bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid
Authors: Lin Da-Wei , Chang Cheng-Chih , Hsu Yung-Chien , Lin Chun-Liang
Published: March 2022

Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system’s role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.
Gut Mucosal Microbiome Is Perturbed in Rheumatoid Arthritis Mice and Partly Restored after TDAG8 Deficiency or Suppression by Salicylanilide Derivative
Authors: Nguyen Ngoc Tuan , Sun Wei-Hsin , Chen Tzu-Hsuan , Tsai Po-Chun , Chen Chih-Chen , Huang Shir-Ly
Published: March 2022

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by chronic joint inflammation and pain. We previously found that the deletion of T-cell death-associated gene 8 (TDAG8) significantly reduces disease severity and pain in RA mice. Whether it is by modulating gut microbiota remains unclear. In this study, 64 intestinal samples of feces, cecal content, and cecal mucus from the complete Freund’s adjuvant-induced arthritis mouse models were compared. The α- and β-diversity indices of the microbiome were significantly lower in RA mice. Cecal mucus showed a higher ratio of Firmicutes to Bacteroidetes in RA than healthy mice, suggesting the ratio could serve as an RA indicator. Four core genera, Eubacterium_Ventriosum, Alloprevotella, Rikenella, and Treponema, were reduced in content in both feces and mucus RA samples, and could serve microbial markers representing RA progression. TDAG8 deficiency decreased the abundance of proinflammation-related Eubacterium_Xylanophilum, Clostridia, Ruminococcus, Paraprevotella, and Rikenellaceae, which reduced local mucosal inflammation to relieve RA disease severity and pain. The pharmacological block of the TDAG8 function by a salicylanilide derivative partly restored the RA microbiome to a healthy composition. These findings provide a further understanding of specific bacteria interactions with host gut mucus in the RA model. The modulation by TDAG8 on particular bacteria can facilitate microbiota-based therapy.
Expression of Irisin/FNDC5 in Breast Cancer
Authors: Cebulski Kamil , Nowińska Katarzyna , Jablońska Karolina , Romanowicz Hanna , Smolarz Beata , Dzięgiel Piotr , Podhorska-Okołów Marzenna
Published: March 2022

Irisin is a myokine formed from fibronectin type III domain-containing protein 5 (FNDC5), which can be found in various cancer tissues. FNDC5 and irisin levels have been poorly studied in the tumor tissues of breast cancer (BC). The aim of this study was to determine the levels of irisin expression in BC tissues and compare them to clinicopathological factors and Ki-67 and PGC-1α expression levels. Tissue microarrays (TMAs) with 541 BC tissues and 61 samples of non-malignant breast disease (NMBD; control) were used to perform immunohistochemical reactions. FNDC5 gene expression was measured in 40 BC tissue samples, 40 samples from the cancer margin, and 16 NMBD samples. RT-PCR was performed for the detection of FNDC5 gene expression. Higher irisin expression was found in BC patients compared to normal breast tissue. FNDC5/irisin expression was higher in patients without lymph node metastases. Longer overall survival was observed in patients with higher irisin expression levels. FNDC5/irisin expression was increased in BC tissues and its high level was a good prognostic factor for survival in BC patients.
A Microfluidic Platform to Monitor Real-Time Effects of Extracellular Vesicle Exchange between Co-Cultured Cells across Selectively Permeable Barriers
Authors: Mason Hunter G. , Bush Joshua , Agrawal Nitin , Hakami Ramin M. , Veneziano Remi
Published: March 2022

Exosomes and other extracellular vesicles (EVs) play a significant yet poorly understood role in cell–cell communication during homeostasis and various pathological conditions. Conventional in vitro and in vivo approaches for studying exosome/EV function depend on time-consuming and expensive vesicle purification methods to obtain sufficient vesicle populations. Moreover, the existence of various EV subtypes with distinct functional characteristics and submicron size makes their analysis challenging. To help address these challenges, we present here a unique chip-based approach for real-time monitoring of cellular EV exchange between physically separated cell populations. The extracellular matrix (ECM)-mimicking Matrigel is used to physically separate cell populations confined within microchannels, and mimics tissue environments to enable direct study of exosome/EV function. The submicron effective pore size of the Matrigel allows for the selective diffusion of only exosomes and other smaller EVs, in addition to soluble factors, between co-cultured cell populations. Furthermore, the use of PEGDA hydrogel with a very small pore size of 1.2 nm in lieu of Matrigel allows us to block EV migration and, therefore, differentiate EV effects from effects that may be mediated by soluble factors. This versatile platform bridges purely in vitro and in vivo assays by enabling studies of EV-mediated cellular crosstalk under physiologically relevant conditions, enabling future exosome/EV investigations across multiple disciplines through real-time monitoring of vesicle exchange.
Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol
Authors: Pantoom Supansa , Hules Larissa , Schöll Christopher , Petrosyan Andranik , Monticelli Maria , Pospech Jola , Cubellis Maria Vittoria , Hermann Andreas , Lukas Jan
Published: March 2022

Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid β-glucosidase (β-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on β-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits β-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant β-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated β-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant β-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional β-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize β-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification.
Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis
Authors: Wu Haili , Du Jin’e , Li Chenglu , Li Hanqing , Guo Huiqin , Li Zhuoyu
Published: March 2022

Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3′-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.
Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer
Authors: Radwan Awwad , Alanazi Fars
Published: March 2022

A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer’s disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aβ42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aβ42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aβ42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aβ42 active site and provide useful information that could benefit the development of new Aβ42 accumulation inhibitors.
Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex)
Authors: Scurtu Lucian G. , Jinga Viorel , Simionescu Olga
Published: March 2022

The incidence of syphilis, gonorrhea, chlamydia, and herpes simplex has increased over the last decade, despite the numerous prevention strategies. Worldwide scientists report a surge in drug-resistant infections, particularly in immunocompromised patients. Antigenic variations in syphilis enable long-term infection, but benzathine penicillin G maintains its efficiency, whereas macrolides should be recommended with caution. Mupirocin and zoliflodacin were recently introduced as therapies against ceftriaxone-resistant gonococcus, which poses a larger global threat. The gastrointestinal and prostatic potential reservoirs of Chlamydia trachomatis may represent the key towards complete eradication. Similar to syphilis, macrolides resistance has to be considered in genital chlamydiosis. Acyclovir-resistant HSV may respond to the novel helicase-primase inhibitors and topical imiquimod, particularly in HIV-positive patients. Novel drugs can overcome these challenges while nanocarriers enhance their potency, particularly in mucosal areas. This review summarizes the most recent and valuable discoveries regarding the immunopathogenic mechanisms of these sexually transmitted infections and discusses the challenges and opportunities of the novel molecules and nanomaterials.
The Cell Adhesion Molecule L1 Interacts with Methyl CpG Binding Protein 2 via Its Intracellular Domain
Authors: Loers Gabriele , Kleene Ralf , Girbes Minguez Maria , Schachner Melitta
Published: March 2022

Cell adhesion molecule L1 regulates multiple cell functions, and L1 deficiency is linked to several neural diseases. Recently, we have identified methyl CpG binding protein 2 (MeCP2) as a potential binding partner of the intracellular L1 domain. By ELISA we show here that L1’s intracellular domain binds directly to MeCP2 via the sequence motif KDET. Proximity ligation assay with cultured cerebellar and cortical neurons suggests a close association between L1 and MeCP2 in nuclei of neurons. Immunoprecipitation using MeCP2 antibodies and nuclear mouse brain extracts indicates that MeCP2 interacts with an L1 fragment of ~55 kDa (L1−55). Proximity ligation assay indicates that metalloproteases, β-site of amyloid precursor protein cleaving enzyme (BACE1) and ɣ-secretase, are involved in the generation of L1−55. Reduction in MeCP2 expression by siRNA decreases L1-dependent neurite outgrowth from cultured cortical neurons as well as the migration of L1-expressing HEK293 cells. Moreover, L1 siRNA, MeCP2 siRNA, or a cell-penetrating KDET-containing L1 peptide leads to reduced levels of myocyte enhancer factor 2C (Mef2c) mRNA and protein in cortical neurons, suggesting that the MeCP2/L1 interaction regulates Mef2c expression. Altogether, the present findings indicate that the interaction of the novel fragment L1−55 with MeCP2 affects L1-dependent functions, such as neurite outgrowth and neuronal migration.
Comparing Microscopic and Macroscopic Dynamics in a Paradigmatic Model of Glass-Forming Molecular Liquid
Authors: Porpora Giuseppe , Rusciano Francesco , Pastore Raffaele , Greco Francesco
Published: March 2022

Glass transition is a most intriguing and long-standing open issue in the field of molecular liquids. From a macroscopic perspective, glass-forming systems display a dramatic slowing-down of the dynamics, with the inverse diffusion coefficient and the structural relaxation times increasing by orders of magnitude upon even modest supercooling. At the microscopic level, single-molecule motion becomes strongly intermittent, and can be conveniently described in terms of “cage-jump” events. In this work, we investigate a paradigmatic glass-forming liquid, the Kob–Andersen Lennard–Jones model, by means of Molecular Dynamics simulations, and compare the macroscopic and microscopic descriptions of its dynamics on approaching the glass-transition. We find that clear changes in the relations between macroscopic timescales and cage-jump quantities occur at the crossover temperature where Mode Coupling-like description starts failing. In fact, Continuous Time Random Walk and lattice model predictions based on cage-jump statistics are also violated below the crossover temperature, suggesting the onset of a qualitative change in cage-jump motion. Interestingly, we show that a fully microscopic relation linking cage-jump time- and length-scales instead holds throughout the investigated temperature range.
Immunotherapy for Cervical Cancer: Are We Ready for Prime Time?
Authors: Turinetto Margherita , Valsecchi Anna A. , Tuninetti Valentina , Scotto Giulia , Borella Fulvio , Valabrega Giorgio
Published: March 2022

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA’s Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers.
MYB2 Is Important for Tapetal PCD and Pollen Development by Directly Activating Protease Expression in Arabidopsis
Authors: Guo Xiaorui , Li Lihong , Liu Xiatong , Zhang Chong , Yao Xiaoyun , Xun Zhili , Zhao Zhijing , Yan Wenwen , Zou Yirong , Liu Di , Li Hui , Lu Hai
Published: March 2022

Tapetal programmed cell death (PCD) is a complex biological process that plays an important role in pollen formation and reproduction. Here, we identified the MYB2 transcription factor expressed in the tapetum from stage 5 to stage 11 that was essential for tapetal PCD and pollen development in Arabidopsis thaliana. Downregulation of MYB2 retarded tapetal degeneration, produced defective pollen, and decreased pollen vitality. EMSA and transcriptional activation analysis revealed that MYB2 acted as an upstream activator and directly regulated expression of the proteases CEP1 and βVPE. The expression of these proteases was lower in the buds of the myb2 mutant. Overexpression of either/both CEP1 or/and βVPE proteases partially recover pollen vitality in the myb2 background. Taken together, our results revealed that MYB2 regulates tapetal PCD and pollen development by directly activating expression of the proteases CEP1 and βVPE. Thus, a transcription factor/proteases regulatory and activated cascade was established for tapetal PCD during another development in Arabidopsis thaliana. Highlight: MYB2 is involved in tapetal PCD and pollen development by directly regulating expression of the protease CEP1 and βVPE and establishes a transcription factor/proteases regulatory and activated cascade.
Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization
Authors: Cantiello Michela , Carletti Monica , Giantin Mery , Gardini Giulia , Capolongo Francesca , Cascio Paolo , Pauletto Marianna , Girolami Flavia , Dacasto Mauro , Nebbia Carlo
Published: March 2022

In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB’s post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs.
Roles of Oxidative Stress in Acute Tendon Injury and Degenerative Tendinopathy—A Target for Intervention
Authors: Lui Pauline Po Yee , Zhang Xing , Yao Shiyi , Sun Haonan , Huang Caihao
Published: March 2022

Both acute and chronic tendon injuries are disabling sports medicine problems with no effective treatment at present. Sustained oxidative stress has been suggested as the major factor contributing to fibrosis and adhesion after acute tendon injury as well as pathological changes of degenerative tendinopathy. Numerous in vitro and in vivo studies have shown that the inhibition of oxidative stress can promote the tenogenic differentiation of tendon stem/progenitor cells, reduce tissue fibrosis and augment tendon repair. This review aims to systematically review the literature and summarize the clinical and pre-clinical evidence about the potential relationship of oxidative stress and tendon disorders. The literature in PubMed was searched using appropriate keywords. A total of 81 original pre-clinical and clinical articles directly related to the effects of oxidative stress and the activators or inhibitors of oxidative stress on the tendon were reviewed and included in this review article. The potential sources and mechanisms of oxidative stress in these debilitating tendon disorders is summarized. The anti-oxidative therapies that have been examined in the clinical and pre-clinical settings to reduce tendon fibrosis and adhesion or promote healing in tendinopathy are reviewed. The future research direction is also discussed.
Regulatory Mechanisms of Mitogen-Activated Protein Kinase Cascades in Plants: More than Sequential Phosphorylation
Authors: Ma Haigang , Gao Yujiao , Wang Yonggang , Dai Yi , Ma Hongxiang
Published: March 2022

Mitogen-activated protein kinase (MAPK) cascades play crucial roles in almost all biological processes in plants. They transduce extracellular cues into cells, typically through linear and sequential phosphorylation and activation of members of the signaling cascades. However, accumulating data suggest various regulatory mechanisms of plant MAPK cascades in addition to the traditional phosphorylation pathway, in concert with their large numbers and coordinated roles in plant responses to complex ectocytic signals. Here, we highlight recent studies that describe the uncanonical mechanism of regulation of MAPK cascades, regarding the activation of each tier of the signaling cascades. More particularly, we discuss the unusual role for MAPK kinase kinases (MAPKKKs) in the regulation of MAPK cascades, as accumulating data suggest the non-MAPKKK function of many MAPKKKs. In addition, future work on the biochemical activation of MAPK members that needs attention will be discussed.
Enhancement Mechanism of Stibnite Dissolution Mediated by Acidithiobacillus ferrooxidans under Extremely Acidic Condition
Authors: Wang Can , Xia Jin-Lan , Liu Hong-Chang , Zhou Yu-Hang , Nie Zhen-Yuan , Chen Lu , Shu Wen-Sheng
Published: March 2022

Oxidative dissolution of stibnite (Sb2S3), one of the most prevalent geochemical processes for antimony (Sb) release, can be promoted by Sb-oxidizing microbes, which were studied under alkaline and neutral conditions but rarely under acidic conditions. This work is dedicated to unraveling the enhancement mechanism of stibnite dissolution by typical acidophile Acidithiobacillus ferrooxidans under extremely acidic conditions. The results of solution behavior showed that the dissolution of Sb2S3 was significantly enhanced by A. ferrooxidans, with lower pH and higher redox potential values and higher [Sb(III)] and [Sb(V)] than the sterile control. The surface morphology results showed that the cells adsorbed onto the mineral surface and formed biofilms. Much more filamentous secondary minerals were formed for the case with A. ferrooxidans. Further mineral phase compositions and Sb/S speciation transformation analyses showed that more secondary products Sb2O3/SbO2−, Sb2O5/SbO3−, SO42−, as well as intermediates, such as S0, S2O32− were formed for the biotic case, indicating that the dissolution of Sb2S3 and the Sb/S speciation transformation was promoted by A. ferrooxidans. These results were further clarified by the comparative transcriptome analysis. This work demonstrated that through the interaction with Sb2S3, A. ferrooxidans promotes S/Sb oxidation, so as to enhance S/Sb transformation and thus the dissolution of Sb2S3.
Neurogenic Interventions for Fear Memory via Modulation of the Hippocampal Function and Neural Circuits
Authors: Park Hee Ra , Cai Mudan , Yang Eun Jin
Published: March 2022

Fear memory helps animals and humans avoid harm from certain stimuli and coordinate adaptive behavior. However, excessive consolidation of fear memory, caused by the dysfunction of cellular mechanisms and neural circuits in the brain, is responsible for post-traumatic stress disorder and anxiety-related disorders. Dysregulation of specific brain regions and neural circuits, particularly the hippocampus, amygdala, and medial prefrontal cortex, have been demonstrated in patients with these disorders. These regions are involved in learning, memory, consolidation, and extinction. These are also the brain regions where new neurons are generated and are crucial for memory formation and integration. Therefore, these three brain regions and neural circuits have contributed greatly to studies on neural plasticity and structural remodeling in patients with psychiatric disorders. In this review, we provide an understanding of fear memory and its underlying cellular mechanisms and describe how neural circuits are involved in fear memory. Additionally, we discuss therapeutic interventions for these disorders based on their proneurogenic efficacy and the neural circuits involved in fear memory.
Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus
Authors: Kostner Karam M. , Kostner Gerhard M.
Published: March 2022

Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of APOA expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA).
Combined Therapy with Dacarbazine and Hyperthermia Induces Cytotoxicity in A375 and MNT-1 Melanoma Cells
Authors: Salvador Diana , Bastos Verónica , Oliveira Helena
Published: March 2022

Melanoma is a drug-resistant cancer, representing a serious challenge in cancer treatment. Dacarbazine (DTIC) is the standard drug in metastatic melanoma treatment, despite the poor results. Hyperthermia has been proven to potentiate chemotherapy. Hence, this work analyzed the combined action of hyperthermia and DTIC on A375 and MNT-1 cell lines. First, temperatures between 40 °C and 45 °C were tested. The effect of DTIC on cell viability was also investigated after exposures of 24, 48, and 72 h. Then, cells were exposed to 43 °C and to the respective DTIC IC10 or IC20 of each time exposure. Overall, hyperthermia reduced cell viability, however, 45 °C caused an excessive cell death (>90%). Combinational treatment revealed that hyperthermia potentiates DTIC’s effect, but it is dependent on the concentration and temperature used. Also, it has different mechanisms from the treatments alone, delaying A375 cells at the G2/M phase and MNT-1 cells at the S and G2/M phases. Intracellular reactive oxygen species (ROS) levels increased after treatment with hyperthermia, but the combined treatment showed no additional differences. Also, hyperthermia highly increased the number of A375 early apoptotic cells. These results suggest that combining hyperthermia and DTIC should be more explored to improve melanoma treatment.
Biological Evaluation of Photodynamic Effect Mediated by Nanoparticles with Embedded Porphyrin Photosensitizer
Authors: Žárská Ludmila , Malá Zuzana , Langová Kateřina , Malina Lukáš , Binder Svatopluk , Bajgar Robert , Henke Petr , Mosinger Jiří , Kolářová Hana
Published: March 2022

Clinically approved photodynamic therapy (PDT) is a minimally invasive treatment procedure that uses three key components: photosensitization, a light source, and tissue oxygen. However, the photodynamic effect is limited by both the photophysical properties of photosensitizers as well as their low selectivity, leading to damage to adjacent normal tissue and/or inadequate biodistribution. Nanoparticles (NPs) represent a new option for PDT that can overcome most of the limitations of conventional photosensitizers and can also promote photosensitizer accumulation in target cells through enhanced permeation and retention effects. In this in vitro study, the photodynamic effect of TPP photosensitizers embedded in polystyrene nanoparticles was observed on the non-tumor NIH3T3 cell line and HeLa and G361 tumor cell lines. The efficacy was evaluated by viability assay, while reactive oxygen species production, changes in membrane mitochondrial potential, and morphological changes before and after treatment were imaged by atomic force microscopy. The tested nanoparticles with embedded TPP were found to become cytotoxic only after activation by blue light (414 nm) due to the production of reactive oxygen species. The photodynamic effect observed in this evaluation was significantly higher in both tumor lines than the effect observed in the non-tumor line, and the resulting phototoxicity depended on the concentration of photosensitizer and irradiation time.
Suppression of Cutibacterium acnes-Mediated Inflammatory Reactions by Fibroblast Growth Factor 21 in Skin
Authors: Yu Ying , Shen Yingjie , Zhang Siyi , Wang Nan , Luo Lan , Zhu Xinyi , Xu Xiejun , Cong Weitao , Jin Litai , Zhu Zhongxin
Published: March 2022

Cutibacterium acnes (C. acnes) is a common commensal bacterium that is closely associated with the pathogenesis of acne. Fibroblast growth factor 21 (FGF21), as a favorable regulator of glucose and lipid metabolism and insulin sensitivity, was recently shown to exert anti-inflammatory effects. The role and mechanism of FGF21 in the inflammatory reactions induced by C. acnes, however, have not been determined. The present study shows that FGF21 in the dermis inhibits epidermal C. acnes-induced inflammation in a paracrine manner while it functions on the epidermal layer through a receptor complex consisting of FGF receptor 1 (FGFR1) and β-Klotho (KLB). The effects of FGF21 in heat-killed C. acnes-induced HaCaT cells and living C. acnes-injected mouse ears were examined. In the presence of C. acnes, FGF21 largely counteracted the activation of Toll-like receptor 2 (TLR2), the downstream nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways induced by C. acnes. FGF21 also significantly reduced the expression of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Taken together, these findings indicate that FGF21 suppresses C. acnes-induced inflammation and might be used clinically in the management and treatment of acne.
Comparison of the Cisterna Maturation-Progression Model with the Kiss-and-Run Model of Intra-Golgi Transport: Role of Cisternal Pores and Cargo Domains
Authors: Beznoussenko Galina V. , Kweon Hee-Seok , Sesorova Irina S. , Mironov Alexander A.
Published: March 2022

The Golgi complex is the central station of the secretory pathway. Knowledge about the mechanisms of intra-Golgi transport is inconsistent. Here, we compared the explanatory power of the cisterna maturation-progression model and the kiss-and-run model. During intra-Golgi transport, conventional cargoes undergo concentration and form cisternal distensions or distinct membrane domains that contain only one membrane cargo. These domains and distension are separated from the rest of the Golgi cisternae by rows of pores. After the arrival of any membrane cargo or a large cargo aggregate at the Golgi complex, the cis-Golgi SNAREs become enriched within the membrane of cargo-containing domains and then replaced by the trans-Golgi SNAREs. During the passage of these domains, the number of cisternal pores decreases. Restoration of the cisternal pores is COPI-dependent. Our observations are more in line with the kiss-and-run model.
Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers
Authors: Kusienicka Anna , Bukowska-Strakova Karolina , Cieśla Maciej , Nowak Witold Norbert , Bronisz-Budzyńska Iwona , Seretny Agnieszka , Żukowska Monika , Jeż Mateusz , Krutyhołowa Rościsław , Taha Hevidar , Kachamakova-Trojanowska Neli , Waś Halina , Kieda Claudine , Józkowicz Alicja
Published: March 2022

Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been questioned by studies showing that single unselected melanoma cells are highly tumorigenic in xenotransplantation assays. Herein, we characterize cells expressing MIC markers (CD20, CD24, CD133, Sca-1, ABCB1, ABCB5, ALDHhigh) in the B16-F10 murine melanoma cell line. We use flow cytometric phenotyping, single-cell sorting followed by in vitro clonogenic assays, and syngeneic in vivo serial transplantation assays to demonstrate that the expression of MIC markers does not select CSC-like cells in this cell line. Previously, our group showed that heme-degrading enzyme heme oxygenase-1 (HO-1) can be upregulated in melanoma and increase its aggressiveness. Here, we show that HO-1 activity is important for non-adherent growth of melanoma and HO-1 overexpression enhances the vasculogenic mimicry potential, which can be considered protumorigenic activity. However, HO-1 overexpression decreases clone formation in vitro and serial tumor initiation in vivo. Thus, HO-1 plays a dual role in melanoma, improving the progression of growing tumors but reducing the risk of melanoma initiation.
MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway
Authors: Compagnoni Chiara , Zelli Veronica , Bianchi Andrea , Di Marco Antinisca , Capelli Roberta , Vecchiotti Davide , Brandolini Laura , Cimini Anna Maria , Zazzeroni Francesca , Allegretti Marcello , Alesse Edoardo , Tessitore Alessandra
Published: March 2022

Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. Methods. Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. Results. Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced interesting target genes and pathways, including that of neurotrophin, when analyzed in depth. Almost 80 unique target genes (e.g., PI3K, AKT, MAPK, KRAS, BRAF, RhoA, Cdc42, Rac1, Bax, Bcl2, FasL) were identified as being among those most involved in neurotrophin signaling and in controlling cell proliferation, growth, and apoptosis. AKT and RhoA immunoblots demonstrated congruence with microRNA expression, providing preliminary validation of in silico data. Conclusions. MicroRNA levels in response to rhNGF were for the first time analyzed in corneal cells. Novel insights about microRNAs, target genes, pathways modulation, and possible biological responses were provided. Importantly, given the putative role of microRNAs as biomarkers or therapeutic targets, our results make available data which might be potentially exploitable for clinical applications.
Implementation of Online Behavior Modification Techniques in the Management of Chronic Musculoskeletal Pain: A Systematic Review and Meta-Analysis
Authors: Cuenca-Martínez Ferran , López-Bueno Laura , Suso-Martí Luis , Varangot-Reille Clovis , Calatayud Joaquín , Herranz-Gómez Aida , Romero-Palau Mario , Casaña José
Published: March 2022

Purpose: The main aim of this systematic review and meta-analysis (MA) was to assess the effectiveness of online behavior modification techniques (e-BMT) in the management of chronic musculoskeletal pain. Methods: We conducted a search of Medline (PubMed), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, APA PsychInfo, and Psychological and Behavioral Collections, from inception to the 30 August 2021. The main outcome measures were pain intensity, pain interference, kinesiophobia, pain catastrophizing and self-efficacy. The statistical analysis was conducted using RStudio software. To compare the outcomes reported by the studies, we calculated the standardized mean difference (SMD) over time and the corresponding 95% confidence interval (CI) for the continuous variables. Results: Regarding pain intensity (vs. usual care/waiting list), we found a statistically significant trivial effect size in favor of e-BMT (n = 5337; SMD = −0.17; 95% CI −0.26, −0.09). With regard to pain intensity (vs. in-person BMT) we found a statistically significant small effect size in favor of in-person BMT (n = 486; SMD = 0.21; 95%CI 0.15, 0.27). With respect to pain interference (vs. usual care/waiting list) a statistically significant small effect size of e-BMT was found (n = 1642; SMD = −0.24; 95%CI −0.44, −0.05). Finally, the same results were found in kinesiophobia, catastrophizing, and self-efficacy (vs. usual care/waiting list) where we found a statistically significant small effect size in favor of e-BMT. Conclusions: e-BMT seems to be an effective option for the management of patients with musculoskeletal conditions although it does not appear superior to in-person BMT in terms of improving pain intensity.
Research on Optimal Model of Maritime Search and Rescue Route for Rescue of Multiple Distress Targets
Authors: Ho Wen-Chih , Shen Jian-Hung , Liu Chung-Ping , Chen Yung-Wei
Published: March 2022

Coastal countries began to develop green energy, and offshore wind power equipment in coastal areas was gradually built. Since coastal wind power generation often requires carrying out maintenance between wind turbines with the assistance of service operation vessels, this situation may cause coastal areas to be prone to people falling into the water. However, traditional maritime search and rescue plans take a long time to gather information from man overboard incidents. In order to minimize injuries to people in distress, the maritime search and rescue process must be as short as possible. Despite that all the search and rescue plans are based on the concept of the shortest path, the efficient plans must not only consider the distance but also consider the cost of search and rescue. Therefore, this study established a set of practices applicable to the on-site commander (OSC) to dispatch rescue ships, as well as the planning of maritime search and rescue route models. Based on the easy-to-observe state of the target in distress, the model is analyzed and calculated by Floyd–Warshall algorithm and Grey relational analysis so as to sort the rescue plan and optimize the effect of the search and rescue route at sea. According to the simulation analysis, when the man overboard incident occurs in the coastal area, the OSC can immediately use this model to plan the best search and rescue route and dispatch a reasonable number of rescue ships.
Co-Operative Biofilm Interactions between Aspergillus fumigatus and Pseudomonas aeruginosa through Secreted Galactosaminogalactan Exopolysaccharide
Authors: Ostapska Hanna , Le Mauff François , Gravelat Fabrice N. , Snarr Brendan D. , Bamford Natalie C. , Van Loon Jaime C. , McKay Geoffrey , Nguyen Dao , Howell P. Lynne , Sheppard Donald C.
Published: March 2022

The mold Aspergillus fumigatus and bacterium Pseudomonas aeruginosa form biofilms in the airways of individuals with cystic fibrosis. Biofilm formation by A. fumigatus depends on the self-produced cationic exopolysaccharide galactosaminogalactan (GAG), while P. aeruginosa biofilms can contain the cationic exopolysaccharide Pel. GAG and Pel are rendered cationic by deacetylation mediated by either the secreted deacetylase Agd3 (A. fumigatus) or the periplasmic deacetylase PelA (P. aeruginosa). Given the similarities between these polymers, the potential for biofilm interactions between these organisms were investigated. P. aeruginosa were observed to adhere to A. fumigatus hyphae in a GAG-dependent manner and to GAG-coated coverslips of A. fumigatus biofilms. In biofilm adherence assays, incubation of P. aeruginosa with A. fumigatus culture supernatants containing de-N-acetylated GAG augmented the formation of adherent P. aeruginosa biofilms, increasing protection against killing by the antibiotic colistin. Fluorescence microscopy demonstrated incorporation of GAG within P. aeruginosa biofilms, suggesting that GAG can serve as an alternate biofilm exopolysaccharide for this bacterium. In contrast, Pel-containing bacterial culture supernatants only augmented the formation of adherent A. fumigatus biofilms when antifungal inhibitory molecules were removed. This study demonstrates biofilm interaction via exopolysaccharides as a potential mechanism of co-operation between these organisms in chronic lung disease.
The Effects of Nitrogen and Phosphorus on Colony Growth and Zoospore Characteristics of Soil Chytridiomycota
Authors: Hanrahan-Tan Deirdre G. , Henderson Linda , Kertesz Michael A. , Lilje Osu
Published: March 2022

The Chytridiomycota phylum contributes to nutrient cycling and the flow of energy between trophic levels in terrestrial and aquatic ecosystems yet remains poorly described or absent from publications discussing fungal communities in these environments. This study contributes to the understanding of three species of soil chytrids in vitro—Gaertneriomyces semiglobifer, Spizellomyces sp. and Rhizophlyctis rosea—in the presence of elevated concentrations of nitrogen and phosphorus and with different sources of nitrogen. Colony growth was measured after 4 weeks as dry weight and total protein. To determine the impacts on zoospore reproduction, motility, lipid content, and attachment to organic substrates, 4- and 8-week incubation times were investigated. Whilst all isolates were able to assimilate ammonium as a sole source of nitrogen, nitrate was less preferred or even unsuitable as a nutrient source for G. semiglobifer and R. rosea, respectively. Increasing phosphate concentrations led to diverse responses between isolates. Zoospore production was also variable between isolates, and the parameters for zoospore motility appeared only to be influenced by the phosphate concentration for Spizellomyces sp. and R. rosea. Attachment rates increased for G. semiglobifer in the absence of an inorganic nitrogen source. These findings highlight variability between the adaptive responses utilised by chytrids to persist in a range of environments and provide new techniques to study soil chytrid biomass and zoospore motility by total protein quantification and fluorescent imaging respectively.
Assessing Susceptibility to Soil Liquefaction Using the Standard Penetration Test (SPT)—A Case Study from the City of Portoviejo, Coastal Ecuador
Authors: Ortiz-Hernández Eduardo , Chunga Kervin , Pastor José Luis , Toulkeridis Theofilos
Published: March 2022

The city of Portoviejo in coastal Ecuador was severely affected during the 16 April 2016, Pedernales earthquake (Mw 7.8). Various coseismic liquefaction phenomena occurred, inducing lateral spreading, sand boils, ground subsidence, and sinkholes in soils with poor geotechnical quality in the alluvial and alluvial–colluvial sedimentary environment. Therefore, the main aim of this study was to collect data from standard penetration tests (SPT) and shear velocity and exploratory trenches and to calculate the liquefaction potential index (LPI) by considering a corresponding seismic hazard scenario with an amax = 0.5 g. From these data, a liquefaction hazard map was constructed for the city of Portoviejo, wherein an Fs of 1.169 was obtained. It was determined that strata at a depth of between 8 and 12 m are potentially liquefiable. Our quantitative results demonstrate that the city of Portoviejo’s urban area has a high probability of liquefaction, whereas the area to the southeast of the city is less sensitive to liquefaction phenomena, due to the presence of older sediments. Our results are in accordance with the environmental effects reported in the aftermath of the 2016 earthquake.
A Model for Analyzing Teachers’ Written Feedback on Adult Beginners’ Writing in Swedish as a Second Language
Authors: Jakobson Liivi
Published: March 2022

This study serves to fill a research gap in the written feedback practices of teachers in a second language (L2) writing by focusing on adult beginners, previously uninvestigated in feedback studies. For investigating this, a feedback analysis model was developed. Unlike previous models in L2 contexts, in this study feedback is divided into two main areas, focus (what the teachers comment on) and manner (how the comments are given). The study was conducted in a web-based Swedish as a second language course and included three experienced teachers and their L2 students. The analysis of teachers’ written comments on 60 texts from 12 of the students revealed that in the two main areas both new and previously used categories of feedback were identified. In the area focus five new subcategories were identified within language accuracy, and in the area manner politeness, and reinforcement of learning outcomes were identified as new categories. Within the area, focus, the teachers concentrated on language accuracy, and within the area, manner, all three teachers mostly provided information, but also made a range of suggestions. There was also individual variation among teachers. The analysis of feedback strengthens the importance of applying the main distinction between ‘focus’ and ‘manner’ in L2 contexts.