Precision Medicine in Glaucoma: Artificial Intelligence, Biomarkers, Genetics and Redox State

Glaucoma is a multifactorial neurodegenerative illness requiring early diagnosis and strict monitoring of the disease progression. Current exams for diagnosis and prognosis are based on clinical examination, intraocular pressure (IOP) measurements, visual field tests, and optical coherence tomography (OCT). In this scenario, there is a critical unmet demand for glaucoma-related biomarkers to enhance clinical testing for early diagnosis and tracking of the disease’s development. The introduction of validated biomarkers would allow for prompt intervention in the clinic to help with prognosis prediction and treatment response monitoring. This review aims to report the latest acquisitions on biomarkers in glaucoma, from imaging analysis to genetics and metabolic markers

Neurotransmitters recognition based on gold nanoparticles and mesoporous silica nanoparticles for sensing and controlled release applications

[ES] La presente tesis doctoral titulada "Reconocimiento de neurotransmisores basado en nanopartículas de oro y de sílice mesoporosa para aplicaciones de detección y liberación controlada" es una tesis realizada por compendio de artículos la cual se centra en el diseño, preparación, caracterización y evaluación de distintos nanodispositivos para la detección colorimétrica de neurotransmisores y sistemas de liberación controlada que responden a neurotransmisores basados en nanopartículas de oro y nanopartículas de sílice mesoporosa, equipadas con ligandos orgánicos, efectores enzimáticos, puertas moleculares y especies cromofluorogénicas o medicamentos. En el primer capítulo se introduce una visión general de lo que son los neurotransmisores, sus principales características y el importante papel que éstos desempeñan en el funcionamiento de nuestro organismo. Además, se presenta una descripción general de las propiedades y potenciales aplicaciones de las nanopartículas de oro funcionalizadas con ligandos orgánicos como sistemas de detección y las nanopartículas mesoporosas de sílice funcionalizadas con puertas moleculares como sistemas de liberación controlada. A continuación, en el segundo capítulo se presentan los objetivos generales que son abordados en los siguientes capítulos experimentales. En el tercer capítulo, se presentan tres sistemas de detección colorimétrica de neurotransmisores basados en la agregación de nanopartículas de oro doblemente funcionalizadas con ligandos orgánicos. El primer sistema es un sensor capaz de detectar de forma selectiva el neurotransmisor serotonina, utilizando nanopartículas de oro funcionalizadas con ditio-bis(propionato de succinimidilo) y N-Acetil-L-Cisteína. El segundo sistema consiste en un sensor para la detección selectiva del neurotransmisor norepinefrina diseñado a partir de nanopartículas de oro funcionalizadas con 4-(liponiloxi)benzaldehído y ácido 4-mercato fenilborónico. El tercer sistema está compuesto por nanopartículas de oro funcionalizadas con 4-(liponiloxi)benzaldehído y N-Acetil-L-Cisteína, para la detección de normetanefrina, un importante biomarcador del tumor feocromocitoma. Todos estos sistemas se evalúan en medios competitivos como suero sanguíneo u orina. En el cuarto capítulo se muestran dos sistemas de liberación controlados enzimáticamente basados en la apertura de puertas moleculares. El primer sistema de liberación controlada responde a la presencia del neurotransmisor acetilcolina. En concreto, se utilizan nanopartículas de sílice mesoporosa funcionalizadas en su superficie con grupos de ácido fenilborónico y tapadas con la enzima acetilcolinesterasa mediante la formación de ésteres cíclicos de ácido fenilborónico entre las cadenas de oligosacáridos de la enzima y los grupos fenilborónicos de la superficie de las nanopartículas. En este caso la reacción enzimática produce ácido acético que da lugar a la hidrolisis de los ésteres borónicos, destapando los poros y liberando la carga contenida en el interior. Además, se evalúa la capacidad del dispositivo diseñado para liberar el citotóxico doxorubicina en células cancerosas en presencia de acetiltiocolina. El segundo sistema consiste en un nanodispositivo para la liberación controlada en respuesta al neurotransmisor L-glutamato. Para esto se utilizan nanopartículas tipo Janus de oro-sílice mesoporosa funcionalizadas con la enzima L-glutamato oxidasa en la parte del oro y con una puerta molecular autoinmolante de arilboronato en la superficie de la sílice. La liberación controlada se basa en el reconocimiento del L-glutamato por la enzima L-glutamato oxidasa y la posterior formación de peróxido de hidrogeno, que es la especie que induce la escisión de la puerta autoinmolante y la subsecuente apertura de los poros. Finalment es mostra que el sistema dissenyat és capaç d'alliberar un fàrmac citotòxic en cèl·lules de càncer de cervell després de detectar la presència de L-glutamat.[CA] La present tesi doctoral titulada "Reconeixement de neurotransmissors basat en nanopartícules d'or i de sílice mesoporosa per a aplicacions de detecció i alliberació controlada" és una tesi realitzada per compendi d'articles la qual se centra en el disseny, preparació, caracterització i avaluació de diferents nanodispositius per a la detecció colorimètrica de neurotransmissors i sistemes d'alliberació controlada que responen a neurotransmissors basats en nanopartícules d'or i nanopartícules de sílice mesoporosa equipades amb lligands orgànics, efectors enzimàtics, portes moleculars i espècies cromofluorogénicos o medicaments. En el primer capítol s'introdueix una visió general del que són els neurotransmissors, les seves principals característiques i l'important paper que aquests tenen en el funcionament del nostre organisme. A més es presenta una descripció general de les propietats i potencials aplicacions de les nanopartícules d'or funcionalitzades amb lligands orgànics com a sistemes de detecció, i de les nanopartícules mesoporoses de sílice funcionalitzades amb portes moleculars com a sistemes d'alliberament controlat. A continuació, en el segon capítol es presenten els objectius generals que són abordats en els següents capítols experimentals. En el tercer capítol, es presenten tres sistemes de detecció colorimètrica de neurotransmissors basats en l'agregació de nanopartícules d'or doblement funcionalitzades amb lligands orgànics. El primer sistema és un sensor capaç de detectar de forma selectiva el neurotransmissor serotonina, utilitzant nanopartícules d'or funcionalitzades amb ditiobis (propionat de succinimidilo) i N acetil-L-cisteïna. El segon sistema consisteix en un sensor per a la detecció selectiva de neurotransmissor norepinefrina dissenyat a partir de nanopartícules d'or funcionalitzades amb 4- (liponiloxi) benzaldehid i Àcid 4-mercatofenilborònic. El tercer sistema està compost per nanopartícules d'or funcionalitzades amb 4- (liponiloxi) benzaldehid i N acetil-L-cisteïna, per a la detecció de normatanefrina un important biomarcador del tumor feocromocitoma. Tots aquests sistemes s'avaluen en mitjans competitius com sèrum sanguini u orina. En el quart capítol es mostren dos sistemes d'alliberament controlats enzimàticament basats en l'obertura de portes moleculars. El primer sistema d'alliberament controlat respon a la presència del neurotransmissor acetilcolina. En concret, s'utilitzen nanopartícules de sílice mesoporosa funcionalitzades en la seva superfície amb grups d'àcid fenilborònic i tapades amb l'enzim acetilcolina esterasa mitjançant la formació d'èsters cíclics d'àcid fenilborònic entre les cadenes d'oligosacàrids de l'enzim i els grups fenilborónicos de la superfície de les nanopartícules. En aquest cas, la reacció enzimàtica produeix àcid acètic que dóna lloc a la hidròlisi dels èsters borònics, destapant els porus i alliberant la càrrega continguda a l'interior. A més, s'avalua la capacitat del dispositiu dissenyat per alliberar el citotòxic doxorubicina en cèl·lules canceroses en presència d'acetiltiocolina. El segon sistema consisteix en un nanodispositiu per alliberació controlada en resposta al neurotransmissor L-glutamat, per al que s'utilitzen nanopartícules tipus Janus d'or-sílice mesoporosa funcionalitzades amb l'enzim L-glutamat oxidasa en la part de l'or i amb una porta molecular autoimmolant d'arilboronat a la superfície de la sílice. La alliberació controlada es basa en el reconeixement de L-glutamat per l'enzim L-glutamat oxidasa i la posterior formació de peròxid d'hidrogen, que és l'espècie que indueix l'escissió de la porta autoimmolant i la subseqüent obertura dels porus. Finalment es mostra que el sistema dissenyat és capaç d'alliberar un fàrmac citotòxic en cèl·lules de càncer de cervell després de detectar la presència de L-glutamat.[EN] This doctoral thesis entitled "Neurotransmitters recognition based on gold and mesoporous silica nanoparticles for sensing and controlled release applications" it is a thesis carried out by compendium of articles, which is focused on the design, preparation, characterization and evaluation of nanodevices for the colorimetric sensing of neurotransmitters and controlled delivery systems responsive to neurotransmitters, based on gold nanoparticles and mesoporous silica nanoparticles equipped with organic ligands, enzymatic effectors, molecular gates and chromo-fluorogenic species or drugs. The first chapter introduces an overview about what neurotransmitters are, their main characteristics and the important role they play in the functioning of our body. In addition, a general description of the properties and potential applications of gold nanoparticles functionalized with organic ligands as detection systems and mesoporous silica nanoparticles functionalized with molecular gates as controlled delivery systems is presented. In the second chapter, the general objectives that are addressed in the following experimental chapters are presented. In the third chapter, three colorimetric detection systems of neurotransmitters based on the aggregation of gold nanoparticles doubly functionalized with organic ligands are presented. The first system is a sensor capable of selectively detecting the neurotransmitter serotonin, using gold nanoparticles functionalized with dithio-bis(succinimidyl propionate) and N acetyl-L-cysteine. The second system consists of a sensor for the selective detection of the neurotransmitter norepinephrine designed from gold nanoparticles functionalized with 4- (liponyloxy)benzaldehyde and 4-mercaptophenylboronic acid. The third system is composed of gold nanoparticles functionalized with 4-(liponyloxy)benzaldehyde and N-Acetyl-L-Cysteine, for the detection of normetanephrine, an important biomarker of the pheochromocytoma tumor. All these systems are evaluated in competitive media such as blood serum or urine. In the fourth chapter, two enzymatic controlled delivery systems based on the opening of molecular gates are developed. The first controlled delivery system responds to the presence of the neurotransmitter acetylcholine. Specifically, it consists of mesoporous silica nanoparticles functionalized on their surface with phenylboronic acid groups and capped with the enzyme acetylcholinesterase, via the formation of cyclic phenylboronic acid esters between the oligosaccharide chains of the enzyme and the phenylboronic groups on the nanoparticles surface. In this case, the enzymatic reaction produces acetic acid that induces the hydrolysis of the boronic esters, uncapping the pores and releasing the entrapped payload. In addition, the ability of the nanodevice to release the cytotoxic doxorubicin in cancer cells in the presence of acetylthiocholine is evaluated. The second delivery system consists of a nanodevice responsive to the neurotransmitter L-glutamate. It is based on Janus gold-silica mesoporous nanoparticles functionalized with the enzyme L-glutamate oxidase in the gold part and with a self-immolative arylboronate molecular gate on the surface of the silica. Controlled delivery is based on the recognition of L-glutamate by the enzyme L-glutamate oxidase and the subsequent formation of hydrogen peroxide, which results in the cleavage of the self-immolative gate and the uncapping of the pores. Finally, it is shown that the designed system is capable of releasing a cytotoxic drug in brain cancer cells after detecting the presence of L-glutamate.The authors acknowledge financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, MAT2015-64139-C4-4-R (MINECO/FEDER) and Project AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Projects PROMETEOII/2014/047 and PROMETEO/2018/024). T. Godoy-Reyes is grateful to Generalitat Valenciana for her Santiago Grisolía fellowship. A. García-Fernández is grateful to the Spanish Government for her FPU fellowship. A. Llopis-Lorente thanks “La Caixa” Foundation for his PhD grant. SCSIE (Universitat de València) is gratefully acknowledged for all the equipment employed.Godoy Reyes, TM. (2020). Neurotransmitters recognition based on gold nanoparticles and mesoporous silica nanoparticles for sensing and controlled release applications [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/158420TESI

Special oils for halal and safe cosmetics

Three types of non conventional oils were extracted, analyzed and tested for toxicity. Date palm kernel oil (DPKO), mango kernel oil (MKO) and Ramputan seed oil (RSO). Oil content for tow cultivars of dates Deglect Noor and Moshkan was 9.67% and 7.30%, respectively. The three varieties of mango were found to contain about 10% oil in average. The red yellow types of Ramputan were found to have 11 and 14% oil, respectively. The phenolic compounds in DPKO, MKO and RSO were 0.98, 0.88 and 0.78 mg/ml Gallic acid equivalent, respectively. Oils were analyzed for their fatty acid composition and they are rich in oleic acid C18:1 and showed the presence of (dodecanoic acid) lauric acid C12:0, which reported to appear some antimicrobial activities. All extracted oils, DPKO, MKO and RSO showed no toxic effect using prime shrimp bioassay. Since these oils are stable, melt at skin temperature, have good lubricity and are great source of essential fatty acids; they could be used as highly moisturizing, cleansing and nourishing oils because of high oleic acid content. They are ideal for use in such halal cosmetics such as Science, Engineering and Technology 75 skin care and massage, hair-care, soap and shampoo products

Advances in Electronic-Nose Technologies Developed for Biomedical Applications

The research and development of new electronic-nose applications in the biomedical field has accelerated at a phenomenal rate over the past 25 years. Many innovative e-nose technologies have provided solutions and applications to a wide variety of complex biomedical and healthcare problems. The purposes of this review are to present a comprehensive analysis of past and recent biomedical research findings and developments of electronic-nose sensor technologies, and to identify current and future potential e-nose applications that will continue to advance the effectiveness and efficiency of biomedical treatments and healthcare services for many years. An abundance of electronic-nose applications has been developed for a variety of healthcare sectors including diagnostics, immunology, pathology, patient recovery, pharmacology, physical therapy, physiology, preventative medicine, remote healthcare, and wound and graft healing. Specific biomedical e-nose applications range from uses in biochemical testing, blood-compatibility evaluations, disease diagnoses, and drug delivery to monitoring of metabolic levels, organ dysfunctions, and patient conditions through telemedicine. This paper summarizes the major electronic-nose technologies developed for healthcare and biomedical applications since the late 1980s when electronic aroma detection technologies were first recognized to be potentially useful in providing effective solutions to problems in the healthcare industry

Effect of Noble Metal Nanomaterials on Endogenous and Dietary Antioxidants and their Combined Interaction with Reactive Oxygen Species

In the last decade, nanotechnology has been extensively exploited in a variety of areas because nanoscaled materials provide a wide range of benefits that bulk materials do not possess. In spite of its advent, when applied to consumer related products, the new technology inevitably brings about side effect especially to biological or environment systems. Many have already determined that the damaging effect of nanomaterials in cell lines is caused by oxidative stress as a result of overproduction of reactive oxygen species (ROS). The present study aims at evaluating the role of noble metal nanomaterials in the generation and scavenging of ROS. It is noteworthy that the behavior of silver nanoparticles (Ag NPs) in the presence of hydrogen peroxide, a continuously generated component in biological systems, is adjusted by the mimetic microenvironment. These Ag NPs were found to be capable of inducing production of ROS hydroxyl radicals and oxygen in acidic and alkaline environments, respectively. The Ag NPs were oxidized to ions at pH 4.6 while they have been found to participate in Ag0-Ag1-Ag0 cyclic reaction at pH 11. As a promising antimicrobial agent, Ag NPs alone barely scavenge free radicals, but they are found to moderate the scavenging capability of thiol-based antioxidants, essential endogenous antioxidants, due to their formation of Ag-S bond. In addition, Platinum nanoparticles (Pt NPs) have been mostly used as catalysts in many chemical reactions. While recent reports suggest antioxidant activity of Pt NPs due to their peroxidase-like activity, there are limitations in the use of Pt NPs as an antioxidant in scavenging hydroxyl radicals. Alternatively, owing to their ascorbate oxidase-like activity, Pt NPs reduce the antioxidant ability of ascorbic acid, an important antioxidant participating in many biological reactions. In addition, they exert tyrosinase-like activity in catalyzing the oxidation of (-)-Epicatechin, caffeic acid, and resveratrol to form pigment compounds. Therefore, Pt NPs vary in their effect on the antioxidant activity of phenolics against various radicals (DPPH radicals > hydroxyl radicals >superoxide radicals). Our study may provide insights for finding new applications for noble metal nanoparticles and for risk assessment

Poultry: Breeding, Health, Nutrition, and Management

Being the largest animal protein producer, the poultry industry is in the focus of mixed-diet consumers (from a welfare point of view, as a medium of functional foods, environmental issues, the use of antibiotics, etc.), as well as the livestock industry in general. The poultry industry is also extremely quick to uptake new technologies (such as biotechnology, mechanization, robotics, and climate and nutrient control) in order to be economically efficient and sustainable. There is constant pressure from pathogens and new threats, such as avian flu, that requires new treatments and biosecurity measures. There are many novel approaches and answers to these challenges. In breeding, molecular genetic tools (genomic selection and genome editing) can be used to increase production efficiency and fitness, especially immunity traits, or to characterize local genetic pools. The One Health approach, which requires a holistic approach, where genetics, nutrition, health treatment, and management need to be considered together, has gained ground in the poultry industry. The gut microbiome seems to be a good indicator of the balanced health of an animal. Artificial intelligence, built into robotic supervision and handling, helps to increase animal comfort and save costs in the workforce. Organic farming takes a different approach and faces different challenges. What could the possible answers be? We are facing a new era in poultry science. The aim of this Special Issue is to highlight the importance of new findings

Biosensors for Diagnosis and Monitoring

Biosensor technologies have received a great amount of interest in recent decades, and this has especially been the case in recent years due to the health alert caused by the COVID-19 pandemic. The sensor platform market has grown in recent decades, and the COVID-19 outbreak has led to an increase in the demand for home diagnostics and point-of-care systems. With the evolution of biosensor technology towards portable platforms with a lower cost on-site analysis and a rapid selective and sensitive response, a larger market has opened up for this technology. The evolution of biosensor systems has the opportunity to change classic analysis towards real-time and in situ detection systems, with platforms such as point-of-care and wearables as well as implantable sensors to decentralize chemical and biological analysis, thus reducing industrial and medical costs. This book is dedicated to all the research related to biosensor technologies. Reviews, perspective articles, and research articles in different biosensing areas such as wearable sensors, point-of-care platforms, and pathogen detection for biomedical applications as well as environmental monitoring will introduce the reader to these relevant topics. This book is aimed at scientists and professionals working in the field of biosensors and also provides essential knowledge for students who want to enter the field

Metabolic Regulation of Ferroptosis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is a notoriously deadly disease having the lowest 5-year survival rate of any major cancer, owing to a lack of effective therapeutic options. A growing body of evidence demonstrates that PDAs reprogram their metabolism to support growth and survival in response to a harsh metabolic tumor environment. This work studies the hypothesis that metabolism can reveal novel therapeutic targets. Uncovering novel nutrient vulnerabilities could provide new ways to target PDA selectively. The goals of this work were two-fold. First, we developed analytical methods to identify metabolic changes in PDA and other biological samples. Employing mass spectrometry metabolomics, we profiled over two hundred metabolites in a single experiment across heterogeneous biological samples and experimental conditions. A meta-analysis of these metabolomics studies revealed insights into metabolite reproducibility, providing analytical benchmarks for quality control. Moreover, through systematic analysis we identified stable and dynamic metabolites, where dynamic metabolites play numerous roles in modulating gene expression and signaling. Together, this work provides benchmarks for metabolomics method development and robust analytical frameworks. Second, we examined nutrient vulnerabilities in PDA to identify novel therapeutic opportunities. We found that pancreatic cancer cells were highly sensitive to cystine deprivation. Cystine was required for the biosynthesis of two versatile redox co-factors, glutathione and coenzyme-A. Starving pancreatic cancer cells and tumors from cysteine triggered ferroptosis: an oxidative, iron-dependent, non-apoptotic form of cell death. Inhibiting cystine metabolism was well tolerated in mice and showed substantial anti-tumor activity, suggesting a new therapeutic strategy for PDA. In addition to identifying cystine as a metabolic vulnerability, we previously described that pancreatic cancers depend on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for redox balance. Inhibiting GOT1 slowed the growth of PDA cells and tumors. We sought to identify metabolic dependencies induced by GOT1 inhibition as a strategy to kill PDAs selectively. We found cystine, glutathione, and lipid antioxidant function were metabolic susceptibilities following GOT1 suppression. Targeting these metabolic nodes triggered ferroptosis in synergy with GOT1 and delayed tumor growth. This effect was due to labile iron release, which augments ferroptosis sensitivity. Together, this work describes the development of mass spectrometry metabolomics tools and reveals how metabolism and ferroptosis are linked. This work presents new methods to study ferroptosis in diverse model systems, reconciling long-standing limitations in the field. We identify several metabolic nodes governing ferroptosis susceptibility, building upon the notion that ferroptosis is a metabolically-coupled form of cell death. Finally, we discuss several strategies to harness ferroptosis for therapy that could lead to novel treatments for PDA.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163213/1/dmkremer_1.pd

Acetylcholine esterase as a possible marker for the detection of halal way of slaughtering

Introduction: Different methods of slaughtering are being practiced because of differences in religious guidelines and environmental issues (use of electricity) or convenience of handling etc. Variation in methods of slaughtering results in different conditions namely, release of varying amount of blood and different degree of movement of its body parts prior to death. These issues are related to the release of neurotransmitter (NT) at the neuro-muscular junction (NMJ) eventually is subject to be released from the body through the blood flow. Experimental design: Muscle samples from chicken in small pieces were collected immediately after slaughtering. Slaughtering was carried out using sharp knife. Two different conditions pertaining to the Islamic guidelines of slaughtering were investigated. such as whether the neck was severed (S+) or not (S-) from the body during slaughtering and whether the animal just after slaughtering was released (R+) or not (R-). The level of acetylecholine esterase mRNA involved in the degradation of acetylecholine, a NT at NMJ was investigated by RT-PCR. Results: The level of acetylecholine esterase mRNA was not detected in the sample obtained from the chicken slaughtered following Islamic guidelines i.e., neck should not be severed and body should be released just after the slaughtering (R+S-). Conclusions: Level of acetylcholine or acetylcholine esterase can be used as a biomarker to identify if the slaughtering is performed following Islamic guidelines

Calophyllum canum : antibacterial and anticancer plant

Human have used plants as a source of medicine throughout the world since time immemorial. Today there are at least 120 distinct chemical substances derived from plants that are considered as important drugs currently in use in one or more countries in the world. In particular, 60% drugs currently in clinical use for treatment of cancer were found to be of natural origin. Calophyllum canum is a large tree which grows in South East Asia and which is popular for its timber. This plant belongs to the family Guttiferae; a family that boasts species which are rich in bioactive phytochemicals. Some species are believed to having medicinal values and are used against several diseases including anti-inflammatory, anti infectious, astringent and antipyretic. We have successfully isolated two compounds from the methanol extract of Calophyllum canum stembarks that active inhibit the growth of Staphylococcus aureus (ATCC 29213 and ATCC 25923). The cytotoxic study on the extracts revealed that the n-hexane extract had the strongest antiproliferation activity, followed by the methanol extract. n-hexane strongly inhibited the growth of TE1 and MCF7 cell lines. IC50 for n-hexane and methanol extract activity on the A549 cell line was found to be 27.96 μg/mL and 78.9 μg/mL respectively.The compounds (CE0 - CE5) isolated from ethyl acetate extract of C. canum are active to inhibit cell proliferation of human cervix adenocarcinoma cells