bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Metabolomics Discovers Two Novel Biomarkers in Pyridoxine-Dependent Epilepsy Caused by ALDH7A1 Deficiency
Authors: Böhm Hans-Otto , Yazdani Mazyar , Sandås Elise Mørk , Østeby Vassli Anja , Kristensen Erle , Rootwelt Helge , Skogvold Hanne Bendiksen , Brodtkorb Eylert , Elgstøen Katja Benedikte Prestø
Published: December 2022

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive developmental and epileptic encephalopathy caused by pathogenic variants in the ALDH7A1 gene (PDE-ALDH7A1), which mainly has its onset in neonates and infants. Early diagnosis and treatment are crucial to prevent severe neurological sequelae or death. Sensitive, specific, and stable biomarkers for diagnostic evaluations and follow-up examinations are essential to optimize outcomes. However, most of the known biomarkers for PDE lack these criteria. Additionally, there is little discussion regarding the interdependence of biomarkers in the PDE-ALDH7A1 metabolite profile. Therefore, the aim of this study was to understand the underlying mechanisms in PDE-ALDH7A1 and to discover new biomarkers in the plasma of patients using global metabolomics. Plasma samples from 9 patients with genetically confirmed PDE-ALDH7A1 and 22 carefully selected control individuals were analyzed by ultra high performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS). Two novel and reliable pyridoxine-independent diagnostic markers, 6-hydroxy-2-aminocaproic acid (HACA) and an isomer of C9H11NO4, were identified. Furthermore, a possible reaction mechanism is proposed for HACA. This study demonstrates the capability of global metabolomics in disease screening to detect established and novel biomarkers.
Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers
Authors: Forkasiewicz Agata , Stach Wojciech , Wierzbicki Jaroslaw , Stach Kamilla , Tabola Renata , Hryniewicz-Jankowska Anita , Augoff Katarzyna
Published: December 2022

Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients.
Amelioration of Hepatic Steatosis by the Androgen Receptor Inhibitor EPI-001 in Mice and Human Hepatic Cells Is Associated with the Inhibition of CYP2E1
Authors: Wang Shuqin , Li Xue , Xu Weizhe , Gao Jing , Wang Yin , Jia Xiaoyuan , Li Gongchu , Pan Qiuwei , Chen Kan
Published: December 2022

Nonalcoholic fatty liver disease (NAFLD) is recognized as a metabolic disease characterized by hepatic steatosis. Despite the growing burden of NAFLD, approved pharmacological treatment is lacking. As an inhibitor of androgen receptor (AR), EPI-001 is being explored for the treatment of prostate cancer. This study aimed to investigate the potential of EPI-001 for treating NAFLD in free fatty acids (FFAs)-induced human hepatic cells and high-fat-high-sugar (HFHS)-feeding mice. Our results showed that EPI-001 reduced lipid accumulation in hepatic cells and ameliorated hepatic steatosis in mouse livers. Further exploration suggested that the effect of EPI-001 was associated with CYP2E1-mediated reduction of reactive oxygen species (ROS). This provides encouraging evidence for further studies on EPI-001 therapy for NAFLD.
Proteomic and Transcriptomic Responses Enable Clams to Correct the pH of Calcifying Fluids and Sustain Biomineralization in Acidified Environments
Authors: Schwaner Caroline , Farhat Sarah , Haley John , Pales Espinosa Emmanuelle , Allam Bassem
Published: December 2022

Seawater pH and carbonate saturation are predicted to decrease dramatically by the end of the century. This process, designated ocean acidification (OA), threatens economically and ecologically important marine calcifiers, including the northern quahog (Mercenaria mercenaria). While many studies have demonstrated the adverse impacts of OA on bivalves, much less is known about mechanisms of resilience and adaptive strategies. Here, we examined clam responses to OA by evaluating cellular (hemocyte activities) and molecular (high-throughput proteomics, RNASeq) changes in hemolymph and extrapallial fluid (EPF—the site of biomineralization located between the mantle and the shell) in M. mercenaria continuously exposed to acidified (pH ~7.3; pCO2 ~2700 ppm) and normal conditions (pH ~8.1; pCO2 ~600 ppm) for one year. The extracellular pH of EPF and hemolymph (~7.5) was significantly higher than that of the external acidified seawater (~7.3). Under OA conditions, granulocytes (a sub-population of hemocytes important for biomineralization) were able to increase intracellular pH (by 54% in EPF and 79% in hemolymph) and calcium content (by 56% in hemolymph). The increased pH of EPF and hemolymph from clams exposed to high pCO2 was associated with the overexpression of genes (at both the mRNA and protein levels) related to biomineralization, acid–base balance, and calcium homeostasis, suggesting that clams can use corrective mechanisms to mitigate the negative impact of OA.
Enhancing Motor and Sensory Axon Regeneration after Peripheral Nerve Injury Using Bioluminescent Optogenetics
Authors: Ecanow Anna , Berglund Ken , Carrasco Dario , Isaacson Robin , English Arthur
Published: December 2022

Introduction—Recovery from peripheral nerve injuries is poor even though injured peripheral axons can regenerate. Novel therapeutic approaches are needed. The most successful preclinical experimental treatments have relied on increasing the activity of the regenerating axons, but the approaches taken are not applicable to many nerve-injured patients. Bioluminescent optogenetics (BL-OG) is a novel method of increasing the excitation of neurons that might be similar to that found with activity-dependent experimental therapies. We investigated the use of BL-OG as an approach to promoting axon regeneration following peripheral nerve injury. Methods—BL-OG uses luminopsins, light-sensing ion channels (opsins) fused with a light-emitting luciferase. When exposed to a luciferase substrate, such as coelenterazine (CTZ), luminopsins expressed in neurons generate bioluminescence and produce excitation through their opsin component. Adeno-associated viral vectors encoding either an excitatory luminopsin (eLMO3) or a mutated form (R115A) that can generate bioluminescence but not excite neurons were injected into mouse sciatic nerves. After retrograde transport and viral transduction, nerves were cut and repaired by simple end-to-end anastomosis, and mice were treated with a single dose of CTZ. Results—Four weeks after nerve injury, compound muscle action potentials (M waves) recorded in response to sciatic nerve stimulation were more than fourfold larger in mice expressing the excitatory luminopsin than in controls expressing the mutant luminopsin. The number of motor and sensory neurons retrogradely labeled from reinnervated muscles in mice expressing eLMO3 was significantly greater than the number in mice expressing the R115A luminopsin and not significantly different from those in intact mice. When viral injection was delayed so that luminopsin expression was induced after nerve injury, a clinically relevant scenario, evoked M waves recorded from reinnervated muscles were significantly larger after injury in eLMO3-expressing mice. Conclusions—Treatment of peripheral nerve injuries using BL-OG has significant potential to enhance axon regeneration and promote functional recovery.
The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
Authors: Horiguchi Taigo , Tanimura Ayako , Miyoshi Keiko , Hagita Hiroko , Minami Hisanori , Noma Takafumi
Published: December 2022

Mitochondrial ATP production plays an important role in most cellular activities, including growth and differentiation. Previously we reported that Adenylate kinase 2 (AK2) is the main ADP supplier in the mitochondrial intermembrane space in hematopoietic cells, especially in the bone marrow. AK2 is crucial for the production of neutrophils and T cells, and its deficiency causes reticular dysgenesis. However, the relationship between ADP supply by AK2 and neutrophil differentiation remains unclear. In this study, we used CRISPR/Cas9 technology to establish two heterozygous AK2 knock-out HL-60 clones as models for reticular dysgenesis. Their AK2 activities were about half that in the wild-type (WT). Furthermore, neutrophil differentiation was impaired in one of the clones. In silico analysis predicted that the obtained mutations might cause a structural change in AK2. Time course microarray analysis of the WT and mutants revealed that similar gene clusters responded to all-trans retinoic acid treatment, but their expression was lower in the mutants than in WT. Application of fructose partially restored neutrophil differentiation in the heterozygous knock-out HL-60 clone after all-trans retinoic acid treatment. Collectively, our study suggests that the mutation of N-terminal region in AK2 might play a role in AK2-dependent neutrophil differentiation and fructose could be used to treat AK2 deficiency.
Anticancer Effects of Fucoxanthin through Cell Cycle Arrest, Apoptosis Induction, Angiogenesis Inhibition, and Autophagy Modulation
Authors: Ahmed Shade’ A. , Mendonca Patricia , Elhag Rashid , Soliman Karam F. A.
Published: December 2022

Cancer accounts for one in seven deaths worldwide and is the second leading cause of death in the United States, after heart disease. One of the standard cancer treatments is chemotherapy which sometimes can lead to chemoresistance and treatment failure. Therefore, there is a great need for novel therapeutic approaches to treat these patients. Novel natural products have exhibited anticancer effects that may be beneficial in treating many kinds of cancer, having fewer side effects, low toxicity, and affordability. Numerous marine natural compounds have been found to inhibit molecular events and signaling pathways associated with various stages of cancer development. Fucoxanthin is a well-known marine carotenoid of the xanthophyll family with bioactive compounds. It is profusely found in brown seaweeds, providing more than 10% of the total creation of natural carotenoids. Fucoxanthin is found in edible brown seaweed macroalgae such as Undaria pinnatifida, Laminaria japonica, and Eisenia bicyclis. Many of fucoxanthin's pharmacological properties include antioxidant, anti-tumor, anti-inflammatory, antiobesity, anticancer, and antihypertensive effects. Fucoxanthin inhibits many cancer cell lines' proliferation, angiogenesis, migration, invasion, and metastasis. In addition, it modulates miRNA and induces cell cycle growth arrest, apoptosis, and autophagy. Moreover, the literature shows fucoxanthin's ability to inhibit cytokines and growth factors such as TNF-α and VEGF, which stimulates the activation of downstream signaling pathways such as PI3K/Akt autophagy, and pathways of apoptosis. This review highlights the different critical mechanisms by which fucoxanthin inhibits diverse cancer types, such as breast, prostate, gastric, lung, and bladder development and progression. Moreover, this article reviews the existing literature and provides critical supportive evidence for fucoxanthin's possible therapeutic use in cancer.
FAAH Inhibition Restores Early Life Stress-Induced Alterations in PFC microRNAs Associated with Depressive-Like Behavior in Male and Female Rats
Authors: Portugalov Anna , Zaidan Hiba , Gaisler-Salomon Inna , Hillard Cecilia J. , Akirav Irit
Published: December 2022

Early life stress (ELS) increases predisposition to depression. We compared the effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, and the selective serotonin reuptake inhibitor paroxetine, on ELS-induced depressive-like behavior and the expression of microRNAs (miRs) associated with depression in the medial prefrontal cortex (mPFC), hippocampal CA1 area, lateral habenula and dorsal raphe in rats. We also examined the mRNA expression of serotonergic (htr1a and slc6a4) and endocannabinoid (cnr1, cnr2 and faah) targets in the mPFC following ELS and pharmacological treatment. Adult males and females exposed to the ‘Limited Bedding and Nesting’ ELS paradigm demonstrated a depressive-like phenotype and late-adolescence URB597 treatment, but not paroxetine, reversed this phenotype. In the mPFC, ELS downregulated miR-16 in males and miR-135a in females and URB597 treatment restored this effect. In ELS females, the increase in cnr2 and decrease in faah mRNAs in the mPFC were reversed by URB597 treatment. We show for the first time that URB597 reversed ELS-induced mPFC downregulation in specific miRs and stress-related behaviors, suggesting a novel mechanism for the beneficial effects of FAAH inhibition. The differential effects of ELS and URB597 on males and females highlight the importance of developing sex-specific treatment approaches.
Identification of the Xyloglucan Endotransglycosylase/Hydrolase (XTH) Gene Family Members Expressed in Boehmeria nivea in Response to Cadmium Stress
Authors: Ma Yu-Shen , Jie Hong-Dong , Zhao Long , Lv Xue-Ying , Liu Xiao-Chun , Tang Yan-Yi , Zhang Ying , He Peng-Liang , Xing Hu-Cheng , Jie Yu-Cheng
Published: December 2022

Xyloglucan endotransglycosylase/hydrolase (XTH) genes play an important role in plant resistance to abiotic stress. However, systematic studies of the response of Boehmeria nivea (ramie) XTH genes (BnXTHs) to cadmium (Cd) stress are lacking. We sought to identify the BnXTH-family genes in ramie through bioinformatics analyses and to investigate their responses to Cd stress. We identified 19 members of the BnXTH gene family from the ramie genome, referred to as BnXTH1-19, among which BnXTH18 and BnXTH19 were located on no chromosomes and the remaining genes were unevenly distributed across 11 chromosomes. The 19 members were divided into four groups, Groups I/II/IIIA/IIIB, according to their phylogenetic relationships, and these groups were supported by analyses of intron–exon structure and conserved motif composition. A highly conserved catalytic site (HDEIDFEFLG) was observed in all BnXTH proteins. Additionally, three gene pairs (BnXTH6–BnXTH16, BnXTH8–BnXTH9, and BnXTH17–BnXTH18) were obtained with a fragment and tandem-repeat event analysis of the ramie genome. An analysis of cisregulatory elements revealed that BnXTH expression might be regulated by multiple hormones and abiotic and biotic stress responses. In particular, 17 cisregulatory elements related to abiotic and biotic stress responses and 11 cisregulatory elements related to hormone responses were identified. We also found that most BnXTH genes responded to Cd stress, and BnXTH1, BnXTH3, BnXTH6, and BnXTH15 were most likely to contribute to the Cd tolerance of ramie, as evidenced by the substantial increases in expression under Cd treatment. Heterologous expression of BnXTH1, BnXTH6, and BnXTH15 significantly enhanced the Cd tolerance of transgenic yeast cells. These results suggest that the BnXTH gene family is involved in Cd stress responses, laying a theoretical foundation for functional studies of BnXTH genes and the innovative breeding of Cd-tolerant ramie.
The Anthocyanin Accumulation Related ZmBZ1, Facilitates Seedling Salinity Stress Tolerance via ROS Scavenging
Authors: Wang Jie , Li Delin , Peng Yixuan , Cai Minghao , Liang Zhi , Yuan Zhipeng , Du Xuemei , Wang Jianhua , Schnable Patrick S. , Gu Riliang , Li Li
Published: December 2022

Anthocyanins are a class of antioxidants that scavenge free radicals in cells and play an important role in promoting human health and preventing many diseases. Here, we characterized a maize Bronze gene (BZ1) from the purple colored W22 introgression line, which encodes an anthocyanin 3-O-glucosyltransferase, a key enzyme in the anthocyanin synthesis pathway. Mutation of ZmBZ1 showed bronze-colored seeds and reduced anthocyanins in seeds aleurone layer, seedlings coleoptile, and stem of mature plants by comparison with purple colored W22 (WT). Furthermore, we proved that maize BZ1 is an aleurone layer-specific expressed protein and sub-located in cell nucleus. Real-time tracing of the anthocyanins in developing seeds demonstrated that the pigment was visible from 16 DAP (day after pollination) in field condition, and first deposited in the crown part then spread all over the seed. Additionally, it was transferred along with the embryo cell activity during seed germination, from aleurone layer to cotyledon and coleoptile, as confirmed by microscopy and real-time qRT-PCR. Finally, we demonstrated that the ZmBZ1 contributes to stress tolerance, especially salinity. Further study proved that ZmBZ1 participates in reactive oxygen scavenging (ROS) by accumulating anthocyanins, thereby enhancing the tolerance to abiotic stress.
A Metabolic Signature of Hereditary Transthyretin Amyloidosis: A Pilot Study
Authors: Luigetti Marco , Guglielmino Valeria , Romano Angela , Sciarrone Maria Ausilia , Vitali Francesca , Sabino Andrea , Gervasoni Jacopo , Primiano Aniello , Santucci Lavinia , Moroni Rossana , Primiano Guido
Published: December 2022

Hereditary transthyretin amyloidosis is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. ATTRv amyloidosis can present as a progressive, axonal sensory autonomic and motor neuropathy or as an infiltrative cardiomyopathy. The definition of biomarkers for the early diagnosis of ATTRv is particularly important in the current era of emerging treatments. In this sense, metabolomics could be an instrument able to provide metabolic profiles with their related metabolic pathways, and we would propose them as possible fluid biomarkers. The aim of this study is to identify altered metabolites (free fatty acids and amino acids) in subjects with a confirmed pathogenic TTR variant. Out of the studied total free fatty acids and amino acids, the serum values of palmitic acid are significantly lower in the ATTRv patients compared to the recruited healthy subjects. The metabolic remodeling identified in this neurogenetic disorder could be the manifestation of pathophysiological processes of the disease, such as mitochondrial dysfunction and neuroinflammation, and contribute to explaining some of its clinical manifestations.
Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
Authors: Yang Shuo , Tang Xiaoqin , Wang Long , Ni Chengyang , Wu Yuesong , Zhou Ling , Zeng Yueying , Zhao Chunling , Wu Anguo , Wang Qiaozhi , Xu Xiyan , Wang Yiwei , Chen Rong , Zhang Xiao , Zou Lile , Huang Xinwu , Wu Jianming
Published: December 2022

Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate. Methods: The impact of ruxolitinib on the differentiation and maturation of K562 and Meg-01 cells megakaryocytes (MKs) was examined by flow cytometry, Giemsa and Phalloidin staining. A mouse model of radiation-injured thrombocytopenia (RIT) was employed to evaluate the action of ruxolitinib on thrombocytopoiesis. Network pharmacology, molecular docking, drug affinity responsive target stability assay (DARTS), RNA sequencing, protein blotting and immunofluorescence analysis were applied to explore the targets and mechanisms of action of ruxolitinib. Results: Ruxolitinib can stimulate MK differentiation and maturation in a dose-dependent manner and accelerates recovery of MKs and thrombocytopoiesis in RIT mice. Biological targeting analysis showed that ruxolitinib binds directly to Toll Like Receptor 2 (TLR2) to activate Rac1/cdc42/JNK, and this action was shown to be blocked by C29, a specific inhibitor of TLR2. Conclusions: Ruxolitinib was first identified to facilitate MK differentiation and thrombocytopoiesis, which may alleviate RIT. The potential mechanism of ruxolitinib was to promote MK differentiation via activating the Rac1/cdc42/JNK pathway through binding to TLR2.
Proteasome Dysfunction Leads to Suppression of the Hypoxic Response Pathway in Arabidopsis
Authors: Xia Xue , Tang Chun-Meng , Chen Gu-Zi , Han Jia-Jia
Published: December 2022

Proteasome is a large proteolytic complex that consists of a 20S core particle (20SP) and 19S regulatory particle (19SP) in eukaryotes. The proteasome degrades most cellular proteins, thereby controlling many key processes, including gene expression and protein quality control. Proteasome dysfunction in plants leads to abnormal development and reduced adaptability to environmental stresses. Previous studies have shown that proteasome dysfunction upregulates the gene expression of proteasome subunits, which is known as the proteasome bounce-back response. However, the proteasome bounce-back response cannot explain the damaging effect of proteasome dysfunction on plant growth and stress adaptation. To address this question, we focused on downregulated genes caused by proteasome dysfunction. We first confirmed that the 20SP subunit PBE is an essential proteasome subunit in Arabidopsis and that PBE1 mutation impaired the function of the proteasome. Transcriptome analyses showed that hypoxia-responsive genes were greatly enriched in the downregulated genes in pbe1 mutants. Furthermore, we found that the pbe1 mutant is hypersensitive to waterlogging stress, a typical hypoxic condition, and hypoxia-related developments are impaired in the pbe1 mutant. Meanwhile, the 19SP subunit rpn1a mutant seedlings are also hypersensitive to waterlogging stress. In summary, our results suggested that proteasome dysfunction downregulated the hypoxia-responsive pathway and impaired plant growth and adaptability to hypoxia stress.
CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation
Authors: Chu Hanh Hong , Kobayashi Yoshiki , Bui Dan Van , Yun Yasutaka , Nguyen Linh Manh , Mitani Akitoshi , Suzuki Kensuke , Asako Mikiya , Kanda Akira , Iwai Hiroshi
Published: December 2022

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β—a specific ligand for CCR5 receptors—was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression—a marker of activated eosinophils—as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)β, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRβ, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.
In Vitro Selection of Lactobacillus and Bifidobacterium Probiotic Strains for the Management of Oral Pathobiont Infections Associated to Systemic Diseases
Authors: Zanetta Paola , Squarzanti Diletta Francesca , di Coste Alessia , Rolla Roberta , Valletti Paolo Aluffi , Garzaro Massimiliano , Dell’Era Valeria , Amoruso Angela , Pane Marco , Azzimonti Barbara
Published: December 2022

The human oral pathobionts Aggregatibacter actinomycetemcomitans, Streptococcus mitis and Streptococcus mutans, in dysbiosis-promoting conditions, lead to oral infections, which also represent a threat to human systemic health. This scenario may be worsened by antibiotic misuse, which favours multi-drug resistance, making the research on pathogen containment strategies more than crucial. Therefore, we aimed to in vitro select the most promising probiotic strains against oral pathogen growth, viability, biofilm formation, and co-aggregation capacity, employing both the viable probiotics and their cell-free supernatants (CFSs). Interestingly, we also assessed probiotic efficacy against the three-pathogen co-culture, mimicking an environment similar to that in vivo. Overall, the results showed that Lactobacillus CFSs performed better than the Bifidobacterium, highlighting Limosilactobacillus reuteri LRE11, Lacticaseibacillus rhamnosus LR04, Lacticaseibacillus casei LC04, and Limosilactobacillus fermentum LF26 as the most effective strains, opening the chance to deeper investigation of their action and CFS composition. Altogether, the methodologies presented in this study can be used for probiotic efficacy screenings, in order to better focus the research on a viable probiotic, or on its postbiotics, suitable in case of infections.
Zinc and Zinc Transporters in Dermatology
Authors: Al-Khafaji Zubaidah , Brito Sofia , Bin Bum-Ho
Published: December 2022

Zinc is an important trace mineral in the human body and a daily intake of zinc is required to maintain a healthy status. Over the past decades, zinc has been used in formulating topical and systemic therapies for various skin disorders owing to its wound healing and antimicrobial properties. Zinc transporters play a major role in maintaining the integrity of the integumentary system by controlling zinc homeostasis within dermal layers. Mutations and abnormal function of zinc-transporting proteins can lead to disease development, such as spondylocheirodysplastic Ehlers–Danlos syndrome (SCD-EDS) and acrodermatitis enteropathica (AE) which can be fatal if left untreated. This review discusses the layers of the skin, the importance of zinc and zinc transporters in each layer, and the various skin disorders caused by zinc deficiency, in addition to zinc-containing compounds used for treating different skin disorders and skin protection.
Angiogenesis–Browning Interplay Mediated by Asprosin-Knockout Contributes to Weight Loss in Mice with Obesity
Authors: Yin Tingting , Chen Sheng , Zeng Guohua , Yuan Wanwan , Lu Yanli , Zhang Yanan , Huang Qianqian , Xiong Xiaowei , Xu Baohua , Huang Qiren
Published: December 2022

Asprosin (ASP) is a recently identified adipokine secreted by white adipose tissue (WAT). It plays important roles in the maintenance of glucose homeostasis in the fasting state and in the occurrence and development of obesity. However, there is no report on whether and how ASP would inhibit angiogenesis and fat browning in the mouse adipose microenvironment. Therefore, the study sought to investigate the effects of ASP-knockout on angiogenesis and fat browning, and to identify the interaction between them in the ASP-knockout mouse adipose microenvironment. In the experiments in vivo, the ASP-knockout alleviated the obesity induced by a high fat diet (HFD) and increased the expressions of the browning-related proteins including uncoupling protein 1 (UCP1), PRD1-BF-1-RIZ1 homologus domain-containing protein-16 (PRDM16) and PPAR gamma coactivator 1 (PGC1-α) and the endothelial cell marker (CD31). In the experiments in vitro, treatment with the conditional medium (CM) from ASP-knockout adipocytes (ASP−/−-CM) significantly promoted the proliferation, migration and angiogenesis of vascular endothelial cells, and increased the expressions of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/endothelial nitric oxide synthase (eNOS) pathway proteins. In addition, the treatment with CM from endothelial cells (EC-CM) markedly reduced the accumulation of lipid droplets and increased the expressions of the browning-related proteins and the mitochondrial contents. Moreover, the treatment with EC-CM significantly improved the energy metabolism in 3T3-L1 adipocytes. These results highlight that ASP-knockout can promote the browning and angiogenesis of WAT, and the fat browning and angiogenesis can interact in the mouse adipose microenvironment, which contributes to weight loss in the mice with obesity.
Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors
Authors: Tomanová Monika , Kozlanská Karolína , Jorda Radek , Jedinák Lukáš , Havlíková Tereza , Řezníčková Eva , Peřina Miroslav , Klener Pavel , Dolníková Alexandra , Cankař Petr , Kryštof Vladimír
Published: December 2022

Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.
Calcium-Dependent Interplay of Lithium and Tricyclic Antidepressants, Amitriptyline and Desipramine, on N-methyl-D-aspartate Receptors
Authors: Boikov Sergei I. , Sibarov Dmitry A. , Stepanenko Yulia D. , Karelina Tatiana V. , Antonov Sergei M.
Published: December 2022

The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li+, which suppresses the sodium–calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li+]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li+]s of 0.5–1 mM cause an increase in ATL and DES IC50s of ~10 folds and ~4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li+. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li+. This Ca2+-dependent interplay between Li+, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li+]s may weaken ATL and DES effects during combined therapy. The data suggest that Li+, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug–drug or ion–drug interaction when these medicines are used together therapeutically.
Advances and Challenges of Cannabidiol as an Anti-Seizure Strategy: Preclinical Evidence
Authors: Zavala-Tecuapetla Cecilia , Luna-Munguia Hiram , López-Meraz María-Leonor , Cuellar-Herrera Manola
Published: December 2022

The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from Cannabis sativa, cannabidiol (CBD), has emerged over the last few years as a promising molecule with anti-seizure potential. Here, we present an overview of recent literature pointing out CBD’s pharmacological profile (solubility, metabolism, drug-drug interactions, etc.,), CBD’s interactions with multiple molecular targets as well as advances in preclinical research concerning its anti-seizure effect on both acute seizure models and chronic models of epilepsy. We also highlight the recent attention that has been given to other natural cannabinoids and to synthetic derivatives of CBD as possible compounds with therapeutic anti-seizure potential. All the scientific research reviewed here encourages to continue to investigate the probable therapeutic efficacy of CBD and its related compounds not only in epilepsy but also and specially in drug-resistant epilepsy, since there is a dire need for new and effective drugs to treat this disease.
Effect of Pre-Heating on the Monomer Elution and Porosity of Conventional and Bulk-Fill Resin-Based Dental Composites
Authors: Dunavári Erika , Berta Gergely , Kiss Tamás , Szalma József , Fráter Márk , Böddi Katalin , Lempel Edina
Published: December 2022

The pre-heating of dental resin-based composites (RBCs) improves adaptability to cavity walls, reducing microleakages. However, the rapid cooling of the pre-heated RBC may change the polymerization kinetics, and thus the final network configuration of the RBC. It is well known that unreacted monomers remaining in the set RBC can leach into the oral cavity. However, it is still not clear how the pre-heating and cooling of RBCs alter monomer elution (ME). Thus, the purpose was to determine the ME from room-temperature and pre-heated RBCs, in addition to determining the closed porosity (CP) volume. Bulk-filled RBCs and layered conventional RBC samples were prepared. The pre-polymerization temperature was set at 24 °C and 55/65 °C. The ME from RBC samples was assessed with high-performance liquid chromatography using standard monomers. CP was measured with micro-computed tomography. ME decreased significantly from bulk fills and increased from layered samples as a result of pre-heating. Pre-heating was unfavorable in terms of CP in most RBCs. Based on the effect size analysis, ME and CP were greatly influenced by both material composition, pre-polymerization temperature, and their interaction. While the pre-heating of high-viscosity bulk-fill RBCs is advantageous from a clinical aspect regarding biocompatibility, it increases CP, which is undesirable from a mechanical point of view.
Relationship of Cognition and Alzheimer’s Disease with Gastrointestinal Tract Disorders: A Large-Scale Genetic Overlap and Mendelian Randomisation Analysis
Authors: Adewuyi Emmanuel O. , O’Brien Eleanor K. , Porter Tenielle , Laws Simon M.
Published: December 2022

Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, the mechanisms underlying their relationships remain unclear. Leveraging large-scale genome-wide association studies’ summary statistics, we comprehensively assessed genetic overlap and potential causality of cognitive traits and Alzheimer’s disease (AD) with several GIT disorders. We demonstrate a strong and highly significant inverse global genetic correlation between cognitive traits and GIT disorders—peptic ulcer disease (PUD), gastritis-duodenitis, diverticulosis, irritable bowel syndrome, and gastroesophageal reflux disease (GERD), but not inflammatory bowel disease (IBD). Further analysis detects 35 significant (p < 4.37 × 10−5) bivariate local genetic correlations between cognitive traits, AD, and GIT disorders (including IBD). Mendelian randomisation analysis suggests a risk-decreasing causality of educational attainment, intelligence, and other cognitive traits on PUD and GERD, but not IBD, and a putative association of GERD with cognitive function decline. Gene-based analysis reveals a significant gene-level genetic overlap of cognitive traits with AD and GIT disorders (IBD inclusive, pbinomial-test = 1.18 × 10−3–2.20 × 10−16). Our study supports the protective roles of genetically-influenced educational attainments and other cognitive traits on the risk of GIT disorders and highlights a putative association of GERD with cognitive function decline. Findings from local genetic correlation analysis provide novel insights, indicating that the relationship of IBD with cognitive traits (and AD) will depend largely on their local effects across the genome.
Plant Disease Resistance-Related Signaling Pathways: Recent Progress and Future Prospects
Authors: Ding Li-Na , Li Yue-Tao , Wu Yuan-Zhen , Li Teng , Geng Rui , Cao Jun , Zhang Wei , Tan Xiao-Li
Published: December 2022

Plant–pathogen interactions induce a signal transmission series that stimulates the plant’s host defense system against pathogens and this, in turn, leads to disease resistance responses. Plant innate immunity mainly includes two lines of the defense system, called pathogen-associated molecular pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). There is extensive signal exchange and recognition in the process of triggering the plant immune signaling network. Plant messenger signaling molecules, such as calcium ions, reactive oxygen species, and nitric oxide, and plant hormone signaling molecules, such as salicylic acid, jasmonic acid, and ethylene, play key roles in inducing plant defense responses. In addition, heterotrimeric G proteins, the mitogen-activated protein kinase cascade, and non-coding RNAs (ncRNAs) play important roles in regulating disease resistance and the defense signal transduction network. This paper summarizes the status and progress in plant disease resistance and disease resistance signal transduction pathway research in recent years; discusses the complexities of, and interactions among, defense signal pathways; and forecasts future research prospects to provide new ideas for the prevention and control of plant diseases.
Special Issue on “Enzymes as Biocatalysts: Current Research Trends and Applications”
Authors: Sousa Sérgio F.
Published: December 2022

Enzymes are able to catalyze a wide diversity of chemical reactions in nature, and they do it at an amazing level [...]
DNA Methylation Alterations in Fractionally Irradiated Rats and Breast Cancer Patients Receiving Radiotherapy
Authors: Sallam Magy , Mysara Mohamed , Benotmane Mohammed , Tamarat Radia , Santos Susana Constantino Rosa , Crijns Anne , Spoor Daan , Van Nieuwerburgh Filip , Deforce Dieter , Baatout Sarah , Guns Pieter-Jan , Aerts An , Ramadan Raghda
Published: December 2022

Radiation-Induced CardioVascular Disease (RICVD) is an important concern in thoracic radiotherapy with complex underlying pathophysiology. Recently, we proposed DNA methylation as a possible mechanism contributing to RICVD. The current study investigates DNA methylation in heart-irradiated rats and radiotherapy-treated breast cancer (BC) patients. Rats received fractionated whole heart X-irradiation (0, 0.92, 6.9 and 27.6 Gy total doses) and blood was collected after 1.5, 3, 7 and 12 months. Global and gene-specific methylation of the samples were evaluated; and gene expression of selected differentially methylated regions (DMRs) was validated in rat and BC patient blood. In rats receiving an absorbed dose of 27.6 Gy, DNA methylation alterations were detected up to 7 months with differential expression of cardiac-relevant DMRs. Of those, SLMAP showed increased expression at 1.5 months, which correlated with hypomethylation. Furthermore, E2F6 inversely correlated with a decreased global longitudinal strain. In BC patients, E2F6 and SLMAP exhibited differential expression directly and 6 months after radiotherapy, respectively. This study describes a systemic radiation fingerprint at the DNA methylation level, elucidating a possible association of DNA methylation to RICVD pathophysiology, to be validated in future mechanistic studies.
Assessment of Novel Genetic Diversity Induced by Mutagenesis and Estimation of Genetic Parameters in Sesame M4 Mutant Lines
Authors: Kouighat Mohamed , Hanine Hafida , Chetto Oumaima , Fakhour Samir , El Fechtali Mohamed , Nabloussi Abdelghani
Published: December 2022

Sesame (Sesamum indicum L.) is an ancient oilseed, aromatic, and medicinal crop widely used for its high-quality oil and seeds. The available genetic diversity in Morocco is too limited; thus, a mutagenesis breeding program was adopted. This study was carried out to evaluate the novel variability induced and observed in 11 M4 mutant lines and to estimate some valuable genetic parameters. The experiment was conducted in two different environments using a randomized complete block design with three replications. Phenological, morphological, and agronomic traits were recorded. To estimate the effect of genotype, environment, and their interaction, ANOVA and planned contrast analyses were performed. To examine relatedness among genotypes, cluster analysis was performed. Significant differences among mutants and between parent cultivars and their respective mutant lines were observed. Genetic parameters such as genotypic (GCV) and phenotypic (PCV) coefficients of variation, broad-sense heritability (H2 b.s), genetic advance (GA), and genetic advance over the mean (GAM) were high in most traits. Highly productive mutants, ‘US2-1’ and ‘US1-2’, were observed, exhibiting the highest number of capsules per plant and seed yield ever reported. Additionally, there are other promising mutants with early flowering, early maturity, and a reduced height of the first capsule. This suggests that mutagenesis can be successfully applied to develop high-yielding sesame varieties along with other improved phenological and agromorphological traits. All these mutant lines can be used as promising germplasm to develop competitive sesame cultivars to meet the increasing demand for sesame oil and seeds in the actual context of climate change.
LPCOCN: A Layered Paddy Crop Optimization-Based Capsule Network Approach for Anomaly Detection at IoT Edge
Authors: Narayanavadivoo Gopinathan Bhuvaneswari Amma , Sarveshwaran Velliangiri , Ravi Vinayakumar , Chaganti Rajasekhar
Published: December 2022

Cyberattacks have increased as a consequence of the expansion of the Internet of Things (IoT). It is necessary to detect anomalies so that smart devices need to be protected from these attacks, which must be mitigated at the edge of the IoT network. Therefore, efficient detection depends on the selection of an optimal IoT traffic feature set and the learning algorithm that classifies the IoT traffic. There is a flaw in the existing anomaly detection systems because the feature selection algorithms do not identify the most appropriate set of features. In this article, a layered paddy crop optimization (LPCO) algorithm is suggested to choose the optimal set of features. Furthermore, the use of smart devices generates tremendous traffic, which can be labelled as either normal or attack using a capsule network (CN) approach. Five network traffic benchmark datasets are utilized to evaluate the proposed approach, including NSL KDD, UNSW NB, CICIDS, CSE-CIC-IDS, and UNSW Bot-IoT. Based on the experiments, the presented approach yields assuring results in comparison with the existing base classifiers and feature selection approaches. Comparatively, the proposed strategy performs better than the current state-of-the-art approaches.
Hybrid No-Reference Quality Assessment for Surveillance Images
Authors: Ye Zhongchang , Ye Xin , Zhao Zhonghua
Published: December 2022

Intelligent video surveillance (IVS) technology is widely used in various security systems. However, quality degradation in surveillance images (SIs) may affect its performance on vision-based tasks, leading to the difficulties in the IVS system extracting valid information from SIs. In this paper, we propose a hybrid no-reference image quality assessment (NR IQA) model for SIs that can help to identify undesired distortions and provide useful guidelines for IVS technology. Specifically, we first extract two main types of quality-aware features: the low-level visual features related to various distortions, and the high-level semantic information, which is extracted by a state-of-the-art (SOTA) vision transformer backbone. Then, we fuse these two kinds of features into the final quality-aware feature vector, which is mapped into the quality index through the feature regression module. Our experimental results on two surveillance content quality databases demonstrate that the proposed model achieves the best performance compared to the SOTA on NR IQA metrics.
Comparative Analysis of Mitogenomes of Chironomus (Diptera: Chironomidae)
Authors: Li Shu-Yi , Zhao Yan-Min , Guo Bing-Xin , Li Chen-Hong , Sun Bing-Jiao , Lin Xiao-Long
Published: December 2022

(1) Background: Chironomids are biological indicators, playing an important role in monitoring and assessing the changes in water ecosystems. Mitochondrial genomes have been widely applied as a molecular marker to analyze the taxonomy and phylogeny of insects. However, knowledge of the mitogenomes of Chironomus species is scarce at present, which limits our understanding of the evolutionary relationships among Chironomus. (2) Methods: In our study, the mitogenomes and their basic structure of 12 Chironomus species and one Microchironomus species were newly sequenced. Combined with reported mitogenomes, a total of 15 mitogenomes of Chironomus were selected for a comparative mitogenomic analysis and phylogenetic reconstruction of Chironomus. (3) Results: Each mitogenome of the Chironomus species has the typical 37 genes and a control region. The basic structure of the whole mitogenomes of Chironomus species is relatively conservative, and the genetic arrangements stay the same as the ancestral mitogenome. (4) Conclusions: Our study enriches the library of mitogenomes of chironomids and provides a valuable resource for understanding the evolutionary history of Chironomus.