Showing papers in "BioMed Research International in 2020"

Sars-CoV-2 Envelope and Membrane Proteins: Structural Differences Linked to Virus Characteristics?

Abstract: The Coronavirus Disease 2019 (COVID-19) is a new viral infection caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2). Genomic analyses have revealed that SARS-CoV-2 is related to Pangolin and Bat coronaviruses. In this report, a structural comparison between the Sars-CoV-2 Envelope and Membrane proteins from different human isolates with homologous proteins from closely related viruses is described. The analyses here reported show the high structural similarity of Envelope and Membrane proteins to the counterparts from Pangolin and Bat coronavirus isolates. However, the comparisons have also highlighted structural differences specific of Sars-CoV-2 proteins which may be correlated to the cross-species transmission and/or to the properties of the virus. Structural modelling has been applied to map the variant sites onto the predicted three-dimensional structure of the Envelope and Membrane proteins.

Design of a Multiepitope-Based Peptide Vaccine against the E Protein of Human COVID-19: An Immunoinformatics Approach.

Abstract: Background. A new endemic disease has spread across Wuhan City, China, in December 2019. Within few weeks, the World Health Organization (WHO) announced a novel coronavirus designated as coronavirus disease 2019 (COVID-19). In late January 2020, WHO declared the outbreak of a “public-health emergency of international concern” due to the rapid and increasing spread of the disease worldwide. Currently, there is no vaccine or approved treatment for this emerging infection; thus, the objective of this study is to design a multiepitope peptide vaccine against COVID-19 using an immunoinformatics approach. Method. Several techniques facilitating the combination of the immunoinformatics approach and comparative genomic approach were used in order to determine the potential peptides for designing the T-cell epitope-based peptide vaccine using the envelope protein of 2019-nCoV as a target. Results. Extensive mutations, insertion, and deletion were discovered with comparative sequencing in the COVID-19 strain. Additionally, ten peptides binding to MHC class I and MHC class II were found to be promising candidates for vaccine design with adequate world population coverage of 88.5% and 99.99%, respectively. Conclusion. The T-cell epitope-based peptide vaccine was designed for COVID-19 using the envelope protein as an immunogenic target. Nevertheless, the proposed vaccine rapidly needs to be validated clinically in order to ensure its safety and immunogenic profile to help stop this epidemic before it leads to devastating global outbreaks.

Mathematical Model for Coronavirus Disease 2019 (COVID-19) Containing Isolation Class.

Abstract: The deadly coronavirus continues to spread across the globe, and mathematical models can be used to show suspected, recovered, and deceased coronavirus patients, as well as how many people have been tested Researchers still do not know definitively whether surviving a COVID-19 infection means you gain long-lasting immunity and, if so, for how long? In order to understand, we think that this study may lead to better guessing the spread of this pandemic in future We develop a mathematical model to present the dynamical behavior of COVID-19 infection by incorporating isolation class First, the formulation of model is proposed; then, positivity of the model is discussed The local stability and global stability of proposed model are presented, which depended on the basic reproductive For the numerical solution of the proposed model, the nonstandard finite difference (NSFD) scheme and Runge-Kutta fourth order method are used Finally, some graphical results are presented Our findings show that human to human contact is the potential cause of outbreaks of COVID-19 Therefore, isolation of the infected human overall can reduce the risk of future COVID-19 spread

The Impact of COVID-19 Pandemic on Long-Term Care Facilities Worldwide: An Overview on International Issues.

Abstract: The COVID-19 pandemic had a great negative impact on nursing homes, with massive outbreaks being reported in care facilities all over the world, affecting not only the residents but also the care workers and visitors. Due to their advanced age and numerous underlying diseases, the inhabitants of long-term care facilities represent a vulnerable population that should benefit from additional protective measures against contamination. Recently, multiple countries such as France, Spain, Belgium, Canada, and the United States of America reported that an important fraction from the total number of deaths due to the SARS-CoV-2 infection emerged from nursing homes. The scope of this paper was to present the latest data regarding the COVID-19 spread in care homes worldwide, identifying causes and possible solutions that would limit the outbreaks in this overlooked category of population. It is the authors' hope that raising awareness on this matter would encourage more studies to be conducted, considering the fact that there is little information available on the impact of the SARS-CoV-2 pandemic on nursing homes. Establishing national databases that would register all nursing home residents and their health status would be of great help in the future not only for managing the ongoing pandemic but also for assessing the level of care that is needed in this particularly fragile setting.

D-Dimer and Prothrombin Time Are the Significant Indicators of Severe COVID-19 and Poor Prognosis.

Abstract: Objective. To investigate the value of coagulation indicators D-dimer (DD), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (Fg) in predicting the severity and prognosis of COVID-19. Methods. A total of 115 patients with confirmed COVID-19, who were admitted to Tianyou Hospital of Wuhan University of Science and Technology between January 18, 2020, and March 5, 2020, were included. The dynamic changes of DD, PT, APTT, and Fg were tested, and the correlation with CT imaging, clinical classifications, and prognosis was studied. Results. Coagulation disorder occurred at the early stage of COVID-19 infection, with 50 (43.5%) patients having DD increased and 74 (64.3%) patients having Fg increased. The levels of DD and Fg were correlated with clinical classification. Among 23 patients who deceased, 18 had DD increased at the first lab test, 22 had DD increased at the second and third lab tests, and 18 had prolonged PT at the third test. The results from ROC analyses for mortality risk showed that the AUCs of DD were 0.742, 0.818, and 0.851 in three times of test, respectively; PT was 0.643, 0.824, and 0.937. In addition, with the progression of the disease, the change of CT imaging was closely related to the increase of the DD value ( ). Conclusions. Coagulation dysfunction is more likely to occur in severe and critically ill patients. DD and PT could be used as the significant indicators in predicting the mortality of COVID-19.

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms.

Abstract: Objective The P2Y6 receptor has been shown to be involved in many cardiovascular diseases, including hypertension and atherosclerosis. The study is aimed at exploring the role of the P2Y6 receptor in Ang II-induced abdominal aortic aneurysm (AAA) formation in apolipoprotein E-deficient (apoE-/-) mice by using its selective antagonist. Methods Male apoE-/- mice were fed with high-fat diet and infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Mice were divided into four groups: normal saline (NS, placebo control) group (n = 8), Ang II+vehicle (Ang II) group (n = 14), Ang II-low dose MRS2578 (Ang II+MRS-16 mg) group (n = 14), and Ang II-high dose MRS2578 (Ang II+MRS-32 mg) group (n = 14). Daily intraperitoneal injection with vehicle or MRS2578 was pretreated one week before Ang II infusion. On postoperative day 10, aorta imaging of each group was taken by ultrasonography. After 4 weeks of Ang II infusion, the excised aortas were processed for diameter measurement and quantification of aneurysm severity and tissue characteristics; the blood samples were collected for measurement of the lipid profile and levels of cytokines. Verhoeff's Van Gieson (EVG) staining and immunochemistry staining were performed to evaluate disruption of the extracellular matrix (ECM) and infiltration of macrophages. Expression and activity of matrix metalloproteinases (MMPs) was measured by gelatin zymography. Results Treatment with MRS2578 made no significant difference in AAA formation, and maximal aortic diameter yet caused higher AAA rupture-induced mortality from 7% (Ang II) to 21.4% (Ang II+MRS-16 mg) or 42.9% (Ang II+MRS-32 mg), respectively (p < 0.05). Consistently, the severity of aneurysm tended to be more deteriorated in MRS2578-treated groups, especially the high-dosage group. The ratios of type III and IV aneurysm were much higher in the MRS2578-coadministered groups (p < 0.05). Furthermore, histological analyses showed that administration of MRS2578 significantly increased infiltration of macrophages, expression of monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and activities of MMP-2 and MMP-9 followed by aggravating degradation elastin in vivo (p < 0.05). However, the multiple effects of MRS2578 on the development of AAA are independent of changes in systolic blood pressure and lipid profiles. Conclusions The present study demonstrated that administration of MRS2578 exacerbated the progression and rupture of experimental AAA through promoting proinflammatory response and MMP expression and activity, which indicated a crucial role of the P2Y6 receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y12 receptor antagonist had been successfully applied in clinical practice. Elucidating the underlying mechanisms of AAA and exploring potential therapeutic strategies are essential to prevent its progression and reduce the mortality rate.

The Effects of Secretory IgA in the Mucosal Immune System.

Abstract: Immunoglobulin A (IgA) is the most abundant antibody isotype in the mucosal immune system. Structurally, IgA in the mucosal surface is a polymeric structure, while serum IgA is monomeric. Secretory IgA (sIgA) is one of the polymeric IgAs composed of dimeric IgA, J chain, and secretory component (SC). Most of sIgAs were generated by gut and have effects in situ. Besides the function of “immune exclusion,” a nonspecific immune role, recent studies found it also played an important role in the specific immunity and immunoregulation. Thanks to the critical role of sIgA during the mucosal immune system homeostasis between commensal microorganisms and pathogens; it has been an important field exploring the relationship between sIgA and commensal microorganisms.

RANKL/RANK/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling.

Abstract: Bones as an alive organ consist of about 70% mineral and 30% organic component. About 200 million people are suffering from osteopenia and osteoporosis around the world. There are multiple ways of protecting bone from endogenous and exogenous risk factors. Planned physical activity is another useful way for protecting bone health. It has been investigated that arranged exercise would effectively regulate bone metabolism. Until now, a number of systems have discovered how exercise could help bone health. Previous studies reported different mechanisms of the effect of exercise on bone health by modulation of bone remodeling. However, the regulation of RANKL/RANK/OPG pathway in exercise and physical performance as one of the most important remodeling systems is not considered comprehensive in previous evidence. Therefore, the aim of this review is to clarify exercise influence on bone modeling and remodeling, with a concentration on its role in regulating RANKL/RANK/OPG pathway.

A Survey on Recent Advances in Wearable Fall Detection Systems

Abstract: With advances in medicine and healthcare systems, the average life expectancy of human beings has increased to more than 80 yrs. As a result, the demographic old-age dependency ratio (people aged 65 or above relative to those aged 15–64) is expected to increase, by 2060, from ∼28% to ∼50% in the European Union and from ∼33% to ∼45% in Asia (Ageing Report European Economy, 2015). Therefore, the percentage of people who need additional care is also expected to increase. For instance, per studies conducted by the National Program for Health Care of the Elderly (NPHCE), elderly population in India will increase to 12% of the national population by 2025 with 8%–10% requiring utmost care. Geriatric healthcare has gained a lot of prominence in recent years, with specific focus on fall detection systems (FDSs) because of their impact on public lives. According to a World Health Organization report, the frequency of falls increases with increase in age and frailty. Older people living in nursing homes fall more often than those living in the community and 40% of them experience recurrent falls (World Health Organization, 2007). Machine learning (ML) has found its application in geriatric healthcare systems, especially in FDSs. In this paper, we examine the requirements of a typical FDS. Then we present a survey of the recent work in the area of fall detection systems, with focus on the application of machine learning. We also analyze the challenges in FDS systems based on the literature survey.

Qualitative Analysis of a Mathematical Model in the Time of COVID-19.

Abstract: In this article, a qualitative analysis of the mathematical model of novel corona virus named COVID-19 under nonsingular derivative of fractional order is considered. The concerned model is composed of two compartments, namely, healthy and infected. Under the new nonsingular derivative, we, first of all, establish some sufficient conditions for existence and uniqueness of solution to the model under consideration. Because of the dynamics of the phenomenon when described by a mathematical model, its existence must be guaranteed. Therefore, via using the classical fixed point theory, we establish the required results. Also, we present the results of stability of Ulam's type by using the tools of nonlinear analysis. For the semianalytical results, we extend the usual Laplace transform coupled with Adomian decomposition method to obtain the approximate solutions for the corresponding compartments of the considered model. Finally, in order to support our study, graphical interpretations are provided to illustrate the results by using some numerical values for the corresponding parameters of the model.

Mortality and Disease Burden of Injuries from 2008 to 2017 in Anhui Province, China.

Abstract: Objective. To investigate the temporal trends in mortality and disease burden of injuries in Anhui province from 2008 to 2017, so as to provide reference for injury control and prevention. Methods. Data of mortality were collected from 9 national surveillance points in Anhui province during 2008-2017 in the Information System for Death Cause Register and Management. The surveillance data were analyzed by using crude mortality, standardized mortality rate (SMR), potential year of life lost (PYLL), PYLL rate (PYLLR), and average of year life lost (AYLL). Results. There were a total of 44855 people died from injury, accounted for 9.44% of the all-cause mortality, ranked as the fifth leading cause of deaths in the whole population, and denoted the first leading cause of deaths in the 0-44 year’s group. The leading causes of injury deaths were road traffic accidents, suicide, accidental falls, drowning, and poisoning. Road traffic accidents was the primary cause of injury deaths among the male population, while suicide was the dominate cause of injury deaths among the female population. Drowning, traffic accidents, and suicide accounted for the most injury deaths among the population aged 0-14 years, 15-64 years, and above 60 years, respectively. The road traffic accidents accounted for the largest proportion of injury PYLL and PYLLR, and drowning caused the highest AYLL among injury deaths. Conclusion. In Anhui province, road traffic accidents, suicide, accidental falls, drowning, and poisoning were the top five causes of injury deaths that harm the health of local residents; corresponding injury prevention strategies should be formulated.

Effect of Silver Nanoparticles on Biofilm Formation and EPS Production of Multidrug-Resistant Klebsiella pneumoniae.

Abstract: Antibiotic resistance against present antibiotics is rising at an alarming rate with need for discovery of advanced methods to treat infections caused by resistant pathogens. Silver nanoparticles are known to exhibit satisfactory antibacterial and antibiofilm activity against different pathogens. In the present study, the AgNPs were synthesized chemically and characterized by UV-Visible spectroscopy, scanning electron microscopy, and X-ray diffraction. Antibacterial activity against MDR K. pneumoniae strains was evaluated by agar diffusion and broth microdilution assay. Cellular protein leakage was determined by the Bradford assay. The effect of AgNPs on production on extracellular polymeric substances was evaluated. Biofilm formation was assessed by tube method qualitatively and quantitatively by the microtiter plate assay. The cytotoxic potential of AgNPs on HeLa cell lines was also determined. AgNPs exhibited an MIC of 62.5 and 125 μg/ml, while their MBC is 250 and 500 μg/ml. The production of extracellular polymeric substance decreased after AgNP treatment while cellular protein leakage increased due to higher rates of cellular membrane disruption by AgNPs. The percentage biofilm inhibition was evaluated to be 64% for K. pneumoniae strain MF953600 and 86% for MF953599 at AgNP concentration of 100 μg/ml. AgNPs were evaluated to be minimally cytotoxic and safe at concentrations of 15-120 μg/ml. The data evaluated by this study provided evidence of AgNPs being safe antibacterial and antibiofilm compounds against MDR K. pneumoniae.

Phytochemicals as Potential Anticancer Drugs: Time to Ponder Nature's Bounty.

Abstract: Medicinal plants have been used from the beginning of human civilization, which is mostly evident from the ancient script and traditional herbal medicine recipe. Despite the historically enriched demonstration about the use of plant as therapeutics, the pharmaceutical industries lack interest on phytochemical research compared with synthetic drug. Mostly, the absence of information about plant-based medicinal therapeutics is responsible to draw the attention of researchers to think about natural products as potential drug for detrimental diseases, such as cancer. This review will cover about clinically successful plant-based anticancer drugs and underappreciated, but potential, drugs to bridge the information gap between plant biologists and clinical researchers. Additionally, unprecedented advancement of synthetic chemistry, omics study to pin point the target genes/proteins, and efficient drug delivery system have made it easier for researchers to develop a phytochemical as an efficient anticancer drug.

Improving an Intelligent Detection System for Coronary Heart Disease Using a Two-Tier Classifier Ensemble.

Abstract: Coronary heart disease (CHD) is one of the severe health issues and is one of the most common types of heart diseases. It is the most frequent cause of mortality across the globe due to the lack of a healthy lifestyle. Owing to the fact that a heart attack occurs without any apparent symptoms, an intelligent detection method is inescapable. In this article, a new CHD detection method based on a machine learning technique, e.g., classifier ensembles, is dealt with. A two-tier ensemble is built, where some ensemble classifiers are exploited as base classifiers of another ensemble. A stacked architecture is designed to blend the class label prediction of three ensemble learners, i.e., random forest, gradient boosting machine, and extreme gradient boosting. The detection model is evaluated on multiple heart disease datasets, i.e., Z-Alizadeh Sani, Statlog, Cleveland, and Hungarian, corroborating the generalisability of the proposed model. A particle swarm optimization-based feature selection is carried out to choose the most significant feature set for each dataset. Finally, a two-fold statistical test is adopted to justify the hypothesis, demonstrating that the performance differences of classifiers do not rely upon an assumption. Our proposed method outperforms any base classifiers in the ensemble with respect to 10-fold cross validation. Our detection model has performed better than current existing models based on traditional classifier ensembles and individual classifiers in terms of accuracy, , and AUC. This study demonstrates that our proposed model adds a considerable contribution compared to the prior published studies in the current literature.

Biomimetic Effect of Nano-Hydroxyapatite in Demineralized Enamel before Orthodontic Bonding of Brackets and Attachments: Visual, Adhesion Strength, and Hardness in In Vitro Tests.

Abstract: Dietary habits with high consumption of acidic food can induce in orthodontic patients an increased risk of demineralization lesions around orthodontic brackets and bands. The purpose of the present laboratory study is to assess the in vitro visual efficacy of a biomimetic nano-hydroxyapatite remineralizing solution in a hypomineralized enamel surface and its effect on adhesion of fixed orthodontic appliances and on enamel microhardness. Intact teeth were demineralized, and subsequently the areas of demineralization were visually recorded using a 0-100 scale. Subsequently, a remineralizing solution (Biorepair® Repair Shock Treatment) was applied for ten minutes once a day/for one week per month for a total remineralizing treatment of 3 months. Visual effects were recorded. Moreover, bond strength was recorded and adhesive remnant index scores were measured for both orthodontic brackets and composite attachments both before demineralization and after demineralization and application of remineralizing solution. Also, Vickers microhardness was measured. All data were submitted to statistical analysis. The application of remineralizing solution induced a significant in vitro reduction of demineralized areas after the first week of application. No significant differences between untreated enamel surfaces and remineralized surfaces were detected after 2 months of remineralizing treatment. Bond strength values were significantly reduced for both brackets and attachments after remineralizing treatment. However, attachments showed higher adhesion values than brackets in both conditions tested. Remineralized enamel showed significantly higher microhardness values than demineralized enamel and lower values than intact enamel.

Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury.

Abstract: Uric acid is the end product of purine metabolism in humans, and its excessive accumulation leads to hyperuricemia and urate crystal deposition in tissues including joints and kidneys. Hyperuricemia is considered an independent risk factor for cardiovascular and renal diseases. Although the symptoms of hyperuricemia-induced renal injury have long been known, the pathophysiological molecular mechanisms are not completely understood. In this review, we focus on the research advances in the mechanisms of hyperuricemia-caused renal injury, primarily on oxidative stress, endothelial dysfunction, renal fibrosis, and inflammation. Furthermore, we discuss the progress in hyperuricemia management.

An Overview of Lipid Metabolism and Nonalcoholic Fatty Liver Disease

Abstract: The occurrence of nonalcoholic fatty liver disease (NAFLD) is associated with major abnormalities of hepatic lipid metabolism. We propose that lipid abnormalities directly or indirectly contribute to NAFLD, especially fatty acid accumulation, arachidonic acid metabolic disturbance, and ceramide overload. The effects of lipid intake and accumulation on NAFLD and NAFLD treatment are explained with theoretical and experimental details. Overall, these findings provide further understanding of lipid metabolism in NAFLD and may lead to novel therapies.

Sleep Deprivation and Neurological Disorders.

Abstract: Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended.

Space Radiation Biology for “Living in Space”

Abstract: Space travel has advanced significantly over the last six decades with astronauts spending up to 6 months at the International Space Station. Nonetheless, the living environment while in outer space is extremely challenging to astronauts. In particular, exposure to space radiation represents a serious potential long-term threat to the health of astronauts because the amount of radiation exposure accumulates during their time in space. Therefore, health risks associated with exposure to space radiation are an important topic in space travel, and characterizing space radiation in detail is essential for improving the safety of space missions. In the first part of this review, we provide an overview of the space radiation environment and briefly present current and future endeavors that monitor different space radiation environments. We then present research evaluating adverse biological effects caused by exposure to various space radiation environments and how these can be reduced. We especially consider the deleterious effects on cellular DNA and how cells activate DNA repair mechanisms. The latest technologies being developed, e.g., a fluorescent ubiquitination-based cell cycle indicator, to measure real-time cell cycle progression and DNA damage caused by exposure to ultraviolet radiation are presented. Progress in examining the combined effects of microgravity and radiation to animals and plants are summarized, and our current understanding of the relationship between psychological stress and radiation is presented. Finally, we provide details about protective agents and the study of organisms that are highly resistant to radiation and how their biological mechanisms may aid developing novel technologies that alleviate biological damage caused by radiation. Future research that furthers our understanding of the effects of space radiation on human health will facilitate risk-mitigating strategies to enable long-term space and planetary exploration.

D-Lactic Acid as a Metabolite: Toxicology, Diagnosis, and Detection

Abstract: Two enantiomers of lactic acid exist While L-lactic acid is a common compound of human metabolism, D-lactic acid is produced by some strains of microorganism or by some less relevant metabolic pathways While L-lactic acid is an endogenous compound, D-lactic acid is a harmful enantiomer Exposure to D-lactic acid can happen by various ways including contaminated food and beverages and by microbiota during some pathological states like short bowel syndrome The exposure to D-lactic acid cannot be diagnosed because the common analytical methods are not suitable for distinguishing between the two enantiomers In this review, pathways for D-lactic acid, pathological processes, and diagnostical and analytical methods are introduced followed by figures and tables The current literature is summarized and discussed

Gut Microbiome Alterations Precede Cerebral Amyloidosis and Microglial Pathology in a Mouse Model of Alzheimer's Disease.

Abstract: Emerging evidence suggests that the gut microbiome actively regulates cognitive functions and that gut microbiome imbalance is associated with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. However, the changes in gut microbiome composition in AD and their association with disease pathology, especially in the early stages, are unclear. Here, we compared the profiles of gut microbiota between APP/PS1 transgenic mice (an AD mouse model) and their wild-type littermates at different ages by amplicon-based sequencing of 16S ribosomal RNA genes. Microbiota composition started diverging between the APP/PS1 and wild-type mice at young ages (i.e., 1-3 months), before obvious amyloid deposition and plaque-localized microglial activation in the cerebral cortex in APP/PS1 mice. At later ages (i.e., 6 and 9 months), there were distinct changes in the abundance of inflammation-related bacterial taxa including Escherichia-Shigella, Desulfovibrio, Akkermansia, and Blautia in APP/PS1 mice. These findings suggest that gut microbiota alterations precede the development of key pathological features of AD, including amyloidosis and plaque-localized neuroinflammation. Thus, the investigation of gut microbiota might provide new avenues for developing diagnostic biomarkers and therapeutic targets for AD.

Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer.

Abstract: Colorectal cancer (CRC) is a common malignancy with high morbidity and mortality worldwide. To date, chemotherapy plays an important role in the treatment of CRC patients. Multidrug resistance (MDR) is one of the major hurdles in chemotherapy for CRC, and the underlying mechanisms need to be explored. Studies have demonstrated that Wnt/β-catenin signaling plays a critical role in oncogenesis and tumor development, and its function in inhibiting apoptosis could facilitate tumor chemoresistance. Recent investigations have also suggested the regulatory effects of the Wnt/β-catenin signaling pathway in response to chemotherapeutic agents in CRC. Here, we particularly focus on reviewing the evidences suggesting the mechanisms of Wnt/β-catenin signaling in the chemoresistance modulation of colorectal cancer.

The Biomarkers for Acute Myocardial Infarction and Heart Failure

Abstract: The use of a large number of cardiovascular biomarkers, meant to complement the use of the electrocardiogram, echocardiography cardiac imaging, and clinical symptom assessment, has become a routine in clinical diagnosis, differential diagnosis, risk stratification, and prognosis and guides the management of patients with suspected cardiovascular diseases. There is a broad consensus that cardiac troponin and natriuretic peptides are the preferred biomarkers in clinical practice for the diagnosis of the acute coronary syndrome and heart failure, respectively, while the roles and possible clinical applications of several other potential biomarkers are still under study. This review mainly focuses on the recent studies of the roles and clinical applications of troponin and natriuretic peptides, which seem to be the best-validated markers in distinguishing and predicting the future cardiac events of patients with suspected cardiovascular diseases. Additionally, the review briefly discusses some of the large number of potential markers that may play a more prominent role in the future.

Isolation and Characterization of Plant Growth-Promoting Endophytic Bacteria Paenibacillus polymyxa SK1 from Lilium lancifolium.

Abstract: Paenibacillus polymyxa is a plant growth-promoting rhizobacterium that has immense potential to be used as an environmentally friendly replacement of chemical fertilizers and pesticides. In the present study, Paenibacillus polymyxa SK1 was isolated from bulbs of Lilium lancifolium. The isolated endophytic strain showed antifungal activities against important plant pathogens like Botryosphaeria dothidea, Fusarium oxysporum, Botrytis cinerea, and Fusarium fujikuroi. The highest percentage of growth inhibition, i.e., 66.67 ± 2.23%, was observed for SK1 against Botryosphaeria dothidea followed by 61.19 ± 3.12%, 60.71 ± 3.53%, and 55.54 ± 2.89% against Botrytis cinerea, Fusarium fujikuroi, and Fusarium oxysporum, respectively. The metabolite profiling of ethyl acetate fraction was assessed through the UHPLC-LTQ-IT-MS/MS analysis, and putative identification was done with the aid of the GNPS molecular networking workflow. A total of 29 compounds were putatively identified which included dipeptides, tripeptides, cyclopeptides (cyclo-(Leu-Leu), cyclo(Pro-Phe)), 2-heptyl-3-hydroxy 4-quinolone, 6-oxocativic acid, anhydrobrazilic acid, 1-(5-methoxy-1H-indol-3-yl)-2-piperidin-1-ylethane-1,2-dione, octadecenoic acid, pyochelin, 15-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid, (Z)-7-[(2R,3S)-3-[(2Z,5E)-Undeca-2,5-dienyl]oxiran-2-yl]hept-5-enoic acid, arginylasparagine, cholic acid, sphinganine, elaidic acid, gossypin, L-carnosine, tetrodotoxin, and ursodiol. The high antifungal activity of SK1 might be attributed to the presence of these bioactive compounds. The isolated strain SK1 showed plant growth-promoting traits such as the production of organic acids, ACC deaminase, indole-3-acetic acid (IAA), siderophores, nitrogen fixation, and phosphate solubilization. IAA production was strongly correlated with the application of exogenous tryptophan concentrations in the medium. Furthermore, inoculation of SK1 enhanced plant growth of two Lilium varieties, Tresor and White Heaven, under greenhouse condition. In the light of these findings, the P. polymyxa SK1 may be utilized as a source of plant growth promotion and disease control in sustainable agriculture.

Multitarget Therapeutic Strategies for Alzheimer's Disease: Review on Emerging Target Combinations.

Abstract: Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer's disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

Alkaloids from Cryptolepis sanguinolenta as Potential Inhibitors of SARS-CoV-2 Viral Proteins: An In Silico Study

Abstract: The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.

Effect of Quercetin on PC12 Alzheimer's Disease Cell Model Induced by Aβ25-35 and Its Mechanism Based on Sirtuin1/Nrf2/HO-1 Pathway.

Abstract: Objective This study is aimed at studying the effect of quercetin on the Alzheimer disease cell model induced by Aβ 25-35 in PC12 cells and its mechanism of action. Methods The AD cell model was established by Aβ 25-35. Quercetin was used at different concentrations (0, 10, 20, 40, and 80 μmol/L). The morphology of cells was observed, and the effect on cell survival rate was detected by the MTT method. Cell proliferation was detected by the SRB method. The contents of LDH, SOD, MDA, GSH-Px, AChE, CAT, and T-AOC were detected by kits. The expression of sirtuin1/Nrf2/HO-1 was detected by RT-qPCR and Western blot. Results PC12 cells in the control group grew quickly and adhered well to the wall, most of which had extended long axons and easily grew into clusters. In the model group, cells were significantly damaged and the number of cells was significantly reduced. It was found that PC12 cells were swollen, rounded, protruding, and retracting, with reduced adherent function and floating phenomenon. Quercetin could increase the survival rate and proliferation rate of PC12 cells; reduce the levels of LDH, AChE, MDA, and HO-1 protein; and increase the levels of SOD, GSH-Px, CAT, T-AOC, sirtuin1, and Nrf2 protein. Conclusion Quercetin can increase the survival rate of PC12 injured by Aβ 25-35, promote cell proliferation, and antagonize the toxicity of Aβ; it also has certain neuroprotective effects. Therefore, quercetin is expected to become a drug for the treatment of AD.

Exosomes Derived from Brain Metastatic Breast Cancer Cells Destroy the Blood-Brain Barrier by Carrying lncRNA GS1-600G8.5.

Abstract: Brain metastasis is a major cause of death in breast cancer patients. The greatest event for brain metastasis is the breaching of the blood-brain barrier (BBB) by cancer cells. The role of exosomes in cancer metastasis is clear, whereas the role of exosomes in the integrity of the BBB is unknown. Here, we established a highly brain metastatic breast cancer cell line by three cycles of in vivo selection. The effect of exosomes on the BBB was evaluated in vitro by tracking, transepithelial/transendothelial electrical resistance (TEER), and permeability assays. BBB-associated exosomal long noncoding RNA (lncRNA) was selected from the GEO dataset and verified by real-time PCR, TEER, permeability, and Transwell assays. The cells obtained by the in vivo selection showed higher brain metastatic capacity in vivo and higher migration and invasion in vitro compared to the parental cells. Exosomes from the highly brain metastatic cells were internalized by brain microvascular endothelial cells (BMECs), which reduced TEER and increased permeability of BBB. The exosomes derived from the highly metastatic cells promoted invasion of the breast cancer cells in the BBB model. lncRNA GS1-600G8.5 was highly expressed in the highly brain metastatic cells and their exosomes, as compared to the samples with reduced metastatic behavior. Silencing of GS1-600G8.5 significantly abrogated the BBB destructive effect of exosomes. GS1-600G8.5-deficient exosomes failed to promote the infiltration of cancer cells through the BBB. Furthermore, BMECs treated with GS1-600G8.5-deprived exosomes expressed higher tight junction proteins than those treated with the control exosomes. These data suggest the exosomes derived from highly brain metastatic breast cancer cells might destroy the BBB system and promote the passage of cancer cells across the BBB, by transferring lncRNA GS1-600G8.5.

Study of the Relationship between Microbiome and Colorectal Cancer Susceptibility Using 16SrRNA Sequencing.

Abstract: A lot of previous studies have recently reported that the gut microbiota influences the development of colorectal cancer (CRC) in Western countries, but the role of the gut microbiota in Chinese population must be investigated fully. The goal of this study was to determine the role of the gut microbiome in the initiation and development of CRC. We collected fecal samples of 206 Chinese individuals: 59 with polyp (group P), 54 with adenoma (group A), 51 with colorectal cancer (group CC), and 42 healthy controls (group HC).16S ribosomal RNA (rRNA) was used to compare the microbiota community structures among healthy controls, patients with polyp, and those with adenoma or colorectal cancer. Our study proved that intestinal flora, as a specific indicator, showed significant differences in its diversity and composition. Sobs, Chao, and Ace indexes of group CC were significantly lower than those of the healthy control group (CC group: Sobs, Chao, and Ace indexes were 217.3 ± 69, 4265.1 ± 80.7, and 268.6 ± 78.1, respectively; HC group: Sobs, Chao, and Ace indexes were 228.8 ± 44.4, 272.9 ± 58.6, and 271.9 ± 57.2, respectively). When compared with the healthy individuals, the species richness and diversity of intestinal flora in patients with colorectal cancer were significantly reduced: PCA and PCoA both revealed that a significant separation in bacterial community composition between the CC group and HC group (with PCA using the first two principal component scores of PC1 14.73% and PC2 10.34% of the explained variance, respectively; PCoA : PC1 = 14%, PC2 = 9%, PC3 = 6%). Wilcox tests was used to analyze differences between the two groups, it reveals that Firmicutes (P=0.000356), Fusobacteria (P=0.000001), Proteobacteria (P=0.000796), Spirochaetes (P=0.013421), Synergistetes (P=0.005642) were phyla with significantly different distributions between cases and controls. The proportion of microorganism composition is varying at different stages of colon cancer development: Bacteroidetes (52.14%) and Firmicutes (35.88%) were enriched in the healthy individuals; on the phylum level, the abundance of Bacteroidetes (52.14%-53.92%-52.46%-47.06%) and Firmicutes (35.88%-29.73%-24.27%-25.36%) is decreasing with the development of health-polyp-adenomas-CRC, and the abundance of Proteobacteria (9.33%-12.31%-16.51%-22.37%) is increasing. PCA and PCOA analysis showed there was no significant (P < 0.05) difference in species similarity between precancerous and carcinogenic states. However, the composition of the microflora in patients with precancerous lesions (including patients with adenoma and polyp) was proved to have no significant disparity (P < 0.05). Our study provides insights into new angles to dig out potential biomarkers in diagnosis and treatment of colorectal cancer and to provide scientific advice for a healthy lifestyle for the sake of gut microbiota.

Exosomal miRNA-215-5p Derived from Adipose-Derived Stem Cells Attenuates Epithelial–Mesenchymal Transition of Podocytes by Inhibiting ZEB2

Abstract: Background Podocyte migration is actively involved in the process of podocyte loss and proteinuria production, which is closely associated with the development of diabetic nephropathy (DN). Exosomes from adipose-derived stem cells (ADSCs-Exos) effectively inhibit podocyte apoptosis in the treatment of DN. However, how ADSCs-Exos affect the migration of podocytes is obscure. This study is aimed at exploring the regulatory role of ADSCs-Exos on cell migration and the underlying mechanism. Methods ADSCs-Exo was authenticated by transmission electron microscopy (TEM), western blotting, and flow cytometry. Cell viability and migration ability of podocytes were measured by CCK8 and Transwell assays, respectively. Relative expressions of miRNAs and mRNAs were determined by qRT-PCR. The transmitting between PKH26-labeled exosome and podocytes was evaluated by IF assay. Dual luciferase reporter assay was employed to detect the relationship between miR-215-5p and ZEB2. Results The exposure to serum from DN patient (hDN-serum) significantly inhibited cell viability of podocytes, but ADSCs-Exo addition notably blunts cytotoxicity induced by the transient stimulus of hDN-serum. Besides, ADSCs-Exo administration powerfully impeded high glucose- (HG-) induced migration and injury of podocyte. With the podocyte dysfunction, several miRNAs presented a significant decline under the treatment of HG including miR-251-5p, miR-879-5p, miR-3066-5p, and miR-7a-5p, all of which were rescued by the addition of ADSCs-Exo. However, only miR-251-5p was a key determinant in the process of ADSCs-Exo-mediated protective role on podocyte damage. The miR-251-5p inhibitor counteracted the improvement from the ADSCs-Exo preparation on HG-induced proliferation inhibition and migration promotion. Additionally, miR-215-5p mimics alone remarkably reversed HG-induced EMT process of podocyte. Mechanistically, we confirmed that ADSCs-Exos mediated the shuttling of miR-215-5p to podocyte, thereby protecting against HG-induced metastasis, possibly through inhibiting the transcription of ZEB2. Conclusion ADSCs-Exo has the protective effect on HG-evoked EMT progression of podocytes thru a mechanism involving ZEB2. Potentially, the ADSCs-Exo preparation is a useful therapeutic strategy for improving podocyte dysfunction and DN symptoms clinically.