bluuebunny/crossref_metadata_2025 huggingface dataset:
The Correlation of Frequency of Work-Related Disorders with Type of Work among Polish Employees
Authors: Kliniec Katarzyna , Mendowski Mateusz , Zuziak Patrycja , Sobieski Mateusz , Grata-Borkowska Urszula
Published: January 2023

Musculoskeletal disorders have a significant negative impact on the quality of life of the population. These conditions, as well as other work-related disorders, generate costs associated with treatment and work absence, which makes it a growing problem in industrialized countries. Available data from studies on individual populations of workers indicate a higher incidence of certain symptoms in these groups. Due to the lack of studies on the general population, we aimed to perform the preliminary study evaluating the occurrence of pain and work-related conditions depending on the type of occupational work among Polish employees to identify further possible areas for research. Data was collected using an electronic self-administered questionnaire, which was distributed in groups bringing together various professionals. The data obtained from 379 participants have been analyzed and divided according to performed work into sedentary, forced posture, standing, physical and requiring physical activity. Our study reveals a correlation between the frequency of work-related disorders and type of work performed in the Polish population. A significant correlation between the type of occupational work and prevalence of ankle, knee and shoulder pain, as well as heavy legs or upper limb paresthesia was found. According to our findings, female employees may be more vulnerable to lower limb symptoms. A place of residence also seems to affect the prevalence of upper back pain and heavy legs. The analysis also showed a correlation between the occurrence of hip, knee and ankle pain and the level of education of the participants. Surprisingly, lower extremity paresthesia was significantly more common among participants undertaking additional physical activity, compared to non-physically active respondents.
Family Socioeconomic Status and Adolescent Mental Health Problems during the COVID-19 Pandemic: The Mediating Roles of Trait Mindfulness and Perceived Stress
Authors: Yuan Yue , Zhou Aibao , Kang Manying
Published: January 2023

The present study was conducted twice over one year during the COVID-19 pandemic with Chinese adolescents (n = 1582) to investigate the relationships among family socioeconomic status (SES), adolescent mental health problems, trait mindfulness, and perceived stress using self-reported measures. We administered the Mindful Attention Awareness Scale (MAAS), the Perceived Stress Scale (PPS), the Self-rating Anxiety Scale (SAS), the Epidemiologic Studies Depression Scale (CES-D), and Conduct Problem Tendency Inventory (CPTDI) to a sample of Chinese adolescents. The results prove that (1) there were significant correlations among socioeconomic status, trait mindfulness, perceived stress, and adolescent mental health problems, and the (2) serial mediation analysis indicated that trait mindfulness and perceived stress performed as mediators on the path from SES to anxiety, depression, and externalizing problems. Our findings provide a contribution by showing the connection between socioeconomic position and adolescent mental health problems and by offering a reference for the treatment of psychological issues affecting adolescents.
Spatiotemporal Changes of Cultivated Land System Health Based on PSR-VOR Model—A Case Study of the Two Lake Plains, China
Authors: Li Xigui , Wu Qing , Liu Yujie
Published: January 2023

Cultivated land resources are the material basis of sustainable agricultural development. Climate change, food security, land pollution, and other issues highlight the value of sustainable agricultural development, and the health of the cultivated land system has attracted much attention. By constructing “PSR-VOR” cultivated land system health evaluation framework under the 5 km grid scale and using GIS spatial analysis and mathematical statistics to comprehensively evaluate the health status of the cultivated land system in the two lake plains from 2000 to 2019. The major results have shown that: (1) Over the past 20 years, both the highest and average values of the health index of the cultivated land system have gone down, and the health status of the cultivated land system has changed and gotten worse over time. (2) The health status in the two lake plains has been generally good, mainly in Class I and Class II areas. However, the area of cultivated land with general and poor health status has increased rapidly. On the whole, the health level presents the characteristic of gradually decreasing from the northeast to the southwest and southeast. (3) During the study period, the global Moran’s I value of the cultivated land system health index in the two lake plains increased from 0.686 to 0.729, with significant spatial positive autocorrelation, and the spatial heterogeneity of the cultivated land system health index gradually increased. As shown by the spatial distribution characteristics of high in the north, low in the south, and decreasing from the middle to the outside, the distribution of the high-value cluster area and the low-value cluster area of the cultivated land system health index in the two lake plains has not changed significantly over the past 20 years. (4) The two lake plains are divided into five areas: a moderate optimization area, a collaborative optimization area, a potential improvement area, a key improvement area, and a priority improvement area. The urgency of regulating the health status from the moderate optimization area to the priority improvement area has gradually increased, and the differentiated utilization and management of cultivated land resources need to be carried out according to local conditions.
Environmental Pollution Liability Insurance Pricing and the Solvency of Insurance Companies in China: Based on the Black–Scholes Model
Authors: Chen Shuai , Yang Jiameng
Published: January 2023

Environmental pollution liability insurance is becoming increasingly important for China to achieve its emission reduction targets. Insurance pricing is a crucial factor restricting the market share of environment pollution liability insurance, from the perspective of the Black–Scholes pricing model, which in turn has influenced the solvency of insurance companies in China. Firstly, this study analyzes the problems existing in compulsory liability insurance for environmental pollution in China. It proceeds with analyzing the price of compulsory environmental pollution liability insurance using the Black–Scholes pricing model, and derives a high premium insurance rate of 2.44%. Moreover, it performs a multivariate regression analysis using the asset and liability data, taken from the annual report, to identify three key factors affecting the solvency adequacy ratio, namely, capital debt ratio, reflecting the company asset structure; net interest rate on assets, reflecting the asset scale with actual solvency; and claim ratio, reflecting the business quality. Based on the results of regression analysis and robustness test for the China Insurance Clauses (CIC) company, People’s Insurance Company of China (PICC), and Asia-Pacific Property & Casualty Insurance (API) company, it is shown that the effect of total asset, total debt, capital debt ratio, claim ratio, and net interest rate on assets on the solvency adequacy ratio is significant, with respect to the size of the coefficients. Based on the Black–Scholes pricing model found in the previous cycle of liability insurance, and keeping in view the existing problems of environmental pollution liability insurance expenditure, this paper presents suggestions that are conducive to improving the solvency of insurance companies in China.
Genome-Wide Identification of the Odorant Receptor Gene Family and Revealing Key Genes Involved in Sexual Communication in Anoplophora glabripennis
Authors: Zhang Sainan , Li Meng , Xu Yabei , Zhao Yuxuan , Niu Yiming , Zong Shixiang , Tao Jing
Published: January 2023

Insects use a powerful and complex olfactory recognition system to sense odor molecules in the external environment to guide behavior. A large family of odorant receptors (ORs) mediates the detection of pheromone compounds. Anoplophora glabripennis is a destructive pest that harms broad-leaved tree species. Although olfactory sensation is an important factor affecting the information exchange of A. glabripennis, little is known about the key ORs involved. Here, we identified ninety-eight AglaORs in the Agla2.0 genome and found that the AglaOR gene family had expanded with structural and functional diversity. RT-qPCR was used to analyze the expression of AglaORs in sex tissues and in adults at different developmental stages. Twenty-three AglaORs with antennal-biased expression were identified. Among these, eleven were male-biased and two were female-biased and were more significantly expressed in the sexual maturation stage than in the post-mating stage, suggesting that these genes play a role in sexual communication. Relatively, two female-biased AglaORs were overexpressed in females seeking spawning grounds after mating, indicating that these genes might be involved in the recognition of host plant volatiles that may regulate the selection of spawning grounds. Our study provides a theoretical basis for further studies into the molecular mechanism of A. glabripennis olfaction.
Gut Microbial Perturbation and Host Response Induce Redox Pathway Upregulation along the Gut–Liver Axis during Giardiasis in C57BL/6J Mouse Model
Authors: Karpe Avinash V. , Hutton Melanie L. , Mileto Steven J. , James Meagan L. , Evans Chris , Ghodke Amol B. , Shah Rohan M. , Metcalfe Suzanne S. , Liu Jian-Wei , Walsh Tom , Lyras Dena , Palombo Enzo A. , Beale David J.
Published: January 2023

Apicomplexan infections, such as giardiasis and cryptosporidiosis, negatively impact a considerable proportion of human and commercial livestock populations. Despite this, the molecular mechanisms of disease, particularly the effect on the body beyond the gastrointestinal tract, are still poorly understood. To highlight host–parasite–microbiome biochemical interactions, we utilised integrated metabolomics-16S rRNA genomics and metabolomics–proteomics approaches in a C57BL/6J mouse model of giardiasis and compared these to Cryptosporidium and uropathogenic Escherichia coli (UPEC) infections. Comprehensive samples (faeces, blood, liver, and luminal contents from duodenum, jejunum, ileum, caecum and colon) were collected 10 days post infection and subjected to proteome and metabolome analysis by liquid and gas chromatography–mass spectrometry, respectively. Microbial populations in faeces and luminal washes were examined using 16S rRNA metagenomics. Proteome–metabolome analyses indicated that 12 and 16 key pathways were significantly altered in the gut and liver, respectively, during giardiasis with respect to other infections. Energy pathways including glycolysis and supporting pathways of glyoxylate and dicarboxylate metabolism, and the redox pathway of glutathione metabolism, were upregulated in small intestinal luminal contents and the liver during giardiasis. Metabolomics-16S rRNA genetics integration indicated that populations of three bacterial families—Autopobiaceae (Up), Desulfovibrionaceae (Up), and Akkermanasiaceae (Down)—were most significantly affected across the gut during giardiasis, causing upregulated glycolysis and short-chained fatty acid (SCFA) metabolism. In particular, the perturbed Akkermanasiaceae population seemed to cause oxidative stress responses along the gut–liver axis. Overall, the systems biology approach applied in this study highlighted that the effects of host–parasite–microbiome biochemical interactions extended beyond the gut ecosystem to the gut–liver axis. These findings form the first steps in a comprehensive comparison to ascertain the major molecular and biochemical contributors of host–parasite interactions and contribute towards the development of biomarker discovery and precision health solutions for apicomplexan infections.
Classes of Lipid Mediators and Their Effects on Vascular Inflammation in Atherosclerosis
Authors: Lubrano Valter , Ndreu Rudina , Balzan Silvana
Published: January 2023

It is commonly believed that the inactivation of inflammation is mainly due to the decay or cessation of inducers. In reality, in connection with the development of atherosclerosis, spontaneous decay of inducers is not observed. It is now known that lipid mediators originating from polyunsaturated fatty acids (PUFAs), which are important constituents of all cell membranes, can act in the inflamed tissue and bring it to resolution. In fact, PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are precursors to both pro-inflammatory and anti-inflammatory compounds. In this review, we describe the lipid mediators of vascular inflammation and resolution, and their biochemical activity. In addition, we highlight data from the literature that often show a worsening of atherosclerotic disease in subjects deficient in lipid mediators of inflammation resolution, and we also report on the anti-proteasic and anti-thrombotic properties of these same lipid mediators. It should be noted that despite promising data observed in both animal and in vitro studies, contradictory clinical results have been observed for omega-3 PUFAs. Many further studies will be required in order to clarify the observed conflicts, although lifestyle habits such as smoking or other biochemical factors may often influence the normal synthesis of lipid mediators of inflammation resolution.
Ultrastructural Remodeling of the Blood–Brain Barrier and Neurovascular Unit by Lipopolysaccharide-Induced Neuroinflammation
Authors: Erickson Michelle A. , Shulyatnikova Tatyana , Banks William A. , Hayden Melvin R.
Published: January 2023

The blood–brain barrier (BBB) is an interface primarily comprised of brain endothelial cells (BECs), separating the central nervous system (CNS) from the systemic circulation while carefully regulating the transport of molecules and inflammatory cells, and maintaining the required steady-state environment. Inflammation modulates many BBB functions, but the ultrastructural cytoarchitectural changes of the BBB with inflammation are understudied. Inflammation was induced in male 8–10-week-old CD-1 mice with intraperitoneal lipopolysaccharide (LPS), using a regimen (3 mg/kg at 0, 6, and 24 h) that caused robust BBB disruption but had minimal lethality at the study timepoint of 28 h. Perfusion-fixed brains were collected and the frontal cortical layer III regions were analyzed using a transmission electron microscopy (TEM). The LPS-treated mice had pronounced ultrastructural remodeling changes in BECs that included plasma membrane ruffling, increased numbers of extracellular microvesicles, small exosome formation, aberrant BEC mitochondria, increased BEC transcytosis, while tight junctions appeared to be unaltered. Aberrant pericytes were contracted with rounded nuclei and a loss of their elongated cytoplasmic processes. Surveilling microglial cells were attracted to the neurovascular unit (NVU) of BECs, and astrocyte detachment and separation were associated with the formation of a perivascular space and pericapillary edema. The LPS treatment resulted in numerous ultrastructural aberrant remodeling changes to the neurovascular unit’s BECs, microglia, pericytes, and astrocytes. In summary, a disturbance of the NVU morphology is a consequence of LPS treatment.
Genome-Wide Identification and Expression Analysis of the 4-Coumarate: CoA Ligase Gene Family in Solanum tuberosum
Authors: Nie Tengkun , Sun Xinxin , Wang Shenglan , Wang Dongdong , Ren Yamei , Chen Qin
Published: January 2023

4-coumarate: CoA ligase (4CL) is not only involved in the biosynthetic processes of flavonoids and lignin in plants but is also closely related to plant tolerance to abiotic stress. UV irradiation can activate the expression of 4CL genes in plants, and the expression of 4CL genes changed significantly in response to different phytohormone treatments. Although the 4CL gene has been cloned in potatoes, there have been fewer related studies of the 4CL gene family on the potato genome-wide scale. In this study, a total of 10 potato 4CL genes were identified in the potato whole genome. Through multiple sequence alignment, phylogenetic analysis as well as gene structure analysis indicated that the potato 4CL gene family could be divided into two subgroups. Combined with promoter cis-acting element analysis, transcriptome data, and RT-qPCR results indicated that potato 4CL gene family was involved in potato response to white light, UV irradiation, ABA treatment, MeJA treatment, and PEG simulated drought stress. Abiotic stresses such as UV, ABA, MeJA, and PEG could promote the up-regulated expression of St4CL6 and St4CL8 but inhibits the expression of St4CL5. The above results will increase our understanding of the evolution and expression regulation of the potato 4CL gene family and provide reference value for further research on the molecular biological mechanism of 4CL participating in response to diverse environmental signals in potatoes.
Recent Pharmacological Options in Type 2 Diabetes and Synergic Mechanism in Cardiovascular Disease
Authors: Andreadi Aikaterini , Muscoli Saverio , Tajmir Rojin , Meloni Marco , Muscoli Carolina , Ilari Sara , Mollace Vincenzo , Della Morte David , Bellia Alfonso , Di Daniele Nicola , Tesauro Manfredi , Lauro Davide
Published: January 2023

Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The development through the years of pharmacological options allowed us to reduce the persistence of chronic hyperglycemia and reduce diabetic complications. This review aims to highlight the specific mechanisms with which the new treatments for type 2 diabetes reduce oxidative stress and insulin resistance and improve cardiovascular outcomes.
BMPR2 Variants Underlie Nonsyndromic Oligodontia
Authors: Zheng Jinglei , Liu Haochen , Yu Miao , Lin Bichen , Sun Kai , Liu Hangbo , Feng Hailan , Liu Yang , Han Dong
Published: January 2023

Oligodontia manifests as a congenital reduction in the number of permanent teeth. Despite the major efforts that have been made, the genetic etiology of oligodontia remains largely unknown. Bone morphogenetic protein receptor type 2 (BMPR2) variants have been associated with pulmonary arterial hypertension (PAH). However, the genetic significance of BMPR2 in oligodontia has not been previously reported. In the present study, we identified a novel heterozygous variant (c.814C > T; p.Arg272Cys) of BMPR2 in a family with nonsyndromic oligodontia by performing whole-exome sequencing. In addition, we identified two additional heterozygous variants (c.1042G > A; p.Val348Ile and c.1429A > G; p.Lys477Glu) among a cohort of 130 unrelated individuals with nonsyndromic oligodontia by performing Sanger sequencing. Functional analysis demonstrated that the activities of phospho-SMAD1/5/8 were significantly inhibited in BMPR2-knockout 293T cells transfected with variant-expressing plasmids, and were significantly lower in BMPR2 heterozygosity simulation groups than in the wild-type group, indicating that haploinsufficiency may represent the genetic mechanism. RNAscope in situ hybridization revealed that BMPR2 transcripts were highly expressed in the dental papilla and adjacent inner enamel epithelium in mice tooth germs, suggesting that BMPR2 may play important roles in tooth development. Our findings broaden the genetic spectrum of oligodontia and provide clinical and genetic evidence supporting the importance of BMPR2 in nonsyndromic oligodontia.
Structural Basis of the Inhibition of L-Methionine γ-Lyase from Fusobacterium nucleatum
Authors: Bu Tingting , Lan Jing , Jo Inseong , Zhang Jie , Bai Xue , He Shanru , Jin Xiaoling , Wang Lulu , Jin Yu , Jin Xiaoyu , Zhang Liying , Piao Hailong , Ha Nam-Chul , Quan Chunshan , Nam Ki Hyun , Xu Yongbin
Published: January 2023

Fusobacterium nucleatum is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (FN0625, FN1055, FN1220, and FN1419) of F. nucleatum are involved in producing hydrogen sulfide (H2S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 Å, showing the unique conformation of the PLP-binding site when compared with L-methionine γ-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H2S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5′-phosphate-binding site. Gallic acid has little effect on the other H2S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from F. nucleatum and found a new lead compound for inhibitor development.
Glycoalkaloid Composition and Flavonoid Content as Driving Forces of Phytotoxicity in Diploid Potato
Authors: Szajko Katarzyna , Smyda-Dajmund Paulina , Ciekot Jarosław , Marczewski Waldemar , Sołtys-Kalina Dorota
Published: January 2023

Despite their advantages, biotechnological and omic techniques have not been applied often to characterize phytotoxicity in depth. Here, we show the distribution of phytotoxicity and glycoalkaloid content in a diploid potato population and try to clarify the source of variability of phytotoxicity among plants whose leaf extracts have a high glycoalkaloid content against the test plant species, mustard. Six glycoalkaloids were recognized in the potato leaf extracts: solasonine, solamargine, α-solanine, α-chaconine, leptinine I, and leptine II. The glycoalkaloid profiles of the progeny of the group with high phytotoxicity differed from those of the progeny of the group with low phytotoxicity, which stimulated mustard growth. RNA sequencing analysis revealed that the upregulated flavonol synthase/flavonone 3-hydroxylase-like gene was expressed in the progeny of the low phytotoxicity group, stimulating plant growth. We concluded that the metabolic shift among potato progeny may be a source of different physiological responses in mustard. The composition of glycoalkaloids, rather than the total glycoalkaloid content itself, in potato leaf extracts, may be a driving force of phytotoxicity. We suggest that, in addition to glycoalkaloids, other metabolites may shape phytotoxicity, and we assume that these metabolites may be flavonoids.
Synthesis of Fluorescent, Dumbbell-Shaped Polyurethane Homo- and Heterodendrimers and Their Photophysical Properties
Authors: Poudel Dhruba P. , Taylor Richard T.
Published: January 2023

Fluorescent dendrimers have wide applications in biomedical and materials science. Here, we report the synthesis of fluorescent polyurethane homodendrimers and Janus dendrimers, which often pose challenges due to the inherent reactivity of isocyanates. Polyurethane dendrons (G1–G3) were synthesized via a convergent method using a one-pot multicomponent Curtius reaction as a crucial step to establish urethane linkages. The alkyne periphery of the G1–G3 dendrons was modified by a copper catalyzed azide–alkyne click reaction (CuAAC) to form fluorescent dendrons. In the reaction of the surfaces functionalized two different dendrons with a difunctional core, a mixture of three dendrimers consisting of two homodendrimers and a Janus dendrimer were obtained. The Janus dendrimer accounted for a higher proportion in the products’ distribution, being as high as 93% for G3. The photophysical properties of Janus dendrimers showed the fluorescence resonance energy transfer (FRET) from one to the other fluorophore of the dendrimer. The FRET observation accompanied by a large Stokes shift make these dendrimers potential candidates for the detection and tracking of interactions between the biomolecules, as well as potential candidates for fluorescence imaging.
Morphological and Molecular Functional Evidence of the Pharyngeal Sac in the Digestive Tract of Silver Pomfret, Pampus argenteus
Authors: Jiang Huan , Hu Jiabao , Xie Huihui , Zhang Man , Guo Chunyang , Zhang Youyi , Li Yaya , Zhang Cheng , Xu Shanliang , Wang Danli , Yan Xiaojun , Wang Yajun , Wang Xubo
Published: January 2023

The pharyngeal sac is a comparatively rare organ in the digestive tract among teleost fishes. However, our understanding of this remarkable organ in the silver pomfret (Pampus argenteus) is limited. In the present study, we examined the various morphological and histological characteristics of the pharyngeal sac using histochemical techniques and electron microscopy. The pharyngeal sac showed unique characteristics such as well-developed muscular walls, weakly keratinized epithelium, numerous goblet cells, and needle-like processes on the papillae. The porous cavity of the papillae contained numerous adipocytes and was tightly enveloped by type I collagen fibers. These structures might provide mechanical protection and excellent biomechanical properties for grinding and shredding prey. A comparison of gene expression levels between the pharyngeal sac and esophagus using RNA-seq showed that phenotype-associated genes (epithelial genes and muscle genes) were upregulated, whereas genes related to nutrient digestion and absorption were downregulated in the pharyngeal sac. These results support the role of the pharyngeal sac in shredding and predigesting food. Overall, these findings provide a clearer understanding of the pharyngeal sac morphology and explain the morphological adaptations of the digestive tract for feeding on gelatinous prey. To our knowledge, this is the first report on pharyngeal sac gene expression in P. argenteus.
ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury
Authors: Huo Shengqi , Wang Qian , Shi Wei , Peng Lulu , Jiang Yue , Zhu Mengying , Guo Junyi , Peng Dewei , Wang Moran , Men Lintong , Huang Bingyu , Lv Jiagao , Lin Li
Published: January 2023

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.
Selective Eradication of Colon Cancer Cells Harboring PI3K and/or MAPK Pathway Mutations in 3D Culture by Combined PI3K/AKT/mTOR Pathway and MEK Inhibition
Authors: Atanasova Velina S. , Riedl Angelika , Strobl Marcus , Flandorfer Julia , Unterleuthner Daniela , Weindorfer Claudia , Neuhold Patrick , Stang Simone , Hengstschläger Markus , Bergmann Michael , Dolznig Helmut
Published: January 2023

Colorectal cancer (CRC) is the second deadliest cancer in the world. Besides APC and p53 alterations, the PI3K/AKT/MTOR and MAPK pathway are most commonly mutated in CRC. So far, no treatment options targeting these pathways are available in routine clinics for CRC patients. We systematically analyzed the response of CRC cells to the combination of small molecular inhibitors targeting the PI3K and MAPK pathways. We used CRC cells in 2D, 3D spheroid, collagen gel cultures and freshly isolated organoids for drug response studies. Readout for drug response was spheroid or organoid growth, spheroid outgrowth, metabolic activity, Western blotting and immunofluorescence. We found profound tumor cell destruction under treatment with a combination of Torin 1 (inhibiting mTOR), MK2206 (targeting AKT) and selumetinib (inhibiting MEK) in 3D but not in 2D. Induction of cell death was due to apoptosis. Western blot analysis revealed efficient drug action. Gedatolisib, a dual PI3K/mTOR inhibitor, could replace Torin1/MK2206 with similar efficiency. The presence of PI3K and/or RAS-RAF-MAPK pathway mutations accounted for treatment responsiveness. Here, we identified a novel, efficient therapy, which induced proliferation stop and tumor cell destruction in vitro based on the genetic background. These preclinical findings show promise to further test this combi-treatment in vivo in mice and to potentially develop a mutation specific targeted therapy for CRC patients.
The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study
Authors: d’Angelo Debora Mariarita , Attanasi Marina , Di Donato Giulia , Lapergola Giuseppe , Flacco Mariarosaria , Chiarelli Francesco , Altobelli Emma , Breda Luciana
Published: January 2023

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace’s criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan–Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.
Morpho-Functional Characterisation of the Rat Ventral Caudal Nerve in a Model of Axonal Peripheral Neuropathy
Authors: Pozzi Eleonora , Monza Laura , Ballarini Elisa , Bossi Mario , Rodriguez-Menendez Virginia , Canta Annalisa , Chiorazzi Alessia , Carozzi Valentina Alda , Crippa Luca , Marmiroli Paola , Cavaletti Guido , Alberti Paola
Published: January 2023

Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.
Exogenous H2S Attenuates Hypertension by Regulating Renin Exocytosis under Hyperglycaemic and Hyperlipidaemic Conditions
Authors: Liu Ning , Li Mingyu , Liu Siyuan , Kang Jiaxin , Chen Lingxue , Huang Jiayi , Wang Yan , Chen He , Zhang Weihua
Published: January 2023

Obesity, along with type 2 diabetes mellitus (T2DM), is a major contributor to hypertension. The renin-angiotensin-aldosterone system is involved in the occurrence of diabetes and hypertension. However, the mechanism by which obesity is related to T2DM induced hypertension is unclear. In this study, we observed that blood pressure and serum renin content were increased in patients with diabetes and hypertension. Hydrogen sulfide (H2S), as an endogenous bioactive molecule, has been shown to be a vasodilator. Db/db mice, characterized by obesity and T2DM, and juxtaglomerular (JG) cells, which line the afferent arterioles at the entrance of the glomeruli to produce renin, treated with glucose, palmitic acid (PA) and oleic acid (OA), were used as animal and cellular models. NaHS, the H2S donor, was administered to db/db mice through intraperitoneal injection. NaHS significantly alleviated blood pressure in db/db mice, decreased the renin content in the serum of db/db mice and reduced renin secretion from JG cells. NaHS modulated renin release via cAMP and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2), which mediate renin exocytosis. Furthermore, NaHS increased the levels of autophagy-related proteins and colocalization with EGFP-LC3 puncta with renin-containing granules and VAMP2 to consume excessive renin to maintain intracellular homeostasis. Therefore, exogenous H2S attenuates renin release and promotes renin-vesicular autophagy to relieve diabetes-induced hypertension.
Modulation of Cell Death Pathways for Cellular Protection and Anti-Tumoral Activity: The Role of Thymus spp. Extracts and Their Bioactive Molecules
Authors: Martins-Gomes Carlos , Nunes Fernando M. , Silva Amélia M.
Published: January 2023

Natural products used for their health-promoting properties have accompanied the evolution of humanity. Nowadays, as an effort to scientifically validate the health-promoting effects described by traditional medicine, an ever-growing number of bioactivities are being described for natural products and the phytochemicals that constitute them. Among them, medicinal plants and more specifically the Thymus genus spp., arise as products already present in the diet and with high acceptance, that are a source of phytochemicals with high pharmacological value. Phenolic acids, flavonoid glycoside derivatives, and terpenoids from Thymus spp. have been described for their ability to modulate cell death and survival pathways, much-valued bioactivities in the pharmaceutical industry, that continually sought-after new formulations to prevent undesired cell death or to control cell proliferation. Among these, wound treatment, protection from endogenous/exogenous toxic molecules, or the induction of selective cell death, such as the search for new anti-tumoral agents, arise as main objectives. This review summarizes and discusses studies on Thymus spp., as well as on compounds present in their extracts, with regard to their health-promoting effects involving the modulation of cell death or survival signaling pathways. In addition, studies regarding the main bioactive molecules and their cellular molecular targets were also reviewed. Concerning cell survival and proliferation, Thymus spp. present themselves as an option for new formulations designed for wound healing and protection against chemicals-induced toxicity. However, Thymus spp. extracts and some of their compounds regulate cell death, presenting anti-tumoral activity. Therefore Thymus spp. is a rich source of compounds with nutraceutical and pharmaceutical value.
Recombinant Protein Vaccines against Human Betacoronaviruses: Strategies, Approaches and Progress
Authors: Kovalenko Angelina , Ryabchevskaya Ekaterina , Evtushenko Ekaterina , Nikitin Nikolai , Karpova Olga
Published: January 2023

Betacoronaviruses have already troubled humanity more than once. In 2002–2003 and 2012, the SARS-CoV and MERS-CoV, respectively, caused outbreaks of respiratory syndromes with a fatal outcome. The spread of the SARS-CoV-2 coronavirus has become a pandemic. These three coronaviruses belong to the genus Betacoronavirus and have a zoonotic origin. The emergence of new coronavirus infections in the future cannot be ruled out, and vaccination is the main way to prevent the spread of the infection. Previous experience in the development of vaccines against SARS and MERS has helped to develop a number of vaccines against SARS-CoV-2 in a fairly short time. Among them, there are quite a few recombinant protein vaccines, which seem to be very promising in terms of safety, minimization of side effects, storage and transportation conditions. The problem of developing a universal betacoronavirus vaccine is also still relevant. Here, we summarize the information on the designing of vaccines based on recombinant proteins against highly pathogenic human betacoronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2.
A Novel Indole Derivative with Superior Photophysical Performance for Fluorescent Probe, pH-Sensing, and Logic Gates
Authors: Liu Hai-Ling , Zhan Kan , Zhong Kai-Liang , Chen Xing-Liang , Xia Xing-Hua
Published: January 2023

An indole-related molecules have been considered as the potential fluorescent probes for biological and electrochemical sensing. However, most of the indole probes have been usually used in a single detection mode. Indolium probes that enable accurate detection in complex environments are rarely reported. Here, four novel indole derivatives including the phenyl group substituted with different functional moieties were designed on the basis of the donor-π-acceptor (D-π-A) concept. These derivatives exhibit positive solvatochromism owing to their varied molecular conformations upon contacting to various solvents and the different HOMO-LUMO gaps caused by the difference in electronic push-pull capability of the substituents. Their solid-state fluorescence emissions and multiple chromisms are observed due to the inherent twisted geometries and aggregation modes. In addition, these derivatives show dramatic color and fluorescence responses due to the protonation of the nitrogen and oxygen containing groups, and thus novel colorimetric pH sensors, fluorescent papers and logic gates have been designed.
Hemodialysis-Associated Immune Dysregulation in SARS-CoV-2-Infected End-Stage Renal Disease Patients
Authors: González-Cuadrado Cecilia , Caro-Espada Paula Jara , Chivite-Lacaba Marta , Utrero-Rico Alberto , Lozano-Yuste Claudia , Gutierrez-Solis Elena , Morales Enrique , Sandino-Pérez Justo , Gil-Etayo Francisco Javier , Allende-Martínez Luis , Laguna-Goya Rocio , Paz-Artal Estela
Published: January 2023

Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1β and IL-8 and CXCL10 (p < 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection.
Sleeve Gastrectomy-Induced Weight Loss Increases Insulin Clearance in Obese Mice
Authors: Soares Gabriela Moreira , Lopes Luana Emanuelly Sinhori , Balbo Sandra Lucinei , Marmentini Carine , Bronczek Gabriela Alves , Kurauti Mirian Ayumi , Bonfleur Maria Lúcia , Velloso Licio Augusto , Carneiro Everardo Magalhães , Boschero Antonio Carlos , Costa-Júnior José Maria
Published: January 2023

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose–insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.
Plasma-Derived Exosomes from NAFLD Patients Modulate the Cannabinoid Receptors’ Expression in Cultured HepaRG Cells
Authors: De Nunzio Valentina , Carrieri Livianna , Scavo Maria Principia , Lippolis Tamara , Cofano Miriam , Caponio Giusy Rita , Tutino Valeria , Rizzi Federica , Depalo Nicoletta , Osella Alberto Ruben , Notarnicola Maria
Published: January 2023

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors’ expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.