ABSTRACT
It is widely known that the immune system becomes slower to respond among elderly people, making them more susceptible to viral infection and cancer. The mechanism of aging-related immune deficiency remained mostly elusive. In this article, we report that plasmalogens (Pls), special phospholipids found to be reduced among the elderly population, critically control cytolytic activity of human NK cells, which is associated with activation of a cell surface receptor, G protein-coupled receptor 21 (GPCR21). We found the extracellular glycosylation site of GPCR21, which is conserved among the mammalian species, to be critically important for the activation of NK cells by Pls. The Pls-GPCR21 signaling cascade induces the expression of Perforin-1, a cytolytic pore-forming protein, via activation of STAT5 transcription factor. Inhibition of STAT5 abrogates GPCR21-mediated cytolytic activation of NK cells against the target cancer cells. In addition, oral ingestion of Pls inhibited cancer growth in SCID mice and inhibited the systemic spread of murine CMV in adult C57BL/6J mice. These findings advocate that Pls-GPCR21 signaling could be critical in maintaining NK cell function, and that the age-related reduction of this signaling cascade could be one of the factors behind immune deficiency in mammals, including humans.
Subject(s)
Killer Cells, Natural , Plasmalogens , Receptors, Leukotriene/metabolism , Adult , Aged , Animals , Cytotoxicity, Immunologic , Humans , Mammals , Mice , Mice, Inbred C57BL , Mice, SCID , Perforin/metabolism , Plasmalogens/metabolism , Pore Forming Cytotoxic Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal TransductionABSTRACT
Plasmalogens (Pls) are one kind of phospholipids enriched in the brain and other organs. These lipids were thought to be involved in the membrane bilayer formation and anti-oxidant function. However, extensive studies revealed that Pls exhibit various beneficial biological activities including prevention of neuroinflammation, improvement of cognitive function, and inhibition of neuronal cell death. The biological activities of Pls were associated with the changes in cellular signaling and gene expression. Membrane-bound GPCRs were identified as possible receptors of Pls, suggesting that Pls might function as ligands or hormones. Aging, stress, and inflammatory stimuli reduced the Pls contents in cells, and addition of Pls inhibited inflammatory processes, which could suggest that reduction of Pls might be one of the risk factors for the diseases associated with inflammation. Oral ingestion of Pls showed promising health benefits among Alzheimer's disease (AD) patients, suggesting that Pls might have therapeutic potential in other neurodegenerative diseases.
Subject(s)
Alzheimer Disease/metabolism , Plasmalogens/metabolism , Alzheimer Disease/drug therapy , Brain/drug effects , Brain/metabolism , Cell Death/drug effects , Humans , Inflammation/drug therapy , Inflammation/metabolism , Plasmalogens/administration & dosage , Plasmalogens/pharmacology , Plasmalogens/therapeutic useABSTRACT
It has been reported in recent years that blood levels of plasmalogens (Pls) are decreased in various diseases. None of those reports, however, conducted any clinical trials to examine the effect of Pls on those diseases. This article describes our recent report on a therapeutic efficacy of orally administered Pls in mild cognitive impairment (MCI), mild to severe Alzheimer's disease (AD), and Parkinson's disease (PD). A 24-week, multicenter, randomized, double-blind, placebo-controlled trial was performed in patients with MCI (n = 178) and mild AD (n = 98). The study design for moderate AD (n = 57) and severe AD (n = 18) was 12-week open-labeled, and the design for patients with PD (n = 10) was 24-week open-labeled. They showed a significant improvement in cognitive function and other clinical symptoms with elevation of the blood Pls levels. No adverse events were reported. The baseline levels of plasma ethanolamine plasmalogen and erythrocyte ethanolamine plasmalogen in MCI, AD, and PD were significantly lower than those of normal aged. The degree of reduction in the blood Pls levels was in the order of MCI ⺠mild AD ⺠moderate AD ⺠severe AD ⺠PD. The findings suggest that the blood levels of Pls may be a beneficial biomarker for assessing AD severity. Based on these results, we have proposed a new hypothesis for the etiology of AD and other neuropsychiatric disorders.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/etiology , Cognitive Dysfunction/drug therapy , Parkinson Disease/drug therapy , Plasmalogens/therapeutic use , Alzheimer Disease/blood , Cognitive Dysfunction/blood , Cognitive Dysfunction/etiology , Double-Blind Method , Humans , Parkinson Disease/blood , Plasmalogens/administration & dosage , Plasmalogens/blood , Randomized Controlled Trials as TopicABSTRACT
Neuroinflammation characterized by activation of glial cells is observed in various neurodegenerative diseases including Alzheimer's disease (AD). Although the reduction of ether-type glycerophospholipids, plasmalogens (Pls), in the brain is reported in AD patients, the mechanism of the reduction and its impact on neuroinflammation remained elusive. In the present study, we found for the first time that various inflammatory stimuli reduced Pls levels in murine glial cells via NF-κB activation, which then downregulated a Pls-synthesizing enzyme, glycerone phosphate O-acyltransferase (Gnpat) through increased c-Myc recruitment onto the Gnpat promoter. We also found that systemic injection of lipopolysaccharide, aging, and chronic restraint stress reduced brain Pls contents that were associated with glial NF-κB activation, an increase in c-Myc expression, and downregulation of Gnpat in the mouse cortex and hippocampus. More interestingly, the reduction of Pls contents in the murine cortex itself could increase the activated phenotype of microglial cells and the expression of proinflammatory cytokines, suggesting further acceleration of neuroinflammation by reduction of brain Pls. A similar mechanism of Gnpat reduction was also found in human cell lines, triple-transgenic AD mouse brain, and postmortem human AD brain tissues. These findings suggest a novel mechanism of neuroinflammation that may explain prolonged progression of AD and help us to explore preventive and therapeutic strategies to treat neurodegenerative diseases.SIGNIFICANCE STATEMENT Ether-type glycerophospholipids, plasmalogens (Pls), are reduced in the brain of Alzheimer disease (AD) patients. We found that inflammatory stimuli reduced Pls contents by downregulation of the Pls-synthesizing enzyme glycerone phosphate O-acyltransferase (Gnpat) through NF-κB-mediated recruitment of c-Myc onto the Gnpat promoter in both murine and human cell lines. Murine brains after systemic lipopolysaccharide, chronic stress, and aging, as well as triple-transgenic AD mice and postmortem human AD brain tissues all showed increased c-Myc and reduced Gnpat expression. Interestingly, knockdown of Gnpat itself activated NF-κB in glial cell lines and microglia in mouse cortex. Our findings provide a new insight into the mechanism of neuroinflammation and may help to develop a novel therapeutic approach for neurodegenerative diseases such as AD.
Subject(s)
Acyltransferases/metabolism , Glycerophospholipids/metabolism , Microglia/metabolism , NF-kappa B/pharmacology , Plasmalogens/metabolism , Animals , Cell Line, Tumor , Ether , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/drug effectsABSTRACT
Activation of protein kinase C delta (PKCδ) has been linked to the neuroinflammation but the relationship with the various neurodegenerative diseases including the Alzheimer's disease (AD) was mostly elusive. In the AD brains, the special phospholipids, ethanolamine plasmalogens (Pls), were found to be reduced and our previous study showed that these lipids possess neuroprotective and anti-inflammatory functions. In the present study, we could find that these lipids can significantly attenuate the microglial expression of PKCδ in the neuroinflammation model and in the AD model mice brains. We also show an increase of PKCδ in the human postmortem AD brains. In addition, we also report that scallop derived Pls (sPls) inhibited the p38MAPK and JNK protein expression which are involved in the expressional regulation of PKCδ in the microglial cells. In addition, the lentiviral shRNA-mediated knockdown of PKCδ attenuated the LPS-induced p65 (NF-kB) activation and inflammatory cytokine expression, suggesting that the PKCδ can induce the inflammatory response which can be inhibited by the sPls. Taken together, our recent findings suggest that the sPls can attenuate the increased expression of PKCδ associated with the neuro-inflammation in the murine brain.
Subject(s)
Encephalitis/enzymology , Pectinidae/chemistry , Plasmalogens/pharmacology , Protein Kinase C-delta/metabolism , Animals , Cell Line , Cytokines/metabolism , Encephalitis/genetics , Enzyme Activation/drug effects , HEK293 Cells , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Microglia/drug effects , Microglia/enzymology , Plasmalogens/administration & dosage , Protein Kinase C-delta/genetics , RNA Interference , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Plasmalogens (Pls) are the special phospholipids which were reported to be reduced in brain and blood samples of Alzheimer's disease (AD) patients, suggested a possibility that an oral ingestion of Pls may prevent the disease progression. Interestingly, the clinical study showed that the daily oral ingestion of Pls among the mild AD patients improved cognition. However, it is unknown of whether the oral ingestion of Pls inhibits the AD like changes in brain e.g., glial activation and accumulation of amyloid beta (Aß) proteins. To elucidate the beneficial effects of the Pls oral ingestion, we have used the chronic lipopolysaccharide (LPS) injection model mice where the glial activation and Aß accumulation were well reported. In the present study, we have found that the Pls drinking at the doses of 0.1⯵g/ml and 10⯵g/ml for 3 months attenuated the glial activation and accumulation of amyloid beta (Aß) proteins in the murine brain. Interestingly, the LPS injection reduced the hippocampal dependent memory in the control mice but the groups of Pls drinking mice showed a better performance in the memory test, suggesting that oral intake of Pls can inhibit LPS-mediated memory loss associated with a reduction of glial activation and Aß accumulation in the brain. We, therefore, suggest that the oral ingestion of Pls among the AD patients may also inhibit the glial activation resulting in the improvement of cognition.
Subject(s)
Amyloid beta-Peptides/immunology , Brain/immunology , Memory Disorders/prevention & control , Memory Disorders/physiopathology , Microglia/drug effects , Microglia/immunology , Plasmalogens/administration & dosage , Administration, Oral , Animals , Brain/drug effects , Brain/pathology , Dietary Supplements , Dose-Response Relationship, Drug , Drinking , Lipopolysaccharides , Male , Memory Disorders/chemically induced , Mice , Mice, Inbred C57BL , Microglia/pathology , Treatment OutcomeABSTRACT
The novel human gene family encoding neuronal leucine rich repeat (NLRR) proteins were identified as prognostic markers from our previous screening of primary neuroblastoma (NB) cDNA libraries. Of the NLRR gene family members, NLRR1 and NLRR3 are associated with the regulation of cellular proliferation and differentiation, respectively. However, the functional regulation and clinical significance of NLRR2 in NB remain unclear. Here, we evaluated the differential expression of NLRR2, where high expressions of NLRR2 were significantly associated with a poor prognosis of NB (P = 0.0009), in 78 NBs. Enforced expression of NLRR2 in NB cells enhanced cellular proliferation and induced resistance to retinoic acid (RA)-mediated cell growth inhibition. In contrast, knockdown of NLRR2 exhibited growth inhibition effects and enhanced RA-induced cell differentiation in NB cells. After RA treatment, NLRR2 expression was increased and correlated with the upregulation of c-Jun, a member of the activator protein-1 (AP-1) family in NB cells. Moreover, the expressions of NLRR2 and c-Jun were suppressed by treatment with a JNK inhibitor, which ameliorated the promoter activity of the NLRR2 gene while knockdown of c-Jun reduced NLRR2 expression. We then searched AP-1 binding consensus in the NLRR2 promoter region and confirmed c-Jun recruitment at a consensus. Conclusively, NLRR2 must be an inducible gene regulated by the JNK pathway to enhance cell survival and inhibit NB cell differentiation. Therefore, NLRR2 should have an important role in NB aggressiveness and be a potential therapeutic target for the treatment of RA resistant and aggressive NB.
Subject(s)
Cell Adhesion Molecules, Neuronal/genetics , MAP Kinase Signaling System , Neuroblastoma/genetics , Neuroblastoma/metabolism , Transcriptional Activation , Animals , Cell Adhesion Molecules, Neuronal/metabolism , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Disease Models, Animal , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Heterografts , Humans , Mice , Neuroblastoma/mortality , Neuroblastoma/pathology , Prognosis , Promoter Regions, Genetic , Protein Binding , Proto-Oncogene Proteins c-jun/metabolism , RNA, Small Interfering/genetics , Stress, Physiological/genetics , Tretinoin/pharmacologyABSTRACT
The bioactive lipids plasmalogens (Pls), especially the ethanolamine types, PlsEtn, are found to be enriched in the central nervous system (CNS). Previous reports showed that the brain and serum Pls levels were reduced in Alzheimer's disease (AD). However, the role of the Pls in AD is mostly elusive. Furthermore Pls have been suggested to have pathophysiological significance in ageing and stress responses in the CNS, which often involve neuroinflammation characterized by glial cell activation. Focusing on these lipids function in the murine brain, we first show that Pls can ameliorate microglial activation induced by systemic inflammatory stimuli. Then their protective effects on the neuronal cell death are demonstrated. The precise mechanism of how these lipids function in the brain is now under investigation but our study will reveal the myth of these crucial lipid components in the CNS. Future study also could suggest novel therapeutics to safeguard our brain from various stresses including ageing, neuroinflammation as well as the memory disturbance in AD.
Subject(s)
Brain/metabolism , Lipid Metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Cell Death , Humans , Inflammation/metabolism , Lipids , Plasminogen/metabolismABSTRACT
Plasmalogens (vinyl-ether phospholipids) are an emergent class of lipid drugs against various diseases involving neuro-inflammation, oxidative stress, mitochondrial dysfunction, and altered lipid metabolism. They can activate neurotrophic and neuroprotective signaling pathways but low bioavailabilities limit their efficiency in curing neurodegeneration. Here, liquid crystalline lipid nanoparticles (LNPs) are created for the protection and non-invasive intranasal delivery of purified scallop-derived plasmalogens. The in vivo results with a transgenic mouse Parkinson's disease (PD) model (characterized by motor impairments and α-synuclein deposition) demonstrate the crucial importance of LNP composition, which determines the self-assembled nanostructure type. Vesicle and hexosome nanostructures (characterized by small-angle X-ray scattering) display different efficacy of the nanomedicine-mediated recovery of motor function, lipid balance, and transcriptional regulation (e.g., reduced neuro-inflammation and PD pathogenic gene expression). Intranasal vesicular and hexosomal plasmalogen-based LNP treatment leads to improvement of the behavioral PD symptoms and downregulation of the Il6, Il33, and Tnfa genes. Moreover, RNA-sequencing and lipidomic analyses establish a dramatic effect of hexosomal nanomedicines on PD amelioration, lipid metabolism, and the type and number of responsive transcripts that may be implicated in neuroregeneration.
Subject(s)
Administration, Intranasal , Disease Models, Animal , Nanomedicine , Nanoparticles , Parkinson Disease , Plasmalogens , Animals , Plasmalogens/chemistry , Plasmalogens/pharmacology , Mice , Parkinson Disease/metabolism , Parkinson Disease/drug therapy , Nanoparticles/chemistry , Nanomedicine/methods , Mice, Transgenic , Lipid Metabolism/drug effects , Gene Expression Regulation/drug effects , LiposomesABSTRACT
INTRODUCTION: Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage. METHOD: This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aß, BChE, GSK-3ß, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme's pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives. RESULT: This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations. CONCLUSION: Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer's disease.
ABSTRACT
COVID-19 vaccines have been effective in preventing severe illness, hospitalization and death, however, the effectiveness diminishes with time. Here, we evaluated the longevity of antibodies generated by COIVD-19 vaccines and the risk of (re)infection in Bangladeshi population. Adults receiving two doses of AstraZeneca, Pfizer, Moderna or Sinopharm vaccines were enrolled at 2-4 weeks after second dosing and followed-up at 4-monthly interval for 1 year. Data on COVID-like symptoms, confirmed COVID-19 infection, co-morbidities, and receipt of booster dose were collected; blood was collected for measuring spike (S)- and nucleocapsid (N)-specific antibodies. S-specific antibody titers reduced by ~ 50% at 1st follow-up visit and continued to decline unless re-stimulated by booster vaccine dose or (re)infection. Individuals infected between follow-up visits showed significantly lower S-antibody titers at preceding visits compared to the uninfected individuals. Pre-enrolment infection between primary vaccination dosing exhibited 60% and 50% protection against reinfection at 5 and 9 months, respectively. mRNA vaccines provided highest odds of protection from (re)infection up to 5 months (Odds Ratio (OR) = 0.08), however, protection persisted for 9 months in AstraZeneca vaccine recipients (OR = 0.06). In conclusion, vaccine-mediated protection from (re)infection is partially linked to elevated levels of S-specific antibodies. AstraZeneca vaccine provided the longest protection.
Subject(s)
Antibodies, Viral , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Humans , Bangladesh/epidemiology , COVID-19/prevention & control , COVID-19/immunology , COVID-19/epidemiology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Male , Female , Adult , SARS-CoV-2/immunology , Longitudinal Studies , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Middle Aged , Vaccination , Spike Glycoprotein, Coronavirus/immunology , Young Adult , Immunization, SecondaryABSTRACT
Neuroinflammation (NF) is defined as the activation of brain glial cells that are found in neurodegenerative diseases including Alzheimer's disease (AD). It has been known that an increase in NF could reduce the memory process in the brain but the key factors, associated with NF, behind the dysregulation of memory remained elusive. We previously reported that the NF and aging processes reduced the special phospholipids, plasmalogens (Pls), in the murine brain by a mechanism dependent on the activation of transcription factors, NF-kB and c-MYC. A similar mechanism has also been found in postmortem human brain tissues with AD pathologies and in the AD model mice. Recent evidence showed that these phospholipids enhanced memory and reduced neuro-inflammation in the murine brain. Pls can stimulate the cellular signaling molecules, ERK and Akt, by activating the membrane-bound G protein-coupled receptors (GPCRs). Therefore, recent findings suggest that plasmalogens could be one of the key phospholipids in the brain to enhance memory and inhibit NF.
Subject(s)
Alzheimer Disease , Plasmalogens , Animals , Mice , Humans , Plasmalogens/pharmacology , Signal Transduction , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Cognition , Brain/metabolism , NF-kappa B/metabolismABSTRACT
Cyclic-AMP-response element-binding protein (CREB) is a leucine zipper class transcription factor that is activated through phosphorylation. Ample CREB phosphorylation is required for neurotrophin expression, which is of key importance for preventing and regenerating neurological disorders, including the sequelae of long COVID syndrome. Here we created lipid-peptide nanoassemblies with different liquid crystalline structural organizations (cubosomes, hexosomes, and vesicles) as innovative nanomedicine delivery systems of bioactive PUFA-plasmalogens (vinyl ether phospholipids with polyunsaturated fatty acid chains) and a neurotrophic pituitary adenylate cyclase-activating polypeptide (PACAP). Considering that plasmalogen deficiency is a potentially causative factor for neurodegeneration, we examined the impact of nanoassemblies type and incubation time in an in vitro Parkinson's disease (PD) model as critical parameters for the induction of CREB phosphorylation. The determined kinetic changes in CREB, AKT, and ERK-protein phosphorylation reveal that non-lamellar PUFA-plasmalogen-loaded liquid crystalline lipid nanoparticles significantly prolong CREB activation in the neurodegeneration model, an effect unattainable with free drugs, and this effect can be further enhanced by the cell-penetrating peptide PACAP. Understanding the sustained CREB activation response to neurotrophic nanoassemblies might lead to more efficient use of nanomedicines in neuroregeneration.
ABSTRACT
The monkeypox virus poses a new pandemic threat while we are still recovering from COVID-19. Despite the fact that monkeypox is not as lethal and contagious as COVID-19, new patient cases are recorded every day. If preparations are not made, a global pandemic is likely. Deep learning (DL) techniques are now showing promise in medical imaging for figuring out what diseases a person has. The monkeypox virus-infected human skin and the region of the skin can be used to diagnose the monkeypox early because an image has been used to learn more about the disease. But there is still no reliable Monkeypox database that is available to the public that can be used to train and test DL models. As a result, it is essential to collect images of monkeypox patients. The "MSID" dataset, short form of "Monkeypox Skin Images Dataset", which was developed for this research, is free to use and can be downloaded from the Mendeley Data database by anyone who wants to use it. DL models can be built and used with more confidence using the images in this dataset. These images come from a variety of open-source and online sources and can be used for research purposes without any restrictions. Furthermore, we proposed and evaluated a modified DenseNet-201 deep learning-based CNN model named MonkeyNet. Using the original and augmented datasets, this study suggested a deep convolutional neural network that was able to correctly identify monkeypox disease with an accuracy of 93.19% and 98.91% respectively. This implementation also shows the Grad-CAM which indicates the level of the model's effectiveness and identifies the infected regions in each class image, which will help the clinicians. The proposed model will also help doctors make accurate early diagnoses of monkeypox disease and protect against the spread of the disease.
Subject(s)
COVID-19 , Mpox (monkeypox) , Humans , Mpox (monkeypox)/diagnostic imaging , Mpox (monkeypox)/epidemiology , COVID-19/diagnostic imaging , Databases, Factual , Neural Networks, Computer , PandemicsABSTRACT
Furosemide (4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoyl benzoic acid) is a widely used, FDA-approved drug prescribed for several symptoms associated with heart, kidney, liver failure, or chronic high blood pressure. In this work, a glassy carbon working electrode modified with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate is developed to detect furosemide (FURO) with high sensitivity and precise selectivity. The modified electrode was also characterized using field emission scanning electron microscopy, attenuated total reflectance-Fourier transform infrared, and cyclic voltammetry. Here, an efficient and cost- and time-efficient technique to study the furosemide mechanism of reaction in an acidic liquid medium is presented. An electrochemical oxidation of loop diuretic furosemide was investigated in a supporting electrolyte, 0.01 M of phosphate buffer (at a pH level of 4.0) at 25 ± 0.1 °C using a differential pulse voltammetric (DPV) technique. Under optimized parameters, the developed sensor displays a wide detection range of furosemide concentrations of 6.0 × 10-6 to 1.0 × 10-4 M with a detection limit of 2.0 × 10-6 M using DPV. The presented sensor offers a robust and high-precision technique with an excellent reproducibility to detect furosemide in as a real sample such as urine and pharmaceutical products.
ABSTRACT
Plasmalogens (Pls), a kind of glycerophospholipids, have shown potent biological effects but their role in hippocampus-dependent memory remained mostly elusive. Here, we first report Pls can enhance endogenous expression of brain-derived neurotrophic factor (Bdnf) in the hippocampus and promotes neurogenesis associated with improvement of learning and memory in mice. Genomic and proteomic studies revealed that Pls enhanced recruitment of CREB transcription factor onto the murine Bdnf promoter region via upregulating ERK-Akt signaling pathways in neuronal cells. Reduction of endogenous Pls in murine hippocampus significantly reduced learning and memory associated with the reduction of memory-related protein expression, suggesting that Pls can regulate memory-related gene expression in the hippocampus.
ABSTRACT
Skin cancer is one of the most common diseases that can be initially detected by visual observation and further with the help of dermoscopic analysis and other tests. As at an initial stage, visual observation gives the opportunity of utilizing artificial intelligence to intercept the different skin images, so several skin lesion classification methods using deep learning based on convolution neural network (CNN) and annotated skin photos exhibit improved results. In this respect, the paper presents a reliable approach for diagnosing skin cancer utilizing dermoscopy images in order to improve health care professionals' visual perception and diagnostic abilities to discriminate benign from malignant lesions. The swarm intelligence (SI) algorithms were used for skin lesion region of interest (RoI) segmentation from dermoscopy images, and the speeded-up robust features (SURF) was used for feature extraction of the RoI marked as the best segmentation result obtained using the Grasshopper Optimization Algorithm (GOA). The skin lesions are classified into two groups using CNN against three data sets, namely, ISIC-2017, ISIC-2018, and PH-2 data sets. The proposed segmentation and classification techniques' results are assessed in terms of classification accuracy, sensitivity, specificity, F-measure, precision, MCC, dice coefficient, and Jaccard index, with an average classification accuracy of 98.42 percent, precision of 97.73 percent, and MCC of 0.9704 percent. In every performance measure, our suggested strategy exceeds previous work.
Subject(s)
Deep Learning , Skin Diseases , Skin Neoplasms , Artificial Intelligence , Dermoscopy/methods , Humans , Skin Neoplasms/diagnostic imagingABSTRACT
Microglia (MG) are resident phagocytes in the brain responsible for neuronal maintenance. The regulation of MG necroptosis is required for protecting neurons during neurodegenerative diseases. Therefore, this study proposed to elucidate the molecular mechanisms underlying microglia necroptosis during long-time apoptotic stimuli (lipopolysaccharide, LPS). The protective role of plasmalogens (PLS) was also investigated against LPS insult in MG cells (including BV2 and MG6 cell lines). LPS produced time-dependent decreases in the survival of BV2 and MG6 cells mediated by the caspase signaling pathway. Interestingly, MG death was mediated by caspase-8 and 9 signaling pathways suggesting that MG necroptosis was actively attributed to long-time LPS treatment through intrinsic and extrinsic pathways. Notably, caspase signaling was markedly inhibited in the PLS-pretreated cells; thereby, PLS were capable of maintaining the MG cell population and inhibit the MG necroptosis against the longtime of LPS administration via its antioxidant and anti-inflammatory properties.
Subject(s)
Microglia , Plasmalogens , Lipopolysaccharides , Neurons , Signal TransductionABSTRACT
Green Synthesis of Metal Nanoparticles is becoming a more common method for producing nanoparticles with a diameter of 1-100 nm that may be employed in a variety of medical applications. The antibacterial efficacy of silver nanoparticles (AgNPs) derived from Cinnamomum tamala (Tejpata) leaf extract against antibiotic-resistant Pseudomonas aeruginosa is investigated in this study. Green AgNP synthesis is safe, cost-effective, and ecologically friendly. The biosynthesized AgNPs were studied using UV-Visible spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), Dynamic Light Scattering (DLS), X-ray Diffraction (XRD), and Transmission Electron Microscopy (TEM). The AgNPs were virtually spherical, with an average size of 25-30 nm, according to TEM observations. Biochemical and molecular identification were used to isolate multidrug-resistant P. aeruginosa from the hospital's drainage water. The antibacterial potential of AgNPs against P. aeruginosa is determined using the agar diffusion method. Silver nanoparticles produced from Cinnamomum tamala (Tejpata) leaf extract were shown to be effective in inhibiting four strains of P. aeruginosa. According to the agar disc diffusion method, AgNPs had the largest inhibition zone of 17.67 ± 0.577 mm, while aqueous extract had 5.67 ± 0.5777 mm, indicating that AgNPs had antibacterial activity. This study on AgNPs might assist with managing multidrug resistant pathogenic bacteria and be a possible source of medicinal application due to its potential antibacterial effect.
ABSTRACT
The plant growth-boosting biofilm-forming bacteria Bacillus pseudomycoides is able to promote growth and drought stress tolerance in wheat by suppressing the MYB gene, which synthesizes Myb protein (TaMpc1-D4) through secreted volatile compounds. In the present study, Triticum aestivum seeds were inoculated with five distinct bacterial strains. The growth, germination rate, root-shoot length, RWC, and chlorophyll content of seedlings were investigated. Furthermore, the levels of soluble sugars, proteins, H2O2, NO, cell death, and antioxidant enzymes (CAT, SOD, POD, and APX) were observed throughout the growth stage. All of the results showed that B. pseudomycoides had a substantially higher ability to form biofilm and promote these traits than the other strains. In terms of molecular gene expression, B. pseudomycoides inoculation strongly expressed the Dreb1 gene by silencing the expression of MYB gene through secreted volatile compounds. For identifying the specific volatile compound that silenced the MYB gene, molecular docking with Myb protein was performed. Out of 45 volatile compounds found, 2,6-ditert-butylcyclohexa-2,5-diene-1,4-dione and 3,5-ditert-butylphenol had a binding free energy of - 6.2 and - 6.5, Kcal/mol, respectively, which predicted that these compounds could suppress this protein's expression. In molecular dynamics simulations, the RMSD, SASA, Rg, RMSF, and hydrogen bonding values found assured the docked complexes' binding stability. These findings suggest that these targeted compounds may be suppressing Myb protein expression as well as the expression of Dreb1 and other drought response genes in wheat. More research (field trial) into plant growth and drought stress is needed to support the findings of this study.