bluuebunny/crossref_metadata_2025 huggingface dataset:
ORAI1-Regulated Gene Expression in Breast Cancer Cells: Roles for STIM1 Binding, Calcium Influx and Transcription Factor Translocation
Authors: Robitaille Mélanie , Chan Shao Ming , Peters Amelia A. , Dai Limin , So Choon Leng , Bong Alice H. L. , Sadras Francisco , Roberts-Thomson Sarah J. , Monteith Gregory R.
Published: May 2022

A remodeling of calcium homeostasis, including calcium influx via store-operated calcium entry (SOCE), is a feature of breast cancers. SOCE is critical to maintain calcium balance in the endoplasmic reticulum calcium store and is an important mechanism for calcium signaling in a variety of cell types, including breast cancer cells. The canonical mechanism of SOCE is stromal interacting molecule 1 (STIM1)-mediated activation of ORAI. Elevated ORAI1 expression is a feature of basal breast cancer cells. However, the role of ORAI1 in the regulation of transcription in breast cancer cells of the basal molecular subtype is still unclear. Using CRISPR-Cas9 gene editing, ORAI1 protein expression was disrupted in MDA-MB-231 and MDA-MB-468 basal breast cancer cells. The ORAI1 wild-type and mutants were reintroduced into ORAI1 knockout cells to study the role of ORAI1 in gene transcriptional regulation. In the absence of calcium store depletion, ORAI1 regulated PTGS2 in MDA-MB-231 cells, and this was dependent on ORAI1 pore function and STIM1 binding. The activation of SOCE by thapsigargin resulted in ORAI1-dependent increases in IL6 transcription in MDA-MB-468 cells; this was also dependent on ORAI1 pore function and STIM1 binding and was associated with the translocation of NFAT1. Given the upregulation of ORAI1 in basal breast cancer cells, our results provide further evidence that ORAI1 may contribute to cancer progression through regulation of gene expression.
Genomic Studies of Plant-Environment Interactions
Authors: Li Man-Wah , Lam Hon-Ming
Published: May 2022

Plants have been evolving for millions of years to survive in their fast-changing environments, by promoting beneficial interactions with other organisms or taking advantage of new conditions in the physical environment, while finding ways to repel pathogens and pests or tolerate unfavorable conditions [...]
Interplay between Mast Cells and Regulatory T Cells in Immune-Mediated Cholangiopathies
Authors: Krajewska Natalia M. , Fiancette Rémi , Oo Ye H.
Published: May 2022

Immune-mediated cholangiopathies are characterised by the destruction of small and large bile ducts causing bile acid stasis, which leads to subsequent inflammation, fibrosis, and eventual cirrhosis of the liver tissue. A breakdown of peripheral hepatic immune tolerance is a key feature of these diseases. Regulatory T cells (Tregs) are a major anti-inflammatory immune cell subset, and their quantities and functional capacity are impaired in autoimmune liver diseases. Tregs can undergo phenotypic reprogramming towards pro-inflammatory Th1 and Th17 profiles. The inflamed hepatic microenvironment influences and can impede normal Treg suppressive functions. Mast cell (MC) infiltration increases during liver inflammation, and active MCs have been shown to be an important source of pro-inflammatory mediators, thus driving pathogenesis. By influencing the microenvironment, MCs can indirectly manipulate Treg functions and inhibit their suppressive and proliferative activity. In addition, direct cell-to-cell interactions have been identified between MCs and Tregs. It is critical to consider the effects of MCs on the inflammatory milieu of the liver and their influence on Treg functions. This review will focus on the roles and crosstalk of Tregs and MCs during autoimmune cholangiopathy pathogenesis progression.
A Rice R2R3-Type MYB Transcription Factor OsFLP Positively Regulates Drought Stress Response via OsNAC
Authors: Qu Xiaoxiao , Zou Junjie , Wang Junxue , Yang Kezhen , Wang Xiaoqin , Le Jie
Published: May 2022

Abiotic stresses adversely affect plant growth and the yield of crops worldwide. R2R3-MYB transcriptional factors have been found to be vital for plants to confer stress response. In Arabidopsis, FOUR LIPS (FLP, MYB124) and its paralogous MYB88 function redundantly regulated the symmetric division of guard mother cells (GMCs) and abiotic stress response. Here, OsFLP was identified as an R2R3-MYB transcriptional activator and localized in the nucleus. OsFLP was transiently induced by drought, salt stress and abscisic acid (ABA). Overexpression of OsFLP showed enhanced tolerance to drought and salt stresses. The stomatal density in OsFLP-OE plants was not changed, whereas the stomatal closure was sensitive to ABA treatment compared to wild-type plants. In contrast, OsFLP-RNAi plants had abnormal stomata and were sensitive to drought. Moreover, the transcripts of stomatal closure-related genes DST and peroxidase 24 precursor, which are identified as downstream of OsNAC1, were inhibited in OsFLP-RNAi plants. The yeast-one-hybrid assay indicated that OsFLP can specifically bind and positively regulate OsNAC1 and OsNAC6. Meanwhile, stress response genes, such as OsLEA3 and OsDREB2A, were up-regulated in OsFLP-OE plants. These findings suggested that OsFLP positively participates in drought stress, mainly through regulating regulators’ transcripts of OsNAC1 and OsNAC6.
SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells
Authors: López-Moncada Fernanda , Torres María José , Lavanderos Boris , Cerda Oscar , Castellón Enrique A. , Contreras Héctor R.
Published: May 2022

Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial–mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway.
Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics
Authors: Jo Hyein , Shim Kyeonghee , Jeoung Dooil
Published: May 2022

MicroRNAs (miRNAs) are small non-coding RNAs (18–24 nucleotides) that play significant roles in cell proliferation, development, invasion, cancer development, cancer progression, and anti-cancer drug resistance. miRNAs target multiple genes and play diverse roles. miRNAs can bind to the 3′UTR of target genes and inhibit translation or promote the degradation of target genes. miR-200 family miRNAs mostly act as tumor suppressors and are commonly decreased in cancer. The miR-200 family has been reported as a valuable diagnostic and prognostic marker. This review discusses the clinical value of the miR-200 family, focusing on the role of the miR-200 family in the development of cancer and anti-cancer drug resistance. This review also provides an overview of the factors that regulate the expression of the miR-200 family, targets of miR-200 family miRNAs, and the mechanism of anti-cancer drug resistance regulated by the miR-200 family.
The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology
Authors: Cabou Cendrine , Martinez Laurent O.
Published: May 2022

The endothelium plays a key role in blood vessel health. At the interface of the blood, it releases several mediators that regulate local processes that protect against the development of cardiovascular disease. In this interplay, there is increasing evidence for a role of extracellular nucleotides and endothelial purinergic P2Y receptors (P2Y-R) in vascular protection. Recent advances have revealed that endothelial P2Y1-R and P2Y2-R mediate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration, which are processes involved in the regeneration of damaged endothelium. However, endothelial P2Y2-R, and possibly P2Y1-R, have also been reported to promote vascular inflammation and atheroma development in mouse models, with endothelial P2Y2-R also being described as promoting vascular remodeling and neointimal hyperplasia. Interestingly, at the interface with lipid metabolism, P2Y12-R has been found to trigger HDL transcytosis through endothelial cells, a process known to be protective against lipid deposition in the vascular wall. Better characterization of the role of purinergic P2Y-R and downstream signaling pathways in determination of the endothelial cell phenotype in healthy and pathological environments has clinical potential for the prevention and treatment of cardiovascular diseases.
A Potential Role of Keratinocyte-Derived Bilirubin in Human Skin Yellowness and Its Amelioration by Sucrose Laurate/Dilaurate
Authors: Fang Bin , Card Patrick D. , Chen Junjun , Li Lijuan , Laughlin Timothy , Jarrold Bradley , Zhao Wenzhu , Benham Adam M. , Määttä Arto T. , Hawkins Timothy J. , Hakozaki Tomohiro
Published: May 2022

Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin may be synthesized in other cells/organs, including the skin. We found human keratinocytes express the transcripts involved in bilirubin biosynthesis. In parallel, we also found human keratinocytes could indeed synthesize bilirubin in monolayer keratinocytes and in a 3D human skin-equivalent model. The synthesized amount was substantial enough to contribute to skin yellowness. In addition, oxidative stress enhanced bilirubin production. Using UnaG, a protein that forms a fluorescent species upon binding to bilirubin, we also visualized the intracellular expression of bilirubin in keratinocytes. Finally, we screened a compound library and discovered that the sucrose laurate/dilaurate (SDL) combination significantly reduced bilirubin levels, as well as bilirubin-mediated yellowness. In conclusion, bilirubin is indeed synthesized in epidermal keratinocytes and can be upregulated by oxidative stress, which could contribute to chronic or transient yellow skin tone appearance. Application of SDL diminishes bilirubin generation and may be a potential solution to mitigate yellowish and/or dull skin appearance.
Substituted Syndecan-2-Derived Mimetic Peptides Show Improved Antitumor Activity over the Parent Syndecan-2-Derived Peptide
Authors: Jang Bohee , Kim Ayoung , Lee Yejin , Hwang Jisun , Sung Jee-Young , Jang Eun-Ju , Kim Yong-Nyun , Yun Ji-Hye , Han Jeongmin , Song Ji-Joon , Lee Weontae , Oh Eok-Soo
Published: May 2022

We previously showed that a synthetic peptide (S2-P) corresponding to a portion of the human syndecan-2 (SDC2) sequence can bind to the pro-domain of matrix metalloproteinase-7 (MMP-7) to inhibit colon cancer activities. Since S2-P had a relatively weak binding affinity for the MMP-7 pro-domain, we herein modified the amino acid sequence of S2-P to improve the anticancer potential. On the basis of the interaction structure of S2-P and MMP-7, four peptides were generated by replacing amino acids near Tyr 51, which is critical for the interaction. The SDC2-mimetic peptides harboring an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-D) or with an Ala-to-Phe substitution at the N-terminal side of Tyr 51 and an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-FE) showed improved interaction affinities for the MMP-7 pro-domain. Compared to S2-P, S2-FE was better able to inhibit the SDC2–MMP-7 interaction, the cell surface localization of MMP-7, the gelatin degradation activity of MMP-7, and the cancer activities (cell migration, invasion, and colony-forming activity) of human HCT116 colon cancer cells in vitro. In vivo, S2-FE inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a xenograft mouse model. Together, these data suggest that S2-FE could be useful therapeutic anticancer peptides for colon cancer.
The Multidirectional Effect of Azelastine Hydrochloride on Cervical Cancer Cells
Authors: Trybus Ewa , Król Teodora , Trybus Wojciech
Published: May 2022

A major cause of cancer cell resistance to chemotherapeutics is the blocking of apoptosis and induction of autophagy in the context of cell adaptation and survival. Therefore, new compounds are being sought, also among drugs that are commonly used in other therapies. Due to the involvement of histamine in the regulation of processes occurring during the development of many types of cancer, antihistamines are now receiving special attention. Our study concerned the identification of new mechanisms of action of azelastine hydrochloride, used in antiallergic treatment. The study was performed on HeLa cells treated with different concentrations of azelastine (15–90 µM). Cell cycle, level of autophagy (LC3 protein activity) and apoptosis (annexin V assay), activity of caspase 3/7, anti-apoptotic protein of Bcl-2 family, ROS concentration, measurement of mitochondrial membrane potential (Δψm), and level of phosphorylated H2A.X in response to DSB were evaluated by cytometric method. Cellular changes were also demonstrated at the level of transmission electron microscopy and optical and fluorescence microscopy. Lysosomal enzyme activities-cathepsin D and L and cell viability (MTT assay) were assessed spectrophotometrically. Results: Azelastine in concentrations of 15–25 µM induced degradation processes, vacuolization, increase in cathepsin D and L activity, and LC3 protein activation. By increasing ROS, it also caused DNA damage and blocked cells in the S phase of the cell cycle. At the concentrations of 45–90 µM, azelastine clearly promoted apoptosis by activation of caspase 3/7 and inactivation of Bcl-2 protein. Fragmentation of cell nucleus was confirmed by DAPI staining. Changes were also found in the endoplasmic reticulum and mitochondria, whose damage was confirmed by staining with rhodamine 123 and in the MTT test. Azelastine decreased the mitotic index and induced mitotic catastrophe. Studies demonstrated the multidirectional effects of azelastine on HeLa cells, including anti-proliferative, cytotoxic, autophagic, and apoptotic properties, which were the predominant mechanism of death. The revealed novel properties of azelastine may be practically used in anti-cancer therapy in the future.
Virulence Factors of Candida spp. and Host Immune Response Important in the Pathogenesis of Vulvovaginal Candidiasis
Authors: Czechowicz Paulina , Nowicka Joanna , Gościniak Grażyna
Published: May 2022

Vulvovaginal candidiasis (VVC) is one of the most common types of vaginal infections in women around the world and is often underestimated by both patients and doctors. Research on the pathogenesis of fungal vaginal infections over the last 20 years has resulted in a closer understanding of the virulence factors involved in Candida epithelial invasion and their mechanisms of action. Recently, attention was drawn to the enormous complexity of the interaction between yeast-like fungi and host cells, as well as the level of complexity of the host’s response to infection and their impact on the course and treatment of VVC. Our work provides a broad description of already known and some new reports on Candida virulence factors (such as phenotypic switching or biofilm formation capacity) and their importance for tissue invasion in VVC. At the same time, we also focus on interactions with host cells and local innate immune mechanisms involved in the response to vaginal fungal invasion that are now considered equally important in this case. The presented review describes the most important aspects of the still unknown pathogenicity of Candida associated with vaginal infections.
Heart Ferroportin Protein Content Is Regulated by Heart Iron Concentration and Systemic Hepcidin Expression
Authors: Berezovsky Betty , Frýdlová Jana , Gurieva Iuliia , Rogalsky Daniel W. , Vokurka Martin , Krijt Jan
Published: May 2022

The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, to approximately 200% of control values. This increase in heart ferroportin protein is very probably caused by a decrease in systemic hepcidin expression, in accordance with the classical regulation of ferroportin by hepcidin. However, the control of heart ferroportin protein by systemic hepcidin could apparently be overridden by changes in heart non-heme iron content since injection of ferric carboxymaltose to mice at 300 mg Fe/kg resulted in an increase in liver hepcidin expression, heart non-heme iron content, and also a threefold increase in heart ferroportin protein content. In a separate experiment, feeding an iron-deficient diet to young Wistar rats dramatically decreased liver hepcidin expression, while heart non-heme iron content and heart ferroportin protein content decreased to 50% of controls. It is, therefore, suggested that heart ferroportin protein is regulated primarily by the iron regulatory protein/iron-responsive element system and that the regulation of heart ferroportin by the hepcidin-ferroportin axis plays a secondary role.
CkREV Enhances the Drought Resistance of Caragana korshinskii through Regulating the Expression of Auxin Synthetase Gene CkYUC5
Authors: Li Jia-Yang , Ren Jie-Jie , Zhang Tian-Xin , Cui Jin-Hao , Gong Chun-Mei
Published: May 2022

As a common abiotic stress, drought severely impairs the growth, development, and even survival of plants. Here we report a transcription factor, Caragana korshinskii REVOLUTA(CkREV), which can bidirectionally regulate the expression of the critical enzyme gene CkYUC5 in auxin synthesis according to external environment changes, so as to control the biosynthesis of auxin and further enhance the drought resistance of plants. Quantitative analysis reveals that the expression level of both CkYUC5 and AtYUC5 is down-regulated after C. korshinskii and Arabidopsis thaliana are exposed to drought. Functional verification of CkREV reveals that CkREV up-regulates the expression of AtYUC5 in transgenic A. thaliana under common conditions, while down-regulating it under drought conditions. Meanwhile, the expression of CkYUC5 is also down-regulated in C. korshinskii leaves instantaneously overexpressing CkREV. We apply a dual-luciferase reporter system to discover that CkREV can bind to the promoter of CkYUC5 to regulate its expression, which is further proved by EMSA and Y1H esxperiments. Functional verification of CkREV in C. korshinskii and transgenic A. thaliana shows that CkREV can regulate the expression of CkYUC5 and AtYUC5 in a contrary way, maintaining the equilibrium of plants between growth and drought resisting. CkREV can positively regulate the expression of CkYUC5 to promote auxin synthesis in favor of growth under normal development. However, CkREV can also respond to external signals and negatively regulate the expression of CkYUC5, which inhibits auxin synthesis in order to reduce growth rate, lower water demands, and eventually improve the drought resistance of plants.
Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds
Authors: Sirakanyan Samvel N. , Spinelli Domenico , Geronikaki Athina , Zuppiroli Luca , Zuppiroli Riccardo , Kartsev Victor G. , Hakobyan Elmira K. , Yegoryan Hasmik A. , Hovakimyan Anush A.
Published: May 2022

In this paper we describe an efficient method for the synthesis of new heterocyclic systems: furo[2,3-c]-2,7-naphthyridines 6, as well as a new method for the preparation of 1,3-diamino-2,7-naphthyridines 11. For the first time, a Smiles rearrangement was carried out in the 2,7-naphthyridine series, thus gaining the opportunity to synthesize 1-amino-3-oxo-2,7-naphthyridines 4, which are the starting compounds for obtaining furo[2,3-c]-2,7-naphthyridines. The cyclization of alkoxyacetamides 9 proceeds via two different processes: the expected formation of furo[2,3-c]-2,7-naphthyridines 10 and the ‘unexpected’ formation of 1,3-diamino-2,7-naphthyridines 11 (via a Smiles type rearrangement).
High-Amylose Corn Starch Regulated Gut Microbiota and Serum Bile Acids in High-Fat Diet-Induced Obese Mice
Authors: Hu Jiamiao , Zheng Peiying , Qiu Jinhui , Chen Qingyan , Zeng Shaoxiao , Zhang Yi , Lin Shaoling , Zheng Baodong
Published: May 2022

High-amylose corn starch is well known for its anti-obesity activity, which is mainly based on the regulatory effects on gut microbiota. Recently, the gut microbiota has been reported to improve metabolic health by altering circulating bile acids. Therefore, in this study, the influence of high-amylose corn starch (HACS) on intestinal microbiota composition and serum bile acids was explored in mice fed with a high fat diet (HFD). The results demonstrated HACS treatment reduced HFD-induced body weight gain, hepatic lipid accumulation, and adipocyte hypertrophy as well as improved blood lipid profiles. Moreover, HACS also greatly impacted the gut microbiota with increased Firmicutes and decreased Bacteroidetes relative abundance being observed. Furthermore, compared to ND-fed mice, the mice with HFD feeding exhibited more obvious changes in serum bile acids profiles than the HFD-fed mice with the HACS intervention, showing HACS might restore HFD-induced alterations to bile acid composition in blood. In summary, our results suggested that the underlying mechanisms of anti-obesity activity of HACS may involve its regulatory effects on gut microbiota and circulating bile acids.
The B-Type Cyclin CYCB1-1 Regulates Embryonic Development and Seed Size in Maize
Authors: Zhao Bingbing , Zhou Miaoyi , Ren Wen , Li Hanshuai , Zhang Qian , He Guangming , Liu Ya , He Haohua
Published: May 2022

Progress through the cell cycle is a critical process during plant embryo and seed development and its progression is regulated by cyclins. Despite extensive study of cyclins in other systems, their role in embryo and seed development of maize is unclear. In this study, we demonstrate that ZmCYCB1-1 overexpression significantly accelerated embryo growth and increased seed size. In situ hybridization and toluidine blue staining indicated that ZmCYCB1-1 was highly expressed in the plumule of embryos, and the cells of the plumule were smaller, denser, and more regularly arranged in ZmCYCB1-1 overexpression plants. Overexpression of ZmCYCB1-1 in maize also resulted in an increased ear length and enhanced kernel weight by increasing kernel width. Transcriptome analysis indicated that the overexpression of ZmCYCB1-1 affected several different metabolic pathways, including photosynthesis in embryos and leaves, and lipid metabolism in leaves. Conversely, knocking out ZmCYCB1-1 resulted in plants with slow growth. Our results suggest that ZmCYCB1-1 regulates embryo growth and seed size, making it an ideal target for efforts aimed at maize yield improvement.
New Metallophthalocyanines Bearing 2-Methylimidazole Moieties—Potential Photosensitizers against Staphylococcus aureus
Authors: Wierzchowski Marcin , Ziental Daniel , Łażewski Dawid , Korzanski Artur , Gielara-Korzanska Agnieszka , Tykarska Ewa , Dlugaszewska Jolanta , Sobotta Lukasz
Published: May 2022

Newly developed tetra- and octasubstituted methimazole-phthalocyanine conjugates as potential photosensitizers have been obtained. Synthesized intermediates and final products were characterized by the MALD-TOF technique and various NMR techniques, including 2D methods. Single-crystal X-ray diffraction was used to determine the crystal structures of dinitriles. The studied phthalocyanines revealed two typical absorption bands—the Soret band and the Q band. The most intense fluorescence was observed for octasubstituted magnesium(II) phthalocyanine in DMF (ΦFL = 0.022). The best singlet oxygen generators were octasubstituted magnesium(II) and zinc(II) phthalocyanines (Φ∆ 0.56 and 0.81, respectively). The studied compounds presented quantum yields of photodegradation at the level between 10−5 and 10−6. Due to their low solubility in a water environment, the liposomal formulations were prepared. Within the studied group, octasubstituted zinc(II) phthalocyanine at the concentration of 100 µM activated with red light showed the highest antibacterial activity against S. aureus equal to a 5.68 log reduction of bacterial growth.
Cutaneous Melanomas: A Single Center Experience on the Usage of Immunohistochemistry Applied for the Diagnosis
Authors: Ricci Costantino , Dika Emi , Ambrosi Francesca , Lambertini Martina , Veronesi Giulia , Barbara Corti
Published: May 2022

Cutaneous melanoma (cM) is the deadliest of all primary skin cancers. Its prognosis is strongly influenced by the stage at diagnosis, with early stages having a good prognosis and being potentially treatable with surgery alone; advanced stages display a much worse prognosis, with a high rate of recurrence and metastasis. For this reason, the accurate and early diagnosis of cM is crucial—misdiagnosis may have extremely dangerous consequences for the patient and drastically reduce their chances of survival. Although the histological exam remains the “gold standard” for the diagnosis of cM, a continuously increasing number of immunohistochemical markers that could help in diagnosis, prognostic characterization, and appropriate therapeutical choices are identified every day, with some of them becoming part of routine practice. This review aims to discuss and summarize all the data related to the immunohistochemical analyses that are potentially useful for the diagnosis of cM, thus rendering it easier to appropriately applicate to routine practice. We will discuss these topics, as well as the role of these molecules in the biology of cM and potential impact on diagnosis and treatment, integrating the literature data with the experience of our surgical pathology department.
A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress
Authors: Guy Reut , Volkman Rotem , Wilczynski Ella , Yagil Chana , Yagil Yoram , Findler Michael , Auriel Eitan , Nevo Uri , Offen Daniel
Published: May 2022

Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. Manifestations of CSVD include cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models have been found to reproduce most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. Here, we described a novel model for CSVD using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y), which display chronic hypertension and enhanced peripheral oxidative stress. SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham-operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex vivo MRI and biochemical and histological analyses. SBH/y-DOCA rats show a neurological decline and cognitive impairment and present multiple cerebrovascular pathologies associated with CSVD, such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models. Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for testing novel therapeutics.
Extracellular Vesicles in Corneal Fibrosis/Scarring
Authors: Yeung Vincent , Boychev Nikolay , Farhat Wissam , Ntentakis Dimitrios P. , Hutcheon Audrey E. K. , Ross Amy E. , Ciolino Joseph B.
Published: May 2022

Communication between cells and the microenvironment is a complex, yet crucial, element in the development and progression of varied physiological and pathological processes. Accumulating evidence in different disease models highlights roles of extracellular vesicles (EVs), either in modulating cell signaling paracrine mechanism(s) or harnessing their therapeutic moiety. Of interest, the human cornea functions as a refractive and transparent barrier that protects the intraocular elements from the external environment. Corneal trauma at the ocular surface may lead to diminished corneal clarity and detrimental effects on visual acuity. The aberrant activation of corneal stromal cells, which leads to myofibroblast differentiation and a disorganized extracellular matrix is a central biological process that may result in corneal fibrosis/scarring. In recent years, understanding the pathological and therapeutic EV mechanism(s) of action in the context of corneal biology has been a topic of increasing interest. In this review, we describe the clinical relevance of corneal fibrosis/scarring and how corneal stromal cells contribute to wound repair and their generation of the stromal haze. Furthermore, we will delve into EV characterization, their subtypes, and the pathological and therapeutic roles they play in corneal scarring/fibrosis.
Metformin Protects the Intestinal Barrier by Activating Goblet Cell Maturation and Epithelial Proliferation in Radiation-Induced Enteropathy
Authors: Jang Hyosun , Kim Soyeon , Kim Hyewon , Oh Su Hyun , Kwak Seo Young , Joo Hyun-Woo , Lee Seung Bum , Jang Won Il , Park Sunhoo , Shim Sehwan
Published: May 2022

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/β-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/β-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.
The Rationale for “Laser-Induced Thermal Therapy (LITT) and Intratumoral Cisplatin” Approach for Cancer Treatment
Authors: de Brito Renan Vieira , Mancini Marília Wellichan , Palumbo Marcel das Neves , Moraes Luis Henrique Oliveira de , Rodrigues Gerson Jhonatan , Cervantes Onivaldo , Sercarz Joel Avram , Paiva Marcos Bandiera
Published: May 2022

Cisplatin is one of the most widely used anticancer drugs in the treatment of various types of solid human cancers, as well as germ cell tumors, sarcomas, and lymphomas. Strong evidence from research has demonstrated higher efficacy of a combination of cisplatin and derivatives, together with hyperthermia and light, in overcoming drug resistance and improving tumoricidal efficacy. It is well known that the antioncogenic potential of CDDP is markedly enhanced by hyperthermia compared to drug treatment alone. However, more recently, accelerators of high energy particles, such as synchrotrons, have been used to produce powerful and monochromatizable radiation to induce an Auger electron cascade in cis-platinum molecules. This is the concept that makes photoactivation of cis-platinum theoretically possible. Both heat and light increase cisplatin anticancer activity via multiple mechanisms, generating DNA lesions by interacting with purine bases in DNA followed by activation of several signal transduction pathways which finally lead to apoptosis. For the past twenty-seven years, our group has developed infrared photo-thermal activation of cisplatin for cancer treatment from bench to bedside. The future development of photoactivatable prodrugs of platinum-based agents injected intratumorally will increase selectivity, lower toxicity and increase efficacy of this important class of antitumor drugs, particularly when treating tumors accessible to laser-based fiber-optic devices, as in head and neck cancer. In this article, the mechanistic rationale of combined intratumor injections of cisplatin and laser-induced thermal therapy (CDDP–LITT) and the clinical application of such minimally invasive treatment for cancer are reviewed.
Morpho-Physiological Traits, Phytochemical Composition, and Antioxidant Activity of Canephora Coffee Leaves at Various Stages
Authors: Maxiselly Yudithia , Anusornwanit Pisamai , Rugkong Adirek , Chiarawipa Rawee , Chanjula Pin
Published: May 2022

Coffee leaves contain a wide range of leaf compounds, which vary by growth stage. Recently, the importance of coffee leaf metabolites with beneficial phytochemicals has been widely identified. This research investigated Canephora coffee’s morphological and physiological development and analyzed the phytochemical composition of the main leaf stage. Canephora coffee leaves were harvested and classified into the following five growth stages: S1 (leaf age of 1–4 days), S2 (leaf age of 5–8 days), S3 (leaf age of 9–14 days), S4 (leaf age of 15–20 days), and S5 (leaf age of 21–27 days). The antioxidant activity, total phenol content, flavonoids, and tannin content of coffee leaves at different stages were observed. The results indicated that the highest values for the leaf area, dry weight, greenness, chlorophyll content, and carotenoid content were found at the last stage (S5). The specific leaf area (SLA) differences had higher values in the S3 and S1 growth stages. The youngest leaf phase (S1) was less green, more yellow, and brighter in color than the mature phase. By comparing the assays, it was found that a significant increase in the antioxidant activity and the contents of phenolic compounds, flavonoids, and tannins were observed in the S1 and S2 growth stages.
Lack of Monitoring Is Associated with Risk of Acute Kidney Events among Patients with Inflammatory Bowel Disease
Authors: Achit Hamza , Peyrin-Biroulet Laurent , Ayav Carole , Guillemin Francis , Frimat Luc
Published: May 2022

Background: Although the iatrogenic risk of kidney failure is infrequent with treatment for inflammatory bowel disease (IBD), the repercussions for the patient could be major. The aim of this study was to assess the incidence of kidney events in IBD and to examine the protective effect of kidney function monitoring. Methods: In the French National Health Insurance database, 94,363 patients had a diagnosis of IBD between January 2010 and December 2016. By using a survival model with time-dependent covariates, we analyzed the time from inclusion in this IBD cohort to the first hospitalization for acute kidney impairment (AKI) according to patient characteristics, comorbidities, IBD phenotype and presence of monitoring. Results: A total of 693 patients were hospitalized for AKI, with an incidence of 1.36/1000 person–years (95% confidence interval [CI] 1.26–1.47). The incidence of AKI was lower than those without 5-aminosalicylic acid (5-ASA) use. Patients with 5-ASA use rarely had any lack of monitoring as compared with those not under 5-ASA use (3% vs. 17%). On multivariate analysis, lack of monitoring was associated with a substantial risk of AKI (hazard ratio 3.96, 95% CI [3.20–4.90], p < 0.0001). Conclusions: Increased frequency of monitoring is essential to identify nephropathy at an early stage and avoid the progression to chronic kidney disease.
Multi-Modality Imaging for Prevention of Coronary Artery Disease and Myocardial Infarction in the General Population: Ready for Prime Time?
Authors: Ties Daan , van Dorp Paulien , Pundziute Gabija , Lipsic Erik , van der Aalst Carlijn M. , Oudkerk Matthijs , de Koning Harry J. , Vliegenthart Rozemarijn , van der Harst Pim
Published: May 2022

Cardiovascular disease (CVD) remains a leading cause of death and disability worldwide. Acute myocardial infarction (AMI) causes irreversible myocardial damage, heart failure, life-threatening arrythmias and sudden cardiac death (SCD), and is a main driver of CVD mortality and morbidity. To control the forecasted increase in CVD burden for both the individual and society, improved strategies for the prevention of AMI and SCD are required. Current prevention of AMI and SCD is directed towards risk-modifying interventions, guided by risk assessment using clinical risk prediction scores (CRPSs) and the coronary artery calcium score (CACS). Early detection of more advanced coronary artery disease (CAD), beyond risk assessment by CRPSs or CACS, is a promising strategy to allow personalized treatment for the improved prevention of AMI and SCD in the general population. We review evidence for further testing, beyond CRPSs and CACS, and therapies focusing on promising targets, including subclinical obstructive CAD, high-risk plaques, and silent myocardial ischemia. We also evaluate the potential of multi-modality imaging to enhance the conduction of adequately powered trials to provide high-quality evidence on the impact of add-on tests and therapies in the prevention of AMI and SCD in asymptomatic individuals. To conclude, we discuss the occurrence of AMI and SCD in individuals currently estimated to be at “low-risk” by the current strategy based on CRPSs, and methods to improve prevention of AMI and SCD in this “low-risk” population.
Effect of Dexmedetomidine on Early Postoperative Cognitive Function in Patients Undergoing Arthroscopic Shoulder Surgery in Beach Chair Position: A Randomized Double-Blind Study
Authors: Kim Namo , Kim Kwan Hyung , Choi Yong Seon , Song Sei Han , Choi Seung Ho
Published: May 2022

This study sought to determine whether intraoperative dexmedetomidine infusion might reduce the incidence of postoperative cognitive dysfunction (POCD) and alleviate the neuroinflammatory response in patients who have undergone arthroscopic shoulder surgery. A total of 80 patients over 60 years of age who had undergone arthroscopic shoulder surgery in the beach chair position were randomly allocated to either the dexmedetomidine group (Group D) or the control group (Group C). Dexmedetomidine (0.6 μg/kg/h) or a comparable amount of normal saline was infused into each group during the surgery. The early incidence of POCD was assessed by comparing cognitive tests on the day before and 1 d after surgery. The neuroinflammatory response with the S100 calcium-binding protein B (S100β) assay was compared prior to anesthetic induction and 1 h following surgery. The incidence of POCD was comparable between groups D (n = 9, 22.5%) and C (n = 9, 23.7%) (p = 0.901). However, the results of the cognitive test revealed a significant difference between the groups after surgery (p = 0.004). Although the S100β levels measured at the end of surgery were significantly higher than those at baseline in both groups (p < 0.001), there was no difference between the groups after the surgery (p = 0.236). Our results suggest that intraoperative dexmedetomidine infusion neither reduce the incidence of early POCD nor alleviated the neuroinflammatory response in patients undergoing arthroscopic shoulder surgery.
Rare Occurrence of Blastocystis in Pet Animals and Their Owners in the Pomeranian Voivodeship in Poland in the Light of Literature Data
Authors: Rudzińska Monika , Kowalewska Beata , Kurpas Monika , Szostakowska Beata
Published: May 2022

Blastocystis is an intestinal microeukaryote with ambiguous pathogenicity, commonly detected in human feces worldwide. It comprises at least 28 genetically diverse subtypes (STs), 12 of which also occur in a wide range of animal species, giving rise to suspicion of zoonotic transmission. To investigate this, we conducted a molecular study of 145 stool samples of pet animals, and 67 of their owners, living in an urban area in Poland. Blastocystis was detected in only three (2.1%) animal samples (of two bearded agamas and a leopard gecko), while all dogs, cats, and pet rodents were Blastocystis-negative. Blastocystis was also present in three (4.5%) owners of animals, but they were cat owners, not reptile owners, and the subtypes identified in them differed significantly from those of reptiles. Additionally, the frequency of Blastocystis in different groups of dogs (depending on how they were kept) was analyzed. This work is the first to find Blastocystis in pet reptiles, and we encourage further investigation of Blastocystis in this poorly examined group of animals, as well as continued study on the transmission of this microorganism between humans and animals.
Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How?
Authors: Sindone Andrew , Doehner Wolfram , Manito Nicolas , McDonagh Theresa , Cohen-Solal Alain , Damy Thibaud , Núñez Julio , Pfister Otmar , van der Meer Peter , Comin-Colet Josep
Published: May 2022

Iron deficiency (ID) is a comorbid condition frequently seen in patients with heart failure (HF). Iron has an important role in the transport of oxygen, and is also essential for skeletal and cardiac muscle, which depend on iron for oxygen storage and cellular energy production. Thus, ID per se, even without anaemia, can be harmful. In patients with HF, ID is associated with a poorer quality of life (QoL) and exercise capacity, and a higher risk of hospitalisations and mortality, even in the absence of anaemia. Despite its negative clinical consequences, ID remains under-recognised. However, it is easily diagnosed and managed, and the recently revised 2021 European Society of Cardiology (ESC) guidelines on HF provide specific recommendations for its diagnosis and treatment. Prospective randomised controlled trials in patients with symptomatic HF with reduced ejection fraction (HFrEF) show that correction of ID using intravenous iron (principally ferric carboxymaltose [FCM]) provides improvements in symptoms of HF, exercise capacity and QoL, and a recent trial demonstrated that FCM therapy following hospitalisation due to acute decompensated HF reduced the risk of subsequent HF hospitalisations. This review provides a summary of the epidemiology and pathophysiology of ID in HFrEF, and practical guidance on screening, diagnosing, and treating ID.
Comparison of PCWP and LVEDP Measurements in Patients with Severe Aortic Stenosis Undergoing TAVI—Same Same but Different?
Authors: Boxhammer Elke , Mirna Moritz , Bäz Laura , Alushi Brunilda , Franz Marcus , Kretzschmar Daniel , Hoppe Uta C. , Lauten Alexander , Lichtenauer Michael
Published: May 2022

Background: Pulmonary capillary wedge pressure (PCWP) and left ventricular end-diastolic pressure (LVEDP) are often used as equivalents for determination of pulmonary hypertension (PH). PH is a comorbidity in patients with severe aortic valve stenosis (AS) and associated with limited prognosis. The aim of the study was to examine the role of differentiated classification basis of PCWP and LVEDP in patients planning for transcatheter aortic valve implantation (TAVI). Methods: 284 patients with severe AS completed a combined left (LHC) and right heart catheterization (RHC) as part of a TAVI planning procedure. Patients were categorized twice into subtypes of PH according to 2015 European Society of Cardiology (ESC) guidelines—on the one hand with PCWP and on the other hand with LVEDP as classification basis. PCWP-LVEDP relationships were figured out using Kaplan-Meier curves, linear regressions and Bland-Altman analysis. Results: Regarding 1-year mortality, Kaplan-Meier analyses showed similar curves in spite of different classification bases of PH subtypes according to PCWP or LVEDP with exception of pre-capillary PH subtype. PCWP-LVEDP association in the overall cohort was barely present (R = 0.210, R2 = 0.044). When focusing analysis on PH patients only a slightly increased linear regression was noted compared to the overall cohort (R = 0.220, R2 = 0.048). The strongest regression was observed in patients with creatinine ≥ 132 µmol/L (R = 0.357, R2 = 0.127) and in patients with mitral regurgitation ≥ II° (R = 0.326, R2 = 0.106). Conclusions: In patients with severe AS, there is a weak association between hemodynamic parameters measured by LHC and RHC. RHC measurements alone are not suitable for risk stratification with respect to one-year mortality. If analysis of hemodynamic parameters is necessary in patients with severe AS scheduled for TAVI, measurement results of LHC and RHC should be combined and LVEDP could serve as a helpful indicator for risk assessment.
Preoperative Serum Alkaline Phosphatase and Neurological Outcome of Cerebrovascular Surgery
Authors: Park Seongjoo , Choi Eun-Su , Jung Hee-Won , Lee Ji-Youn , Park Jin-Woo , Bang Jae-Seung , Jeon Yeong-Tae
Published: May 2022

This study evaluated the relationship between the preoperative alkaline phosphatase (ALP) level and major postoperative neurological complications in patients undergoing cerebral bypass surgery. This was a retrospective analysis of a prospective database of all patients undergoing cerebral bypass surgery after a diagnosis of cerebrovascular stenosis or occlusion between May 2003 and August 2017. The patients were divided into tertiles based on serum alkaline phosphatase (ALP) levels (low: <63, intermediate: 63~79, and high: ALP > 79 IU/mL). The incidence of neurological events according to ALP level was analyzed. The study analyzed 211 cases. The incidence of acute infarction was highest in the third serum ALP tertile (5.7% vs. 2.9% vs. 16.9% in the first, second, and third tertile, respectively, p = 0.007). Logistic regression analysis showed that the third tertile of serum ALP was an independent predictor of acute cerebral infarction (odds ratio 3.346, 95% confidence interval 1.026–10.984, p = 0.045). On Kaplan–Meier time-to-event curves, the incidence of acute infarction increased significantly with ALP (log rank = 0.048). Preoperative serum ALP level can be used as a biomarker to predict acute cerebral infarction in patients undergoing cerebral bypass surgery for vascular stenosis or occlusion.