Comparative metabolism of fargesin in human, dog, monkey, mouse, and rat hepatocytes.

Fargesin, a bioactive lignan derived from Flos Magnoliae, possesses anti-inflammatory, anti-oxidative, anti-melanogenic, and anti-apoptotic effects. This study compared the metabolic profiles of fargesin in human, dog, monkey, mouse, and rat hepatocytes using liquid chromatography-high resolution mass spectrometry. In addition, we investigated the human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for fargesin metabolism. The hepatic extraction ratio of fargesin among the five species ranged from 0.59 to 0.78, suggesting that it undergoes a moderate-to-extensive degree of hepatic metabolism. During metabolism, fargesin generates three phase 1 metabolites, including fargesin catechol (M1) and O-desmethylfargesin (M2 and M3), and 11 phase 2 metabolites, including O-methyl-M1 (M4 and M5) via catechol O-methyltransferase (COMT), glucuronides of M1, M2, M4, and M5, and sulfates of M1-M5. The production of M1 from fargesin via O-demethylenation is catalyzed by CYP2C9, CYP3A4, CYP2C19, and CYP2C8 enzymes, whereas the formation of M2 and M3 (O-desmethylfargesin) is catalyzed by CYP2C9, CYP2B6, CYP2C19, CYP3A4, CYP1A2, and CYP2D6 enzymes. M4 is metabolized to M4 glucuronide by UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17 enzymes, whereas M4 sulfate is generated by multiple SULT enzymes. Fargesin is extensively metabolized in human hepatocytes by CYP, COMT, UGT, and SULT enzymes. These findings help to elucidate the pharmacokinetics and drug interactions of fargesin.

Correlation Between the Social Network Structure and Well-Being of Health Care Workers in Intensive Care Units: Prospective Observational Study.

BACKGROUND: Effective communication strategies are becoming increasingly important in intensive care units (ICUs) where patients at high risk are treated. Distributed leadership promotes effective communication among health care professionals (HCPs). Moreover, beyond facilitating patient care, it may improve well-being among HCPs by fostering teamwork. However, the impact of distributed leadership on the communication structure and well-being of HCPs remains unclear. OBJECTIVE: We performed a social network analysis (SNA) to assess the characteristics of each HCP in the network, identify the number of HCP connections, analyze 4 centralities that can measure an HCP's importance, and evaluate the impact of distributed leadership structure on the well-being and communication structure of the medical staff. METHODS: Wearable sensors were used to obtain face-to-face interaction data from the ICU medical staff at Mie University Hospital, Japan. Participants wore a badge on the front of their clothing during working hours to measure the total frequency of face-to-face interactions. We collected data about the well-being of medical staff using the Center for Epidemiological Studies-Depression (CES-D) questionnaire and measured 4 centralities using SNA analysis. A CES-D questionnaire was administered during the study to measure the well-being of the HCPs. RESULTS: Overall, 247 ICU workers participated in this clinical study for 4 weeks yearly in February 2016, 2017, and 2018. The distributed leadership structure was established within the ICU in 2017 and 2018. We compared these results with those of the traditional leadership structure used in 2016. Most face-to-face interactions in the ICU were among nurses or between nurses and other professionals. In 2016, overall, 10 nurses could perform leadership tasks, which significantly increased to 24 in 2017 (P=.046) and 20 in 2018 (P=.046). Considering the increased number of nurses who could perform leadership duties and the collaboration created within the organization, SNA in 2018 showed that the betweenness (P=.001), degree (P<.001), and closeness (P<.001) centralities significantly increased compared with those in 2016. However, the eigenvector centrality significantly decreased in 2018 compared with that in 2016 (P=.01). The CES-D scores in 2018 also significantly decreased compared with those in 2016 (P=.01). The betweenness (r=0.269; P=.02), degree (r=0.262; P=.03), and eigenvector (r=0.261; P=.03) centralities and CES-D scores were positively correlated in 2016, whereas the closeness centrality and CES-D scores were negatively correlated (r=-0.318; P=.01). In 2018, the degree (r=-0.280; P=.01) and eigenvector (r=-0.284; P=.01) centralities were negatively correlated with CES-D scores. CONCLUSIONS: Face-to-face interactions of HCPs in the ICU were measured using wearable sensors, and nurses were found to be centrally located. However, the introduction of distributed leadership created collaboration and informal leadership in the organization, altering the social network structure of HCPs and increasing organizational well-being. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) UMIN000037046; https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000042211.

A subfamily of the small heat shock proteins of the marine red alga Neopyropia yezoensis localizes in the chloroplast.

Small heat shock proteins (sHSPs) play a crucial role under abiotic stress and are present in all organisms, from eukaryotes to prokaryotes. However, studies on the sHSP gene family in red alga are limited. In this study, we aimed to identify and characterize NysHSP genes from the genome of N. yezoensis, a marine red alga adapted to the stressful intertidal zone. We identified seven NysHSP genes distributed on all three chromosomes. Expression analysis revealed that all NysHSP genes responded to H2O2 and heat stress in the gametophytic thalli, but these genes responded only to heat stress in the sporophytic conchocelis. NysHSP20.3, which has an acidic isoelectric point (pI) and short N-terminal region, was localized as granules in the cytosol. Fluorescence imaging of the NysHSP25.8-GFP and NysHSP28.4-GFP fusion proteins revealed that these proteins were located in the chloroplast. Based on their characteristics and cellular localization, the NysHSPs are divided into two subfamilies. Subfamily I includes four sHSP genes that strongly respond to heat stress and encode a protein localized in the cytosol. The NysHSP gene of subfamily II encodes a polypeptide with a long N-terminal region located in the chloroplast. This study provides insights into the evolution and function of the sHSP gene family of the marine red alga N. yezoensis and how it adapts to the stressful intertidal zone.

Recombinant soluble thrombomodulin attenuates cisplatin-induced intestinal injury by inhibiting intestinal epithelial cell-derived cytokine secretion.

BACKGROUND: Intestinal injury is one of the main side-effects of cisplatin chemotherapy, impairing the quality of life in patients with cancer. In this study, we investigated the protective effects of recombinant soluble thrombomodulin (rsTM), which is a potent anti-inflammatory agent, on cisplatin-induced intestinal injury. METHODS: We first evaluated the effects of rsTM on intestinal injury caused by cisplatin in mice in vivo. Disease progression was monitored by analyzing loss of body weight and histological changes in intestinal tissue. We then investigated the effects of rsTM on mouse intestinal organoid formation and growth in vitro. Gene expression levels were analyzed by quantitative real-time polymerase chain reaction and Western blotting. RESULTS: rsTM treatment significantly attenuated the loss of body weight, histological damage and gene expression levels of pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α and high-mobility group box-1 in a cisplatin-treated mouse model. Furthermore, rsTM alleviated the inflammatory response and apoptosis in a cisplatin-treated intestinal epithelial organoid model. CONCLUSION: rsTM suppresses cisplatin-induced intestinal epithelial cell-derived cytokine production and alleviates intestinal mucositis.

Integrin-Mediated Exosomal Homing to Organs.

Exosomes, the small extracellular vesicles of 40-150 nm in size, are secreted by nearly all types of cells and play a dynamic role in intercellular and interorgan communications. These vesicles secreted by source cells contain a variety of biologically active materials such as microRNAs (miRNAs) or proteins, thereby utilizing these cargoes in modifying molecular functionalities of the target cells in the remote tissues. Consequently, several key functions of microenvironmental niches in the tissues are regulated in an exosome-dependent manner. The precise mechanisms by which the exosomes bind and home to different organs remained largely unknown. In recent years, integrins, a large family of cell adhesion molecules, have been revealed to play a crucial role in guiding homing of exosomes to target tissues, as integrins regulate tissue-specific homing of cells. In this regard, it is imperative to experimentally determine the roles played by integrins on the exosomes in their tissue-specific homing. This chapter presents a protocol to investigate exosomal homing regulated by integrins in in vitro and in vivo settings. We focus on ß7 integrin, as its role in mediating the gut-specific homing of lymphocytes has been well established.

Overexpression of putative glutathione peroxidase from Neopyropia-associated microorganisms in Chlamydomonas to respond to abiotic stress.

Lipid accumulation in microalgae can be substantially enhanced by exposing the microalgae to abiotic stress, thus increasing biofuel production. However, this also generates reactive oxygen species (ROS), which disrupts cell metabolism and reduces their productivity. Previous mRNA sequencing analyses in Neopyropia yezoensis and its associated microorganisms elucidated a putative glutathione peroxidase (PuGPx) gene. Here, this putative glutathione peroxidase was overexpressed in the microalga Chlamydomonas reinhardtii, which increased cell growth and survival rates compared to the control group under abiotic stress. Additionally, increased lipid accumulation was observed under salinity stress, high-temperature stress, and hydrogen peroxide (H2O2)-induced oxidative stress. These results suggest that PuGPx plays a protective role against abiotic stress in C. reinhardtii and stimulates lipid accumulation, which could be considered advantageous in terms of biofuel production.

MicroRNA Profiles in Intestinal Epithelial Cells in a Mouse Model of Sepsis.

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly miR-149-5p, miR-466q, miR-495, and miR-511-3p, were seen to exhibit complex and global effects on gene regulation networks. Interestingly, miR-511-3p has emerged as a diagnostic marker in this sepsis model due to its increase in blood in addition to IECs. As expected, mRNAs in the IECs were remarkably altered by sepsis; specifically, 2248 mRNAs were decreased, while 612 mRNAs were increased. This quantitative bias may be possibly derived, at least partly, from the direct effects of the sepsis-increased miRNAs on the comprehensive expression of mRNAs. Thus, current in silico data indicate that there are dynamic regulatory responses of miRNAs to sepsis in IECs. In addition, the miRNAs that were increased with sepsis had enriched downstream pathways including Wnt signaling, which is associated with wound healing, and FGF/FGFR signaling, which has been linked to chronic inflammation and fibrosis. These modifications in miRNA networks in IECs may lead to both pro- and anti-inflammatory effects in sepsis. The four miRNAs discovered above were shown to putatively target LOX, PTCH1, COL22A1, FOXO1, or HMGA2, via in silico analysis, which were associated with Wnt or inflammatory pathways and selected for further study. The expressions of these target genes were downregulated in sepsis IECs, possibly through posttranscriptional modifications of these miRNAs. Taken together, our study suggests that IECs display a distinctive miRNA profile which is capable of comprehensively and functionally reshaping the IEC-specific mRNA landscape in a sepsis model.

Overexpression of S-Adenosylmethionine Synthetase in Recombinant Chlamydomonas for Enhanced Lipid Production.

Microalgae are attracting much attention as promising, eco-friendly producers of bioenergy due to their fast growth, absorption of carbon dioxide from the atmosphere, and production capacity in wastewater and salt water. However, microalgae can only accumulate large quantities of lipid in abiotic stress, which reduces productivity by decreasing cell growth. In this study, the strategy was investigated to increase cell viability and lipid production by overexpressing S-adenosylmethionine (SAM) synthetase (SAMS) in the microalga Chlamydomonas reinhardtii. SAM is a substance that plays an important role in various intracellular biochemical reactions, such as cell proliferation and stress response, and the overexpression of SAMS could allow cells to withstand the abiotic stress and increase productivity. Compared to wild-type C. reinhardtii, recombinant cells overexpressing SAMS grew 1.56-fold faster and produced 1.51-fold more lipids in a nitrogen-depleted medium. Furthermore, under saline-stress conditions, the survival rate and lipid accumulation were 1.56 and 2.04 times higher in the SAMS-overexpressing strain, respectively. These results suggest that the overexpression of SAMS in recombinant C. reinhardtii has high potential in the industrial-scale production of biofuels and various other high-value-added materials.

Possible Metastatic Stage-Dependent ILC2 Activation Induces Differential Functions of MDSCs through IL-13/IL-13Rα1 Signaling during the Progression of Breast Cancer Lung Metastasis.

Breast cancer is the most common cancer in women worldwide, and lung metastasis is one of the most frequent distant metastases. When breast cancer metastasizes to the lung, group 2 innate lymphoid cells (ILC2s) are thought to promote tumor growth via the activation of myeloid-derived suppressor cells (MDSCs), which are known to negatively regulate anticancer immune responses. However, it remains to be elucidated exactly how this ILC2-MDSC interaction is involved in tumor growth during metastases formation. Using a 4T1/LM4 breast cancer mouse model, we found that ILC2s were activated in both the micro- and macrometastatic regions, suggesting sustained activation throughout the metastatic cascades via IL-33/ST2 signaling. Consistent with IL-13 secretion from activated ILC2s, the frequencies of polymorphonuclear (PMN)- and monocytic (M)-MDSCs were also significantly elevated during the progression from micro- to macrometastatic cancer. However, the effects of ILC2-induced MDSC functionality on the microenvironment differed in a metastatic-stage-specific manner. Our findings indicate that ILC2s may induce the immunosuppressive functions of MDSCs during the later stages of metastasis. Concomitantly, ILC2 may instigate extracellular matrix remodeling by PMN-MDSC activation during the early stages of metastasis. These metastatic-stage-specific changes may contribute to metastatic tumor growth in the microenvironment of breast cancer lung metastasis.

Functional Flexibility of Exosomes and MicroRNAs of Intestinal Epithelial Cells in Affecting Inflammation.

Intestinal epithelial cells (IECs) are a mucosal immune barrier essential to coordinate host-microbe crosstalk. Sepsis is a systemic inflammatory syndrome with dysfunction in multiple organs including the intestine whose epithelial barrier is deregulated. Thus, IECs are a main contributor to intestinal permeability and inflammation in sepsis. Exosomes emerge as a mediator of intercellular and inter-organic communications. Recently, IEC-derived exosomes and their cargoes, such as microRNAs (miRNAs), in sepsis were shown to regulate the expression of proinflammatory mediators in the inflamed gut tissues. It is a compelling hypothesis that these IEC exosomes exhibit their dynamic activity to deliver their functional miRNA cargoes to immune cells in local and distant organs to regulate proinflammatory responses and alleviate tissue injury. Also, epithelial tight junction (TJ) proteins are downregulated on gut inflammation. Some of the IEC miRNAs were reported to deteriorate the epithelial integrity by diminishing TJ expressions in intestines during sepsis and aging. Thus, it is worth revisiting and discussing the diverse functions of IEC exosomes and miRNAs in reshaping inflammations. This review includes both iterative and hypothetical statements based on current knowledge in this field.

Vitamin D deficiency and mortality among critically ill surgical patients in an urban Korean hospital.

Critically ill patients in intensive care units (ICUs) are exposed to various risk factors for vitamin D deficiency. Vitamin D deficiency in extended-stay patients may result in decreased muscle mass and increased fat tissue, which may impair rehabilitation and recovery. Our study aimed to evaluate the degree of serum vitamin D deficiency in critically ill surgical patients and its association with clinical outcomes. Clinical data from 186 adult male (n = 121; 65.1%) and female (n = 65; 34.9%) patients hospitalized in surgical ICUs at Ajou University Hospital from April 2015 to September 2016 were retrospectively analyzed. All adult surgical patients between the age of 18 and 88 years were enrolled. The mean serum 25-hydroxyvitamin D (25[OH]D) level of all patients was 17.8 ng/mL. A total of 120 patients (64.5%) with serum 25(OH)D levels < 20 ng/mL were classified as the deficiency group. A prolonged hospital stay was observed among the deficiency group but was not statistically significant (p = 0.824). Serum 25(OH)D levels were significantly correlated with age but inversely correlated with Sequential Organ Failure Assessment (SOFA) score, selenium, triglycerides, and C-reactive protein levels. There was no significant difference in mortality rates between the group with a vitamin D injection and the group without a vitamin D injection (14.6% vs. 16.9%, p = 0.074). Vitamin D deficiency was common in surgical ICU patients; however, vitamin D levels were higher in older patients. In conclusion, vitamin D deficiency was inversely associated with the SOFA severity score (correlation coefficient -0.165, p = 0.024) but was not associated with the length of hospital or ICU stay and mortality.

miRNA-200c-3p targets talin-1 to regulate integrin-mediated cell adhesion.

The ability of integrins on the cell surface to mediate cell adhesion to the extracellular matrix ligands is regulated by intracellular signaling cascades. During this signaling process, the talin (TLN) recruited to integrin cytoplasmic tails plays the critical role of the major adaptor protein to trigger integrin activation. Thus, intracellular levels of TLN are thought to determine integrin-mediated cellular functions. However, the epigenetic regulation of TLN expression and consequent modulation of integrin activation remain to be elucidated. Bioinformatics analysis led us to consider miR-200c-3p as a TLN1-targeting miRNA. To test this, we have generated miR-200c-3p-overexpressing and miR-200c-3p-underexpressing  cell lines, including HEK293T, HCT116, and LNCaP cells. Overexpression of miR-200c-3p resulted in a remarkable decrease in the expression of TLN1, which was associated with the suppression of integrin-mediated cell adhesion to fibronectin. In contrast, the reduction in endogenous miR-200c-3p levels led to increased expression of TLN1 and enhanced cell adhesion to fibronectin and focal adhesion plaques formation. Moreover, miR-200c-3p was found to target TLN1 by binding to its 3'-untranslated region (UTR). Taken together, our data indicate that miR-200c-3p contributes to the regulation of integrin activation and cell adhesion via the targeting of TLN1.

Elevated Plasma Soluble PD-L1 Levels in Out-of-Hospital Cardiac Arrest Patients.

Background: A deregulated immune system has been implicated in the pathogenesis of post-cardiac arrest syndrome (PCAS). A soluble form of programmed cell death-1 (PD-1) ligand (sPD-L1) has been found at increased levels in cancer and sustained inflammation, thereby deregulating immune functions. Here, we aim to study the possible involvement of sPD-L1 in PCAS. Methods: Thirty out-of-hospital cardiac arrest (OHCA) patients consecutively admitted to the ER of Mie University Hospital were prospectively enrolled. Plasma concentrations of sPD-L1 were measured by an enzyme-linked immunosorbent assay in blood samples of all 30 OHCA patients obtained during cardiopulmonary resuscitation (CPR). In 13 patients who achieved return-of-spontaneous-circulation (ROSC), sPD-L1 levels were also measured daily in the ICU. Results: The plasma concentrations of sPD-L1 in OHCA were significantly increased; in fact, to levels as high as those observed in sepsis. sPD-L1 levels during CPR correlated with reduced peripheral lymphocyte counts and increased C-reactive protein levels. Of 13 ROSC patients, 7 cases survived in the ICU for more than 4 days. A longitudinal analysis of sPD-L1 levels in the 7 ROSC cases revealed that sPD-L1 levels occurred in parallel with organ failure. Conclusions: This study suggests that ischemia- reperfusion during CPR may aberrantly activate immune and endothelial cells to release sPD-L1 into circulation, which may play a role in the pathogenesis of immune exhaustion and organ failures associated with PCAS.

Recombinant soluble thrombomodulin accelerates epithelial stem cell proliferation in mouse intestinal organoids and promotes the mucosal healing in colitis.

BACKGROUND AND AIM: Epithelial regeneration, a critical step for the mucosal healing in inflammatory bowel disease, is tightly regulated by stem cells. Therefore, identification of the specific factors that induce stem cell proliferation could contribute to the development of effective strategies for treating inflammatory bowel disease. Recombinant soluble thrombomodulin (rsTM) has previously been shown to promote cell proliferation in skin and corneal wound healing in murine models, but its effects on intestinal epithelial cell proliferation remains unclear. METHODS: Mouse intestinal organoids and dextran sulfate sodium (DSS)-induced colitis mouse model were used to assess the effects of rsTM on proliferation of intestinal epithelial cells. The size and budding morphologies of organoids were studied by confocal microscopy. The gene expression levels were analyzed by quantitative real-time polymerase chain reaction and immunofluorescence analysis. The effects of rsTM on DSS-induced colitis were investigated by evaluating body weight changes, colon length, histological score, and survival rate. RESULTS: The rsTM markedly stimulated the growth of intestinal organoids, thereby increasing the surface areas and budding phenotypes of the organoids. rsTM also significantly upregulated the gene expression of intestinal stem cell-specific and epithelial cell-specific markers in a dose-dependent manner. Furthermore, the treatment with high concentrations of rsTM significantly improved the recovery of body weight, histological outcomes, colon length shortening, and prolonged the survival of mice with colitis. CONCLUSIONS: The rsTM promotes intestinal stem cell proliferation in intestinal organoids and enhances the mucosal healing during recovery phase in DSS-induced colitis.

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations.

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.

Endothelial connexin-integrin crosstalk in vascular inflammation.

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment - including vascular stiffness and shear stress - modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.

Distinct Age-Specific miRegulome Profiling of Isolated Small and Large Intestinal Epithelial Cells in Mice.

The intestinal epithelium serves as a dynamic barrier to protect the host tissue from exposure to a myriad of inflammatory stimuli in the luminal environment. Intestinal epithelial cells (IECs) encompass differentiated and specialized cell types that are equipped with regulatory genes, which allow for sensing of the luminal environment. Potential inflammatory cues can instruct IECs to undergo a diverse set of phenotypic alterations. Aging is a primary risk factor for a variety of diseases; it is now well-documented that aging itself reduces the barrier function and turnover of the intestinal epithelium, resulting in pathogen translocation and immune priming with increased systemic inflammation. In this study, we aimed to provide an effective epigenetic and regulatory outlook that examines age-associated alterations in the intestines through the profiling of microRNAs (miRNAs) on isolated mouse IECs. Our microarray analysis revealed that with aging, there is dysregulation of distinct clusters of miRNAs that was present to a greater degree in small IECs (22 miRNAs) compared to large IECs (three miRNAs). Further, miRNA-mRNA interaction network and pathway analyses indicated that aging differentially regulates key pathways between small IECs (e.g., toll-like receptor-related cascades) and large IECs (e.g., cell cycle, Notch signaling and small ubiquitin-related modifier pathway). Taken together, current findings suggest novel gene regulation pathways by epithelial miRNAs in aging within the gastrointestinal tissues.

The Spike Glycoprotein of SARS-CoV-2 Binds to ß1 Integrins Expressed on the Surface of Lung Epithelial Cells.

The spike glycoprotein attached to the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to and exploits angiotensin-converting enzyme 2 (ACE2) as an entry receptor to infect pulmonary epithelial cells. A subset of integrins that recognize the arginyl-glycyl-aspartic acid (RGD) sequence in the cognate ligands has been predicted in silico to bind the spike glycoprotein and, thereby, to be exploited for viral infection. Here, we show experimental evidence that the ß1 integrins predominantly expressed on human pulmonary epithelial cell lines and primary mouse alveolar epithelial cells bind to this spike protein. The cellular ß1 integrins support adhesive interactions with the spike protein independently of ACE2, suggesting the possibility that the ß1 integrins may function as an alternative receptor for SARS-CoV-2, which could be targeted for the prevention of viral infections.