bluuebunny/crossref_metadata_2025 huggingface dataset:
GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation
Authors: Joo Mina , Kim Donghyun , Lee Myung-Won , Lee Hyo Jin , Kim Jin-Man
Published: February 2023

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial–mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.
Herpes Simplex Virus 1 (HSV-1) Infected Cell Protein 0 (ICP0) Targets of Ubiquitination during Productive Infection of Primary Adult Sensory Neurons
Authors: Harrell Telvin L. , Davido David J. , Bertke Andrea S.
Published: February 2023

Herpes simplex virus 1 (HSV-1) enters sensory neurons with the potential for productive or latent infection. For either outcome, HSV-1 must curtail the intrinsic immune response, regulate viral gene expression, and remove host proteins that could restrict viral processes. Infected cell protein 0 (ICP0), a virus-encoded E3 ubiquitin ligase, supports these processes by mediating the transfer of ubiquitin to target proteins to change their location, alter their function, or induce their degradation. To identify ubiquitination targets of ICP0 during productive infection in sensory neurons, we immunoprecipitated ubiquitinated proteins from primary adult sensory neurons infected with HSV-1 KOS (wild-type), HSV-1 n212 (expressing truncated, defective ICP0), and uninfected controls using anti-ubiquitin antibody FK2 (recognizing K29, K48, K63 and monoubiquitinated proteins), followed by LC-MS/MS and comparative analyses. We identified 40 unique proteins ubiquitinated by ICP0 and 17 ubiquitinated by both ICP0 and host mechanisms, of which High Mobility Group Protein I/Y (HMG I/Y) and TAR DNA Binding Protein 43 (TDP43) were selected for further analysis. We show that ICP0 ubiquitinates HMG I/Y and TDP43, altering protein expression at specific time points during productive HSV-1 infection, demonstrating that ICP0 manipulates the sensory neuronal environment in a time-dependent manner to regulate infection outcome in neurons.
Covalently Grafted Peptides to Decellularized Pericardium: Modulation of Surface Density
Authors: Cassari Leonardo , Todesco Martina , Zamuner Annj , Imran Saima Jalil , Casarin Martina , Sandrin Deborah , Ródenas-Rochina Joaquin , Gomez Ribelles José Luis , Romanato Filippo , Bagno Andrea , Gerosa Gino , Dettin Monica
Published: February 2023

The covalent functionalization of synthetic peptides allows the modification of different biomaterials (metallic, polymeric, and ceramic), which are enriched with biologically active sequences to guide cell behavior. Recently, this strategy has also been applied to decellularized biological matrices. In this study, the covalent anchorage of a synthetic peptide (REDV) to a pericardial matrix decellularized via Schiff base is realized starting from concentrated peptide solutions (10−4 M and 10−3 M). The use of a labeled peptide demonstrated that as the concentration of the working solution increased, the surface density of the anchored peptide increased as well. These data are essential to pinpointing the concentration window in which the peptide promotes the desired cellular activity. The matrices were extensively characterized by Water Contact Angle (WCA) analysis, Differential Scanning Calorimetry (DSC) analysis, geometric feature evaluation, biomechanical tests, and preliminary in vitro bioassays.
Melatonin Delays Postharvest Senescence through Suppressing the Inhibition of BrERF2/BrERF109 on Flavonoid Biosynthesis in Flowering Chinese Cabbage
Authors: Yue Lingqi , Kang Yunyan , Zhong Min , Kang Dengjin , Zhao Puyan , Chai Xirong , Yang Xian
Published: February 2023

Flowering Chinese cabbage is prone to withering, yellowing and deterioration after harvest. Melatonin plays a remarkable role in delaying leaf senescence and increasing flavonoid biosynthesis. However, the underlying molecular mechanisms of melatonin procrastinating postharvest senescence by regulating flavonoid biosynthesis remain largely unknown. In this study, melatonin could promote flavonoid accumulation and delay the postharvest senescence of flowering Chinese cabbage. Surprisingly, we observed that BrFLS1 and BrFLS3.2 were core contributors in flavonoid biosynthesis, and BrERF2 and BrERF109 were crucial ethylene response factors (ERFs) through the virus-induced gene silencing (VIGS) technique, which is involved in regulating the postharvest senescence under melatonin treatment. Furthermore, yeast one-hybrid (Y1H), dual luciferase (LUC), and β-glucuronidase (GUS) tissue staining experiments demonstrated that BrERF2/BrERF109 negatively regulated the transcripts of BrFLS1 and BrFLS3.2 by directly binding to their promoters, respectively. Silencing BrERF2/BrERF109 significantly upregulated the transcripts of BrFLS1 and BrFLS3.2, promoting flavonoid accumulation, and postponing the leaf senescence. Our results provided a new insight into the molecular regulatory network of melatonin delaying leaf senescence and initially ascertained that melatonin promoted flavonoid accumulation by suppressing the inhibition of BrERF2/BrERF109 on the transcripts of BrFLS1 and BrFLS3.2, which led to delaying the leaf senescence of postharvest flowering Chinese cabbage.
Fascia Layer—A Novel Target for the Application of Biomaterials in Skin Wound Healing
Authors: Ye Haifeng , Rinkevich Yuval
Published: February 2023

As the first barrier of the human body, the skin has been of great concern for its wound healing and regeneration. The healing of large, refractory wounds is difficult to be repaired by cell proliferation at the wound edges and usually requires manual intervention for treatment. Therefore, therapeutic tools such as stem cells, biomaterials, and cytokines have been applied to the treatment of skin wounds. Skin microenvironment modulation is a key technology to promote wound repair and skin regeneration. In recent years, a series of novel bioactive materials that modulate the microenvironment and cell behavior have been developed, showing the ability to efficiently facilitate wound repair and skin attachment regeneration. Meanwhile, our lab found that the fascial layer has an indispensable role in wound healing and repair, and this review summarizes the research progress of related bioactive materials and their role in wound healing.
The Relationship between Serum miRNAs and Early Mortality in Multiple Myeloma Patients Treated with Bortezomib-Based Regimens
Authors: Puła Anna , Robak Paweł , Jarych Dariusz , Mikulski Damian , Misiewicz Małgorzata , Drozdz Izabela , Fendler Wojciech , Szemraj Janusz , Robak Tadeusz
Published: February 2023

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment. Despite the progress made in treatment, some MM patients still die within the first year of diagnosis. Numerous studies investigating microRNA (miRNA) expression patterns suggest they may be good prognostic markers. The primary aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients who were later treated with bortezomib-based regimens, and to determine their potential to predict early mortality. The study was conducted in 70 prospectively recruited patients with newly diagnosed MM admitted to the Department of Hematology of the Copernicus Memorial Hospital, Lodz (Poland) between 2017 and 2021. Among them, 17 patients experienced death within 12 months of diagnosis. The expression of 31 selected miRNAs was determined using a miRCURY LNA miRNA Custom PCR Panel. The obtained clinical data included patient characteristics on diagnosis, treatment regimen, response to treatment, and follow-up. Differential expression analysis found two miRNAs to be significantly downregulated in the early mortality group: hsa-miR-328-3p (fold change—FC: 0.72, p = 0.0342) and hsa-miR-409-3p (FC: 0.49, p = 0.0357). Univariate and multivariate logistic regression analyses were performed to assess the early mortality rate. The final model consisted of hsa-miR-409-3p, hsa-miR-328-3p, age, and R-ISS 3. It yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761–0.965) with 88.2% sensitivity and 77.5% specificity. Further external validation of our model is needed to confirm its clinical value.
Mechanisms of Prostate Cancer Cells Survival and Their Therapeutic Targeting
Authors: Pejčić Tomislav , Todorović Zoran , Đurašević Siniša , Popović Lazar
Published: February 2023

Prostate cancer (PCa) is today the second most common cancer in the world, with almost 400,000 deaths annually. Multiple factors are involved in the etiology of PCa, such as older age, genetic mutations, ethnicity, diet, or inflammation. Modern treatment of PCa involves radical surgical treatment or radiation therapy in the stages when the tumor is limited to the prostate. When metastases develop, the standard procedure is androgen deprivation therapy, which aims to reduce the level of circulating testosterone, which is achieved by surgical or medical castration. However, when the level of testosterone decreases to the castration level, the tumor cells adapt to the new conditions through different mechanisms, which enable their unhindered growth and survival, despite the therapy. New knowledge about the biology of the so-called of castration-resistant PCa and the way it adapts to therapy will enable the development of new drugs, whose goal is to prolong the survival of patients with this stage of the disease, which will be discussed in this review.
Chromium Nanoparticles Together with a Switch Away from High-Fat/Low-Fiber Dietary Habits Enhances the Pro-Healthy Regulation of Liver Lipid Metabolism and Inflammation in Obese Rats
Authors: Fotschki Bartosz , Ognik Katarzyna , Fotschki Joanna , Napiórkowska Dorota , Cholewińska Ewelina , Krauze Magdalena , Juśkiewicz Jerzy
Published: February 2023

The study on Wistar rats was conducted to investigate the effects of a pharmacologically relevant dose 0.3 mg/kg body weight of chromium supplementation (commonly used picolinate or novel form as nanoparticles) and switching away from obesogenic dietary habits on the parameters of lipid metabolism, inflammation, and oxidative stress in liver and plasma. Favorable effects related to dietary changes from the obesogenic diet were considerably enhanced when the diet was supplemented with chromium nanoparticles. This combination exerted the strongest fat content and cholesterol reduction in the liver. Moreover, in this group, a favorable antioxidative effect was observed through GSH/GSSG elevation in the liver as well as ALT activity reduction in the plasma and IL-6 levels in the liver. The molecular mechanisms associated with regulating lipid metabolism, oxidative stress and inflammation might be related to lower expression of HIF-1α, COX-2, and LOX-1 and upregulation of PPARα in the liver. Supplementation with chromium nanoparticles without changes in the obesogenic diet also favorably affected lipid metabolism and oxidative stress in the liver; however, the examined effects were moderate. In conclusion, the favorable effects of switching from an obesogenic to a balanced diet on hepatic lipid metabolism, oxidative stress, and inflammation induced by an obesogenic diet might be enhanced by supplementation with chromium nanoparticles.
Molecular Analysis of MgO Nanoparticle-Induced Immunity against Fusarium Wilt in Tomato
Authors: Takehara Yushi , Fijikawa Isamu , Watanabe Akihiro , Yonemura Ayumi , Kosaka Tomoyuki , Sakane Kosei , Imada Kiyoshi , Sasaki Kazunori , Kajihara Hiroshi , Sakai Shoji , Mizukami Yoichi , Haider Muhammad Salman , Jogaiah Sudisha , Ito Shin-ichi
Published: February 2023

Fusarium wilt, caused by Fusarium oxysporum f. sp. lycopersici (FOL), is a devastating soilborne disease in tomatoes. Magnesium oxide nanoparticles (MgO NPs) induce strong immunity against Fusarium wilt in tomatoes. However, the mechanisms underlying this immunity remain poorly understood. Comparative transcriptome analysis and microscopy of tomato roots were performed to determine the mechanism of MgO NP-induced immunity against FOL. Eight transcriptomes were prepared from tomato roots treated under eight different conditions. Differentially expressed genes were compared among the transcriptomes. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that in tomato roots pretreated with MgO NPs, Rcr3 encoding apoplastic protease and RbohD encoding NADPH oxidase were upregulated when challenge-inoculated with FOL. The gene encoding glycine-rich protein 4 (SlGRP4) was chosen for further analysis. SlGRP4 was rapidly transcribed in roots pretreated with MgO NPs and inoculated with FOL. Immunomicroscopy analysis showed that SlGRP4 accumulated in the cell walls of epidermal and vascular vessel cells of roots pretreated with MgO NPs, but upon FOL inoculation, SlGRP4 further accumulated in the cell walls of cortical tissues within 48 h. The results provide new insights into the probable mechanisms of MgO NP-induced tomato immunity against Fusarium wilt.
Lipoprotein Metabolism, Protein Aggregation, and Alzheimer’s Disease: A Literature Review
Authors: Grao-Cruces Elena , Claro-Cala Carmen M. , Montserrat-de la Paz Sergio , Nobrega Clevio
Published: February 2023

Alzheimer’s disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features: amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role; however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain; apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD.
Overview of Antimicrobial Biodegradable Polyester-Based Formulations
Authors: Gherasim Oana , Grumezescu Valentina , Irimiciuc Stefan Andrei
Published: February 2023

As the clinical complications induced by microbial infections are known to have life-threatening side effects, conventional anti-infective therapy is necessary, but not sufficient to overcome these issues. Some of their limitations are connected to drug-related inefficiency or resistance and pathogen-related adaptive modifications. Therefore, there is an urgent need for advanced antimicrobials and antimicrobial devices. A challenging, yet successful route has been the development of new biostatic or biocide agents and biomaterials by considering the indisputable advantages of biopolymers. Polymers are attractive materials due to their physical and chemical properties, such as compositional and structural versatility, tunable reactivity, solubility and degradability, and mechanical and chemical tunability, together with their intrinsic biocompatibility and bioactivity, thus enabling the fabrication of effective pharmacologically active antimicrobial formulations. Besides representing protective or potentiating carriers for conventional drugs, biopolymers possess an impressive ability for conjugation or functionalization. These aspects are key for avoiding malicious side effects or providing targeted and triggered drug delivery (specific and selective cellular targeting), and generally to define their pharmacological efficacy. Moreover, biopolymers can be processed in different forms (particles, fibers, films, membranes, or scaffolds), which prove excellent candidates for modern anti-infective applications. This review contains an overview of antimicrobial polyester-based formulations, centered around the effect of the dimensionality over the properties of the material and the effect of the production route or post-processing actions.
Protective Effect of Avenanthramide-C on Auditory Hair Cells against Oxidative Stress, Inflammatory Cytokines, and DNA Damage in Cisplatin-Induced Ototoxicity
Authors: Umugire Alphonse , Nam Yoon Seok , Nam Ye Eun , Choi Young Mi , Choi Se Myeong , Lee Sungsu , Cho Jong Hyun , Cho Hyong-Ho
Published: February 2023

Cisplatin-induced ototoxicity leads to hearing impairment, possibly through reactive oxygen species (ROS) production and DNA damage in cochlear hair cells (HC), although the exact mechanism is unknown. Avenanthramide-C (AVN-C), a natural, potent antioxidant, was evaluated in three study groups of normal adult C57Bl/6 mice (control, cisplatin, and AVN-C+cisplatin) for the prevention of cisplatin-induced hearing loss. Auditory brainstem responses and immunohistochemistry of outer hair cells (OHCs) were ascertained. Cell survival, ROS production, Phospho-H2AX-enabled tracking of DNA damage-repair kinetics, and expression levels of inflammatory cytokines (TNF-α, IL-1β, IL6, iNOS, and COX2) were assessed using House Ear Institute-Organ of Corti 1 (HEI-OC1 Cells). In the in vivo mouse model, following cisplatin-induced damage, AVN-C decreased the hearing thresholds and sheltered all cochlear turns’ OHCs. In HEI-OC1 cells, AVN-C preserved cell viability and decreased ROS production, whereas cisplatin enhanced both ROS levels and cell viability. In HEI-OC1 cells, AVN-C downregulated IL6, IL-1β, TNF-α, iNOS, and COX2 production that was upregulated by cisplatin treatment. AVN-C attenuated the cisplatin-enhanced nuclear H2AX activation. AVN-C had a strong protective effect against cisplatin-induced ototoxicity through inhibition of ROS and inflammatory cytokine production and DNA damage and is thus a promising candidate for preventing cisplatin-induced sensorineural hearing loss.
The Protective Role of Glutathione on Zinc-Induced Neuron Death after Brain Injuries
Authors: Park Min Kyu , Choi Bo Young , Kho A Ra , Lee Song Hee , Hong Dae Ki , Kang Beom Seok , Lee Si Hyun , Suh Sang Won
Published: February 2023

Glutathione (GSH) is necessary for maintaining physiological antioxidant function, which is responsible for maintaining free radicals derived from reactive oxygen species at low levels and is associated with improved cognitive performance after brain injury. GSH is produced by the linkage of tripeptides that consist of glutamic acid, cysteine, and glycine. The adequate supplementation of GSH has neuroprotective effects in several brain injuries such as cerebral ischemia, hypoglycemia, and traumatic brain injury. Brain injuries produce an excess of reactive oxygen species through complex biochemical cascades, which exacerbates primary neuronal damage. GSH concentrations are known to be closely correlated with the activities of certain genes such as excitatory amino acid carrier 1 (EAAC1), glutamate transporter-associated protein 3–18 (Gtrap3-18), and zinc transporter 3 (ZnT3). Following brain-injury-induced oxidative stress, EAAC1 function is negatively impacted, which then reduces cysteine absorption and impairs neuronal GSH synthesis. In these circumstances, vesicular zinc is also released into the synaptic cleft and then translocated into postsynaptic neurons. The excessive influx of zinc inhibits glutathione reductase, which inhibits GSH’s antioxidant functions in neurons, resulting in neuronal damage and ultimately in the impairment of cognitive function. Therefore, in this review, we explore the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death. Furthermore, we seek to understand how the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury.
Design, Synthesis and Antimicrobial Evaluation of New N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase
Authors: Šlechta Petr , Needle Adam Anthony , Jand’ourek Ondřej , Paterová Pavla , Konečná Klára , Bárta Pavel , Kuneš Jiří , Kubíček Vladimír , Doležal Martin , Kučerová-Chlupáčová Marta
Published: February 2023

Tuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides 1–19 via the acylation of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol with various activated (hetero)arylcarboxylic acids. These novel compounds have been tested in vitro against a panel of clinically important fungi and bacteria, including mycobacteria. Some of the compounds inhibited the growth of mycobacteria in the range of micromolar concentrations and retained this activity also against multidrug-resistant clinical isolates. Half the maximal inhibitory concentrations against the HepG2 cell line indicated an acceptable toxicological profile. No growth inhibition of other bacteria and fungi demonstrated selectivity of the compounds against mycobacteria. The structure–activity relationships have been derived and supported with a molecular docking study, which confirmed a selectivity toward the potential target leucyl-tRNA synthetase without an impact on the human enzyme. The presented compounds can become important materials in antimycobacterial research.
Ubiquitin-Related Modifier 1 (URM-1) Modulates Cx43 in Breast Cancer Cell Lines
Authors: El-Hajjar Layal , Saliba Jessica , Karam Mario , Shaito Abdullah , El Hajj Hiba , El-Sabban Marwan
Published: February 2023

Gap-junction-forming connexins are exquisitely regulated by post-translational modifications (PTMs). In particular, the PTM of connexin 43 (Cx43), a tumor suppressor protein, regulates its turnover and activity. Here, we investigated the interaction of Cx43 with the ubiquitin-related modifier 1 (URM-1) protein and its impact on tumor progression in two breast cancer cell lines, highly metastatic triple-negative MDA-MB-231 and luminal breast cancer MCF-7 cell lines. To evaluate the subsequent modulation of Cx43 levels, URM-1 was downregulated in these cells. The transcriptional levels of epithelial-to-mesenchymal transition (EMT) markers and the metastatic phenotype were assessed. We demonstrated that Cx43 co-localizes and interacts with URM-1, and URMylated Cx43 was accentuated upon cellular stress. The significant upregulation of small ubiquitin-like modifier-1 (SUMO-1) was also observed. In cells with downregulated URM-1, Cx43 expression significantly decreased, and SUMOylation by SUMO-1 was affected. The concomitant expression of EMT markers increased, leading to increased proliferation, migration, and invasion potential. Inversely, the upregulation of URM-1 increased Cx43 expression and reversed EMT-induced processes, underpinning a role for this PTM in the observed phenotypes. This study proposes that the URMylation of Cx43 in breast cancer cells regulates its tumor suppression properties and contributes to breast cancer cell malignancy.
The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation
Authors: Poljšak Borut , Kovač Vito , Špalj Stjepan , Milisav Irina
Published: February 2023

The molecule NAD+ is a coenzyme for enzymes catalyzing cellular redox reactions in several metabolic pathways, encompassing glycolysis, TCA cycle, and oxidative phosphorylation, and is a substrate for NAD+-dependent enzymes. In addition to a hydride and electron transfer in redox reactions, NAD+ is a substrate for sirtuins and poly(adenosine diphosphate–ribose) polymerases and even moderate decreases in its cellular concentrations modify signaling of NAD+-consuming enzymes. Age-related reduction in cellular NAD+ concentrations results in metabolic and aging-associated disorders, while the consequences of increased NAD+ production or decreased degradation seem beneficial. This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.
A New Signature of Sarcoma Based on the Tumor Microenvironment Benefits Prognostic Prediction
Authors: Zhang Guanran , Jian Aiwen , Zhang Yundi , Zhang Xiaoli
Published: February 2023

Sarcomas are a group of malignant tumors derived from mesenchymal tissues that display complex and variable pathological types. The impact of the immune properties of the tumor microenvironment (TME) on the prognosis, treatment, and management of sarcomas has attracted attention, requiring the exploration of sensitive and accurate signatures. In this study, The Cancer Genome Atlas (TCGA) database was searched to screen for an RNA sequencing dataset, retrieving 263 sarcoma and 2 normal samples with survival data. Genes associated with immune regulation in sarcomas were retrieved from the Tumor Immune Estimation Resource database to estimate tumor purity and immune cell infiltration levels. The samples were then divided into the immune-high and immune-low groups. Then, we screened for differentially expressed genes (DEGs) between the two groups. The intersection between immune-related genes and DEGs was then determined. Univariate Cox and least absolute shrinkage and selection operator analyses were used to select ideal genes for prognostic prediction and subsequent construction of a risk signature. A survival analysis was performed to reveal the dissimilarity in survival between the high- and low-score groups. Finally, a nomogram was generated to verify the accuracy and reliability of the signature. Through Estimation of STromal and Immune cells in MAlignant Tumour tissues using Expression (ESTIMATE) analysis, high ESTIMATE, and low tumor purity were significantly associated with a favorable prognosis. Moreover, a total of 5259 DEGs were retrieved, the majority of which were downregulated. In total, 590 immune-associated genes overlapped with the DEGs, among which nine hub genes were identified. Finally, two candidate genes, ACVR2B and NFYA, were identified, based on which a risk signature was constructed. The risk signature constructed in this study is accurate and reliable for the prognostic prediction and phenotyping of sarcomas.
Hepatic Glucose Metabolism Disorder Induced by Adipose Tissue-Derived miR-548ag via DPP4 Upregulation
Authors: Chu Xiaolong , Hou Yanting , Zhang Xueting , Li Menghuan , Ma Dingling , Tang Yihan , Yuan Chenggang , Sun Chaoyue , Liang Maodi , Liu Jie , Wei Qianqian , Chang Yongsheng , Wang Cuizhe , Zhang Jun
Published: February 2023

The present study aimed to explore the molecular mechanism underlying the regulation of glucose metabolism by miR-548ag. For the first time, we found that miR-548ag expression was elevated in the abdominal adipose tissue and serum of subjects with obesity and type 2 diabetes mellitus (T2DM). The conditional knockout of adipose tissue Dicer notably reduced the expression and content of miR-548ag in mouse adipose tissue, serum, and liver tissue. The combined use of RNAseq, an miRNA target gene prediction software, and the dual luciferase reporter assay confirmed that miR-548ag exerts a targeted regulatory effect on DNMT3B and DPP4. miR-548ag and DPP4 expression was increased in the adipose tissue, serum, and liver tissue of diet-induced obese mice, while DNMT3B expression was decreased. It was subsequently confirmed both in vitro and in vivo that adipose tissue-derived miR-548ag impaired glucose tolerance and insulin sensitivity by inhibiting DNMT3B and upregulating DPP4. Moreover, miR-548ag inhibitors significantly improved the adverse metabolic phenotype in both obese mice and db/db mice. These results revealed that the expression of the adipose tissue-derived miR-548ag increased in obese subjects, and that this could upregulate the expression of DPP4 by targeting DNMT3B, ultimately leading to glucose metabolism disorder. Therefore, miR-548ag could be utilized as a potential target in the treatment of T2DM.
Do Circulating Extracellular Vesicles Strictly Reflect Bronchoalveolar Lavage Extracellular Vesicles in COPD?
Authors: Tinè Mariaenrica , Neri Tommaso , Biondini Davide , Bernardinello Nicol , Casara Alvise , Conti Maria , Minniti Marianna , Cosio Manuel G. , Saetta Marina , Celi Alessandro , Nieri Dario , Bazzan Erica
Published: February 2023

Cell-derived extracellular vesicles (EVs) found in the circulation and body fluids contain biomolecules that could be used as biomarkers for lung and other diseases. EVs from bronchoalveolar lavage (BAL) might be more informative of lung abnormalities than EVs from blood, where information might be diluted. To compare EVs’ characteristics in BAL and blood in smokers with and without COPD. Same-day BAL and blood samples were obtained in 9 nonsmokers (NS), 11 smokers w/o COPD (S), and 9 with COPD (SCOPD) (FEV1: 59 ± 3% pred). After differential centrifugation, EVs (200–500 nm diameter) were identified by flow cytometry and labeled with cell-type specific antigens: CD14 for macrophage-derived EVs, CD326 for epithelial-derived EVs, CD146 for endothelial-derived EVs, and CD62E for activated-endothelial-derived EVs. In BAL, CD14-EVs were increased in S compared to NS [384 (56–567) vs. 172 (115–282) events/μL; p = 0.007] and further increased in SCOPD [619 (224–888)] compared to both S (p = 0.04) and NS (p < 0.001). CD326-EVs were increased in S [760 (48–2856) events/μL, p < 0.001] and in SCOPD [1055 (194–11,491), p < 0.001] when compared to NS [15 (0–68)]. CD146-EVs and CD62E-EVs were similar in the three groups. In BAL, significant differences in macrophage and epithelial-derived EVs can be clearly detected between NS, S and SCOPD, while these differences were not found in plasma. This suggests that BAL is a better medium than blood to study EVs in lung diseases.
Unique Features of Satellite DNA Transcription in Different Tissues of Caenorhabditis elegans
Authors: Subirana Juan A. , Messeguer Xavier
Published: February 2023

A large part of the genome is known to be transcribed as non-coding DNA including some tandem repeats (satellites) such as telomeric/centromeric satellites in different species. However, there has been no detailed study on the eventual transcription of the interspersed satellites found in many species. In the present paper, we studied the transcription of the abundant DNA satellites in the nematode Caenorhabditis elegans using available RNA-Seq results. We found that many of them have been transcribed, but usually in an irregular manner; different regions of a satellite have been transcribed with variable efficiency. Satellites with a similar repeat sequence also have a different transcription pattern depending on their position in the genome. We also describe the peculiar features of satellites associated with Helitron transposons in C. elegans. Our demonstration that some satellite RNAs are transcribed adds a new family of non-coding RNAs, a new element in the world of RNA interference, with new paths for the control of mRNA translation. This is a field that requires further investigation and will provide a deeper understanding of gene expression and control.
Insights of Endocytosis Signaling in Health and Disease
Authors: Pathak Chandramani , Vaidya Foram U. , Waghela Bhargav N. , Jaiswara Pradip Kumar , Gupta Vishal Kumar , Kumar Ajay , Rajendran Barani Kumar , Ranjan Kishu
Published: February 2023

Endocytosis in mammalian cells is a fundamental cellular machinery that regulates vital physiological processes, such as the absorption of metabolites, release of neurotransmitters, uptake of hormone cellular defense, and delivery of biomolecules across the plasma membrane. A remarkable characteristic of the endocytic machinery is the sequential assembly of the complex proteins at the plasma membrane, followed by internalization and fusion of various biomolecules to different cellular compartments. In all eukaryotic cells, functional characterization of endocytic pathways is based on dynamics of the protein complex and signal transduction modules. To coordinate the assembly and functions of the numerous parts of the endocytic machinery, the endocytic proteins interact significantly within and between the modules. Clathrin-dependent and -independent endocytosis, caveolar pathway, and receptor mediated endocytosis have been attributed to a greater variety of physiological and pathophysiological roles such as, autophagy, metabolism, cell division, apoptosis, cellular defense, and intestinal permeabilization. Notably, any defect or alteration in the endocytic machinery results in the development of pathological consequences associated with human diseases such as cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. In this review, an in-depth endeavor has been made to illustrate the process of endocytosis, and associated mechanisms describing pathological manifestation associated with dysregulated endocytosis machinery.
The Functional Meaning of 5′UTR in Protein-Coding Genes
Authors: Ryczek Natalia , Łyś Aneta , Makałowska Izabela
Published: February 2023

As it is well known, messenger RNA has many regulatory regions along its sequence length. One of them is the 5′ untranslated region (5’UTR), which itself contains many regulatory elements such as upstream ORFs (uORFs), internal ribosome entry sites (IRESs), microRNA binding sites, and structural components involved in the regulation of mRNA stability, pre-mRNA splicing, and translation initiation. Activation of the alternative, more upstream transcription start site leads to an extension of 5′UTR. One of the consequences of 5′UTRs extension may be head-to-head gene overlap. This review describes elements in 5′UTR of protein-coding transcripts and the functional significance of protein-coding genes 5′ overlap with implications for transcription, translation, and disease.
Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu
Authors: Cunha Andreia E. S. , Loureiro Rui J. S. , Simões Carlos J. V. , Brito Rui M. M.
Published: February 2023

Influenza viruses are responsible for significant morbidity and mortality worldwide in winter seasonal outbreaks and in flu pandemics. Influenza viruses have a high rate of evolution, requiring annual vaccine updates and severely diminishing the effectiveness of the available antivirals. Identifying novel viral targets and developing new effective antivirals is an urgent need. One of the most promising new targets for influenza antiviral therapy is non-structural protein 1 (NS1), a highly conserved protein exclusively expressed in virus-infected cells that mediates essential functions in virus replication and pathogenesis. Interaction of NS1 with the host proteins PI3K and TRIM25 is paramount for NS1’s role in infection and pathogenesis by promoting viral replication through the inhibition of apoptosis and suppressing interferon production, respectively. We, therefore, conducted an analysis of the druggability of this viral protein by performing molecular dynamics simulations on full-length NS1 coupled with ligand pocket detection. We identified several druggable pockets that are partially conserved throughout most of the simulation time. Moreover, we found out that some of these druggable pockets co-localize with the most stable binding regions of the protein–protein interaction (PPI) sites of NS1 with PI3K and TRIM25, which suggests that these NS1 druggable pockets are promising new targets for antiviral development.
Recent Advancements in Topical Anti-Psoriatic Nanostructured Lipid Carrier-Based Drug Delivery
Authors: Patil Tulshidas S. , Gujarathi Nayan A. , Aher Abhijeet A. , Pachpande Hemal E. , Sharma Charu , Ojha Shreesh , Goyal Sameer N. , Agrawal Yogeeta O.
Published: February 2023

Psoriasis is linked with unusual differentiation and hyperproliferation of epidermal keratinocytes that significantly impair the quality of life (QoL) of patients. The present treatment options only provide symptomatic relief and are surrounded by various adverse effects. Recently, nanostructured lipid carriers (NLCs) have emerged as next-generation nanocarriers with better physicochemical characteristics. The current manuscript provides background information on psoriasis, its pathophysiology, existing treatment options, and its limitations. It highlights the advantages, rationale, and mechanism of the permeation of NLCs for the treatment of psoriasis. It further gives a detailed account of various NLC nanoformulations for the treatment of psoriasis. In addition, tabular information is provided on the most relevant patents on NLCs for treating psoriasis. Lastly, light is shed on regulatory considerations related to NLC-like nanoformulations. In the treatment of psoriasis, NLCs display a sustained release drug profile, an ability to incorporate both hydrophobic and hydrophilic drugs, an enhancement in skin hydration, penetrability, retention, and bioavailability of the drug, along with reduced staining potential as compared to conventional ointments, and decreased side effects of drug molecules. This affirms the bright future of NLC nanoformulations in the treatment of psoriasis. However, academic industry collaboration and more sound regulatory controls are required to commercialize the NLC nanoformulations for psoriasis treatment.
Emerging RUNX2-Mediated Gene Regulatory Mechanisms Consisting of Multi-Layered Regulatory Networks in Skeletal Development
Authors: Hojo Hironori
Published: February 2023

Skeletal development is tightly coordinated by chondrocytes and osteoblasts, which are derived from skeletal progenitors, and distinct cell-type gene regulatory programs underlie the specification and differentiation of cells. Runt-related transcription factor 2 (Runx2) is essential to chondrocyte hypertrophy and osteoblast differentiation. Genetic studies have revealed the biological functions of Runx2 and its involvement in skeletal genetic diseases. Meanwhile, molecular biology has provided a framework for our understanding of RUNX2-mediated transactivation at a limited number of cis-regulatory elements. Furthermore, studies using next-generation sequencing (NGS) have provided information on RUNX2-mediated gene regulation at the genome level and novel insights into the multiple layers of gene regulatory mechanisms, including the modes of action of RUNX2, chromatin accessibility, the concept of pioneer factors and phase separation, and three-dimensional chromatin organization. In this review, I summarize the emerging RUNX2-mediated regulatory mechanism from a multi-layer perspective and discuss future perspectives for applications in the treatment of skeletal diseases.
Endogenous DNase Activity in an Animal Model of Acute Liver Failure
Authors: Janovičová Ľubica , Kmeťová Katarína , Pribulová Nikola , Janko Jakub , Gromová Barbora , Gardlík Roman , Celec Peter
Published: February 2023

Deoxyribonucleases (DNases) cleave extracellular DNA (ecDNA) and are under intense research as interventions for diseases associated with high ecDNA, such as acute live injury. DNase I treatment decreases morbidity and mortality in this animal model. Endogenous DNase activity has high interindividual variability. In this study, we tested the hypothesis that high endogenous DNase activity is beneficial in an animal model of acute liver failure. DNase activity was measured in the plasma of adult male mice taken before i.p. injection of thioacetamide to induce acute liver failure. The survival of mice was monitored for 48 h. Mice were retrospectively divided into two groups based on the median DNase activity assessed using the gel-based single-radial enzyme diffusion assay. In acute liver failure, mice with a higher baseline DNase activity had lower mortality after 48 h (by 25%). Different protection of ecDNA against nucleases by vesicles or DNA-binding proteins could play a role and should be further evaluated. Similarly, the role of endogenous DNase activity should be analyzed in other disease models associated with high ecDNA.
Chronic Kidney Disease as a Comorbidity in Heart Failure
Authors: Szlagor Magdalena , Dybiec Jill , Młynarska Ewelina , Rysz Jacek , Franczyk Beata
Published: February 2023

Heart failure (HF) is one of the greatest problems in healthcare and it often coexists with declining renal function. The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration. It is also associated with difficulties in the treatment of aggravating HF and chronic kidney disease (CKD) and, as a consequence, recurrent hospitalizations and death. As the worsening of renal function has an undeniably negative impact on the outcomes in patients with HF, searching for new treatment strategies and identification of biomarkers is necessary. This review is focused on the pathomechanisms in chronic kidney disease in patients with HF and therapeutic strategies for co-existing CKD and HF.
Effect of Probiotic Lactobacillus plantarum on Streptococcus mutans and Candida albicans Clinical Isolates from Children with Early Childhood Caries
Authors: Zeng Yan , Fadaak Ahmed , Alomeir Nora , Wu Yan , Wu Tong Tong , Qing Shuang , Xiao Jin
Published: February 2023

Probiotics interfere with pathogenic microorganisms or reinstate the natural microbiome. Streptococcus mutans and Candida albicans are well-known emerging pathogenic bacteria/fungi for dental caries. In this study, three probiotic Lactobacilli strains (Lactobacillus plantarum 8014, L. plantarum 14917, and Lactobacillus salivarius 11741) were tested on S. mutans and C. albicans clinical isolates using a multispecies biofilm model simulating clinical cariogenic conditions. The ten pairs of clinical isolates of S. mutans and C. albicans were obtained from children with severe early childhood caries. Our study findings show a remarkable inhibitory effect of L. plantarum 14917 on S. mutans and C. albicans clinical isolates, resulting in significantly reduced growth of S. mutans and C. albicans, a compromised biofilm structure with a significantly smaller microbial and extracellular matrix and a less virulent microcolony structure. FurTre, plantaricin, an antimicrobial peptide produced by L. plantarum, inhibited the growth of S. mutans and C. albicans. The mechanistic assessment indicated that L. plantarum 14917 had a positive inhibitory impact on the expression of S. mutans and C. albicans virulence genes and virulent structure, such as C. albicans hypha formation. Future utilization of L. plantarum 14917 and/or its antimicrobial peptide plantaricin could lead to a new paradigm shift in dental caries prevention.
Endometrial Microbiota and Immune Tolerance in Pregnancy
Authors: Inversetti Annalisa , Zambella Enrica , Guarano Alice , Dell’Avanzo Marinella , Di Simone Nicoletta
Published: February 2023

Recent studies have demonstrated that the uterus has its own microbiota. However, there is no consensus on endometrial microbiota composition, thus its role in the healthy uterine environment is still a frontier topic. Endometrial receptivity is key to embryo implantation, and in this specific context immunological tolerance against fetal antigens and the tightly regulated expression of inflammatory mediators are fundamental. According to recent evidence, endometrial microbiota may interact in a very dynamic way with the immune system during the peri-conceptional stage and later during pregnancy. For this reason, a condition of dysbiosis might lead to adverse pregnancy outcomes. The aim of this review is to summarize the evidence on the molecular mechanisms by which the endometrial microbiota may interact with the immune system. For this purpose, the link between dysbiosis and reproductive disorders, such as infertility, recurrent pregnancy loss (RPL), and preterm birth, will be discussed. In conclusion, the most recent findings from molecular analyses will be reported to illustrate and possibly overcome the intrinsic limitations of uterine microbiota detection (low endometrial biomass, high risk of contamination during sampling, and lack of standardization).
From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children
Authors: Root-Bernstein Robert
Published: February 2023

Neutrophilia and the production of neutrophil extracellular traps (NETs) are two of many measures of increased inflammation in severe COVID-19 that also accompany its autoimmune complications, including coagulopathies, myocarditis and multisystem inflammatory syndrome in children (MIS-C). This paper integrates currently disparate measures of innate hyperactivation in severe COVID-19 and its autoimmune complications, and relates these to SARS-CoV-2 activation of innate immunity. Aggregated data include activation of Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) receptors, NOD leucine-rich repeat and pyrin-domain-containing receptors (NLRPs), retinoic acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA-5). SARS-CoV-2 mainly activates the virus-associated innate receptors TLR3, TLR7, TLR8, NLRP3, RIG-1 and MDA-5. Severe COVID-19, however, is characterized by additional activation of TLR1, TLR2, TLR4, TLR5, TLR6, NOD1 and NOD2, which are primarily responsive to bacterial antigens. The innate activation patterns in autoimmune coagulopathies, myocarditis and Kawasaki disease, or MIS-C, mimic those of severe COVID-19 rather than SARS-CoV-2 alone suggesting that autoimmunity follows combined SARS-CoV-2-bacterial infections. Viral and bacterial receptors are known to synergize to produce the increased inflammation required to support autoimmune disease pathology. Additional studies demonstrate that anti-bacterial antibodies are also required to account for known autoantigen targets in COVID-19 autoimmune complications.