bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigallocatechin-3-gallate Can Prevent Type 2 Human Papillomavirus E7 from Suppressing Interferon-Stimulated Genes
Authors: Song Ji Young , Han Ju Hee , Song Yumee , Lee Ji Hyun , Choi Soon Yong , Park Young Min
Published: March 2021

Human papillomavirus (HPV) in high-risk groups is known to suppress the type I interferon (IFN) signaling pathway leading to the transcription of interferon-stimulated genes (ISGs), which have many antiviral functions. However, the effects of HPV on the action of various ISGs in low-risk groups are not fully understood. We aimed to investigate whether antiviral ISGs are expressed in transfected keratinocytes with type 2 HPV (HPV-2) E7. The mRNA and protein expressions of ISGs and type I IFN signaling pathway components were evaluated by quantitative real-time polymerase chain reaction, western blot, immunofluorescence, and/or immunohistochemistry. Compared with normal skin, mRNA expression of all ISGs in HPV-2 positive cutaneous warts was significantly decreased (p < 0.05). In comparison with empty vector transfection, E7 transfection significantly down-regulated the mRNA and protein expressions of ISGs and type I IFN signaling pathway components, which were significantly up-regulated by E7 siRNA transfection (p < 0.05). Interestingly, epigallocatechin-3-gallate (EGCG) pretreatment up-regulated the mRNA and protein expressions of ISGs and type I IFN signaling pathway components, which were significantly down-regulated by E7 transfection (p < 0.05). Our results demonstrate that EGCG is a potential candidate for cutaneous wart prevention.
Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma
Authors: Tabak Saray , Schreiber-Avissar Sofia , Beit-Yannai Elie
Published: March 2021

Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.
The ALS-Associated FUS (P525L) Variant Does Not Directly Interfere with Microtubule-Dependent Kinesin-1 Motility
Authors: Seifert Anne , Drechsler Hauke , Japtok Julia , Korten Till , Diez Stefan , Hermann Andreas
Published: March 2021

Deficient intracellular transport is a common pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility in vitro. Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms.
Salivary Outer Membrane Vesicles and DNA Methylation of Small Extracellular Vesicles as Biomarkers for Periodontal Status: A Pilot Study
Authors: Han Pingping , Bartold Peter Mark , Salomon Carlos , Ivanovski Sašo
Published: March 2021

Periodontitis is an inflammatory disease, associated with a microbial dysbiosis. Early detection using salivary small extracellular vesicles (sEVs) biomarkers may facilitate timely prevention. sEVs derived from different species (i.e., humans, bacteria) are expected to circulate in saliva. This pilot study recruited 22 participants (seven periodontal healthy, seven gingivitis and eight periodontitis) and salivary sEVs were isolated using the size-exclusion chromatography (SEC) method. The healthy, gingivitis and periodontitis groups were compared in terms of salivary sEVs in the CD9+ sEV subpopulation, Gram-negative bacteria-enriched lipopolysaccharide (LPS+) outer membrane vesicles (OMVs) and global DNA methylation pattern of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and N6-Methyladenosine (m6dA). It was found that LPS+ OMVs, global 5mC methylation and four periodontal pathogens (T. denticola, E. corrodens, P. gingivalis and F. nucleatum) that secreted OMVs were significantly increased in periodontitis sEVs compared to those from healthy groups. These differences were more pronounced in sEVs than the whole saliva and were more superior in distinguishing periodontitis than gingivitis, in comparison to healthy patients. Of note, global 5mC hypermethylation in salivary sEVs can distinguish periodontitis patients from both healthy controls and gingivitis patients with high sensitivity and specificity (AUC = 1). The research findings suggest that assessing global sEV methylation may be a useful biomarker for periodontitis.
Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE
Authors: Burns Marie , Ostendorf Lennard , Biesen Robert , Grützkau Andreas , Hiepe Falk , Mei Henrik E. , Alexander Tobias
Published: March 2021

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14++CD16+ monocytes, CD56+ CD16dim natural killer cells, marginal zone-like IgD+CD27+ B cells, and on CD4+ and CD8+ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.
Hyaluronic Acid and a Short Peptide Improve the Performance of a PCL Electrospun Fibrous Scaffold Designed for Bone Tissue Engineering Applications
Authors: Rachmiel Dana , Anconina Inbar , Rudnick-Glick Safra , Halperin-Sternfeld Michal , Adler-Abramovich Lihi , Sitt Amit
Published: March 2021

Bone tissue engineering is a rapidly developing, minimally invasive technique for regenerating lost bone with the aid of biomaterial scaffolds that mimic the structure and function of the extracellular matrix (ECM). Recently, scaffolds made of electrospun fibers have aroused interest due to their similarity to the ECM, and high porosity. Hyaluronic acid (HA) is an abundant component of the ECM and an attractive material for use in regenerative medicine; however, its processability by electrospinning is poor, and it must be used in combination with another polymer. Here, we used electrospinning to fabricate a composite scaffold with a core/shell morphology composed of polycaprolactone (PCL) polymer and HA and incorporating a short self-assembling peptide. The peptide includes the arginine-glycine-aspartic acid (RGD) motif and supports cellular attachment based on molecular recognition. Electron microscopy imaging demonstrated that the fibrous network of the scaffold resembles the ECM structure. In vitro biocompatibility assays revealed that MC3T3-E1 preosteoblasts adhered well to the scaffold and proliferated, with significant osteogenic differentiation and calcium mineralization. Our work emphasizes the potential of this multi-component approach by which electrospinning, molecular self-assembly, and molecular recognition motifs are combined, to generate a leading candidate to serve as a scaffold for bone tissue engineering.
The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis
Authors: Myngbay Askhat , Manarbek Limara , Ludbrook Steve , Kunz Jeannette
Published: March 2021

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.
N-(1,3,4-Oxadiazol-2-yl)Benzamides as Antibacterial Agents against Neisseria gonorrhoeae
Authors: Naclerio George A. , Abutaleb Nader S. , Alhashimi Marwa , Seleem Mohamed N. , Sintim Herman O.
Published: March 2021

The Centers for Disease Control and Prevention (CDC) recognizes Neisseria gonorrhoeae as an urgent-threat Gram-negative bacterial pathogen. Additionally, resistance to frontline treatment (dual therapy with azithromycin and ceftriaxone) has led to the emergence of multidrug-resistant N. gonorrhoeae, which has caused a global health crisis. The drug pipeline for N. gonorrhoeae has been severely lacking as new antibacterial agents have not been approved by the FDA in the last twenty years. Thus, there is a need for new chemical entities active against drug-resistant N. gonorrhoeae. Trifluoromethylsulfonyl (SO2CF3), trifluoromethylthio (SCF3), and pentafluorosulfanyl (SF5) containing N-(1,3,4-oxadiazol-2-yl)benzamides are novel compounds with potent activities against Gram-positive bacterial pathogens. Here, we report the discovery of new N-(1,3,4-oxadiazol-2-yl)benzamides (HSGN-237 and -238) with highly potent activity against N. gonorrhoeae. Additionally, these new compounds were shown to have activity against clinically important Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Listeria monocytogenes (minimum inhibitory concentrations (MICs) as low as 0.25 µg/mL). Both compounds were highly tolerable to human cell lines. Moreover, HSGN-238 showed an outstanding ability to permeate across the gastrointestinal tract, indicating it would have a high systemic absorption if used as an anti-gonococcal therapeutic.
Effects of Tyrosine and Tryptophan in Rats with Diet-Induced Obesity
Authors: Shipelin Vladimir A. , Trusov Nikita V. , Apryatin Sergey A. , Shumakova Antonina A. , Balakina Anastasia S. , Riger Nikolay A. , Gmoshinski Ivan V. , Nikityuk Dmitry B.
Published: March 2021

Amino acids tyrosine (Tyr) and tryptophan (Trp) play a significant role in the regulation of energy metabolism, locomotor activity, and eating behavior. We studied the possibility of modulating these processes in obesity by increasing the pool of Tyr and Trp in the experimental diet. As a model of obesity, we used Wistar rats fed a diet with an excess specific energy value (HFCD) for 64 days. Trp led to a normalization of the rats’ body weight almost to the control level, but increased anxiety-like behavior and decreased long-term memory. The consumption of amino acids resulted in increased grip strength and impairment of short-term memory. The locomotor activity of animals decreased with age as a result of Tyr consumption, while Trp, on the contrary, prevented this. The Tyr supplementation led to the normalization of triglycerides and LDL. In the spleen cell lysates, amino acids suppressed the production of proinflammatory cytokines. The liver tissue morphology showed that the consumption of Tyr noticeably weakened the signs of fatty degeneration. The addition of Trp, on the contrary, led to an unfavorable effect, consisting of the appearance of a high number of large rounded fatty vacuoles. The data obtained indicate a more pronounced anti-inflammatory effect of Tyr as compared to Trp.
Osthol Ameliorates Kidney Damage and Metabolic Syndrome Induced by a High-Fat/High-Sugar Diet
Authors: García-Arroyo Fernando E. , Gonzaga-Sánchez Guillermo , Tapia Edilia , Muñoz-Jiménez Itzel , Manterola-Romero Lino , Osorio-Alonso Horacio , Arellano-Buendía Abraham S. , Pedraza-Chaverri José , Roncal-Jiménez Carlos A. , Lanaspa Miguel A. , Johnson Richard J. , Sánchez-Lozada Laura Gabriela
Published: March 2021

Excessive intake of fructose results in metabolic syndrome (MS) and kidney damage, partly mediated by its metabolism by fructokinase-C or ketohexokinase-C (KHK-C). Osthol has antioxidant properties, is capable of regulating adipogenesis, and inhibits KHK-C activity. Here, we examined the potential protective role of osthol in the development of kidney disease induced by a Western (high-fat/high-sugar) diet. Control rats fed with a high-fat/high-sugar diet were compared with two groups that also received two different doses of osthol (30 mg/kg/d or 40 mg/kg/d body weight BW). A fourth group served as a normal control and received regular chow. At the end of the follow-up, kidney function, metabolic markers, oxidative stress, and lipogenic enzymes were evaluated. The Western diet induced MS (hypertension, hyperglycemia, hypertriglyceridemia, obesity, hyperuricemia), a fall in the glomerular filtration rate, renal tubular damage, and increased oxidative stress in the kidney cortex, with increased expression of lipogenic enzymes and increased kidney KHK expression. Osthol treatment prevented the development of MS and ameliorated kidney damage by inhibiting KHK activity, preventing oxidative stress via nuclear factor erythroid 2-related factor (Nrf2) activation, and reducing renal lipotoxicity. These data suggest that the nutraceutical osthol might be an ancillary therapy to slow the progression of MS and kidney damage induced by a Western diet.
Emerging Immunotherapies against Novel Molecular Targets in Breast Cancer
Authors: Sivaganesh Vignesh , Promi Nazifa , Maher Salma , Peethambaran Bela
Published: March 2021

Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administration, much research has been done on novel molecular targets that can especially be useful for triple-negative breast cancer (TNBC) immunotherapy. Combining emerging immunotherapeutics with tumor marker discovery sets the stage for highly targeted immunotherapy to be the future of cancer treatments. This review highlights the principles of CAR-T and BsAb therapy, improvements in CAR and BsAb engineering, and recently identified human breast cancer markers in the context of in vitro or in vivo CAR-T or BsAb treatment.
Effect of Different Wavelengths of Laser Irradiation on the Skin Cells
Authors: Cios Aleksandra , Ciepielak Martyna , Szymański Łukasz , Lewicka Aneta , Cierniak Szczepan , Stankiewicz Wanda , Mendrycka Mariola , Lewicki Sławomir
Published: March 2021

The invention of systems enabling the emission of waves of a certain length and intensity has revolutionized many areas of life, including medicine. Currently, the use of devices emitting laser light is not only an indispensable but also a necessary element of many diagnostic procedures. It also contributed to the development of new techniques for the treatment of diseases that are difficult to heal. The use of lasers in industry and medicine may be associated with a higher incidence of excessive radiation exposure, which can lead to injury to the body. The most exposed to laser irradiation is the skin tissue. The low dose laser irradiation is currently used for the treatment of various skin diseases. Therefore appropriate knowledge of the effects of lasers irradiation on the dermal cells’ metabolism is necessary. Here we present current knowledge on the clinical and molecular effects of irradiation of different wavelengths of light (ultraviolet (UV), blue, green, red, and infrared (IR) on the dermal cells.
Alteration of 3D Matrix Stiffness Regulates Viscoelasticity of Human Mesenchymal Stem Cells
Authors: Kao Ting-Wei , Chiou Arthur , Lin Keng-Hui , Liu Yi-Shiuan , Lee Oscar Kuang-Sheng
Published: March 2021

Human mesenchymal stem cells (hMSCs) possess potential of bone formation and were proposed as ideal material against osteoporosis. Although interrogation of directing effect on lineage specification by physical cues has been proposed, how mechanical stimulation impacts intracellular viscoelasticity during osteogenesis remained enigmatic. Cyto-friendly 3D matrix was prepared with polyacrylamide and conjugated fibronectin. The hMSCs were injected with fluorescent beads and chemically-induced toward osteogenesis. The mechanical properties were assessed using video particle tracking microrheology. Inverted epifluorescence microscope was exploited to capture the Brownian trajectory of hMSCs. Mean square displacement was calculated and transformed into intracellular viscoelasticity. Two different stiffness of microspheres (12 kPa, 1 kPa) were established. A total of 45 cells were assessed. hMSCs possessed equivalent mechanical traits initially in the first week, while cells cultured in rigid matrix displayed significant elevation over elastic (G′) and viscous moduli (G″) on day 7 (p < 0.01) and 14 (p < 0.01). However, after two weeks, soft niches no longer stiffened hMSCs, whereas the effect by rigid substrates was consistently during the entire differentiation course. Stiffness of matrix impacted the viscoelasticity of hMSCs. Detailed recognition of how microenvironment impacts mechanical properties and differentiation of hMSCs will facilitate the advancement of tissue engineering and regenerative medicine.
Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients
Authors: Wang Qun , Vattai Aurelia , Vilsmaier Theresa , Kaltofen Till , Steger Alexander , Mayr Doris , Mahner Sven , Jeschke Udo , Heidegger Helene Hildegard
Published: March 2021

Cervical cancer is primarily caused by the infection of high-risk human papillomavirus (hrHPV). Moreover, tumor immune microenvironment plays a significant role in the tumorigenesis of cervical cancer. Therefore, it is necessary to comprehensively identify predictive biomarkers from immunogenomics associated with cervical cancer prognosis. The Cancer Genome Atlas (TCGA) public database has stored abundant sequencing or microarray data, and clinical data, offering a feasible and reliable approach for this study. In the present study, gene profile and clinical data were downloaded from TCGA, and the Immunology Database and Analysis Portal (ImmPort) database. Wilcoxon-test was used to compare the difference in gene expression. Univariate analysis was adopted to identify immune-related genes (IRGs) and transcription factors (TFs) correlated with survival. A prognostic prediction model was established by multivariate cox analysis. The regulatory network was constructed and visualized by correlation analysis and Cytoscape, respectively. Gene functional enrichment analysis was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 204 differentially expressed IRGs were identified, and 22 of them were significantly associated with the survival of cervical cancer. These 22 IRGs were actively involved in the JAK-STAT pathway. A prognostic model based on 10 IRGs (APOD, TFRC, GRN, CSK, HDAC1, NFATC4, BMP6, IL17RD, IL3RA, and LEPR) performed moderately and steadily in squamous cell carcinoma (SCC) patients with FIGO stage I, regardless of the age and grade. Taken together, a risk score model consisting of 10 novel genes capable of predicting survival in SCC patients was identified. Moreover, the regulatory network of IRGs associated with survival (SIRGs) and their TFs provided potential molecular targets.
Nitric Oxide (NO) Scaffolds the Peroxisomal Protein–Protein Interaction Network in Higher Plants
Authors: Corpas Francisco J. , González-Gordo Salvador , Palma José M.
Published: March 2021

The peroxisome is a single-membrane subcellular compartment present in almost all eukaryotic cells from simple protists and fungi to complex organisms such as higher plants and animals. Historically, the name of the peroxisome came from a subcellular structure that contained high levels of hydrogen peroxide (H2O2) and the antioxidant enzyme catalase, which indicated that this organelle had basically an oxidative metabolism. During the last 20 years, it has been shown that plant peroxisomes also contain nitric oxide (NO), a radical molecule than leads to a family of derived molecules designated as reactive nitrogen species (RNS). These reactive species can mediate post-translational modifications (PTMs) of proteins, such as S-nitrosation and tyrosine nitration, thus affecting their function. This review aims to provide a comprehensive overview of how NO could affect peroxisomal metabolism and its internal protein-protein interactions (PPIs). Remarkably, many of the identified NO-target proteins in plant peroxisomes are involved in the metabolism of reactive oxygen species (ROS), either in its generation or its scavenging. Therefore, it is proposed that NO is a molecule with signaling properties with the capacity to modulate the peroxisomal protein-protein network and consequently the peroxisomal functions, especially under adverse environmental conditions.
Heat-Responsive miRNAs Participate in the Regulation of Male Fertility Stability in Soybean CMS-Based F1 under High Temperature Stress
Authors: Ding Xianlong , Guo Jinfeng , Zhang Qiqi , Yu Lifeng , Zhao Tuanjie , Yang Shouping
Published: March 2021

MicroRNAs (miRNAs), a class of noncoding small RNAs (sRNAs), are widely involved in the response to high temperature (HT) stress at both the seedling and flowering stages. To dissect the roles of miRNAs in regulating male fertility in soybean cytoplasmic male sterility (CMS)-based F1 under HT, sRNA sequencing was performed using flower buds from HT-tolerant and HT-sensitive CMS-based F1 combinations (NF1 and YF1, respectively). A total of 554 known miRNAs, 59 new members of known miRNAs, 712 novel miRNAs, and 1145 target genes of 580 differentially expressed miRNAs (DEMs) were identified under normal temperature and HT conditions. Further integrated analysis of sRNA and transcriptome sequencing found that 21 DEMs and 15 differentially expressed target genes, such as gma-miR397a/Laccase 2, gma-miR399a/Inorganic phosphate transporter 1-4, and gma-miR4413a/PPR proteins, mitochondrial-like, were negatively regulated under HT stress. Furthermore, all members of the gma-miR156 family were suppressed by HT stress in both NF1 and YF1, but were highly expressed in YF1 under HT condition. The negative correlation between gma-miR156b and its target gene squamosa promoter-binding protein-like 2b was confirmed by expression analysis, and overexpression of gma-miR156b in Arabidopsis led to male sterility under HT stress. With these results, we proposed that miRNAs play an important role in the regulation of male fertility stability in soybean CMS-based F1 under HT stress.
Dysregulation of Nociceptin/Orphanin FQ and Dynorphin Systems in the Extended Amygdala of Alcohol Preferring Marchigian Sardinian (msP) Rats
Authors: Caputi Francesca Felicia , Stopponi Serena , Rullo Laura , Palmisano Martina , Ubaldi Massimo , Candeletti Sanzio , Ciccocioppo Roberto , Romualdi Patrizia
Published: March 2021

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.
Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?
Authors: Kotyla Przemysław J. , Engelmann Małgorzata , Giemza-Stokłosa Joanna , Wnuk Bartosz , Islam Md Asiful
Published: March 2021

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.
Isolation and Assessment of a Highly-Active Anti-Inflammatory Exopolysaccharide from Mycelial Fermentation of a Medicinal Fungus Cs-HK1
Authors: Li Long-Qing , Song Ang-Xin , Wong Wing-Tak , Wu Jian-Yong
Published: March 2021

The purpose of this work was to fractionate the complex exopolysaccharide (EPS) from a medicinal fungus Ophiocordyceps sinensis Cs-HK1 based on the molecular weight (MW) range and to assess the in vitro anti-inflammatory activity of different EPS fractions in THP-1 cell culture. The lower MW fraction (EPS-LM-1) showed a much higher anti-inflammatory activity. EPS-LM-1 was identified as a heteropolysaccharide consisting of mannose, glucose, and galactose residues with an average MW of 360 kDa. EPS-LM-1 significantly inhibited the lipopolysaccharide-induced inflammatory responses with the effective concentrations for 50% inhibition below 5 µg/mL on a few major proinflammatory markers. With such a notable in vitro anti-inflammatory activity, EPS-LM-1 is a promising candidate for the development of a new anti-inflammation therapy.
The Biochemistry of Phytocannabinoids and Metabolic Engineering of Their Production in Heterologous Systems
Authors: Blatt-Janmaat Kaitlyn , Qu Yang
Published: March 2021

The medicinal properties of cannabis and the its legal status in several countries and jurisdictions has spurred the massive growth of the cannabis economy around the globe. The value of cannabis stems from its euphoric activity offered by the unique phytocannabinoid tetrahydrocannabinol (THC). However, this is rapidly expanding beyond THC owing to other non-psychoactive phytocannabinoids with new bioactivities that will contribute to their development into clinically useful drugs. The discovery of the biosynthesis of major phytocannabinoids has allowed the exploration of their heterologous production by synthetic biology, which may lead to the industrial production of rare phytocannabinoids or novel synthetic cannabinoid pharmaceuticals that are not easily offered by cannabis plants. This review summarizes the biosynthesis of major phytocannabinoids in detail, the most recent development of their metabolic engineering in various systems, and the engineering approaches and strategies used to increase the yield.
Participation of Amyloid and Tau Protein in Post-Ischemic Neurodegeneration of the Hippocampus of a Nature Identical to Alzheimer's Disease
Authors: Pluta Ryszard , Ouyang Liang , Januszewski Sławomir , Li Yang , Czuczwar Stanisław J.
Published: March 2021

Recent evidence suggests that amyloid and tau protein are of vital importance in post-ischemic death of CA1 pyramidal neurons of the hippocampus. In this review, we summarize protein alterations associated with Alzheimer's disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia, as well as their roles in post-ischemic hippocampus neurodegeneration. In recent years, multiple studies aimed to elucidate the post-ischemic processes in the development of hippocampus neurodegeneration. Their findings have revealed the dysregulation of genes for amyloid protein precursor, β-secretase, presenilin 1 and 2, tau protein, autophagy, mitophagy, and apoptosis identical in nature to Alzheimer's disease. Herein, we present the latest data showing that amyloid and tau protein associated with Alzheimer's disease and their genes play a key role in post-ischemic neurodegeneration of the hippocampus with subsequent development of dementia. Therefore, understanding the underlying process for the development of post-ischemic CA1 area neurodegeneration in the hippocampus in conjunction with Alzheimer's disease-related proteins and genes will provide the most important therapeutic development goals to date.
Specific Mycoparasite-Fusarium Graminearum Molecular Signatures in Germinating Seeds Disabled Fusarium Head Blight Pathogen’s Infection
Authors: Kim Seon Hwa , Lahlali Rachid , Karunakaran Chithra , Vujanovic Vladimir
Published: March 2021

Advances in Infrared (IR) spectroscopies have entered a new era of research with applications in phytobiome, plant microbiome and health. Fusarium graminearum 3-ADON is the most aggressive mycotoxigenic chemotype causing Fusarium head blight (FHB) in cereals; while Sphaerodes mycoparasitica is the specific Fusarium mycoparasite with biotrophic lifestyle discovered in cereal seeds and roots. Fourier transform infrared (FTIR) spectroscopy analyses depicted shifts in the spectral peaks related to mycoparasitism mainly within the region of proteins, lipids, also indicating a link between carbohydrates and protein regions, involving potential phenolic compounds. Especially, S. mycoparasitica contributes to significant changes in lipid region 3050–2800 cm−1, while in the protein region, an increasing trend was observed for the peaks 1655–1638 cm−1 (amide I) and 1549–1548 cm−1 (amide II) with changes in indicative protein secondary structures. Besides, the peak extending on the region 1520–1500 cm−1 insinuates a presence of aromatic compounds in presence of mycoparasite on the F. graminearum root sample. Monitoring shift in improved seed germination, fungus-fungus interface through scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM), and FTIR molecular signatures combined with principal component analysis (PCA) proved useful tools to detect an early mycoparasitism as a vital asset of the preventive biocontrol strategy against plant pathogens.
Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones
Authors: Perużyńska Magdalena , Borzyszkowska-Ledwig Aleksandra , Sośnicki Jacek G. , Struk Łukasz , Idzik Tomasz J. , Maciejewska Gabriela , Skalski Łukasz , Piotrowska Katarzyna , Łukasik Paweł , Droździk Marek , Kurzawski Mateusz
Published: March 2021

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine analogue (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.
An Integrated Bioinformatics Study of a Novel Niclosamide Derivative, NSC765689, a Potential GSK3β/β-Catenin/STAT3/CD44 Suppressor with Anti-Glioblastoma Properties
Authors: Mokgautsi Ntlotlang , Wen Ya-Ting , Lawal Bashir , Khedkar Harshita , Sumitra Maryam , Wu Alexander , Huang Hsu-Shan
Published: March 2021

Despite management efforts with standard surgery, radiation, and chemotherapy, glioblastoma multiform (GBM) remains resistant to treatment, which leads to tumor recurrence due to glioma stem cells (GSCs) and therapy resistance. In this study, we used random computer-based prediction and target identification to assess activities of our newly synthesized niclosamide-derived compound, NSC765689, to target GBM oncogenic signaling. Using target prediction analyses, we identified glycogen synthase kinase 3β (GSK3β), β-Catenin, signal transducer and activator of transcription 3 (STAT3), and cluster of differentiation 44 (CD44) as potential druggable candidates of NSC765689. The above-mentioned signaling pathways were also predicted to be overexpressed in GBM tumor samples compared to adjacent normal samples. In addition, using bioinformatics tools, we also identified microRNA (miR)-135b as one of the most suppressed microRNAs in GBM samples, which was reported to be upregulated through inhibition of GSK3β, and subsequently suppresses GBM tumorigenic properties and stemness. We further performed in silico molecular docking of NSC765689 with GBM oncogenes; GSK3β, β-Catenin, and STAT3, and the stem cell marker, CD44, to predict protein-ligand interactions. The results indicated that NSC765689 exhibited stronger binding affinities compared to its predecessor, LCC09, which was recently published by our laboratory, and was proven to inhibit GBM stemness and resistance. Moreover, we used available US National Cancer Institute (NCI) 60 human tumor cell lines to screen in vitro anticancer effects, including the anti-proliferative and cytotoxic activities of NSC765689 against GBM cells, and 50% cell growth inhibition (GI50) values ranged 0.23~5.13 μM. In summary, using computer-based predictions and target identification revealed that NSC765689 may be a potential pharmacological lead compound which can regulate GBM oncogene (GSK3β/β-Catenin/STAT3/CD44) signaling and upregulate the miR-135b tumor suppressor. Therefore, further in vitro and in vivo investigations will be performed to validate the efficacy of NSC765689 as a novel potential GBM therapeutic.
Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids
Authors: Mamouni Kenza , Kallifatidis Georgios , Lokeshwar Bal L.
Published: March 2021

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.
Effect of Aminated Chitosan-Coated Fe3O4 Nanoparticles with Applicational Potential in Nanomedicine on DPPG, DSPC, and POPC Langmuir Monolayers as Cell Membrane Models
Authors: Piosik Emilia , Ziegler-Borowska Marta , Chełminiak-Dudkiewicz Dorota , Martyński Tomasz
Published: March 2021

An adsorption process of magnetite nanoparticles functionalized with aminated chitosan (Fe3O4-AChit) showing application potential in nanomedicine into cell membrane models was studied. The cell membrane models were formed using a Langmuir technique from three selected phospholipids with different polar head-groups as well as length and carbon saturation of alkyl chains. The research presented in this work reveals the existence of membrane model composition-dependent regulation of phospholipid-nanoparticle interactions. The influence of the positively charged Fe3O4-AChit nanoparticles on a Langmuir film stability, phase state, and textures is much greater in the case of these formed by negatively charged 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) than those created by zwitterionic 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC). The adsorption kinetics recorded during penetration experiments show that this effect is caused by the strongest adsorption of the investigated nanoparticles into the DPPG monolayer driven very likely by the electrostatic attraction. The differences in the adsorption strength of the Fe3O4-AChit nanoparticles into the Langmuir films formed by the phosphatidylcholines were also observed. The nanoparticles adsorbed more easily into more loosely packed POPC monolayer.
Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats
Authors: Szkudelska Katarzyna , Deniziak Marzanna , Sassek Maciej , Szkudelski Ignacy , Noskowiak Wojciech , Szkudelski Tomasz
Published: March 2021

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue.
Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells
Authors: Han Jang Mi , Sohng Jae Kyung , Lee Woo-Haeng , Oh Tae-Jin , Jung Hye Jin
Published: March 2021

We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA.