bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Mitochondrial Genome Fragmentation Pattern in the Buffalo Louse Haematopinus tuberculatus (Psocodea: Haematopinidae)
Authors: Fu Yi-Tian , Suleman  , Yao Chaoqun , Wang Hui-Mei , Wang Wei , Liu Guo-Hua
Published: October 2022

Sucking lice are obligate ectoparasites of mammalian hosts, causing serious public health problems and economic losses worldwide. It is well known that sucking lice have fragmented mitochondrial (mt) genomes, but many remain undetermined. To better understand patterns of mt genome fragmentation in the sucking lice, we sequenced the mt genome of the buffalo louse Haematopinus tuberculatus using next-generation sequencing (NGS). The mt genome of H. tuberculatus has ten circular minichromosomes containing a total of 37 genes. Each minichromosome is 2.9–5.0 kb long and carries one to eight genes plus one large non-coding region. The number of mt minichromosomes of H. tuberculatus (ten) is different from those of congeneric species (horse louse H. asini, domestic pig louse H. suis and wild pig louse H. apri) and other sucking lice. Two events (gene translocation and merger of mt minichromosome) are observed in Haematopinus. Compared to other studies, our phylogeny generated from mt genome datasets showed a different topology, suggesting that inclusion of data other than mt genomes would be required to resolve phylogeny of sucking lice. To our knowledge, this is the first report of a ten mt minichromosomes genome in sucking lice, which opens a new outlook into unexplored mt genome fragmentation patterns in sucking lice.
Magnesium Isoglycyrrhizinate Reduces the Target-Binding Amount of Cisplatin to Mitochondrial DNA and Renal Injury through SIRT3
Authors: Wang Xinyu , Zhu Hutailong , Hu Jiayin , Li Haobin , Guo Suhan , Chen Bin , Liu Changxiao , Wang Guangji , Zhou Fang
Published: October 2022

Nephrotoxicity is the dose-limiting factor of cisplatin treatment. Magnesium isoglycyrrhizinate (MgIG) has been reported to ameliorate renal ischemia–reperfusion injury. This study aimed to investigate the protective effect and possible mechanisms of MgIG against cisplatin-induced nephrotoxicity from the perspective of cellular pharmacokinetics. We found that cisplatin predominantly accumulated in mitochondria of renal tubular epithelial cells, and the amount of binding with mitochondrial DNA (mtDNA) was more than twice that with nuclear DNA (nDNA). MgIG significantly lowered the accumulation of cisplatin in mitochondria and, in particular, the degree of target-binding to mtDNA. MgIG notably ameliorated cisplatin-induced changes in mitochondrial membrane potential, morphology, function, and cell viability, while the magnesium donor drugs failed to work. In a mouse model, MgIG significantly alleviated cisplatin-caused renal dysfunction, pathological changes of renal tubules, mitochondrial ultrastructure variations, and disturbed energy metabolism. Both in vitro and in vivo data showed that MgIG recovered the reduction of NAD+-related substances and NAD+-dependent deacetylase sirtuin-3 (SIRT3) level caused by cisplatin. Furthermore, SIRT3 knockdown weakened the protective effect of MgIG on mitochondria, while SIRT3 agonist protected HK-2 cells from cisplatin and specifically reduced platinum-binding activity with mtDNA. In conclusion, MgIG reduces the target-binding amount of platinum to mtDNA and exerts a protective effect on cisplatin-induced renal injury through SIRT3, which may provide a new strategy for the treatment of cisplatin-induced nephrotoxicity.
Increase in Cd Tolerance through Seed-Borne Endophytic Fungus Epichloë gansuensis Affected Root Exudates and Rhizosphere Bacterial Community of Achnatherum inebrians
Authors: Jin Jie , Huang Rong , Wang Jianfeng , Wang Chao , Liu Ronggui , Zhang Hanwen , Deng Maohua , Li Shicai , Li Xinglu , Tang Rong , Li Chunjie
Published: October 2022

Soil cadmium (Cd) pollution is a serious environmental problem imperiling food safety and human health. The endophyte Epichloë gansuensis can improve the tolerance of Achnatherum inebrians to Cd stress. However, it is still unknown whether and how the endophyte helps host plants build up a specific bacterial community when challenged by CdCl2. In this study, the responses of the structure and function of bacterial community and root exudates of E+ (E. gansuensis infected) and E− (E. gansuensis uninfected) plants to Cd stress were investigated. Analysis of bacterial community structure indicated that the rhizosphere bacterial community predominated over the root endosphere bacterial community in enhancing the resistance of CdCl2 in a host mediated by E. gansuensis. E+ plant strengthened the interspecific cooperation of rhizosphere bacterial species. Moreover, the analysis of root exudates demonstrated E. gansuensis and increased the contents of organic acids and amino acids under Cd stress, and most root exudates were significantly correlated with rhizosphere bacteria. These results suggested that E. gansuensis employed a specific strategy to recruit distinct rhizosphere bacterial species and relevant functions by affecting root exudates to improve the tolerance of the host to Cd stress. This study provides a firm foundation for the potential application of symbionts in improving phytostabilization efficiency.
Induced Pluripotent Stem Cell (iPSC) Lines from a Family with Resistant Epileptic Encephalopathy Caused by Compound Heterozygous Mutations in SZT2 Gene
Authors: Cattelani Cecilia , Battistella Ingrid , Di Leva Francesca , Fioravanti Giulia , Benedicenti Francesco , Stanzial Franco , Schwienbacher Christine , Fanelli Francesca , Pramstaller Peter P. , Hicks Andrew A. , Conti Luciano , Corti Corrado
Published: October 2022

Mutations in the SZT2 gene have been associated with developmental and epileptic encephalopathy-18, a rare severe autosomal recessive neurologic disorder, characterized by psychomotor impairment/intellectual disability, dysmorphic facial features and early onset of refractory seizures. Here we report the generation of the first induced pluripotent stem cell (iPSC) lines from a patient with treatment-resistant epilepsy, carrying compound heterozygous mutations in SZT2 (Mut1: c.498G>T and Mut2: c.6553C>T), and his healthy heterozygous parents. Peripheral blood mononuclear cells were reprogrammed by a non-integrating Sendai virus-based reprogramming system. The generated human iPSC lines exhibited expression of the main pluripotency markers, the potential to differentiate into all three germ layers and presented a normal karyotype. These lines represent a valuable resource to study neurodevelopmental alterations, and to obtain mature, pathology-relevant neuronal populations as an in vitro model to perform functional assays and test the patient’s responsiveness to novel antiepileptic treatments.
Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo
Authors: Stern Noa , Gacs Alexandra , Tátrai Enikő , Flachner Beáta , Hajdú István , Dobi Krisztina , Bágyi István , Dormán György , Lőrincz Zsolt , Cseh Sándor , Kígyós Attila , Tóvári József , Goldblum Amiram
Published: October 2022

Alzheimer’s disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Aβ) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (β-secretase) and AChE (acetylcholinesterase) by a single inhibitor may be an effective therapeutic approach, as compared to blocking one of these targets or by combining two drugs, one for each of these targets. We used our ISE algorithm to model each of the AChE peripheral site inhibitors and BACE-1 inhibitors, on the basis of published data, and constructed classification models for each. Subsequently, we screened large molecular databases with both models. Top scored molecules were docked into AChE and BACE-1 crystal structures, and 36 Molecules with the best weighted scores (based on ISE indexes and docking results) were sent for inhibition studies on the two enzymes. Two of them inhibited both AChE (IC50 between 4–7 μM) and BACE-1 (IC50 between 50–65 μM). Two additional molecules inhibited only AChE, and another two molecules inhibited only BACE-1. Preliminary testing of inhibition by F681-0222 (molecule 2) on APPswe/PS1dE9 transgenic mice shows a reduction in brain tissue of soluble Aβ42.
The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1
Authors: Eisner Helgit , Riegler-Berket Lina , Gamez Carlos Francisco Rodriguez , Sagmeister Theo , Chalhoub Gabriel , Darnhofer Barbara , Jazleena P J , Birner-Gruenberger Ruth , Pavkov-Keller Tea , Haemmerle Guenter , Schoiswohl Gabriele , Oberer Monika
Published: October 2022

Members of the carboxylesterase 2 (Ces2/CES2) family have been studied intensively with respect to their hydrolytic function on (pro)drugs, whereas their physiological role in lipid and energy metabolism has been realized only within the last few years. Humans have one CES2 gene which is highly expressed in liver, intestine, and kidney. Interestingly, eight homologous Ces2 (Ces2a to Ces2h) genes exist in mice and the individual roles of the corresponding proteins are incompletely understood. Mouse Ces2c (mCes2c) is suggested as potential ortholog of human CES2. Therefore, we aimed at its structural and biophysical characterization. Here, we present the first crystal structure of mCes2c to 2.12 Å resolution. The overall structure of mCes2c resembles that of the human CES1 (hCES1). The core domain adopts an α/β hydrolase-fold with S230, E347, and H459 forming a catalytic triad. Access to the active site is restricted by the cap, the flexible lid, and the regulatory domain. The conserved gate (M417) and switch (F418) residues might have a function in product release similar as suggested for hCES1. Biophysical characterization confirms that mCes2c is a monomer in solution. Thus, this study broadens our understanding of the mammalian carboxylesterase family and assists in delineating the similarities and differences of the different family members.
The NLRP3-Inflammasome in Health and Disease
Authors: Perri Anna
Published: October 2022

The nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3, NLRP3, is a multiprotein complex belonging to the innate immune system that can be activated by pathogens or danger-associated molecular patterns [...]
Anti-HSV Activity of Metallic Nanoparticles Functionalized with Sulfonates vs. Polyphenols
Authors: Tomaszewska Emilia , Ranoszek-Soliwoda Katarzyna , Bednarczyk Katarzyna , Lech Agnieszka , Janicka Martyna , Chodkowski Marcin , Psarski Maciej , Celichowski Grzegorz , Krzyzowska Malgorzata , Grobelny Jarosław
Published: October 2022

Metallic nanoparticles exhibit broad-spectrum activity against bacteria, fungi, and viruses. The antiviral activity of nanoparticles results from the multivalent interactions of nanoparticles with viral surface components, which result from the nanometer size of the material and the presence of functional compounds adsorbed on the nanomaterial surface. A critical step in the virus infection process is docking and entry of the virus into the host cell. This stage of the infection can be influenced by functional nanomaterials that exhibit high affinity to the virus surface and hence can disrupt the infection process. The affinity of the virus to the nanomaterial surface can be tuned by the specific surface functionalization of the nanomaterial. The main purpose of this work was to determine the influence of the ligand type present on nanomaterial on the antiviral properties against herpes simplex virus type 1 and 2. We investigated the metallic nanoparticles (gold and silver) with different sizes (5 nm and 30 nm), coated either with polyphenol (tannic acid) or sulfonates (ligands with terminated sulfonate groups). We found that the antiviral activity of nano-conjugates depends significantly on the ligand type present on the nanoparticle surface.
Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke
Authors: Monsour Molly , Gordon Jonah , Lockard Gavin , Alayli Adam , Elsayed Bassel , Connolly Jacob , Borlongan Cesar V.
Published: October 2022

Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.
Hybrid Gold Nanorod-Based Nanoplatform with Chemo and Photothermal Activities for Bimodal Cancer Therapy
Authors: Arellano-Galindo Lilia , Villar-Alvarez Eva , Varela Alejandro , Figueroa Valeria , Fernandez-Vega Javier , Cambón Adriana , Prieto Gerardo , Barbosa Silvia , Taboada Pablo
Published: October 2022

Metal nanoparticles (NPs), particularly gold nanorods (AuNRs), appear as excellent platforms not only to transport and deliver bioactive cargoes but also to provide additional therapeutic responses for diseased cells and tissues and/or to complement the action of the carried molecules. In this manner, here, we optimized a previous developed metal-based nanoplatform composed of an AuNR core surrounded by a polymeric shell constructed by means of the layer-by-layer approach, and in which very large amounts of the antineoplasic drug doxorubicin (DOXO) in a single loading step and targeting capability thanks to an outer hyaluronic acid layer were incorporated by means of an optimized fabrication process (PSS/DOXO/PLL/HA-coated AuNRs). The platform retained its nanometer size with a negative surface charge and was colloidally stable in a range of physiological conditions, in which only in some of them some particle clustering was noted with no precipitation. In addition, the dual stimuli-responsiveness of the designed nanoplatform to both endogenous proteases and external applied light stimuli allows to perfectly manipulate the chemodrug release rates and profiles to achieve suitable pharmacodynamics. It was observed that the inherent active targeting abilities of the nanoplatfom allow the achievement of specific cell toxicity in tumoral cervical HeLa cells, whilst healthy ones such as 3T3-Balb fibroblast remain safe and alive in agreement with the detected levels of internalization in each cell line. In addition, the bimodal action of simultaneous chemo- and photothermal bioactivity provided by the platform largely enhances the therapeutic outcomes. Finally, it was observed that our PSS/DOXO/PLL/HA-coated AuNRs induced cell mortality mainly through apoptosis in HeLa cells even in the presence of NIR light irradiation, which agrees with the idea of the chemo-activity of DOXO predominating over the photothermal effect to induce cell death, favoring an apoptotic pathway over necrosis for cell death.
Corneal Epithelial Regeneration: Old and New Perspectives
Authors: Nuzzi Alessia , Pozzo Giuffrida Francesco , Luccarelli Saverio , Nucci Paolo
Published: October 2022

Corneal blindness is the fifth leading cause of blindness worldwide, and therapeutic options are still often limited to corneal transplantation. The corneal epithelium has a strong barrier function, and regeneration is highly dependent on limbal stem cell proliferation and basement membrane remodeling. As a result of the lack of corneal donor tissues, regenerative medicine for corneal diseases affecting the epithelium is an area with quite advanced basic and clinical research. Surgery still plays a prominent role in the treatment of epithelial diseases; indeed, innovative surgical techniques have been developed to transplant corneal and non-corneal stem cells onto diseased corneas for epithelial regeneration applications. The main goal of applying regenerative medicine to clinical practice is to restore function by providing viable cells based on the use of a novel therapeutic approach to generate biological substitutes and improve tissue functions. Interest in corneal epithelium rehabilitation medicine is rapidly growing, given the exposure of the corneal outer layers to external insults. Here, we performed a review of basic, clinical and surgical research reports on regenerative medicine for corneal epithelial disorders, classifying therapeutic approaches according to their macro- or microscopic target, i.e., into cellular or subcellular therapies, respectively.
Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study
Authors: Mercer Audrey , Jaunmuktane Zane , Hristova Mariya , Lange Sigrun
Published: October 2022

Over 10 million people worldwide live with Parkinson’s disease (PD) and 4% of affected people are diagnosed before the age of 50. Research on early PD-related pathways is therefore of considerable importance. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that, through post-translational deimination of arginine to citrulline, contribute to changes in protein function, including in pathological processes. Recent studies have highlighted roles for PADs in a range of neurological disorders including PD, but overall, investigations on PADs in Lewy body disease (LBD), including PD, are still scarce. Hence, the current pilot study aimed at performing an immunohistochemistry screen of post-mortem human brain sections from Braak stages 4-6 from PD patients, as well as patients with incidental LBD (ILBD). We assessed differences in PAD isozyme detection (assessing all five PADs), in total protein deimination/citrullination and histone H3 deimination—which is an indicator of epigenetic changes and extracellular trap formation (ETosis), which can elicit immune responses and has involvement in pathogenic conditions. The findings of our pilot study indicate that PADs and deimination are increased in cingulate cortex and hippocampus, particularly in earlier stages of the disease. PAD2 and PAD3 were the most strongly upregulated PAD isozymes, with some elevation also observed for PAD1, while PAD4 and PAD6 increase was less marked in PD brains. Total protein deimination and histone H3 deimination were furthermore increased in PD brains, with a considerable increase at earlier Braak stages, compared with controls. Our findings point to a significant contribution of PADs, which may further aid early disease biomarker discovery, in PD and other LBDs.
Cellular Stress Assay in Peripheral Blood Mononuclear Cells: Factors Influencing Its Results
Authors: Tessema Belay , Riemer Janine , Sack Ulrich , König Brigitte
Published: October 2022

Cellular stress is central to the understanding of pathological mechanisms and the development of new therapeutic strategies and serves as a biomarker for disease progression in neurodegeneration, diabetes, cancer, cardiovascular and other chronic diseases. The common cellular stress assay (CSA) based on Seahorse technology in peripheral blood mononuclear cells (PBMCs) shows inconsistent results, which prevents its use as a biomarker for the progression of chronic diseases. Therefore, the aim of this study was to investigate potential factors that affect the CSA in PBMCs. We measured the CSA parameters in PBMCs from study participants and compared the results according to the potential factors, namely, the PBMC isolation method, age, seasonal variation and the gender of the study participants. PBMCs were isolated by OptiPrep® and RobosepTM-S methods. PBMCs isolated with the OptiPrep method showed much higher extracellular acidification and higher respiration compared to Robosep-isolated cells. Moreover, OptiPrep-isolated cells showed a higher number of outliers for the proton production rate (PPR) and a high respiratory quotient, indicating impurities with other cells, such as platelets, and technical inconsistencies. PBMCs from older individuals showed higher maximal respiration, spare capacity and extracellular acidification than younger participants. Additionally, in winter, maximal respiration and spare capacity decreased. From spring until early autumn, spare capacity and maximal respiration continuously increased. Elderly males also showed higher basal respiration, spare capacity and extracellular acidification than females. In conclusion, the findings of this study clearly demonstrate that the results of CSA parameters measured in PBMCs are influenced by the PBMC isolation method, age, seasonal variation and gender. Therefore, we recommend that researchers and physicians properly interpret the results of CSA parameters in PBMCs by considering these factors. It is important to use separate CSA evaluation standards based on the isolation method, age, gender and season-dependent factors. To assess the cellular stress situation in PBMCs, both extracellular acidification and mitochondrial respiration should be taken into account. Further study of additional factors, such as mitochondrial mass, should be conducted to improve the measurement of CSA parameters for the assessment of the real mitochondrial fitness.
Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease
Authors: Greenfield Susan Adele , Ferrati Giovanni , Coen Clive W. , Vadisiute Auguste , Molnár Zoltan , Garcia-Rates Sara , Frautschy Sally , Cole Gregory M.
Published: October 2022

The substantia nigra is generally considered to show significant cell loss not only in Parkinson’s but also in Alzheimer’s disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer’s pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.
Circulating Soluble TREM2 and Cardiovascular Outcome in Cohort Study of Coronary Atherosclerosis Patients
Authors: Cuciuc Valeri , Tshori Sagi , Grib Livi , Sella Gal , Tuvali Ortal , Volodarsky Igor , Welt Michael , Fassler Michael , Shimoni Sara , George Jacob
Published: October 2022

Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a membrane receptor in myeloid cells that mediates cellular phagocytosis and inflammation. TREM2 and its soluble extracellular domain are clearly implicated in neuroinflammation and neurodegeneration. sTREM2 is also expressed in atherosclerotic macrophages. We hypothesized that sTREM2 would predict cardiovascular mortality in patients with established coronary atherosclerosis (CAD). Consecutive patients undergoing coronary angiography with the establishment of the diagnosis of CAD (n = 230) and without CAD (n = 53) were tested for their baseline serum sTREM2 levels. All patients were followed up for 84 months or until death occurred. sTREM2 correlated with age; however, no association was found between sTREM2 and the number of atherosclerotic vessels involved (p = 0.642). After 84 months of follow-up, 68 out of the 230 CAD patients had died. After adjusting for age and other risk factors, the adjusted hazard ratio for the highest quartile of sTREM2 was 2.37 (95% confidence interval 1.17–4.83) for death. In patients with established CAD, serum sTREM2 appears to predict cardiovascular death as a potential surrogate for plaque rupture. TREM2 and its soluble extracellular form might be implicated in the fate of the atherosclerotic plaque, but corroboration within larger studies is needed.
Antifibrotic TSG-6 Expression Is Synergistically Increased in Both Cells during Coculture of Mesenchymal Stem Cells and Macrophages via the JAK/STAT Signaling Pathway
Authors: Gong Seong Chan , Yoon Yongdae , Jung Pil Young , Kim Moon Young , Baik Soon Koo , Ryu Hoon , Eom Young Woo
Published: October 2022

The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β upregulate TNF-α-stimulated gene 6 (TSG-6); however, current knowledge about the optimal conditions for TSG-6 expression in mesenchymal stem cells (MSCs) is limited. Here, we investigated whether TSG-6 expression varies depending on the polarization state of macrophages co-cultured with adipose tissue-derived stem cells (ASCs) and analyzed the optimal conditions for TSG-6 expression in ASCs. TSG-6 expression increased in ASCs co-cultured with M0, M1, and M2 macrophages indirectly; among them, M1 macrophages resulted in the highest increase in TSG-6 expression in ASCs. TSG-6 expression in ASCs dramatically increased by combination (but not single) treatment of TNF-α, IL-1β, interferon-gamma (IFN-γ), and lipopolysaccharide (LPS). In addition, phosphorylation of signal transducer and activator of transcription (STAT) 1/3 was observed in response to IFN-γ and LPS treatment but not TNF-α and/or IL-1β. STAT1/3 activation synergistically increased TNF-α/IL-1β-dependent TSG-6 expression, and JAK inhibitors suppressed TSG-6 expression both in ASCs and macrophages. In LX-2 hepatic stellate cells, TSG-6 inhibited TGF-β-induced Smad3 phosphorylation, resulting in decreased α-smooth muscle actin (SMA) expression. Moreover, fibrotic activities of LX-2 cells induced by TGF-β were dramatically decreased after indirect co-culture with ASCs and M1 macrophages. These results suggest that a comprehensive inflammatory microenvironment may play an important role in determining the therapeutic properties of ASCs by increasing TSG-6 expression through STAT1/3 activation.
Changes in CoQ10/Lipids Ratio, Oxidative Stress, and Coenzyme Q10 during First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma (mUC)
Authors: Palacka Patrik , Kucharská Jarmila , Obertová Jana , Rejleková Katarína , Slopovský Ján , Mego Michal , Světlovská Daniela , Kollárik Boris , Mardiak Jozef , Gvozdjáková Anna
Published: October 2022

Oxidative stress plays an important role in cancer pathogenesis, and thiobarbituric acid-reactive substance level (TBARS)—a parameter of lipid peroxidation—has prognostic significance in chemotherapy-naive patients with metastatic urothelial carcinoma (mUC). However, the effect of cisplatin (CDDP)-based chemotherapy on oxidative stress, coenzyme Q10, and antioxidants remains unknown. The objective of this prospective study was to determine possible changes in the CoQ10 (coenzyme Q10)/lipids ratio, antioxidants (α-tocopherol, γ-tocopherol, β-carotene, CoQ10), total antioxidant status (TAS), and TBARS in plasma at baseline and during first-line chemotherapy based on CDDP in mUC subjects. In this prospective study, 63 consecutive patients were enrolled. The median age was 66 years (range 39–84), performance status according to the Eastern Cooperative Oncology Group (ECOG) was 2 in 7 subjects (11.1%), and visceral metastases were present in 31 (49.2%) patients. Plasma antioxidants were determined by HPLC and TAS and TBARS spectrophotometrically. After two courses of chemotherapy, we recorded significant enhancements compared to baseline for total cholesterol (p < 0.0216), very low-density lipoprotein (VLDL) cholesterol (p < 0.002), triacylglycerols (p < 0.0083), α-tocopherol (p < 0.0044), and coenzyme Q10-TOTAL (p < 0.0001). Ratios of CoQ10/total cholesterol, CoQ10/HDL-cholesterol, and CoQ10/LDL-cholesterol increased during chemotherapy vs. baseline (p < 0.0048, p < 0.0101, p < 0.0032, respectively), while plasma TBARS declined (p < 0.0004). The stimulation of antioxidants could be part of the defense mechanism during CDDP treatment. The increased index of CoQ10-TOTAL/lipids could reflect the effect of CDDP protecting lipoproteins from peroxidation.
NGF and the Male Reproductive System: Potential Clinical Applications in Infertility
Authors: Ferraguti Giampiero , Fanfarillo Francesca , Tarani Luigi , Blaconà Giovanna , Tarani Francesca , Barbato Christian , Minni Antonio , Ralli Massimo , Francati Silvia , Greco Antonio , Petrella Carla , Fiore Marco
Published: October 2022

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. In recent studies, the potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p–ERK1/2/p–CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus–pituitary–gonadal axis (HPG) with the secretion of GnRH. Lastly, it has been shown that the physiology of mature sperm is affected by both exogenous and endogenous NGF. The NGF impact on the HPG axis and its effect on GnRH neurons might be exploited in the therapy of male hypogonadism or used as a protective strategy against gonadal dysfunction related to chemotherapeutic agents. Moreover, the improving effect of NGF on sperm motility and vitality could be useful to enhance assisted reproduction outcomes. NGF could be supplemented to cryopreserved sperm samples to counteract the oxidative stress induced by the frozen and thawing processes. Indeed, the potential clinical applications of NGF in male infertility treatment have been discussed.
Insights behind the Relationship between Colorectal Cancer and Obesity: Is Visceral Adipose Tissue the Missing Link?
Authors: Chaplin Alice , Rodriguez Ramon Maria , Segura-Sampedro Juan José , Ochogavía-Seguí Aina , Romaguera Dora , Barceló-Coblijn Gwendolyn
Published: October 2022

Colorectal cancer (CRC) is a major health problem worldwide, with an estimated 1.9 million new cases and 915,880 deaths in 2020 alone. The etiology of CRC is complex and involves both genetic and lifestyle factors. Obesity is a major risk factor for CRC, and the mechanisms underlying this link are still unclear. However, the generalized inflammatory state of adipose tissue in obesity is thought to play a role in the association between CRC risk and development. Visceral adipose tissue (VAT) is a major source of proinflammatory cytokines and other factors that contribute to the characteristic systemic low-grade inflammation associated with obesity. VAT is also closely associated with the tumor microenvironment (TME), and recent evidence suggests that adipocytes within the TME undergo phenotypic changes that contribute to tumor progression. In this review, we aim to summarize the current evidence linking obesity and CRC, with a focus on the role of VAT in tumor etiology and progression.
Integrative Genomic Tests in Clinical Oncology
Authors: Imyanitov Evgeny , Sokolenko Anna
Published: October 2022

Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related “genomic scars” are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.
Benzoylpaeoniflorin Activates Anti-Inflammatory Mechanisms to Mitigate Sepsis in Cell-Culture and Mouse Sepsis Models
Authors: Kim Chaeyeong , Sim Hyunchae , Bae Jong-Sup
Published: October 2022

Xuebijing injection (XBJI) (comprising of five herbs) is a widely used traditional Chinese medicine for sepsis treatment. However, the bioactive components of XBJI and the mechanisms responsible for its sepsis-mitigating action have not been experimentally determined. One of the main bioactive compounds in XBJI—benzoylpaeoniflorin (BPF)—inhibits the expressions of key mediators of inflammation such as nuclear factor kappa B (NF-κB), cyclooxygenase-1 (COX-1), and COX-2. However, its effects on sepsis have not been determined yet. Therefore, here, we investigated the immunomodulatory effect of BPF on severely inflamed endothelial cells, THP-1 macrophages, peritoneal macrophages, and mice. Human umbilical vein endothelial cells (HUVECs) and THP-1-macrophages were activated using lipopolysaccharide (LPS) after pretreatment with BPF. Subsequently, changes in the expression profiles of pro-inflammatory molecules including inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were determined using quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis. Furthermore, we monitored the phosphorylation of NF-kB and mitogen-activated protein kinases (MAPKs) to determine their activation levels. Using the LPS-induced mouse model of sepsis, we studied the effects of BPF on inflammatory cytokine production, pulmonary histopathology, and survival rates. Finally, we evaluated whether BPF protects against cecal ligation and puncture (CLP)-induced sepsis, as it closely mimics human sepsis. BPF pretreatment inhibited LPS-induced increase in mRNA and protein levels of iNOS, TNF-α, and IL-6 in HUVECs and THP-1-macrophages. It also suppressed LPS-mediated phosphorylation of p65, p38, JNK, and ERK. Mice with LPS-induced-sepsis who were treated with BPF had lower serum levels of IL-6, TNF-α, IL-1β, CXCL1, and CXCL2 than the control mice treated with BPF. Histopathology revealed that BPF treatment alleviated LPS-induced lung damage. In addition, in mice given a lethal dose of LPS, BPF treatment showed a dose-dependent improvement in survival rates. BPF treatment dose-dependently inhibited the LPS-induced IL-6, TNF-α, and CXCL1 production in peritoneal macrophages. BPF treatment also dose-dependently improved the survival rates in mice with CLP-induced sepsis. These results show that BPF alleviates LPS-stimulated septic conditions and protects mice from CLP-induced sepsis. Our research marks BPF as a potential drug in the treatment of sepsis and various inflammatory diseases.
Molecular Characterization, Expression, Evolutionary Selection, and Biological Activity Analysis of CD68 Gene from Megalobrama amblycephala
Authors: Cui Hujun , Li Hong , Zhang Minying , Li Hongping , Wang Xu , Wang Zirui , Zhai Wei , Chen Xiangning , Cheng Hanliang , Xu Jianhe , Zhao Xiaoheng , Ding Zhujin
Published: October 2022

CD68 is a highly glycosylated transmembrane glycoprotein that belongs to the lysosome-associated membrane glycoprotein family and is involved in various immune processes. In this study, Megalobrama amblycephala CD68 (MaCD68) was cloned and characterized, and its expression patterns and evolutionary characteristics were analyzed. The coding region of MaCD68 was 987 bp, encoding 328 amino acids, and the predicted protein molecular weight was 34.9 kDa. MaCD68 contained two transmembrane helical structures and 18 predicted N-glycosylation sites. Multiple sequence alignments showed that the MaCD68 protein had high homology with other fish, and their functional sites were also highly conserved. Phylogenetic analysis revealed that MaCD68 and other cypriniformes fish clustered into one branch. Adaptive evolution analysis identified several positively selected sites of teleost CD68 using site and branch-site models, indicating that it was under positive selection pressure during evolution. Quantitative real-time reverse transcription polymerase chain reaction analysis showed that MaCD68 was highly expressed in the head kidney, spleen, and heart. After Aeromonas hydrophila infection, MaCD68 was significantly upregulated in all tested tissues, peaking at 12 h post-infection (hpi) in the kidney and head kidney and at 120 hpi in the liver and spleen, suggesting that MaCD68 participated in the innate immune response of the host against bacterial infection. Immunohistochemical and immunofluorescence analyses also showed that positive signals derived from the MaCD68 protein were further enhanced after bacterial and lipopolysaccharide treatment, which suggested that MaCD68 is involved in the immune response and could be used as a macrophage marker. Biological activity analysis indicated that recombinant MaCD68 (rMaCD68) protein had no agglutination or bactericidal effects on A. hydrophila but did have these effects on Escherichia coli. In conclusion, these results suggest that MaCD68 plays a vital role in the immune response against pathogens, which is helpful in understanding the immune responses and mechanisms of M. amblycephala.
4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design
Authors: Roszczenko Piotr , Holota Serhii , Szewczyk Olga Klaudia , Dudchak Rostyslav , Bielawski Krzysztof , Bielawska Anna , Lesyk Roman
Published: October 2022

Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017–2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.
Changes in Ovulation-Related Gene Expression during Induced Ovulation in the Amur Sturgeon (Acipenser schrenckii) Ovarian Follicles
Authors: Surugaya Ryohei , Hasegawa Yuya , Adachi Shinji , Ijiri Shigeho
Published: October 2022

The luteinizing hormone (LH) and maturation-inducing steroids (MIS), such as 17α,20β-dihydroxy-4-pregnen-3-one, regulate the final oocyte maturation in teleosts. Oocyte maturational competence (OMC) and ovulatory competence measure the sensitivity to MIS for oocyte maturation and ovulation, respectively. However, the molecular mechanisms underlying the acquisition of ovulatory competence remain unknown. Sturgeons are an excellent research model for investigating these mechanisms. We examined the seasonal profiles of OMC and ovulatory competence in vitro and the expression of 17 ovulation-related gene candidates using quantitative PCR in Amur sturgeon ovarian follicles. The ovulatory competence was induced by the LH-releasing hormone analog (LHRHa) priming injection after acquiring the OMC, which was spontaneously induced in spring or autumn. Seven genes, including the tissue-type plasminogen activator (plat), were enhanced following the LHRHa priming injection in ovarian follicles sampled from anovulated and ovulated fish. The activin receptor type 1 (acvr1) and prostaglandin G/H synthase 2 (ptgs2) were only upregulated in ovulated fish. Our results suggest that plat/plasmin and prostaglandin (PG)/PG receptor systems are essential for sturgeon ovulation, similar to other vertebrates. Notably, successful ovulation depends on a sufficient PG synthesis, and mediators activating the PG/PG receptor system are essential for acquiring the ovulatory competence. We provide the first report of ovulation-related gene alterations in the ovarian follicles of Amur sturgeons.
Involvement of Hypoxia-Inducible Factor 1-α in Experimental Testicular Ischemia and Reperfusion: Effects of Polydeoxyribonucleotide and Selenium
Authors: Antonuccio Pietro , Pallio Giovanni , Marini Herbert Ryan , Irrera Natasha , Romeo Carmelo , Puzzolo Domenico , Freni Jose , Santoro Giuseppe , Pirrotta Igor , Squadrito Francesco , Minutoli Letteria , Micali Antonio
Published: October 2022

Polydeoxyribonucleotide (PDRN) is an agonist of the A2A adenosine receptor derived from salmon trout sperm. Selenium (Se) is a trace element normally present in the diet. We aimed to investigate the long-term role of PDRN and Se, alone or in association, after ischemia-reperfusion (I/R) in rats. The animals underwent 1 h testicular ischemia followed by 30 days of reperfusion or a sham I/R and were treated with PDRN or Se alone or in association for 30 days. I/R significantly increased hypoxia-inducible factor 1-α (HIF-1α) in Leydig cells, malondialdehyde (MDA), phosphorylated extracellular signal-regulated kinases 1/2 (pErk 1/2), and apoptosis decreased testis weight, glutathione (GSH), testosterone, nuclear factor erythroid 2-related factor 2 (Nrf2), induced testicular structural changes, and eliminated HIF-1α spermatozoa positivity. The treatment with either PDRN or Se significantly decreased MDA, apoptosis, and HIF-1α positivity of Leydig cells, increased testis weight, GSH, testosterone, and Nrf2, and improved the structural organization of the testes. PDRN and Se association showed a higher protective effect on all biochemical, structural, and immunohistochemical parameters. Our data suggest that HIF-1α could play important roles in late testis I/R and that this transcriptional factor could be modulated by PDRN and Se association, which, together with surgery, could be considered a tool to improve varicocele-induced damages.
Red and Blue Light Differently Influence Actinidia chinensis Performance and Its Interaction with Pseudomonas syringae pv. Actinidiae
Authors: Correia Cristiana , Magnani Federico , Pastore Chiara , Cellini Antonio , Donati Irene , Pennisi Giuseppina , Paucek Ivan , Orsini Francesco , Vandelle Elodie , Santos Conceição , Spinelli Francesco
Published: October 2022

Light composition modulates plant growth and defenses, thus influencing plant–pathogen interactions. We investigated the effects of different light-emitting diode (LED) red (R) (665 nm) and blue (B) (470 nm) light combinations on Actinidia chinensis performance by evaluating biometric parameters, chlorophyll a fluorescence, gas exchange and photosynthesis-related gene expression. Moreover, the influence of light on the infection by Pseudomonas syringae pv. actinidiae (Psa), the etiological agent of bacterial canker of kiwifruit, was investigated. Our study shows that 50%R–50%B (50R) and 25%R–75%B (25R) lead to the highest PSII efficiency and photosynthetic rate, but are the least effective in controlling the endophytic colonization of the host by Psa. Monochromatic red light severely reduced ΦPSII, ETR, Pn, TSS and photosynthesis-related genes expression, and both monochromatic lights lead to a reduction of DW and pigments content. Monochromatic blue light was the only treatment significantly reducing disease symptoms but did not reduce bacterial endophytic population. Our results suggest that monochromatic blue light reduces infection primarily by modulating Psa virulence more than host plant defenses.
Recent Advances in the Synthesis, Characterization, and Application of Carbon Nanomaterials for the Removal of Endocrine-Disrupting Chemicals: A Review
Authors: Liao Ze , Zi Yang , Zhou Chunyan , Zeng Wenqian , Luo Wenwen , Zeng Hui , Xia Muqing , Luo Zhoufei
Published: October 2022

The large-scale production and frequent use of endocrine-disrupting chemicals (EDCs) have led to the continuous release and wide distribution of these pollutions in the natural environment. At low levels, EDC exposure may cause metabolic disorders, sexual development, and reproductive disorders in aquatic animals and humans. Adsorption treatment, particularly using nanocomposites, may represent a promising and sustainable method for EDC removal from wastewater. EDCs could be effectively removed from wastewater using various carbon-based nanomaterials, such as carbon nanofiber, carbon nanotubes, graphene, magnetic carbon nanomaterials, carbon membranes, carbon dots, carbon sponges, etc. Important applications of carbon nanocomposites for the removal of different kinds of EDCs and the theory of adsorption are discussed, as well as recent advances in carbon nanocomposite synthesis technology and characterization technology. Furthermore, the factors affecting the use of carbon nanocomposites and comparisons with other adsorbents for EDC removal are reviewed. This review is significant because it helps to promote the development of nanocomposites for the decontamination of wastewater.