximize the therapeutic potential of CBD in various medical conditions. This opinion piece presents the current understanding surrounding CBD bioavailability and considers strategies aimed at improving both its absorption and its bioavailability.
Baicalin Attenuates Panton–Valentine Leukocidin (PVL)-Induced Cytoskeleton Rearrangement via Regulating the RhoA/ROCK/LIMK and PI3K/AKT/GSK-3β Pathways in Bovine Mammary Epithelial Cells
Authors: Yang Jiangliu , Hai Zhenzhen , Hou Ling , Liu Yang , Zhang Dongtao , Zhou Xuezhang
Published: September 2023

Pore-forming toxins (PFTs) exert physiological effects by rearrangement of the host cell cytoskeleton. Staphylococcus aureus-secreted PFTs play an important role in bovine mastitis. In the study, we examined the effects of recombinant Panton–Valentine leukocidin (rPVL) on cytoskeleton rearrangement, and identified the signaling pathways involved in regulating the process in bovine mammary epithelial cells (BMECs) in vitro. Meanwhile, the underlying regulatory mechanism of baicalin for this process was investigated. The results showed that S. aureus induced cytoskeleton rearrangement in BMECs mainly through PVL. S. aureus and rPVL caused alterations in the cell morphology and layer integrity due to microfilament and microtubule rearrangement and focal contact inability. rPVL strongly induced the phosphorylation of cofilin at Ser3 mediating by the activation of the RhoA/ROCK/LIMK pathway, and resulted in the activation of loss of actin stress fibers, or the hyperphosphorylation of Tau at Ser396 inducing by the inhibition of the PI3K/AKT/GSK-3β pathways, and decreased the microtubule assembly. Baicalin significantly attenuated rPVL-stimulated cytoskeleton rearrangement in BMECs. Baicalin inhibited cofilin phosphorylation or Tau hyperphosphorylation via regulating the activation of RhoA/ROCK/LIMK and PI3K/AKT/GSK-3β signaling pathways. These findings provide new insights into the pathogenesis and potential treatment in S. aureus causing bovine mastitis.
Biomarkers for Immunotherapy in Driver-Gene-Negative Advanced NSCLC
Authors: Huang Yiyi , Chau Yi-Fung , Bai Hua , Wu Xinyu , Duan Jianchun
Published: September 2023

Outcome improvement in patients with driver-gene-negative advanced non-small cell lung cancer (NSCLC) has been significantly enhanced through targeting the immune system, specifically the PD-L1/PD-1 axis. Nevertheless, only a subset of patients with advanced NSCLC may derive benefits from immuno-monotherapy or immunotherapy combined with chemotherapy. Hence, in order to identify patients who will gain the maximum advantage from immunotherapy, it is crucial to investigate predictive biomarkers. This review provides a summary of the currently identified biomarkers associated with the extent of benefit from immuno-monotherapy or immunotherapy combined with chemotherapy in patients with advanced NSCLC. These biomarkers can be categorized into three groups: tumor-related, tumor-microenvironment-related, and host-factor-related.Tumor-related factors include PD-L1 expression, tumor mutational burden and specific genetic mutations, while tumor-microenvironment-related factors include extracellular vesicles and T-cell receptors, and host-related factors include systemic inflammation, circulating fatty acid profile, and the microbiome.
Differential Effects of Hypothermia and SZR72 on Cerebral Kynurenine and Kynurenic Acid in a Piglet Model of Hypoxic–Ischemic Encephalopathy
Authors: Domoki Ferenc , Tóth-Szűki Valéria , Kovács Viktória , Remzső Gábor , Körmöczi Tímea , Vécsei László , Berkecz Róbert
Published: September 2023

Kynurenic acid (KYNA), an endogenous neuroprotectant with antiexcitotoxic, antioxidant, and anti-inflammatory effects, is synthesized through the tryptophan-kynurenine (KYN) pathway. We investigated whether brain KYN or KYNA levels were affected by asphyxia in a translational piglet model of hypoxic–ischemic encephalopathy (HIE). We also studied brain levels of the putative blood–brain barrier (BBB) permeable neuroprotective KYNA analogue SZR72, and whether SZR72 or therapeutic hypothermia (TH) modified KYN or KYNA levels. KYN, KYNA, and SZR72 levels were determined using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry in five brain regions 24 h after 20 min of asphyxia in vehicle-, SZR72- and TH-treated newborn piglets (n = 6-6-6) and naive controls (n = 4). Endogenous brain KYN levels (median range 311.2–965.6 pmol/g) exceeded KYNA concentrations (4.5–6.0 pmol/g) ~100-fold. Asphyxia significantly increased cerebral KYN and KYNA levels in all regions (1512.0–3273.9 and 16.9–21.2 pmol/g, respectively), increasing the KYN/Tryptophan-, but retaining the KYNA/KYN ratio. SZR72 treatment resulted in very high cerebral SZR72 levels (13.2–33.2 nmol/g); however, KYN and KYNA levels remained similar to those of the vehicle-treated animals. However, TH virtually ameliorated asphyxia-induced elevations in brain KYN and KYNA levels. The present study reports for the first time that the KYN pathway is altered during HIE development in the piglet. SZR72 readily crosses the BBB in piglets but fails to affect cerebral KYNA levels. Beneficial effects of TH may include restoration of the tryptophan metabolism to pre-asphyxia levels.
The Effect of Hole Geometry on the Nonlinear Nanomechanics of γ-Graphyne Structures: A Finite Element Analysis
Authors: Georgantzinos Stelios K. , Siampanis Sotirios G. , Rogkas Nikolaos , Spitas Vasilios
Published: September 2023

Graphyne is a material that has unique mechanical properties, but little is known about how these properties change when the material has holes. In this work, the effect of hole geometry, considering circular, triangle, and rhombus hole configurations, on the mechanical nonlinear response of γ-graphyne structures is studied. Graphyne, graphdiyne, graphyne-3, and graphyne-4 structures are under investigation. An efficient nonlinear finite element analysis (FEA) method is adequately implemented under large deformations for this purpose. The study varied the size and shape of the holes to understand how these changes affect the nanostructure’s mechanical response. The results indicate that the hole geometry significantly impacts the mechanical nonlinear response of γ-graphyne structures. The holes’ size and shape affect the structures’ elastic behavior, deformation, and strength. The findings can be used to optimize the design of γ-graphyne structures for specific mechanical applications. The study highlights the importance of considering the hole geometries in the design and fabrication of these materials.
Phenotypic and Functional Heterogeneity of Monocytes and Macrophages
Authors: Hellman Lars
Published: September 2023

Macrophages are likely to be the first immune cells to have appeared during the evolution of multicellular organisms [...]
Synthesis and Antimicrobial Analysis of High Surface Area Strontium-Substituted Calcium Phosphate Nanostructures for Bone Regeneration
Authors: Anwar Aneela , Kanwal Qudsia , Sadiqa Ayesha , Razaq Tabassam , Khan Iqra Haider , Javaid Arshad , Khan Safia , Tag-Eldin ElSayed , Ouladsmane Mohamed
Published: September 2023

Continuous microwave-assisted flow synthesis has been used as a simple, more efficient, and low-cost route to fabricate a range of nanosized (<100 nm) strontium-substituted calcium phosphates. In this study, fine nanopowder was synthesized via a continuous flow synthesis with microwave assistance from the solutions of calcium nitrate tetrahydrate (with strontium nitrate as Sr2+ ion source) and diammonium hydrogen phosphate at pH 10 with a time duration of 5 min. The morphological characterization of the obtained powder has been carried out by employing techniques such as transmission electron microscopy, X-ray diffraction, and Brunauer–Emmett–Teller surface area analysis. The chemical structural analysis to evaluate the surface properties was made by using X-ray photoelectron spectroscopy. Zeta potential analysis was performed to evaluate the colloidal stability of the particles. Antimicrobial studies were performed for all the compositions using four bacterial strains and an opportunistic human fungal pathogen Macrophomina phaseolina. It was found that the nanoproduct with high strontium content (15 wt% of strontium) showed pronounced antibacterial potential against M. luteus while it completely arrested the fungal growth after 48 h by all of its concentrations. Thus the synthesis strategy described herein facilitated the rapid production of nanosized Sr-substituted CaPs with excellent biological performance suitable for a bone replacement application.
Krüppel-like Factor 15 Suppresses Ferroptosis by Activating an NRF2/GPX4 Signal to Protect against Folic Acid-Induced Acute Kidney Injury
Authors: Yang Xue , Dong Shihui , Fan Yun , Xia Yuanyuan , Yang Fan , Chen Zhaohong , Chen Dacheng , Zhang Mingchao , Liang Dandan , Zeng Caihong
Published: September 2023

Acute kidney injury (AKI) is a common and serious disease with high morbidity and mortality, and its pathophysiological mechanisms are not fully understood. Increasing evidence suggests an important role of ferroptosis in AKI. Krüppel-like factor 15 (KLF15) is a transcription factor involved in several metabolic diseases, but its role in AKI and ferroptosis remains unclear. In this study, we explored the potential role of KLF15 using a folic acid-induced AKI model. Our study showed that KLF15 expression was reduced in kidney tissues of AKI mice, and KLF15 knockout exacerbated folic acid-induced ferroptosis and kidney injury. In vitro studies revealed that the ferroptosis inducer erastin significantly suppressed KLF15 expression in human tubular epithelial cells. Notably, the overexpression of KLF15 attenuated ferroptosis, as evidenced by a decrease in the lipid peroxidation marker of malondialdehyde and the upregulation of glutathione peroxidase 4 (GPX4), while KLF15 knockdown with shRNA exerted the opposite effect. Mechanistically, KLF15 stabilized the protein of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently increased the GPX4 level. Collectively, KLF15 plays an important role in the modulation of ferroptosis in AKI and may be a potential therapeutic target for treating AKI.
Discovery of Salidroside as a Novel Non-Coding RNA Modulator to Delay Cellular Senescence and Promote BK-Dependent Apoptosis in Cerebrovascular Smooth Muscle Cells of Simulated Microgravity Rats
Authors: Ge Yiling , Zhang Bin , Song Jibo , Cao Qinglin , Bu Yingrui , Li Peijie , Bai Yungang , Yang Changbin , Xie Manjiang
Published: September 2023

Cardiovascular aging has been reported to accelerate in spaceflights, which is a great potential risk to astronauts’ health and performance. However, current exercise routines are not sufficient to reverse the adverse effects of microgravity exposure. Recently, salidroside (SAL), a valuable medicinal herb, has been demonstrated to display an important role for prevention and treatment in cardiovascular and other diseases. In the present work, Sprague–Dawley rats with four-week tail-suspension hindlimb-unloading were used to simulate microgravity effects on the cardiovascular system. We found that intragastrical administration of SAL not only significantly decreased the expressions of senescence biomarkers, such as P65 and P16, but also obviously increased the expressions of BK-dependent apoptotic genes, including the large-conductance calcium-activated K+ channel (BK), Bax, Bcl-2, and cleaved caspase-3, in vascular smooth muscle cells (VSMCs) in vivo and in vitro. In addition, relative non-coding RNAs were screened, and a luciferase assay identified that SAL increased apoptosis by activating LncRNA-FLORPAR, inhibiting miR-193, and then triggering the activity of the BK-α subunit. Our work indicated that SAL is a novel non-coding RNA modulator for regulating the LncRNA-FLORPAR sponging miR-193 pathway, which significantly promoted BK-dependent apoptosis and delayed cerebrovascular aging-like remodeling during simulated microgravity exposure. Our findings may provide a new approach to prevent cardiovascular aging in future spaceflights.
Nitric Oxide as a Determinant of Human Longevity and Health Span
Authors: Poeggeler Burkhard , Singh Sandeep Kumar , Sambamurti Kumar , Pappolla Miguel A.
Published: September 2023

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.
Expression of S100A16 Is Associated with Biological Aggressiveness and Poor Prognosis in Patients with Bladder Cancer Who Underwent Radical Cystectomy
Authors: Katsumata Hiroki , Matsumoto Kazumasa , Yanagita Kengo , Shimizu Yuriko , Hirano Shuhei , Kitajima Kazuki , Koguchi Dai , Ikeda Masaomi , Sato Yuichi , Iwamura Masatsugu
Published: September 2023

S100 calcium binding protein A16 (S100A16) is expressed in various cancers; however, there are few reports on S100A16 in bladder cancer (BC). We retrospectively investigated clinical data including clinicopathological features in 121 patients with BC who underwent radical cystectomy (RC). Immunohistochemical staining was performed to evaluate S100A16 expression in archived specimens. Cases with >5% expression and more than moderate staining intensity on cancer cells were considered positive. S100A16 expression was observed in 54 patients (44.6%). Univariate analysis showed that S100A16 expression was significantly associated with age, pT stage, recurrence, and cancer-specific death. Kaplan–Meier analyses showed that patients with S100A16 expression had shorter overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) than those without S100A16 expression. In multivariate analysis, pT stage was an independent prognostic factor for OS and lymph node metastasis for CSS and RFS. S100A16 expression may be a biomarker of a biologically aggressive phenotype and poor prognosis in patients with BC who underwent RC. The PI3k/Akt signaling pathway is probably associated with S100A16 and may be a therapeutic target.
L-Arginine-eNOS-NO Functional System in Brain Damage and Cognitive Impairments in Cerebral Small Vessel Disease
Authors: Dobrynina Larisa A. , Shabalina Alla A. , Shamtieva Kamila V. , Kremneva Elena I. , Zabitova Maryam R. , Krotenkova Marina V. , Burmak Anastasiia G. , Gnedovskaya Elena V.
Published: September 2023

Cerebral small vessel disease (CSVD) is a significant cause of cognitive impairment (CI), disability, and mortality. The insufficient effectiveness of antihypertensive therapy in curbing the disease justifies the search for potential targets for modifying therapy and indicators supporting its use. Using a laser-assisted optical rotational cell analyzer (LORRCA, Mechatronics, The Netherlands), the rheological properties and deformability of erythrocytes before and after incubation with 10 μmol/L of L-arginine, the nitric oxide (NO) donor, blood–brain barrier (BBB) permeability assessed by dynamic contrast-enhanced MRI, clinical, and MRI signs were studied in 73 patients with CSVD (48 women, mean age 60.1 ± 6.5 years). The control group consisted of 19 volunteers (14 women (73.7%), mean age 56.9 ± 6.4 years). The erythrocyte disaggregation rate (y-dis) after incubation with L-arginine showed better performance than other rheological characteristics in differentiating patients with reduced NO bioavailability/NO deficiency by its threshold values. Patients with y-dis > 113 s−1 had more severe CI, arterial hypertension, white matter lesions, and increased BBB permeability in grey matter and normal-appearing white matter (NAWM). A test to assess changes in the erythrocyte disaggregation rate after incubation with L-arginine can be used to identify patients with impaired NO bioavailability. L-arginine may be part of a therapeutic strategy for CSVD with CI.
The Glioblastoma CircularRNAome
Authors: Tirpe Alexandru , Streianu Cristian , Tirpe Stefana Maria , Kocijancic Anja , Pirlog Radu , Pirlog Bianca , Busuioc Constantin , Pop Ovidiu-Laurean , Berindan-Neagoe Ioana
Published: September 2023

Glioblastoma remains one of the most aggressive cancers of the brain, warranting new methods for early diagnosis and more efficient treatment options. Circular RNAs (circRNAs) are rather new entities with increased stability compared to their linear counterparts that interact with proteins and act as microRNA sponges, among other functions. Herein, we provide a critical overview of the recently described glioblastoma-related circRNAs in the literature, focusing on their roles on glioblastoma cancer cell proliferation, survival, migration, invasion and metastasis, metabolic reprogramming, and therapeutic resistance. The main roles of circRNAs in regulating cancer processes are due to their regulatory roles in essential oncogenic pathways, including MAPK, PI3K/AKT/mTOR, and Wnt, which are influenced by various circRNAs. The present work pictures the wide implication of circRNAs in glioblastoma, thus highlighting their potential as future biomarkers and therapeutic targets/agents.
Harnessing the Genetic Basis of Sorghum Biomass-Related Traits to Facilitate Bioenergy Applications
Authors: Yang Lin , Zhou Qin , Sheng Xuan , Chen Xiangqian , Hua Yuqing , Lin Shuang , Luo Qiyun , Yu Boju , Shao Ti , Wu Yixiao , Chang Junli , Li Yin , Tu Min
Published: September 2023

The extensive use of fossil fuels and global climate change have raised ever-increasing attention to sustainable development, global food security and the replacement of fossil fuels by renewable energy. Several C4 monocot grasses have excellent photosynthetic ability, stress tolerance and may rapidly produce biomass in marginal lands with low agronomic inputs, thus representing an important source of bioenergy. Among these grasses, Sorghum bicolor has been recognized as not only a promising bioenergy crop but also a research model due to its diploidy, simple genome, genetic diversity and clear orthologous relationship with other grass genomes, allowing sorghum research to be easily translated to other grasses. Although sorghum molecular genetic studies have lagged far behind those of major crops (e.g., rice and maize), recent advances have been made in a number of biomass-related traits to dissect the genetic loci and candidate genes, and to discover the functions of key genes. However, molecular and/or targeted breeding toward biomass-related traits in sorghum have not fully benefited from these pieces of genetic knowledge. Thus, to facilitate the breeding and bioenergy applications of sorghum, this perspective summarizes the bioenergy applications of different types of sorghum and outlines the genetic control of the biomass-related traits, ranging from flowering/maturity, plant height, internode morphological traits and metabolic compositions. In particular, we describe the dynamic changes of carbohydrate metabolism in sorghum internodes and highlight the molecular regulators involved in the different stages of internode carbohydrate metabolism, which affects the bioenergy utilization of sorghum biomass. We argue the way forward is to further enhance our understanding of the genetic mechanisms of these biomass-related traits with new technologies, which will lead to future directions toward tailored designing sorghum biomass traits suitable for different bioenergy applications.
A Comprehensive Genomic Analysis of Chinese Indigenous Ningxiang Pigs: Genomic Breed Compositions, Runs of Homozygosity, and Beyond
Authors: Yin Shishu , Li Zhi , Yang Fang , Guo Haimin , Zhao Qinghua , Zhang Yuebo , Yin Yulong , Wu Xiaolin , He Jun
Published: September 2023

Ningxiang pigs are a renowned indigenous pig breed in China, known for their meat quality, disease resistance, and environmental adaptability. In recent decades, consumer demand for meats from indigenous breeds has grown significantly, fueling the selection and crossbreeding of Ningxiang pigs (NXP). The latter has raised concerns about the conservation and sustainable use of Ningxiang pigs as an important genetic resource. To address these concerns, we conducted a comprehensive genomic study using 2242 geographically identified Ningxiang pigs. The estimated genomic breed composition (GBC) suggested 2077 pigs as purebred Ningxiang pigs based on a ≥94% NXP-GBC cut-off. The remaining 165 pigs were claimed to be crosses, including those between Duroc and Ningxiang pigs and between Ningxiang and Shaziling pigs, and non-Ningxiang pigs. Runs of homozygosity (ROH) were identified in the 2077 purebred Ningxiang pigs. The number and length of ROH varied between individuals, with an average of 32.14 ROH per animal and an average total length of 202.4 Mb per animal. Short ROH (1–5 Mb) was the most abundant, representing 66.5% of all ROH and 32.6% of total ROH coverage. The genomic inbreeding estimate was low (0.089) in purebred Ningxiang pigs compared to imported western pig breeds. Nine ROH islands were identified, pinpointing candidate genes and QTLs associated with economic traits of interest, such as reproduction, carcass and growth traits, lipid metabolism, and fat deposition. Further investigation of these ROH islands and candidate genes is anticipated to better understand the genomics of Ningxiang pigs.
Histone and Histone Acetylation-Related Alterations of Gene Expression in Uninvolved Psoriatic Skin and Their Effects on Cell Proliferation, Differentiation, and Immune Responses
Authors: Romhányi Dóra , Szabó Kornélia , Kemény Lajos , Groma Gergely
Published: September 2023

Psoriasis is a chronic immune-mediated skin disease in which the symptom-free, uninvolved skin carries alterations in gene expression, serving as a basis for lesion formation. Histones and histone acetylation-related processes are key regulators of gene expression, controlling cell proliferation and immune responses. Dysregulation of these processes is likely to play an important role in the pathogenesis of psoriasis. To gain a complete overview of these potential alterations, we performed a meta-analysis of a psoriatic uninvolved skin dataset containing differentially expressed transcripts from nearly 300 individuals and screened for histones and histone acetylation-related molecules. We identified altered expression of the replication-dependent histones HIST2H2AA3 and HIST2H4A and the replication-independent histones H2AFY, H2AFZ, and H3F3A/B. Eight histone chaperones were also identified. Among the histone acetyltransferases, ELP3 and KAT5 and members of the ATAC, NSL, and SAGA acetyltransferase complexes are affected in uninvolved skin. Histone deacetylation-related alterations were found to affect eight HDACs and members of the NCOR/SMRT, NURD, SIN3, and SHIP HDAC complexes. In this article, we discuss how histone and histone acetylation-related expression changes may affect proliferation and differentiation, as well as innate, macrophage-mediated, and T cell-mediated pro- and anti-inflammatory responses, which are known to play a central role in the development of psoriasis.
Remodeling of Cardiomyocytes: Study of Morphological Cellular Changes Preceding Symptomatic Ischemic Heart Failure
Authors: Kuprytė Milda , Lesauskaitė Vaiva , Keturakis Vytenis , Bunevičienė Vitalija , Utkienė Lina , Jusienė Lina , Pangonytė Dalia
Published: September 2023

Although major pathogenesis mechanisms of heart failure (HF) are well established, the significance of early (mal)adaptive structural changes of cardiomyocytes preceding symptomatic ischemic HF remains ambiguous. The aim of this study is to present the morphological characterization of changes in cardiomyocytes and their reorganization of intermediate filaments during remodeling preceding symptomatic ischemic HF in an adult human heart. A total of 84 myocardial tissue samples from middle-left heart ventricular segments were analyzed histomorphometrically and immunohistochemically, observing the cardiomyocyte’s size, shape, and desmin expression changes in the remodeling process: Stage A of HF, Stage B of HF, and Stages C/D of HF groups (ACC/AHA classification). Values p < 0.05 were considered significant. The cellular length, diameter, and volume of Stage A of HF increased predominantly by the diameter vs. the control group (p < 0.001) and continued to increase in Stage B of HF in a similar pattern (p < 0.001), increasing even more in the C/D Stages of HF predominantly by length (p < 0.001). Desmin expression was increased in Stage A of HF vs. the control group (p < 0.001), whereas it was similar in Stages A and B of HF (p > 0.05), and most intense in Stages C/D of HF (p < 0.001). Significant morphological changes of cardiomyocytes and their cytoskeletal reorganization were observed during the earliest remodeling events preceding symptomatic ischemic HF.
Turmeric and Curcumin—Health-Promoting Properties in Humans versus Dogs
Authors: Kępińska-Pacelik Jagoda , Biel Wioletta
Published: September 2023

The growing popularity of the use of nutraceuticals in the prevention and alleviation of symptoms of many diseases in humans and dogs means that they are increasingly the subject of research. A representative of the nutraceutical that deserves special attention is turmeric. Turmeric belongs to the family Zingiberaceae and is grown extensively in Asia. It is a plant used as a spice and food coloring, and it is also used in traditional medicine. The biologically active factors that give turmeric its unusual properties and color are curcuminoids. It is a group of substances that includes curcumin, de-methoxycurcumin, and bis-demethoxycurcumin. Curcumin is used as a yellow-orange food coloring. The most important pro-health effects observed after taking curcuminoids include anti-inflammatory, anticancer, and antioxidant effects. The aim of this study was to characterize turmeric and its main substance, curcumin, in terms of their properties, advantages, and disadvantages, based on literature data.
Free Energy Profile for the Complete Transport of Nonpolar Molecules through a Carbon Nanotube
Authors: Eun Changsun
Published: September 2023

Gas molecules or weakly interacting molecules are commonly observed to diffuse through and fill space. Therefore, when the molecules initially confined in one compartment are allowed to move through a channel into another empty compartment, we expect that some molecules will be transported into the initially empty compartment. In this work, we thermodynamically analyze this transport process using a simple model consisting of graphene plates, a carbon nanotube (CNT), and nonpolar molecules that are weakly interacting with each other. Specifically, we calculate the free energy change, or the potential of mean force (PMF), as the molecules are transported from one compartment to another compartment. The PMF profile clearly exhibits a global minimum, or a free energy well, at the state wherein the molecules are evenly distributed over the two compartments. To better understand the thermodynamic origin of the well, we calculate the energetic and entropic contributions to the formation of the well, and we show that the entropic change is responsible for it and is the driving force for transport. Our work not only enables a fundamental understanding of the thermodynamic nature of the transport of weakly interacting molecules with molecular details, but also provides a method for calculating the free energy change during transport between two separate spaces connected by a nanochannel.
ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
Authors: Yang Shao-Ying , Liao Li , Hu Shu-Yuan , Deng Ling , Andriani Lisa , Zhang Tai-Mei , Zhang Yin-Ling , Ma Xiao-Yan , Zhang Fang-Lin , Liu Ying-Ying , Li Da-Qiang
Published: September 2023

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.
Special Issue “Advances in Genome Regulation in Cancer”
Authors: Erenpreisa Jekaterina , Giuliani Alessandro , Cragg Mark Steven
Published: September 2023

Cancer is globally increasing [...]
Nicotine: From Discovery to Biological Effects
Authors: Sansone Luigi , Milani Francesca , Fabrizi Riccardo , Belli Manuel , Cristina Mario , Zagà Vincenzo , de Iure Antonio , Cicconi Luca , Bonassi Stefano , Russo Patrizia
Published: September 2023

Nicotine, the primary psychoactive agent in tobacco leaves, has led to the widespread use of tobacco, with over one billion smokers globally. This article provides a historical overview of tobacco and discusses tobacco dependence, as well as the biological effects induced by nicotine on mammalian cells. Nicotine induces various biological effects, such as neoangiogenesis, cell division, and proliferation, and it affects neural and non-neural cells through specific pathways downstream of nicotinic receptors (nAChRs). Specific effects mediated by α7 nAChRs are highlighted. Nicotine is highly addictive and hazardous. Public health initiatives should prioritize combating smoking and its associated risks. Understanding nicotine’s complex biological effects is essential for comprehensive research and informed health policies. While potential links between nicotine and COVID-19 severity warrant further investigation, smoking remains a significant cause of morbidity and mortality globally. Effective public health strategies are vital to promote healthier lifestyles.
Oxidative Damage as a Fundament of Systemic Toxicities Induced by Cisplatin—The Crucial Limitation or Potential Therapeutic Target?
Authors: Katanić Stanković Jelena S. , Selaković Dragica , Rosić Gvozden
Published: September 2023

Cisplatin, an inorganic complex of platinum, is a chemotherapeutic drug that has been used for 45 years. Despite the progress of pharmaceutical sciences and medicine and the successful application of other platinum complexes for the same purpose, cisplatin is still the therapy of choice in many cancers. Treatment for testicular, ovarian, head and neck, urothelial, cervical, esophageal, breast, and pulmonary malignancies is still unthinkable without the use of this drug. However, cisplatin is also known for many side effects, of which the most pronounced are nephrotoxicity leading to acute renal failure, neurotoxicity, and ototoxicity. Mechanistic studies have proven that one of the conditions that plays a major role in the development of cisplatin-induced toxicities is oxidative stress. Knowing the fact that numerous antioxidants can be used to reduce oxidative stress, thereby reducing tissue lesions, organ failure, and apoptosis at the cellular level, many studies have defined antioxidants as a priority for investigation as a cotreatment. To investigate the mechanism of antioxidant action in vivo, many animal models have been employed. In the last few years, studies have mostly used rodents and zebrafish models. In this article, some of the most recent investigations that used animal models are listed, and the advantages and disadvantages of such experimental studies are pointed out.
Phloridzin Docosahexaenoate Inhibits Spheroid Formation by Breast Cancer Stem Cells and Exhibits Cytotoxic Effects against Paclitaxel-Resistant Triple Negative Breast Cancer Cells
Authors: Fernando Wasundara , Clark Rikki F. , Rupasinghe H. P. Vasantha , Hoskin David W. , Coombs Melanie R. Power
Published: September 2023

The eradication of cancer stem cells (CSCs) is vital to successful cancer treatment and overall disease-free survival. CSCs are a sub-population of cells within a tumor that are defined by their capacity for continuous self-renewal and recapitulation of new tumors, demonstrated in vitro through spheroid formation. Flavonoids are a group of phytochemicals with potent anti-oxidant and anti-cancer properties. This paper explores the impact of the flavonoid precursor phloridzin (PZ) linked to the ω-3 fatty acid docosahexaenoate (DHA) on the growth of MCF-7 and paclitaxel-resistant MDA-MB-231-TXL breast cancer cell lines. Spheroid formation assays, acid phosphatase assays, and Western blotting were performed using MCF-7 cells, and the cell viability assays, Annexin-V-488/propidium iodide (PI) staining, and 7-aminoactinomycin D (7-AAD) assays were performed using MDA-MB-231-TXL cells. PZ-DHA significantly reduced spheroid formation, as well as the metabolic activity of MCF-7 breast cancer cells in vitro. Treatment with PZ-DHA also suppressed the metabolic activity of MDA-MB-231-TXL cells and led to apoptosis. PZ-DHA did not have an observable effect on the expression of the drug efflux transporters ATP-binding cassette super-family G member 2 (ABCG2) and multidrug resistance-associated protein 1 (MRP1). PZ-DHA is a potential treatment avenue for chemo-resistant breast cancer and a possible novel CSC therapy. Future pre-clinical studies should explore PZ-DHA as a chemo-preventative agent.
Resveratrol and 3,3′-Diindolylmethane Differentially Regulate Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha Activity through Multiple Transcriptomic Targets in MCF-7 Human Breast Cancer Cells
Authors: Das Siddhartha , Somisetty Venkata S. , Ulven Stine M. , Matthews Jason
Published: September 2023

Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signaling. ERα and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,3′diindolylmethane (DIM) also activate ERα while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome-wide targets and AHR- and ERα-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERα as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ERα bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERα site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ERα and ERα/AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ERα dominates with preferential recruitment of AHR to ERα target genes.
A Novel Mouse Model of Intrahepatic Cholangiocarcinoma Induced by Azoxymethane
Authors: Shirakami Yohei , Kato Junichi , Ohnishi Masaya , Taguchi Daisuke , Maeda Toshihide , Ideta Takayasu , Kubota Masaya , Sakai Hiroyasu , Tomita Hiroyuki , Tanaka Takuji , Shimizu Masahito
Published: September 2023

Cholangiocarcinoma is the second most common primary cancer of the liver and has a poor prognosis. Various animal models, including carcinogen-induced and genetically engineered rodent models, have been established to clarify the mechanisms underlying cholangiocarcinoma development. In the present study, we developed a novel mouse model of malignant lesions in the biliary ducts induced by the administration of the carcinogen azoxymethane to obese C57BLKS/J-db/db mice. A histopathological analysis revealed that the biliary tract lesions in the liver appeared to be an intrahepatic cholangiocarcinoma with higher tumor incidence, shorter experimental duration, and a markedly increased incidence in obese mice. Molecular markers analyzed using a microarray and a qPCR indicated that the cancerous lesions originated from the cholangiocytes and developed in the inflamed livers. These findings indicated that this is a novel mouse model of intrahepatic cholangiocarcinoma in the context of steatohepatitis. This model can be used to provide a better understanding of the pathogenic mechanisms of cholangiocarcinoma and to develop novel therapeutic strategies for this malignancy.
Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics
Authors: Adejuyigbe Babapelumi , Kallini Julie , Chiou Daniel , Kallini Jennifer R.
Published: September 2023

Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by changes in bone homeostasis, which lead to reduced bone mass, impaired bone quality, and an increased risk of fractures. The pathophysiology of osteoporosis is complex and multifactorial, involving imbalances in hormones, cytokines, and growth factors. Understanding the cellular and molecular mechanisms underlying osteoporosis is essential for appropriate diagnosis and management of the condition. This paper provides a comprehensive review of the normal cellular and molecular mechanisms of bone homeostasis, followed by an in-depth discussion of the proposed pathophysiology of osteoporosis through the osteoimmunological, gut microbiome, and cellular senescence models. Furthermore, the diagnostic tools used to assess osteoporosis, including bone mineral density measurements, biochemical markers of bone turnover, and diagnostic imaging modalities, are also discussed. Finally, both the current pharmacological and non-pharmacological treatment algorithms and management options for osteoporosis, including an exploration of the management of osteoporotic fragility fractures, are highlighted. This review reveals the need for further research to fully elucidate the molecular mechanisms underlying the condition and to develop more effective therapeutic strategies.
Detrimental Actions of Chlorinated Nucleosides on the Function and Viability of Insulin-Producing Cells
Authors: Sileikaite-Morvaközi Inga , Hansen William H. , Davies Michael J. , Mandrup-Poulsen Thomas , Hawkins Clare L.
Published: September 2023

Neutrophils are innate immune cells that play a key role in pathogen clearance. They contribute to inflammatory diseases, including diabetes, by releasing pro-inflammatory cytokines, reactive oxygen species, and extracellular traps (NETs). NETs contain a DNA backbone and catalytically active myeloperoxidase (MPO), which produces hypochlorous acid (HOCl). Chlorination of the DNA nucleoside 8-chloro-deoxyguanosine has been reported as an early marker of inflammation in diabetes. In this study, we examined the reactivity of different chlorinated nucleosides, including 5-chloro-(deoxy)cytidine (5ClC, 5CldC), 8-chloro-(deoxy)adenosine (8ClA, 8CldA) and 8-chloro-(deoxy)guanosine (8ClG, 8CldG), with the INS-1E β-cell line. Exposure of INS-1E cells to 5CldC, 8CldA, 8ClA, and 8CldG decreased metabolic activity and intracellular ATP, and, together with 8ClG, induced apoptotic cell death. Exposure to 8ClA, but not the other nucleosides, resulted in sustained endoplasmic reticulum stress, activation of the unfolded protein response, and increased expression of thioredoxin-interacting protein (TXNIP) and heme oxygenase 1 (HO-1). Exposure of INS-1E cells to 5CldC also increased TXNIP and NAD(P)H dehydrogenase quinone 1 (NQO1) expression. In addition, a significant increase in the mRNA expression of NQO1 and GPx4 was seen in INS-1E cells exposed to 8ClG and 8CldA, respectively. However, a significant decrease in intracellular thiols was only observed in INS-1E cells exposed to 8ClG and 8CldG. Finally, a significant decrease in the insulin stimulation index was observed in experiments with all the chlorinated nucleosides, except for 8ClA and 8ClG. Together, these results suggest that increased formation of chlorinated nucleosides during inflammation in diabetes could influence β-cell function and may contribute to disease progression.
Liquid Natural Gas Cold Energy Recovery for Integration of Sustainable District Cooling Systems: A Thermal Performance Analysis
Authors: Luo Yang , Lu Xuesong , Chen Yi , Andresen John , Maroto-Valer Mercedes
Published: September 2023

This paper investigates the heat transfer properties of liquefied natural gas (LNG) in a corrugated plate heat exchanger and explores its application in cold energy recovery for enhanced energy efficiency. The study aims to integrate this technology into a 500 MW gas-fired power plant and a district cooling system to contribute to sustainable city development. Using computational fluid dynamics simulations and experimental validation, the heat transfer behaviour of LNG in the corrugated plate heat exchanger is examined, emphasising the significance of the gas film on the channel wall for efficient heat transfer between LNG and water/ethylene glycol. The study analyses heat exchange characteristics below and above the critical point of LNG. Below the critical point, the LNG behaves as an incompressible fluid, whereas above the critical point, the compressible supercritical state enables a substantial energy recovery and temperature rise at the outlet, highlighting the potential for cold energy recovery. The results demonstrate the effectiveness of cold energy recovery above the critical point, leading to significant energy savings and improved efficiency compared to conventional systems. Optimal operational parameters, such as the number of channels and flow rate ratios, are identified for successful cold energy recovery. This research provides valuable insights for sustainable city planning and the transition towards low-carbon energy systems, contributing to the overall goal of creating environmentally friendly and resilient urban environments.