bluuebunny/crossref_metadata_2025 huggingface dataset:
Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies
Authors: Wang Fan , Xie Xueheng , Xing Xiaoyan , Sun Xiaobo
Published: August 2022

Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).
Property and Stability of Astaxanthin Emulsion Based on Pickering Emulsion Templating with Zein and Sodium Alginate as Stabilizer
Authors: Xu Yan , Jia Zhe , Wang Jiaxing , Sun Jipeng , Song Ru
Published: August 2022

Astaxanthin loaded Pickering emulsion with zein/sodium alginate (SA) as a stabilizer (named as APEs) was developed, and its structure and stability were characterized. The encapsulation efficiency of astaxanthin (Asta) in APEs was up to 86.7 ± 3.8%, with a mean particle size of 4.763 μm. Freeze-dried APEs showed particles stacked together under scanning electronic microscope; whereas dispersed spherical nanoparticles were observed in APEs dilution under transmission electron microscope images. Confocal laser scanning microscope images indicated that zein particles loaded with Asta were aggregated with SA coating. X-ray diffraction patterns and Fourier transform infrared spectra results showed that intermolecular hydrogen bonding, electrostatic attraction and hydrophobic effect were involved in APEs formation. APEs demonstrated non-Newtonian shear-thinning behavior and fit well to the Cross model. Compared to bare Asta extract, APEs maintained high Asta retention and antioxidant activity when heated from 50 to 10 °C. APEs showed different stability at pH (3.0–11.0) and Na+, K+, Ca2+, Cu2+ and Fe2+ conditions by visual, zeta potential and polydispersity index measurements. Additionally, the first order kinetics fit well to describe APEs degradation at pH 3.0 to 9.0, Na+, and K+ conditions. Our results suggest the potential application of Asta-loaded Pickering emulsion in food systems as a fortified additive.
Multi-Omic Investigations of a 17–19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis
Authors: Eisfeldt Jesper , Schuy Jakob , Stattin Eva-Lena , Kvarnung Malin , Falk Anna , Feuk Lars , Lindstrand Anna
Published: August 2022

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient’s cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient’s cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.
Genetic Diversity of Tomato Black Ring Virus Satellite RNAs and Their Impact on Virus Replication
Authors: Minicka Julia , Taberska Agnieszka , Zarzyńska-Nowak Aleksandra , Kubska Katarzyna , Budzyńska Daria , Elena Santiago F. , Hasiów-Jaroszewska Beata
Published: August 2022

Viral satellite RNAs (satRNAs) are small subviral particles that are associated with the genomic RNA of a helper virus (HV). Their replication, encapsidation, and movement depend on the HV. In this paper, we performed a global analysis of the satRNAs associated with different isolates of tomato black ring virus (TBRV). We checked the presence of satRNAs in 42 samples infected with TBRV, performed recombination and genetic diversity analyses, and examined the selective pressure affecting the satRNAs population. We identified 18 satRNAs in total that differed in length and the presence of point mutations. Moreover, we observed a strong effect of selection operating upon the satRNA population. We also constructed infectious cDNA clones of satRNA and examined the viral load of different TBRV isolates in the presence and absence of satRNAs, as well as the accumulation of satRNA molecules on infected plants. Our data provide evidence that the presence of satRNAs significantly affects viral load; however, the magnitude of this effect differs among viral isolates and plant hosts. We also showed a positive correlation between the number of viral genomic RNAs (gRNAs) and satRNAs for two analysed TBRV isolates.
Monitoring of Current Cancer Therapy by Positron Emission Tomography and Possible Role of Radiomics Assessment
Authors: Oriuchi Noboru , Endoh Hideki , Kaira Kyoichi
Published: August 2022

Evaluation of cancer therapy with imaging is crucial as a surrogate marker of effectiveness and survival. The unique response patterns to therapy with immune-checkpoint inhibitors have facilitated the revision of response evaluation criteria using FDG-PET, because the immune response recalls reactive cells such as activated T-cells and macrophages, which show increased glucose metabolism and apparent progression on morphological imaging. Cellular metabolism and function are critical determinants of the viability of active cells in the tumor microenvironment, which would be novel targets of therapies, such as tumor immunity, metabolism, and genetic mutation. Considering tumor heterogeneity and variation in therapy response specific to the mechanisms of therapy, appropriate response evaluation is required. Radiomics approaches, which combine objective image features with a machine learning algorithm as well as pathologic and genetic data, have remarkably progressed over the past decade, and PET radiomics has increased quality and reliability based on the prosperous publications and standardization initiatives. PET and multimodal imaging will play a definitive role in personalized therapeutic strategies by the precise monitoring in future cancer therapy.
Iron Metabolism and Ferroptosis in Physiological and Pathological Pregnancy
Authors: Zhang Yijun , Lu Yun , Jin Liping
Published: August 2022

Iron is a vital element in nearly every living organism. During pregnancy, optimal iron concentration is essential for both maternal health and fetal development. As the barrier between the mother and fetus, placenta plays a pivotal role in mediating and regulating iron transport. Imbalances in iron metabolism correlate with severe adverse pregnancy outcomes. Like most other nutrients, iron exhibits a U-shaped risk curve. Apart from iron deficiency, iron overload is also dangerous since labile iron can generate reactive oxygen species, which leads to oxidative stress and activates ferroptosis. In this review, we summarized the molecular mechanism and regulation signals of placental iron trafficking under physiological conditions. In addition, we revealed the role of iron metabolism and ferroptosis in the view of preeclampsia and gestational diabetes mellitus, which may bring new insight to the pathogenesis and treatment of pregnancy-related diseases.
Exploring the Antitumor Potential of Copper Complexes Based on Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands
Authors: Pellei Maura , Santini Carlo , Bagnarelli Luca , Battocchio Chiara , Iucci Giovanna , Venditti Iole , Meneghini Carlo , Amatori Simone , Sgarbossa Paolo , Marzano Cristina , De Franco Michele , Gandin Valentina
Published: August 2022

Bis(pyrazol-1-yl)acetic acid (HC(pz)2COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pzMe2)2COOH) were converted into the methyl ester derivatives 1 (LOMe) and 2 (L2OMe), respectively, and were used for the preparation of Cu(I) and Cu(II) complexes 3–10. The copper(II) complexes were prepared by the reaction of CuCl2·2H2O or CuBr2 with ligands 1 and 2 in methanol solution. The copper(I) complexes were prepared by the reaction of Cu[(CH3CN)4]PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine with LOMe and L2OMe in acetonitrile solution. Synchrotron radiation-based complementary techniques (XPS, NEXAFS, and XAS) were used to investigate the electronic and molecular structures of the complexes and the local structure around copper ions in selected Cu(I) and Cu(II) coordination compounds. All Cu(I) and Cu(II) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human cancer cell lines, and were able to overcome cisplatin resistance. Noticeably, Cu complexes appeared much more effective than cisplatin in 3D spheroid cultures. Mechanistic studies revealed that the antitumor potential did not correlate with cellular accumulation but was consistent with intracellular targeting of PDI, ER stress, and paraptotic cell death induction.
GcvB Regulon Revealed by Transcriptomic and Proteomic Analysis in Vibrio alginolyticus
Authors: Liu Bing , Fang Jianxiang , Chen Huizhen , Sun Yuehong , Yang Shan , Gao Qian , Zhang Ying , Chen Chang
Published: August 2022

Vibrio alginolyticus is a widely distributed marine bacterium that is a threat to the aquaculture industry as well as human health. Evidence has revealed critical roles for small RNAs (sRNAs) in bacterial physiology and cellular processes by modulating gene expression post-transcriptionally. GcvB is one of the most conserved sRNAs that is regarded as the master regulator of amino acid uptake and metabolism in a wide range of Gram-negative bacteria. However, little information about GcvB-mediated regulation in V. alginolyticus is available. Here we first characterized GcvB in V. alginolyticus ZJ-T and determined its regulon by integrated transcriptome and quantitative proteome analysis. Transcriptome analysis revealed 40 genes differentially expressed (DEGs) between wild-type ZJ-T and gcvB mutant ZJ-T-ΔgcvB, while proteome analysis identified 50 differentially expressed proteins (DEPs) between them, but only 4 of them displayed transcriptional differences, indicating that most DEPs are the result of post-transcriptional regulation of gcvB. Among the differently expressed proteins, 21 are supposed to be involved in amino acid biosynthesis and transport, and 11 are associated with type three secretion system (T3SS), suggesting that GcvB may play a role in the virulence besides amino acid metabolism. RNA-EMSA showed that Hfq binds to GcvB, which promotes its stability.
4-Phenylbutyric Acid (4-PBA) Derivatives Prevent SOD1 Amyloid Aggregation In Vitro with No Effect on Disease Progression in SOD1-ALS Mice
Authors: Alfahel Leenor , Argueti-Ostrovsky Shirel , Barel Shir , Ali Saleh Mahmood , Kahn Joy , Azoulay-Ginsburg Salome , Rothstein Ayelet , Ebbinghaus Simon , Gruzman Arie , Israelson Adrian
Published: August 2022

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the superoxide dismutase (SOD1) gene, causing protein misfolding and aggregation, were suggested as the pathogenic mechanisms involved in familial ALS cases. In the present study, we investigated the potential therapeutic effect of C4 and C5, two derivatives of the chemical chaperone 4-phenylbutyric acid (4-PBA). By combining in vivo and in vitro techniques, we show that, although C4 and C5 successfully inhibited amyloid aggregation of recombinant mutant SOD1 in a dose-dependent manner, they failed to suppress the accumulation of misfolded SOD1. Moreover, C4 or C5 daily injections to SOD1G93A mice following onset had no effect on either the accumulation of misfolded SOD1 or the neuroinflammatory response in the spinal cord and, consequently, failed to extend the survival of SOD1G93A mice or to improve their motor symptoms. Finally, pharmacokinetic (PK) studies demonstrated that high concentrations of C4 and C5 reached the brain and spinal cord but only for a short period of time. Thus, our findings suggest that use of such chemical chaperones for ALS drug development may need to be optimized for more effective results.
Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers
Authors: Matsumoto Tomonori
Published: August 2022

Polyploidy, a condition in which more than two sets of chromosomes are present in a cell, is a characteristic feature of hepatocytes. A significant number of hepatocytes physiologically undergo polyploidization at a young age. Polyploidization of hepatocytes is enhanced with age and in a diseased liver. It is worth noting that polyploid hepatocytes can proliferate, in marked contrast to other types of polyploid cells, such as megakaryocytes and cardiac myocytes. Polyploid hepatocytes divide to maintain normal liver homeostasis and play a role in the regeneration of the damaged liver. Furthermore, polyploid hepatocytes have been shown to dynamically reduce ploidy during liver regeneration. Although it is still unclear why hepatocytes undergo polyploidization, accumulating evidence has revealed that alterations in the ploidy in hepatocytes are involved in the pathophysiology of liver cirrhosis and carcinogenesis. This review discusses the significance of hepatocyte ploidy in physiological liver function, liver injury, and liver cancer.
Novel Potency Assay for MSC Secretome-Based Treatment of Idiopathic Male Infertility Employed Leydig Cells and Revealed Vascular Endothelial Growth Factor as a Promising Potency Marker
Authors: Monakova Anna , Sagaradze Georgy , Basalova Nataliya , Popov Vladimir , Balabanyan Vadim , Efimenko Anastasia
Published: August 2022

Idiopathic male infertility is a highly prevalent diagnosis in developed countries with no specific treatment options. Although empirical medical treatment is widely used to restore male fertility, its efficacy remains limited and inconclusively proven. Therefore, the development of novel therapeutic approaches in this field is a high-priority task. Since the failure of testicular microenvironment components might be involved in the pathogenesis of idiopathic male infertility, application of mesenchymal stromal cells (MSCs) as well as the MSC secretome is worth considering. Previously, we showed that the intratesticular injection of MSCs or the MSC secretome led to the recovery of spermatogenesis at least through replenishing the testicular microenvironment and its maintenance by MSC-secreted paracrine factors. However, the clinical use of such products has been limited to single trials to date. This may be due to the lack of relevant potency tests reflecting mechanisms of action of the MSC secretome in male infertility models. Based on the presumptive MSC secretome mode of action on the testicular microenvironment, we suggest a novel approach to test the potential efficacy of the MSC secretome for idiopathic male infertility treatment. It represents a potency assay based on evaluation of testosterone production by isolated Leydig cells. We demonstrated that the MSC secretome stimulated testosterone secretion by Leydig cells in vitro. We then hypothesized that among the major factors of the MSC secretome, vascular endothelial growth factor (VEGF) could be responsible for the observed effects, which we confirmed by the revealed correlation between the extent of stimulated testosterone production and VEGF concentration in the MSC secretome. The pilot results obtained from the doxorubicin-induced male infertility murine model also indicate the important impact of VEGF in the MSC secretome’s regenerative effects. Utilizing VEGF as a surrogate factor, a novel approach to study the potency of MSC secretome-based products for idiopathic male infertility treatment is suggested. Further validation is required for its implementation into the biopharmaceutical manufacturing process.
Differentiation of SARS-CoV-2 Variants Using RT-qPCRs by Targeting Recurrent Mutation Sites: A Diagnostic Laboratory Experience from Multi-Center Regional Study, August 2020–December 2021, Poland
Authors: Wegrzynska Karolina , Komiazyk Magdalena , Walory Jaroslaw , Kozinska Aleksandra , Wasko Izabela , Baraniak Anna
Published: August 2022

Rapid identification of SARS-CoV-2 variants is essential for epidemiological surveillance. RT-qPCR-based variant differentiation tests can be used to quickly screen large sets of samples for relevant variants of concern/interest; this study was conducted on specimens collected at 11 centers located in Poland during routine SARS-CoV-2 diagnostics between August 2020 and December 2021. A total of 1096 samples (with CT < 30) were screened for Alpha, Beta, Delta, Kappa and Omicron variants using commercial assays targeting repeat mutation sites. Variants were assigned to 434 (39.6%) specimens; the remaining 662 (60.4%) samples were not classified (no tested mutations detected). Alpha (n = 289; 66.59%), Delta (n = 115; 26.5%), Kappa (n = 30; 6.91%) and Omicron (n = 2; 0.46%) variants were identified and their distribution changed over time. The first Alpha variant appeared in October 2020, and it began to gradually increase its proportion of the virus population by June 2021. In July 2021, it was replaced by the Delta variant, which already dominated by the end of the year. The first Kappa was detected in October 2021, while Omicron was found in December 2021. The screening of samples allowed the determination of epidemiological trends over a time interval reflecting the national COVID-19 waves.
Expression of Cell Cycle Markers and Proliferation Factors during Human Eye Embryogenesis and Tumorigenesis
Authors: Marin Lovrić Josipa , Filipović Natalija , Znaor Ljubo , Rančić Anita , Petričević Joško , Kunac Nenad , Šoljić Violeta , Saraga-Babić Mirna , Vukojević Katarina
Published: August 2022

The expression pattern of the markers p19, Ki-67, MSX1, MSX2, PDL1, pRB, and CYCLINA2 was quantitatively and semiquantitatively analyzed in histologic sections of the developing and postnatal human eye at week 8, in retinoblastoma, and in various uveal melanomas post hoc studies by double immunofluorescence. The p19 immunoreactivity characterized retinal and/or choroidal cells in healthy and tumor tissues: expression was lower in the postnatal retina than in the developing retina and retinoblastoma, whereas it was high in epithelioid melanomas. Ki67 expression was high in the developing eye, retinoblastoma, and choroidal melanomas. MSX1 and MSX2 expression was similar in the developing eye and retinoblastoma, whereas it was absent in the postnatal eye. Their different expression was evident between epithelioid and myxoid melanomas. Similarly, PDL1 was absent in epithelioid melanomas, whereas it was highly expressed in developing and tumor tissues. Expression of pRB and CYCA2 was characteristic of developing and tumorous eye samples but not of the healthy postnatal eye. The observed expression differences of the analyzed markers correlate with the origin and stage of cell differentiation of the tissue samples. The fine balance of expression could play a role in both human eye development and ocular tumorigenesis. Therefore, understanding their relationship and interplay could open new avenues for potential therapeutic interventions and a better understanding of the mechanisms underlying the developmental plasticity of the eye and the development of neoplasms.
Functional Diversity of Microbial Communities in the Soybean (Glycine max L.) Rhizosphere from Free State, South Africa
Authors: Ajiboye Titilope Tinu , Ayangbenro Ayansina Segun , Babalola Olubukola Oluranti
Published: August 2022

The plant microbiome is involved in enhancing nutrient acquisition, plant growth, stress tolerance, and reducing chemical inputs. The identification of microbial functional diversity offers the chance to evaluate and engineer them for various agricultural processes. Using a shotgun metagenomics technique, this study examined the functional diversity and metabolic potentials of microbial communities in the rhizosphere of soybean genotype link 678. The dominant genera are Geobacter, Nitrobacter, Burkholderia, Candidatus, Bradyrhizobium and Streptomyces. Twenty-one functional categories were present, with fourteen of the functions being dominant in all samples. The dominant functions include carbohydrates, fatty acids, lipids and isoprenoids, amino acids and derivatives, sulfur metabolism, and nitrogen metabolism. A Kruskal–Wallis test was used to test samples’ diversity differences. There was a significant difference in the alpha diversity. ANOSIM was used to analyze the similarities of the samples and there were significant differences between the samples. Phosphorus had the highest contribution of 64.3% and was more prominent among the soil properties that influence the functional diversity of the samples. Given the functional groups reported in this study, soil characteristics impact the functional role of the rhizospheric microbiome of soybean.
Aflibercept versus Faricimab in the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: A Review
Authors: Liberski Sławomir , Wichrowska Małgorzata , Kocięcki Jarosław
Published: August 2022

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are common retinal vascular diseases responsible for most blindness in the working-age and older population in developed countries. Currently, anti-VEGF agents that block VEGF family ligands, including ranibizumab, bevacizumab (off-label use), brolucizumab, and aflibercept, are the first-line treatment for nAMD and DME. However, due to the complex pathophysiological background of nAMD and DME, non-response, resistance during anti-VEGF therapy, and relapses of the disease are still observed. Moreover, frequent injections are a psychological and economic burden for patients, leading to inadequate adhesion to therapy and a higher risk of complications. Therefore, therapeutic methods are strongly needed to develop and improve, allowing for more satisfactory disease management and lower treatment burden. Currently, the Ang/Tie-2 pathway is a promising therapeutic target for retinal vascular diseases. Faricimab is the first bispecific monoclonal antibody for intravitreal use that can neutralize VEGF and Ang-2. Due to the prolonged activity, faricimab allows extending the interval between successive injections up to three or four months in nAMD and DME patients, which can be a significant benefit for patients and an alternative to implanted drug delivery systems.
The Cross-Resistance Pattern and the Metabolic Resistance Mechanism of Acetamiprid in the Brown Planthopper, Nilaparvata lugens (Stål)
Authors: Wu Shuai , He Minrong , Xia Fujin , Zhao Xueyi , Liao Xun , Li Rongyu , Li Ming
Published: August 2022

Acetamiprid is widely used in paddy fields for controlling Nilaparvata lugens (Stål). However, the risk of resistance development, the cross-resistance pattern and the resistance mechanism of acetamiprid in this pest remain unclear. In this study, an acetamiprid-resistant strain (AC-R) was originated from a field strain (UNSEL) through successive selection with acetamiprid for 30 generations, which reached 60.0-fold resistance when compared with a laboratory susceptible strain (AC-S). The AC-R strain (G30) exhibited cross-resistance to thiamethoxam (25.6-fold), nitenpyram (21.4-fold), imidacloprid (14.6-fold), cycloxaprid (11.8-fold), dinotefuran (8.7-fold), sulfoxaflor (7.6-fold) and isoprocarb (8.22-fold), while there was no cross-resistance to etofenprox, buprofezin and chlorpyrifos. Acetamiprid was synergized by the inhibitor piperonyl butoxide (2.2-fold) and the activity of cytochrome P450 monooxygenase was significantly higher in the AC-R strain compared with the AC-S strain, suggesting the critical role of P450. The gene expression results showed that the P450 gene CYP6ER1 was significantly overexpressed in AC-R compared with the AC-S and UNSEL strains. In addition, the RNA interference (RNAi) of CYP6ER1 significantly increased the susceptibility of AC-R to acetamiprid. Molecular docking predicted that acetamiprid and CYP6ER1 had close binding sites, and the nitrogen atoms had hydrogen bond interactions with CYP6ER1. These results demonstrated that the overexpression of CYP6ER1 contributed to acetamiprid resistance in N. lugens.
Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-Expressing Thyroid Cancer Mouse Model
Authors: Watabe Tadashi , Liu Yuwei , Kaneda-Nakashima Kazuko , Sato Tatsuhiko , Shirakami Yoshifumi , Ooe Kazuhiro , Toyoshima Atsushi , Shimosegawa Eku , Wang Yang , Haba Hiromitsu , Nakano Takashi , Shinohara Atsushi , Hatazawa Jun
Published: August 2022

Astatine (211At) is an alpha-emitter with a better treatment efficacy against differentiated thyroid cancer compared with iodine (131I), a conventional beta-emitter. However, its therapeutic comparison has not been fully evaluated. In this study, we compared the therapeutic effect between [211At]NaAt and [131I]NaI. In vitro analysis of a double-stranded DNA break (DSB) and colony formation assay were performed using K1-NIS cells. The therapeutic effect was compared using K1-NIS xenograft mice administered with [211At]NaAt (0.4 MBq (n = 7), 0.8 MBq (n = 9), and 1.2 MBq (n = 4)), and [131I]NaI (1 MBq (n = 4), 3 MBq (n = 4), and 8 MBq (n = 4)). The [211At]NaAt induced higher numbers of DSBs and had a more reduced colony formation than [131I]NaI. In K1-NIS mice, dose-dependent therapeutic effects were observed in both [211At]NaAt and [131I]NaI. In [211At]NaAt, a stronger tumour-growth suppression was observed, while tumour regrowth was not observed until 18, 25, and 46 days after injection of 0.4, 0.8, and 1.2 MBq of [211At]NaAt, respectively. While in [131I]NaI, this was observed within 12 days after injection (1, 3, and 8 MBq). The superior therapeutic effect of [211At]NaAt suggests the promising clinical applicability of targeted alpha therapy using [211At]NaAt in patients with differentiated thyroid cancer refractory to standard [131I]NaI treatment.
Efficient Anchoring of Erianthus arundinaceus Chromatin Introgressed into Sugarcane by Specific Molecular Markers
Authors: Wu Jiayun , Zhang Mingxiao , Liu Jiarui , Huang Yongji , Xu Liangnian , Deng Zuhu , Zhao Xinwang
Published: August 2022

Erianthus arundinaceus is a valuable gene reservoir for sugarcane improvement. However, insufficient molecular markers for high-accuracy identification and tracking of the introgression status of E. arundinaceus chromatin impede sugarcane breeding. Fortunately, suppression subtractive hybridization (SSH) technology provides an excellent opportunity for the development of high-throughput E. arundinaceus-specific molecular markers at a reasonable cost. In this study, we constructed a SSH library of E. arundinaceus. In total, 288 clones of E. arundinaceus-specific repetitive sequences were screened out and their distribution patterns on chromosomes were characterized by fluorescence in situ hybridization (FISH). A subtelomeric repetitive sequence Ea086 and a diffusive repetitive sequence Ea009, plus 45S rDNA-bearing E. arundinaceus chromosome repetitive sequence EaITS were developed as E. arundinaceus-specific molecular markers, namely, Ea086-128, Ea009-257, and EaITS-278, covering all the E. arundinaceus chromosomes for high-accuracy identification of putative progeny. Both Ea086-128 and Ea009-257 were successfully applied to identify the authenticity of F1, BC1, BC2, BC3, and BC4 progeny between sugarcane and E. arundinaceus. In addition, EaITS-278 was a 45S rDNA-bearing E. arundinaceus chromosome-specific molecular marker for rapid tracking of the inherited status of this chromosome in a sugarcane background. Three BC3 progeny had apparently lost the 45S rDNA-bearing E. arundinaceus chromosome. We reported herein a highly effective and reliable SSH-based technology for discovery of high-throughput E. arundinaceus-specific sequences bearing high potential as molecular markers. Given its reliability and savings in time and efforts, the method is also suitable for development of species-specific molecular markers for other important wild relatives to accelerate introgression of wild relatives into sugarcane.
β-Galactosylceramidase Deficiency Causes Upregulation of Long Pentraxin-3 in the Central Nervous System of Krabbe Patients and Twitcher Mice
Authors: Coltrini Daniela , Chandran Adwaid Manu Krishna , Belleri Mirella , Poliani Pietro L. , Cominelli Manuela , Pagani Francesca , Capra Miriam , Calza Stefano , Prioni Simona , Mauri Laura , Prinetti Alessandro , Kofler Julia K. , Escolar Maria L. , Presta Marco
Published: August 2022

Globoid cell leukodystrophy (GLD), or Krabbe disease, is a neurodegenerative sphingolipidosis caused by genetic deficiency of lysosomal β-galactosylceramidase (GALC), characterized by neuroinflammation and demyelination of the central (CNS) and peripheral nervous system. The acute phase protein long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and a regulator of innate immunity. Growing evidence points to the involvement of PTX3 in neurodegeneration. However, the expression and role of PTX3 in the neurodegenerative/neuroinflammatory processes that characterize GLD remain unexplored. Here, immunohistochemical analysis of brain samples from Krabbe patients showed that macrophages and globoid cells are intensely immunoreactive for PTX3. Accordingly, Ptx3 expression increases throughout the course of the disease in the cerebrum, cerebellum, and spinal cord of GALC-deficient twitcher (Galctwi/twi) mice, an authentic animal model of GLD. This was paralleled by the upregulation of proinflammatory genes and M1-polarized macrophage/microglia markers and of the levels of PTX3 protein in CNS and plasma of twitcher animals. Crossing of Galctwi/twi mice with transgenic PTX3 overexpressing animals (hPTX3 mice) demonstrated that constitutive PTX3 overexpression reduced the severity of clinical signs and the upregulation of proinflammatory genes in the spinal cord of P35 hPTX3/Galctwi/twi mice when compared to Galctwi/twi littermates, leading to a limited increase of their life span. However, this occurred in the absence of a significant impact on the histopathological findings and on the accumulation of the neurotoxic metabolite psychosine when evaluated at this late time point of the disease. In conclusion, our results provide the first evidence that PTX3 is produced in the CNS of GALC-deficient Krabbe patients and twitcher mice. PTX3 may exert a protective role by reducing the neuroinflammatory response that occurs in the spinal cord of GALC-deficient animals.
Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0
Authors: Di Meo Sergio , Venditti Paola , Napolitano Gaetana
Published: August 2022

Following the discovery of superoxide dismutase enzymes [...]
Overexpression of PgCBF3 and PgCBF7 Transcription Factors from Pomegranate Enhances Freezing Tolerance in Arabidopsis under the Promoter Activity Positively Regulated by PgICE1
Authors: Wang Lei , Wang Sa , Tong Ruiran , Wang Sen , Yao Jianan , Jiao Jian , Wan Ran , Wang Miaomiao , Shi Jiangli , Zheng Xianbo
Published: August 2022

Cold stress limits plant growth, development and yields, and the C-repeat binding factors (CBFs) function in the cold resistance in plants. However, how pomegranate CBF transcription factors respond to cold signal remains unclear. Considering the significantly up-regulated expression of PgCBF3 and PgCBF7 in cold-tolerant Punica granatum ‘Yudazi’ in comparison with cold-sensitive ‘Tunisia’ under 4 °C, the present study focused on the two CBF genes. PgCBF3 was localized in the nucleus, while PgCBF7 was localized in the cell membrane, cytoplasm, and nucleus, both owning transcriptional activation activity in yeast. Yeast one-hybrid and dual-luciferase reporter assay further confirmed that PgICE1 could specifically bind to and significantly enhance the activation activity of the promoters of PgCBF3 and PgCBF7. Compared with the wild-type plants, the PgCBF3 and PgCBF7 transgenic Arabidopsis thaliana lines had the higher survival rate after cold treatment; exhibited increased the contents of soluble sugar and proline, while lower electrolyte leakage, malondialdehyde content, and reactive oxygen species production, accompanying with elevated enzyme activity of catalase, peroxidase, and superoxide dismutase; and upregulated the expression of AtCOR15A, AtCOR47, AtRD29A, and AtKIN1. Collectively, PgCBFs were positively regulated by the upstream PgICE1 and mediated the downstream COR genes expression, thereby enhancing freezing tolerance.
Optimized Apamin-Mediated Nano-Lipidic Carrier Potentially Enhances the Cytotoxicity of Ellagic Acid against Human Breast Cancer Cells
Authors: Badr-Eldin Shaimaa M. , Aldawsari Hibah M. , Fahmy Usama A. , Ahmed Osama A. A. , Alhakamy Nabil A. , Al-hejaili Omar D. , Alhassan Alhanoof A. , Ammari Ghadeer A. , Alhazmi Shouq I. , Alawadi Raghad M. , Bakhaidar Rana , Alamoudi Abdulmohsen J. , Neamatallah Thikryat , Tima Singkome
Published: August 2022

Ellagic acid has recently attracted increasing attention regarding its role in the prevention and treatment of cancer. Surface functionalized nanocarriers have been recently studied for enhancing cancer cells’ penetration and achieving better tumor-targeted delivery of active ingredients. Therefore, the present work aimed at investigating the potential of APA-functionalized emulsomes (EGA-EML-APA) for enhancing cytototoxic activity of EGA against human breast cancer cells. Phospholipon® 90 G: cholesterol molar ratio (PC: CH; X1, mole/mole), Phospholipon® 90 G: Tristearin weight ratio (PC: TS; X2, w/w) and apamin molar concentration (APA conc.; X3, mM) were considered as independent variables, while vesicle size (VS, Y1, nm) and zeta potential (ZP, Y2, mV) were studied as responses. The optimized formulation with minimized vs. and maximized absolute ZP was predicted successfully utilizing a numerical technique. EGA-EML-APA exhibited a significant cytotoxic effect with an IC50 value of 5.472 ± 0.21 µg/mL compared to the obtained value from the free drug 9.09 ± 0.34 µg/mL. Cell cycle profile showed that the optimized formulation arrested MCF-7 cells at G2/M and S phases. In addition, it showed a significant apoptotic activity against MCF-7 cells by upregulating the expression of p53, bax and casp3 and downregulating bcl2. Furthermore, NF-κB activity was abolished while the expression of TNfα was increased confirming the significant apoptotic effect of EGA-EML-APA. In conclusion, apamin-functionalized emulsomes have been successfully proposed as a potential anti-breast cancer formulation.
Involvement of Porcine β-Defensin 129 in Sperm Capacitation and Rescue of Poor Sperm in Genital Tract Infection
Authors: Zeng Fanwen , Wang Mingming , Li Ju , Li Chengde , Pan Xueqing , Meng Li , Li Li , Wei Hengxi , Zhang Shouquan
Published: August 2022

In mammals, β-defensins have been reported to play pivotal roles in sperm protection and fertilization. However, the function and mechanism of porcine β-defensin 129 (pBD129) in the sperm remain unclear. Here, we demonstrate that pBD129 is a glycosylated protein and broadly exists in accessory sex glands and coats the sperm surface. We inhibited the pBD129 protein on the sperm surface with an anti-pBD129 antibody and found that sperm motility was not significantly affected; however, sperm acrosome integrity and tyrosine phosphorylation levels increased significantly with time (p < 0.05) during capacitation. These changes were accompanied by an increase in sperm Ca2+ influx, resulting in a significantly reduced in vitro fertilization cleavage rate (p < 0.05). Further investigation revealed that treatment with recombinant pBD129 markedly restored the sperm motility in semen contaminated with Escherichia coli. The results suggest that pBD129 is not only associated with poor sperm motility after genital tract infection but can also protect the spermatozoa from premature capacitation, which may be beneficial for semen preservation.
Serotonin 5-HT6 Receptor Ligands and Butyrylcholinesterase Inhibitors Displaying Antioxidant Activity—Design, Synthesis and Biological Evaluation of Multifunctional Agents against Alzheimer’s Disease
Authors: Więckowski Krzysztof , Szałaj Natalia , Gryzło Beata , Wichur Tomasz , Góral Izabella , Sługocka Emilia , Sniecikowska Joanna , Latacz Gniewomir , Siwek Agata , Godyń Justyna , Bucki Adam , Kołaczkowski Marcin , Więckowska Anna
Published: August 2022

Neurodegeneration leading to Alzheimer’s disease results from a complex interplay of a variety of processes including misfolding and aggregation of amyloid beta and tau proteins, neuroinflammation or oxidative stress. Therefore, to address more than one of these, drug discovery programmes focus on the development of multifunctional ligands, preferably with disease-modifying and symptoms-reducing potential. Following this idea, herein we present the design and synthesis of multifunctional ligands and biological evaluation of their 5-HT6 receptor affinity (radioligand binding assay), cholinesterase inhibitory activity (spectroscopic Ellman’s assay), antioxidant activity (ABTS assay) and metal-chelating properties, as well as a preliminary ADMET properties evaluation. Based on the results we selected compound 14 as a well-balanced and potent 5-HT6 receptor ligand (Ki = 22 nM) and human BuChE inhibitor (IC50 = 16 nM) with antioxidant potential expressed as a reduction of ABTS radicals by 35% (150 μM). The study also revealed additional metal-chelating properties of compounds 15 and 18. The presented compounds modulating Alzheimer’s disease-related processes might be further developed as multifunctional ligands against the disease.
The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases
Authors: Chan Pei-Chi , Hsieh Po-Shiuan
Published: August 2022

Brown adipose tissue (BAT) has been considered a vital organ in response to non-shivering adaptive thermogenesis, which could be activated during cold exposure through the sympathetic nervous system (SNS) or under postprandial conditions contributing to diet-induced thermogenesis (DIT). Humans prefer to live within their thermal comfort or neutral zone with minimal energy expenditure created by wearing clothing, making shelters, or using an air conditioner to regulate their ambient temperature; thereby, DIT would become an important mechanism to counter-regulate energy intake and lipid accumulation. In addition, there has been a long interest in the intriguing possibility that a defect in DIT predisposes one to obesity and other metabolic diseases. Due to the recent advances in methodology to evaluate the functional activity of BAT and DIT, this updated review will focus on the role and regulatory mechanism of BAT biology in DIT in health and diseases and whether these mechanisms are applicable to humans.
From Dukes-MAC Staging System to Molecular Classification: Evolving Concepts in Colorectal Cancer
Authors: Banias Laura , Jung Ioan , Chiciudean Rebeca , Gurzu Simona
Published: August 2022

This historical review aimed to summarize the main changes that colorectal carcinoma (CRC) staging systems suffered over time, starting from the creation of the classical Duke’s classification, modified Astler–Coller staging, internationally used TNM (T—primary tumor, N—regional lymph nodes’ status, M—distant metastases) staging system, and ending with molecular classifications and epithelial–mesenchymal transition (EMT) concept. Besides currently used staging parameters, this paper briefly presents the author’s contribution in creating an immunohistochemical (IHC)-based molecular classification of CRC. It refers to the identification of three molecular groups of CRCs (epithelial, mesenchymal and hybrid) based on the IHC markers E-cadherin, β-catenin, maspin, and vimentin. Maspin is a novel IHC antibody helpful for tumor budding assessment, which role depends on its subcellular localization (cytoplasm vs. nuclei). The long road of updating the staging criteria for CRC has not come to an end. The newest prognostic biomarkers, aimed to be included in the molecular classifications, exert predictive roles, and become more and more important for targeted therapy decisions.
Comparative Ubiquitome Analysis Reveals Deubiquitinating Effects Induced by Wolbachia Infection in Drosophila melanogaster
Authors: Zong Qiong , Mao Bin , Zhang Hua-Bao , Wang Bing , Yu Wen-Juan , Wang Zhi-Wei , Wang Yu-Feng
Published: August 2022

The endosymbiotic Wolbachia bacteria frequently cause cytoplasmic incompatibility (CI) in their insect hosts, where Wolbachia-infected males cross with uninfected females, leading to no or fewer progenies, indicating a paternal modification by Wolbachia. Recent studies have identified a Wolbachia protein, CidB, containing a DUB (deubiquitylating enzyme) domain, which can be loaded into host sperm nuclei and involved in CI, though the DUB activity is not necessary for CI in Drosophila melanogaster. To investigate whether and how Wolbachia affect protein ubiquitination in testes of male hosts and are thus involved in male fertility, we compared the protein and ubiquitinated protein expressions in D. melanogaster testes with and without Wolbachia. A total of 643 differentially expressed proteins (DEPs) and 309 differentially expressed ubiquitinated proteins (DEUPs) were identified to have at least a 1.5-fold change with a p-value of <0.05. Many DEPs were enriched in metabolic pathway, ribosome, RNA transport, and post-translational protein modification pathways. Many DEUPs were involved in metabolism, ribosome, and proteasome pathways. Notably, 98.1% DEUPs were downregulated in the presence of Wolbachia. Four genes coding for DEUPs in ubiquitin proteasome pathways were knocked down, respectively, in Wolbachia-free fly testes. Among them, Rpn6 and Rpn7 knockdown caused male sterility, with no mature sperm in seminal vesicles. These results reveal deubiquitylating effects induced by Wolbachia infection, suggesting that Wolbachia can widely deubiquitinate proteins that have crucial functions in male fertility of their hosts, but are not involved in CI. Our data provide new insights into the regulatory mechanisms of endosymbiont/host interactions and male fertility.
Hydrogen Sulfide and Reactive Oxygen Species, Antioxidant Defense, Abiotic Stress Tolerance Mechanisms in Plants
Authors: Zhang Jing , Corpas Francisco J. , Li Jisheng , Xie Yanjie
Published: August 2022

Various stress conditions, such as drought, salt, heavy metals, and extreme temperatures, have severe deleterious effects on plant growth and directly lead to a decline in yield and quality [...]
Differences in Diurnal Rhythm of Rod Outer Segment Renewal between 129T2/SvEmsJ and C57BL/6J Mice
Authors: Vargas Jade A. , Finnemann Silvia C.
Published: August 2022

In all mammalian species tested to date, rod photoreceptor outer segment renewal is a circadian process synchronized by light with a burst of outer segment fragment (POS) shedding and POS phagocytosis by the adjacent retinal pigment epithelium (RPE) every morning at light onset. Recent reports show that RPE phagocytosis also increases shortly after dark onset in C57BL/6 (C57) mice. Genetic differences between C57 mice and 129T2/SvEmsJ (129) mice may affect regulation of outer segment renewal. Here, we used quantitative methods to directly compare outer segment renewal in C57 and 129 mouse retina. Quantification of rhodopsin-positive phagosomes in the RPE showed that in 129 mice, rod POS phagocytosis after light onset was significantly increased compared to C57 mice, but that 129 mice did not show a second peak after dark onset. Cone POS phagosome content of RPE cells did not differ by mouse strain with higher phagosome numbers after light than after dark. We further quantified externalization of the “eat me” signal phosphatidylserine by outer segment tips, which precedes POS phagocytosis. Live imaging of retina ex vivo showed that rod outer segments extended PS exposure in both strains but that frequency of outer segments with exposed PS after light onset was lower in C57 than in 129 retina. Taken together, 129 mice lacked a burst of rod outer segment renewal after dark onset. The increases in rod outer segment renewal after light and after dark onset in C57 mice were attenuated compared to the peak after light onset in 129 mice, suggesting an impairment in rhythmicity in C57 mice.
Hair Growth Regulation by Fibroblast Growth Factor 12 (FGF12)
Authors: Woo Jiwon , Suh Wonhee , Sung Jong-Hyuk
Published: August 2022

The fibroblast growth factor (FGF) family has various biological functions, including cell growth, tissue regeneration, embryonic development, metabolism, and angiogenesis. In the case of hair growth, several members of the FGF family, such as FGF1 and FGF2, are involved in hair growth, while FGF5 has the opposite effect. In this study, the regulation of the hair growth cycle by FGF12 was investigated. To observe its effect, the expression of FGF12 was downregulated in mice and outer root sheath (ORS) by siRNA transfection, while FGF12 overexpression was carried out using FGF12 adenovirus. For the results, FGF12 was primarily expressed in ORS cells with a high expression during the anagen phase of hair follicles. Knockdown of FGF12 delayed telogen-to-anagen transition in mice and decreased the hair length in vibrissae hair follicles. It also inhibited the proliferation and migration of ORS cells. On the contrary, FGF12 overexpression increased the migration of ORS cells. FGF12-overexpressed ORS cells induced the telogen-to-anagen transition in the animal model. In addition, FGF12 overexpression regulated the expression of PDGF-CC, MDK, and HB-EGF, and treatment of these factors exhibited hair growth promotion. Altogether, FGF12 promoted hair growth by inducing the anagen phase of hair follicles, suggesting the potential for hair loss therapy.