bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of a Mentorship Program on the Relationship between Neglect and Depression among Adolescents in Low-Income Families
Authors: Lee Jaewon , Allen Jennifer , Lim Hyejung , Choi Gyuhyun , Jung Jiyu
Published: June 2021

This study examines the moderating effect of a mentorship program on the relationship between parental neglect and depression among adolescents from low-income households since COVID-19. A total of 264 participants from all provinces in South Korea were registered for a mentorship program provided by the Korea Development Bank [KDB] Foundation, which is a charitable and non-profit organization. Two-hundred fifty-five middle and high school students from low-income families were included in the final sample. The mentorship program was provided to students based on mentors’ advice and feedback. A bootstrap method using the PROCESS macro 3.4 for SPSS was utilized to examine the moderating effect of satisfaction with the mentorship program. Neglect was positively related to depression among low-income students. Satisfaction with the mentorship program moderated the relationship between low-income students’ neglect and depression. Visits from social workers or other advocates or volunteers to low-income families with children may be helpful to address depression among low-income students. High quality mentorship programs should be provided to more low-income students for their mental health, funded particularly in the context of corporate social responsibility. Particularly since the COVID-19 pandemic, financial contributions by corporations would be valuable to reconstruct the damage to quality of life and psychological well-being among low-income adolescents.
Feasibility of Using the Hexoskin Smart Garment for Natural Environment Observation of Respiration Topography
Authors: Jayasekera Shehan , Hensel Edward , Robinson Risa
Published: June 2021

Background: Limited research has been done to measure ambulatory respiratory behavior, in particular those associated with tobacco use, in the natural environment due to a lack of monitoring techniques. Respiratory topography parameters provide useful information for modeling particle deposition in the lung and assessing exposure risk and health effects associated with tobacco use. Commercially available Wearable Respiratory Monitors (WRM), such as the Hexoskin Smart Garment, have embedded sensors that measure chest motion and may be adapted for measuring ambulatory lung volume. Methods: Self-reported “everyday” and “some days” Hookah and Cigarette smokers were recruited for a 3-day natural environment observation study. Participants wore the Hexoskin shirt while using their preferred tobacco product. The shirt was calibrated on them prior to, during, and after the observation period. A novel method for calculating the calibration parameters is presented. Results: NH = 5 Hookah and NC = 3 Cigarette participants were enrolled. Calibration parameters were obtained and applied to the observed chest motion waveform from each participant to obtain their lung volume waveform. Respiratory topography parameters were derived from the lung volume waveform. Conclusion: The feasibility of using the Hexoskin for measuring ambulatory respiratory topography parameters in the natural environment is demonstrated.
Review of the Health, Welfare and Care Workforce in Tasmania, Australia: 2011–2016
Authors: Jessup Belinda , Barnett Tony , Obamiro Kehinde , Cross Merylin , Mseke Edwin
Published: June 2021

Background: On a per capita basis, rural communities are underserviced by health professionals when compared to metropolitan areas of Australia. However, most studies evaluating health workforce focus on discrete professional groups rather than the collective contribution of the range of health, care and welfare workers within communities. The objective of this study was therefore to illustrate a novel approach for evaluating the broader composition of the health, welfare and care (HWC) workforce in Tasmania, Australia, and its potential to inform the delivery of healthcare services within rural communities. Methods: Census data (2011 and 2016) were obtained for all workers involved in health, welfare and care service provision in Tasmania and in each statistical level 4 area (SA4) of the state. Workers were grouped into seven categories: medicine, nursing, allied health, dentistry and oral health, health-other, welfare and carers. Data were aggregated for each category to obtain total headcount, total full time equivalent (FTE) positions and total annual hours of service per capita, with changes observed over the five-year period. Results: All categories of the Tasmanian HWC workforce except welfare grew between 2011 and 2016. While this growth occurred in all SA4 regions across the state, the HWC workforce remained maldistributed, with more annual hours of service per capita provided in the Hobart area. Although the HWC workforce remained highly feminised, a move toward gender balance was observed in some categories, including medicine, dentistry and oral health, and carers. The HWC workforce also saw an increase in part-time workers across all categories. Conclusions: Adopting a broad approach to health workforce planning can better reflect the reality of healthcare service delivery. For underserviced rural communities, recognising the diverse range of workers who can contribute to the provision of health, welfare and care services offers the opportunity to realise existing workforce capacity and explore how ‘total care’ may be delivered by different combinations of health, welfare and care workers.
Dose–Response Relationship between Environmental Exposure to Nickel and Pulmonary Function in the Korean General Population Aged 40 or Older
Authors: Joh Joon-Sung , Kang Mo-Yeol , Myong Jun-Pyo
Published: June 2021

Nickel is a well-known skin allergen; however, few studies to date have investigated the association between nickel exposure and lung function impairment. The present study, therefore, evaluated the relationship between blood nickel concentrations and lung function profiles in the Korean general population (n = 1098). Dose–response relationships between blood nickel quartiles and pulmonary function were assessed by sex in multivariate models, after adjustment for potentially confounding factors such as age, height, and smoking status. Quartiles of blood nickel concentrations were significantly associated with markers of pulmonary function in Korean men, such as forced expiratory volume in 1 second (FEV1) and forced expiratory flow 25–75% (FEF25–75%). Relative to the first quartile, the estimated coefficients (standard error (SE)) of blood nickel levels for FEV1 in the third and fourth quartiles of Korean men were −126.6 mL (59.1) and −138.5 mL (59.8), respectively (p < 0.05). Relative to the first quartile, the estimated coefficients (SE) of blood nickel levels for FEF25–75% in the second and fourth quartiles were −244.9 mL (109.5) and −266.8 mL (111.5), respectively (p < 0.05). Dose–response relationships were observed between quartiles of blood nickel concentrations and the pulmonary function markers FEV1 and FEF25–75% in Korean men aged 40 or older.
Investigation of Four Clusters of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Rwanda, 2020
Authors: Nsekuye Olivier , Rwagasore Edson , Muhimpundu Marie Aime , El-Khatib Ziad , Ntabanganyimana Daniel , Kamayirese Eric Noël , Ruyange Laurent , Umutoni Angela , Adeline Adeline Kabeja , Ntaganira Joseph , Nsazimana Sabin , Omolo Jared
Published: June 2021

We reported the findings of the first Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) four clusters identified in Rwanda. Case-investigations included contact elicitation, testing, and isolation/quarantine of confirmed cases. Socio-demographic and clinical data on cases and contacts were collected. A confirmed case was a person with laboratory confirmation of SARS-CoV-2 infection (PCR) while a contact was any person who had contact with a SARS-CoV-2 confirmed case within 72 h prior, to 14 days after symptom onset; or 14 days before collection of the laboratory-positive sample for asymptomatic cases. High risk contacts were those who had come into unprotected face-to-face contact or had been in a closed environment with a SARS-CoV-2 case for >15 min. Forty cases were reported from four clusters by 22 April 2020, accounting for 61% of locally transmitted cases within six weeks. Clusters A, B, C and D were associated with two nightclubs, one house party, and different families or households living in the same compound (multi-family dwelling). Thirty-six of the 1035 contacts tested were positive (secondary attack rate: 3.5%). Positivity rates were highest among the high-risk contacts compared to low-risk contacts (10% vs. 2.2%). Index cases in three of the clusters were imported through international travelling. Fifteen of the 40 cases (38%) were asymptomatic while 13/25 (52%) and 8/25 (32%) of symptomatic cases had a cough and fever respectively. Gatherings in closed spaces were the main early drivers of transmission. Systematic case-investigations contact tracing and testing likely contributed to the early containment of SARS-CoV-2 in Rwanda.
An Emerging Problem of Shisha Smoking among High School Students in Ethiopia
Authors: Hirpa Selamawit , Fogarty Andrew , Addissie Adamu , Bauld Linda , Frese Thomas , Unverzagt Susanne , Kantelhardt Eva Johanna , Getachew Sefonias , Deressa Wakgari
Published: June 2021

Shisha smoking is also known as hookah, water pipe, goza, and nargile. Shisha use among the young is increasing globally. Shisha smoke results in a high concentration of carbon monoxide, tar, nicotine, and heavy metals which can be toxic to humans, especially with chronic exposure. This study aims to determine the prevalence and risk factors of shisha smoking among in-school adolescents in Ethiopia. Four regional states in Ethiopia (Oromia, Amhara, Southern Nations, Nationalities, and Peoples’ Region, Tigray) and the capital city (Addis Ababa) were the study areas. A two-stage cluster sampling approach was employed to produce a representative sample. From the sampling frames in the study areas, 36 high schools were selected randomly. A multi-level logistic regression analysis was used to account for cluster-specific random effects, the effect of individuals’, and school-level variables for ever-use of shisha. A total of 3355 secondary school grade 9 and 10 students aged between 13 and 22 years took part in this study. A total of 86 (2.6%) and 20 (0.6%) of the study participants, reported that they had ever smoked or were current smokers of shisha, respectively. Of all study participants, 38.6% perceived shisha as less harmful than cigarettes and 48.5% reported that they do not know which was more harmful to health. Students were more likely to ever use shisha if they had friend/s who smoke shisha (AOR = 16.8, 95% CI: 6.4–44.3), ever smoked cigarettes (AOR = 8.2, 95% CI: 3.4–19.8), ever used khat (AOR = 4.2, 95% CI: 1.9–10.4), ever used marijuana (AOR = 3.9, 95% CI: 1.4–11.1), ever used smokeless tobacco (AOR = 3.1 95% CI: 1.1–8.4), and students had received income from their parents (AOR = 3.1 CI: 1.1–8.8). Prevalence of ever and current use of shisha among high school students is low in Ethiopia compared to many countries in Africa. The majority of adolescents perceived shisha as less harmful to health than cigarette smoking. Health education about the harmful effects of shisha should be delivered to adolescents, along with information on other substances like khat, cigarettes, marijuana, and smokeless tobacco to prevent initiation of substance use.
Exposure to 16 Hz Pulsed Electromagnetic Fields Protect the Structural Integrity of Primary Cilia and Associated TGF-β Signaling in Osteoprogenitor Cells Harmed by Cigarette Smoke
Authors: Chen Yangmengfan , Aspera-Werz Romina H. , Menger Maximilian M. , Falldorf Karsten , Ronniger Michael , Stacke Christina , Histing Tina , Nussler Andreas K. , Ehnert Sabrina
Published: June 2021

Cigarette smoking (CS) is one of the main factors related to avoidable diseases and death across the world. Cigarette smoke consists of numerous toxic compounds that contribute to the development of osteoporosis and fracture nonunion. Exposure to pulsed electromagnetic fields (PEMF) was proven to be a safe and effective therapy to support bone fracture healing. The aims of this study were to investigate if extremely low frequency (ELF-) PEMFs may be beneficial to treat CS-related bone disease, and which effect the duration of the exposure has. In this study, immortalized human mesenchymal stem cells (SCP-1 cells) impaired by 5% cigarette smoke extract (CSE) were exposed to ELF-PEMFs (16 Hz) with daily exposure ranging from 7 min to 90 min. Cell viability, adhesion, and spreading were evaluated by Sulforhodamine B, Calcein-AM staining, and Phalloidin-TRITC/Hoechst 33342 staining. A migration assay kit was used to determine cell migration. Changes in TGF-β signaling were evaluated with an adenoviral Smad2/3 reporter assay, RT-PCR, and Western blot. The structure and distribution of primary cilia were analyzed with immunofluorescent staining. Our data indicate that 30 min daily exposure to a specific ELF-PEMF most effectively promoted cell viability, enhanced cell adhesion and spreading, accelerated migration, and protected TGF-β signaling from CSE-induced harm. In summary, the current results provide evidence that ELF-PEMF can be used to support early bone healing in patients who smoke.
The Synergic Role of Actomyosin Architecture and Biased Detachment in Muscle Energetics: Insights in Cross Bridge Mechanism beyond the Lever-Arm Swing
Authors: Marcucci Lorenzo , Fukunaga Hiroki , Yanagida Toshio , Iwaki Mitsuhiro
Published: June 2021

Muscle energetics reflects the ability of myosin motors to convert chemical energy into mechanical energy. How this process takes place remains one of the most elusive questions in the field. Here, we combined experimental measurements of in vitro sliding velocity based on DNA-origami built filaments carrying myosins with different lever arm length and Monte Carlo simulations based on a model which accounts for three basic components: (i) the geometrical hindrance, (ii) the mechano-sensing mechanism, and (iii) the biased kinetics for stretched or compressed motors. The model simulations showed that the geometrical hindrance due to acto-myosin spatial mismatching and the preferential detachment of compressed motors are synergic in generating the rapid increase in the ATP-ase rate from isometric to moderate velocities of contraction, thus acting as an energy-conservation strategy in muscle contraction. The velocity measurements on a DNA-origami filament that preserves the motors’ distribution showed that geometrical hindrance and biased detachment generate a non-zero sliding velocity even without rotation of the myosin lever-arm, which is widely recognized as the basic event in muscle contraction. Because biased detachment is a mechanism for the rectification of thermal fluctuations, in the Brownian-ratchet framework, we predict that it requires a non-negligible amount of energy to preserve the second law of thermodynamics. Taken together, our theoretical and experimental results elucidate less considered components in the chemo-mechanical energy transduction in muscle.
Screening of Human Gut Bacterial Culture Collection Identifies Species That Biotransform Quercetin into Metabolites with Anticancer Properties
Authors: Sankaranarayanan Ranjini , Sekhon Prabhjot Kaur , Ambat Achuthan , Nelson Julia , Jose Davis , Bhat G. Jayarama , Scaria Joy
Published: June 2021

We previously demonstrated that flavonoid metabolites inhibit cancer cell proliferation through both CDK-dependent and -independent mechanisms. The existing evidence suggests that gut microbiota is capable of flavonoid biotransformation to generate bioactive metabolites including 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA), 3,4,5-trihyroxybenzoic acid (3,4,5-THBA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In this study, we screened 94 human gut bacterial species for their ability to biotransform flavonoid quercetin into different metabolites. We demonstrated that five of these species were able to degrade quercetin including Bacillus glycinifermentans, Flavonifractor plautii, Bacteroides eggerthii, Olsenella scatoligenes and Eubacterium eligens. Additional studies showed that B. glycinifermentans could generate 2,4,6-THBA and 3,4-DHBA from quercetin while F. plautii generates DOPAC. In addition to the differences in the metabolites produced, we also observed that the kinetics of quercetin degradation was different between B. glycinifermentans and F. plautii, suggesting that the pathways of degradation are likely different between these strains. Similar to the antiproliferative effects of 2,4,6-THBA and 3,4-DHBA demonstrated previously, DOPAC also inhibited colony formation ex vivo in the HCT-116 colon cancer cell line. Consistent with this, the bacterial culture supernatant of F. plautii also inhibited colony formation in this cell line. Thus, as F. plautii and B. glycinifermentans generate metabolites possessing antiproliferative activity, we suggest that these strains have the potential to be developed into probiotics to improve human gut health.
Aberrant Expression of Long Non Coding RNA HOTAIR and De-Regulation of the Paralogous 13 HOX Genes Are Strongly Associated with Aggressive Behavior of Gastro-Entero-Pancreatic Neuroendocrine Tumors
Authors: Di Mauro Annabella , Scognamiglio Giosuè , Aquino Gabriella , Cerrone Margherita , Liguori Giuseppina , Clemente Ottavia , Di Bonito Maurizio , Cantile Monica , Botti Gerardo , Tafuto Salvatore , Tatangelo Fabiana
Published: June 2021

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.
Dietary Sphingolipids Contribute to Health via Intestinal Maintenance
Authors: Yamashita Shinji , Kinoshita Mikio , Miyazawa Teruo
Published: June 2021

As sphingolipids are constituents of the cell and vacuole membranes of eukaryotic cells, they are a critical component acquired from our daily diets. In the present review, we highlight the knowledge regarding how dietary sphingolipids affect our health, particularly our intestinal health. Animal- and plant-derived foods contain, respectively, sphingomyelin (SM) and glucosylceramide (GlcCer) as their representative sphingolipids, and the sphingoid base as a specific structure of sphingolipids also differs depending upon the source and class. For example, sphingosine is predominant among animal sphingolipids, and tri-hydroxy bases are present in free ceramide (Cer) from plants and fungi. Dietary sphingolipids exhibit low absorption ratios; however, they possess various functions. GlcCer facilitates improvements in intestinal impairments, lipid metabolisms, and skin disorders, and SM can exert both similar and different effects compared to those elicited by GlcCer. We discuss the digestion, absorption, metabolism, and function of sphingolipids while focused on the structure. Additionally, we also review old and new classes in the context of current advancements in analytical instruments.
Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer
Authors: Sarantis Panagiotis , Bokas Alexandros , Papadimitropoulou Adriana , Koustas Evangelos , Theocharis Stamatios , Papakotoulas Pavlos , Schizas Dimitrios , Papalampros Alexandros , Felekouras Evangelos , Papavassiliou Athanasios G. , Karamouzis Michalis V.
Published: June 2021

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.
S-Equol Protects Chondrocytes against Sodium Nitroprusside-Caused Matrix Loss and Apoptosis through Activating PI3K/Akt Pathway
Authors: Huang Li-Wen , Huang Tzu-Ching , Hu Yu-Chen , Hsieh Bau-Shan , Cheng Hsiao-Ling , Chiu Pu-Rong , Chang Kee-Lung
Published: June 2021

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol’s efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 μM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.
Nanocarriers for Biomedicine: From Lipid Formulations to Inorganic and Hybrid Nanoparticles
Authors: Kashapov Ruslan , Ibragimova Alsu , Pavlov Rais , Gabdrakhmanov Dinar , Kashapova Nadezda , Burilova Evgenia , Zakharova Lucia , Sinyashin Oleg
Published: June 2021

Encapsulation of cargoes in nanocontainers is widely used in different fields to solve the problems of their solubility, homogeneity, stability, protection from unwanted chemical and biological destructive effects, and functional activity improvement. This approach is of special importance in biomedicine, since this makes it possible to reduce the limitations of drug delivery related to the toxicity and side effects of therapeutics, their low bioavailability and biocompatibility. This review highlights current progress in the use of lipid systems to deliver active substances to the human body. Various lipid compositions modified with amphiphilic open-chain and macrocyclic compounds, peptide molecules and alternative target ligands are discussed. Liposome modification also evolves by creating new hybrid structures consisting of organic and inorganic parts. Such nanohybrid platforms include cerasomes, which are considered as alternative nanocarriers allowing to reduce inherent limitations of lipid nanoparticles. Compositions based on mesoporous silica are beginning to acquire no less relevance due to their unique features, such as advanced porous properties, well-proven drug delivery efficiency and their versatility for creating highly efficient nanomaterials. The types of silica nanoparticles, their efficacy in biomedical applications and hybrid inorganic-polymer platforms are the subject of discussion in this review, with current challenges emphasized.
Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
Authors: Godinho-Pereira Joana , Garcia Ana Rita , Figueira Inês , Malhó Rui , Brito Maria Alexandra
Published: June 2021

Breast cancer (BC) brain metastases is a life-threatening condition to which accounts the poor understanding of BC cells’ (BCCs) extravasation into the brain, precluding the development of preventive strategies. Thus, we aimed to unravel the players involved in the interaction between BCCs and blood–brain barrier (BBB) endothelial cells underlying BBB alterations and the transendothelial migration of malignant cells. We used brain microvascular endothelial cells (BMECs) as a BBB in vitro model, under conditions mimicking shear stress to improve in vivo-like BBB features. Mixed cultures were performed by the addition of fluorescently labelled BCCs to distinguish individual cell populations. BCC–BMEC interaction compromised BBB integrity, as revealed by junctional proteins (β-catenin and zonula occludens-1) disruption and caveolae (caveolin-1) increase, reflecting paracellular and transcellular hyperpermeability, respectively. Both BMECs and BCCs presented alterations in the expression pattern of connexin 43, suggesting the involvement of the gap junction protein. Myosin light chain kinase and phosphorylated myosin light chain were upregulated, revealing the involvement of the endothelial cytoskeleton in the extravasation process. β4-Integrin and focal adhesion kinase were colocalised in malignant cells, reflecting molecular interaction. Moreover, BCCs exhibited invadopodia, attesting migratory properties. Collectively, hub players involved in BC brain metastases formation were unveiled, disclosing possible therapeutic targets for metastases prevention.
Protective Effects of a Hyaluronan-Binding Peptide (P15-1) on Mesenchymal Stem Cells in an Inflammatory Environment
Authors: Kirsch Thorsten , Zhang Fenglin , Braender-Carr Olivia , Cowman Mary K.
Published: June 2021

Mesenchymal stem cells (MSCs) obtained from various sources, including bone marrow, have been proposed as a therapeutic strategy for the improvement of tissue repair/regeneration, including the repair of cartilage defects or lesions. Often the highly inflammatory environment after injury or during diseases, however, greatly diminishes the therapeutic and reparative effectiveness of MSCs. Therefore, the identification of novel factors that can protect MSCs against an inflammatory environment may enhance the effectiveness of these cells in repairing tissues, such as articular cartilage. In this study, we investigated whether a peptide (P15-1) that binds to hyaluronan (HA), a major component of the extracellular matrix of cartilage, protects bone-marrow-derived MSCs (BMSCs) in an inflammatory environment. The results showed that P15-1 reduced the mRNA levels of catabolic and inflammatory markers in interleukin-1beta (IL-1β)-treated human BMSCs. In addition, P15-1 enhanced the attachment of BMSCs to HA-coated tissue culture dishes and stimulated the chondrogenic differentiation of the multipotential murine C3H/10T1/2 MSC line in a micromass culture. In conclusion, our findings suggest that P15-1 may increase the capacity of BMSCs to repair cartilage via the protection of these cells in an inflammatory environment and the stimulation of their attachment to an HA-containing matrix and chondrogenic differentiation.
PEAβ Triggers Cognitive Decline and Amyloid Burden in a Novel Mouse Model of Alzheimer’s Disease
Authors: Camargo Luana Cristina , Schöneck Michael , Sangarapillai Nivethini , Honold Dominik , Shah N. Jon , Langen Karl-Josef , Willbold Dieter , Kutzsche Janine , Schemmert Sarah , Willuweit Antje
Published: June 2021

Understanding the physiopathology of Alzheimer’s disease (AD) has improved substantially based on studies of mouse models mimicking at least one aspect of the disease. Many transgenic lines have been established, leading to amyloidosis but lacking neurodegeneration. The aim of the current study was to generate a novel mouse model that develops neuritic plaques containing the aggressive pyroglutamate modified amyloid-β (pEAβ) species in the brain. The TAPS line was developed by intercrossing of the pEAβ-producing TBA2.1 mice with the plaque-developing line APPswe/PS1ΔE9. The phenotype of the new mouse line was characterized using immunostaining, and different cognitive and general behavioral tests. In comparison to the parental lines, TAPS animals developed an earlier onset of pathology and increased plaque load, including striatal pEAβ-positive neuritic plaques, and enhanced neuroinflammation. In addition to abnormalities in general behavior, locomotion, and exploratory behavior, TAPS mice displayed cognitive deficits in a variety of tests that were most pronounced in the fear conditioning paradigm and in spatial learning in comparison to the parental lines. In conclusion, the combination of a pEAβ- and a plaque-developing mouse model led to an accelerated amyloid pathology and cognitive decline in TAPS mice, qualifying this line as a novel amyloidosis model for future studies.
Procoagulant and Antimicrobial Effects of Chitosan in Wound Healing
Authors: Wang Chih-Hsin , Cherng Juin-Hong , Liu Chuan-Chieh , Fang Tong-Jing , Hong Zhi-Jie , Chang Shu-Jen , Fan Gang-Yi , Hsu Sheng-Der
Published: June 2021

Chitosan, a polysaccharide derived from chitin, has excellent wound healing properties, including intrinsic antimicrobial and hemostatic activities. This study investigated the effectiveness of chitosan dressing and compared it with that of regular gauze dressing in controlling clinically surgical bleeding wounds and profiled the community structure of the microbiota affected by these treatments. The dressings were evaluated based on biocompatibility, blood coagulation factors in rat, as well as antimicrobial and procoagulant activities, and the microbial phylogenetic profile in patients with abdominal surgical wounds. The chitosan dressing exhibited a uniformly fibrous morphology with a large surface area and good biocompatibility. Compared to regular gauze dressing, the chitosan dressing accelerated platelet aggregation, indicated by the lower ratio of prothrombin time and activated partial thromboplastin time, and had outstanding blood absorption ability. Adenosine triphosphate assay results revealed that the chitosan dressing inhibited bacterial growth up to 8 d post-surgery. Moreover, 16S rRNA-based sequencing revealed that the chitosan dressing effectively protected the wound from microbial infection and promoted the growth of probiotic microbes, thereby improving skin immunity and promoting wound healing. Our findings suggest that chitosan dressing is an effective antimicrobial and procoagulant and promotes wound repair by providing a suitable environment for beneficial microbiota.
Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment
Authors: McGinity Christopher L. , Palmieri Erika M. , Somasundaram Veena , Bhattacharyya Dibyangana D. , Ridnour Lisa A. , Cheng Robert Y. S. , Ryan Aideen E. , Glynn Sharon A. , Thomas Douglas D. , Miranda Katrina M. , Anderson Stephen K. , Lockett Stephen J. , McVicar Daniel W. , Wink David A.
Published: June 2021

The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes.
Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis
Authors: Tomc Jana , Debeljak Nataša
Published: June 2021

Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone marrow results in increased erythropoiesis. Any imbalance in these homeostatic mechanisms can lead to dysregulated erythropoiesis and hematological disorders. For example, mutations in genes encoding key players of oxygen-sensing pathway and regulation of EPO production (HIF-EPO pathway), namely VHL, EGLN, EPAS1 and EPO, are well known causative factors that contribute to the development of erythrocytosis. We aimed to investigate additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis. To this end, we conducted an extensive literature search and used several in silico tools. We identified genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport. All these genes may modulate the stability or activity of HIF2α and its partners in the HIF-EPO pathway, thus affecting EPO synthesis. The theoretical information we provide in this work can be a valuable tool for a better understanding of one of the most important regulatory pathways in the process of erythropoiesis. This knowledge is necessary to discover the causative factors that may contribute to the development of hematological diseases and improve current diagnostic and treatment solutions in this regard.
Emerging Evidence for Pleiotropism of Eosinophils
Authors: Rodrigo-Muñoz José M. , Gil-Martínez Marta , Sastre Beatriz , del Pozo Victoria
Published: June 2021

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.
Design, Synthesis, In Silico and In Vitro Studies for New Nitric Oxide-Releasing Indomethacin Derivatives with 1,3,4-Oxadiazole-2-thiol Scaffold
Authors: Sava Alexandru , Buron Frederic , Routier Sylvain , Panainte Alina , Bibire Nela , Constantin Sandra Mădălina , Lupașcu Florentina Geanina , Focșa Alin Viorel , Profire Lenuţa
Published: June 2021

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a–p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects.
Pathophysiology and Clinical Manifestations of COVID-19-Related Acute Kidney Injury—The Current State of Knowledge and Future Perspectives
Authors: Smarz-Widelska Iwona , Grywalska Ewelina , Morawska Izabela , Forma Alicja , Michalski Adam , Mertowski Sebastian , Hrynkiewicz Rafał , Niedźwiedzka-Rystwej Paulina , Korona-Glowniak Izabela , Parczewski Miłosz , Załuska Wojciech
Published: June 2021

The continually evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in a vast number of either acute or chronic medical impairments of a pathophysiology that is not yet fully understood. SARS-CoV-2 tropism for the organs is associated with bilateral organ cross-talks as well as targeted dysfunctions, among which acute kidney injury (AKI) seems to be highly prevalent in infected patients. The need for efficient management of COVID-related AKI patients is an aspect that is still being investigated by nephrologists; however, another reason for concern is a disturbingly high proportion of various types of kidney dysfunctions in patients who have recovered from COVID-19. Even though the clinical picture of AKI and COVID-related AKI seems to be quite similar, it must be considered that regarding the latter, little is known about both the optimal management and long-term consequences. These discrepancies raise an urgent need for further research aimed at evaluating the molecular mechanisms associated with SARS-CoV-2-induced kidney damage as well as standardized management of COVID-related AKI patients. The following review presents a comprehensive and most-recent insight into the pathophysiology, clinical manifestations, recommended patient management, treatment strategies, and post-mortem findings in patients with COVID-related AKI.
Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin
Authors: Lopatynska-Mazurek Malgorzata , Komsta Lukasz , Gibula-Tarlowska Ewa , Kotlinska Jolanta H.
Published: June 2021

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.
The Involvement of Insulin-Like Growth Factor 1 and Nerve Growth Factor in Alzheimer’s Disease-Like Pathology and Survival Role of the Mix of Embryonic Proteoglycans: Electrophysiological Fingerprint, Structural Changes and Regulatory Effects on Neurotrophins
Authors: Aghajanov Michail , Matinyan Senik , Chavushyan Vergine , Danielyan Margarita , Karapetyan Gohar , Mirumyan Margarita , Fereshetyan Katarine , Harutyunyan Hayk , Yenkoyan Konstantin
Published: June 2021

Alzheimer’s disease (AD)-associated neurodegeneration is triggered by different fragments of amyloid beta (Aβ). Among them, Aβ (25–35) fragment plays a critical role in the development of neurodegeneration—it reduces synaptic integrity by disruption of excitatory/inhibitory ratio across networks and alters the growth factors synthesis. Thus, in this study, we aimed to identify the involvement of neurotrophic factors—the insulin-like growth factor 1 (IGF-1) and nerve growth factor (NGF)—of AD-like neurodegeneration induced by Aβ (25–35). Taking into account our previous findings on the neuroprotective effects of the mix of proteoglycans of embryonic genesis (PEG), it was suggested to test its regulatory effect on IGF-1 and NGF levels. To evaluate the progress of neurodegeneration, in vivo electrophysiological investigation of synaptic activity disruption of the entorhinal cortex–hippocampus circuit at AD was performed and the potential recovery effects of PEG with relative structural changes were provided. To reveal the direct effects of PEG on brain functional activity, the electrophysiological pattern of the single cells from nucleus supraopticus, sensomotor cortex and hippocampus after acute injection of PEG was examined. Our results demonstrated that after i.c.v. injection of Aβ (25–35), the level of NGF decreased in cerebral cortex and hypothalamus, and, in contrast, increased in hippocampus, prompting its multidirectional role in case of brain damage. The concentration of IGF-1 significantly increased in all investigated brain structures. The administration of PEG balanced the growth factor levels accompanied by substantial restoration of neural tissue architecture and synaptic activity. Acute injection of PEG activated the hypothalamic nucleus supraopticus and hippocampal neurons. IGF-1 and NGF levels were found to be elevated in animals receiving PEG in an absence of amyloid exposure. We suggest that IGF-1 and NGF play a critical role in the development of AD. At the same time, it becomes clear that the neuroprotective effects of PEG are likely mediated via the regulation of neurotrophins.
Vitamin D Supplementation: Oxidative Stress Modulation in a Mouse Model of Ovalbumin-Induced Acute Asthmatic Airway Inflammation
Authors: Adam-Bonci Teodora-Irina , Bonci Eduard-Alexandru , Pârvu Alina-Elena , Herdean Andrei-Ioan , Moț Augustin , Taulescu Marian , Ungur Andrei , Pop Raluca-Maria , Bocșan Corina , Irimie Alexandru
Published: June 2021

Asthma oxidative stress disturbances seem to enable supplementary proinflammatory pathways, thus contributing to disease development and severity. The current study analyzed the impact of two types of oral vitamin D (VD) supplementation regimens on the redox balance using a murine model of acute ovalbumin-induced (OVA-induced) asthmatic inflammation. The experimental prevention group received a long-term daily dose of 50 µg/kg (total dose of 1300 µg/kg), whereas the rescue group underwent a short-term daily dose of 100 µg/kg (total dose of 400 µg/kg). The following oxidative stress parameters were analyzed in serum, bronchoalveolar lavage fluid (BALF) and lung tissue homogenate (LTH): total oxidative status, total antioxidant response, oxidative stress index, malondialdehyde and total thiols. Results showed that VD significantly reduced oxidative forces and increased the antioxidant capacity in the serum and LTH of treated mice. There was no statistically significant difference between the two types of VD supplementation. VD also exhibited an anti-inflammatory effect in all treated mice, reducing nitric oxide formation in serum and the expression of nuclear factor kappa B p65 in the lung. In conclusion, VD supplementation seems to exhibit a protective role in oxidative stress processes related to OVA-induced acute airway inflammation.