Search results for: nanostructured lipid carriers

Authors: Joana Pimenta, Lorena Coelho, José Silva, Vanessa Miranda, Jorge Laranjeira, Rui Soares

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In this paper, the results of R&D on an innovative food package for increased shelf-life are presented. SAP4MA aims at the development of a printed active device that enables smart packaging solutions for food preservation, targeting the extension of the shelf-life of the packed food through the controlled release of active natural antioxidant agents at the onset of the food degradation process. To do so, SAP4MA focuses on the development of active devices such as printed heaters and batteries/supercapacitors in a label format to be integrated on packaging lids during its injection molding process, promoting the passive release of natural antioxidants after the product is packed, during transportation and in the shelves, and actively when the end-user activates the package, just prior to consuming the product at home. When the active device present on the lid is activated, the release of the natural antioxidants embedded in the inner layer of the packaging lid in direct contact with the headspace atmosphere of the food package starts. This approach is based on the use of active functional coatings composed of nano encapsulated active agents (natural antioxidants species) in the prevention of the oxidation of lipid compounds in food by agents such as oxygen. Thus keeping the product quality during the shelf-life, not only when the user opens the packaging, but also during the period from food packaging up until the purchase by the consumer. The active systems that make up the printed smart label, heating circuit, and battery were developed using screen-printing technology. These systems must operate under the working conditions associated with this application. The printed heating circuit was studied using three different substrates and two different conductive inks. Inks were selected, taking into consideration that the printed circuits will be subjected to high pressures and temperatures during the injection molding process. The circuit must reach a homogeneous temperature of 40ºC in the entire area of the lid of the food tub, promoting a gradual and controlled release of the antioxidant agents. In addition, the circuit design involves a high level of study in order to guarantee maximum performance after the injection process and meet the specifications required by the control electronics component. Furthermore, to characterize the different heating circuits, the electrical resistance promoted by the conductive ink and the circuit design, as well as the thermal behavior of printed circuits on different substrates, were evaluated. In the injection molding process, the serpentine-shaped design developed for the heating circuit was able to resolve the issues connected to the injection point; in addition, the materials used in the support and printing had high mechanical resistance against the pressure and temperature inherent to the injection process. Acknowledgment: This research has been carried out within the Project “Smart and Active Packing for Margarine Product” (SAP4MA) running under the EURIPIDES Program being co-financed by COMPETE 2020 – the Operational Programme for Competitiveness and Internationalization and under Portugal 2020 through the European Regional Development Fund (ERDF).

Keywords: smart package, printed heat circuits, printed batteries, flexible and printed electronic

Procedia PDF Downloads 89

Authors: P. J. Sweeney, T. Ahtoniemi, J. Puoliväli, T. Laitinen, K. Lehtimäki, A. Nurmi, D. Wells

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Duchenne muscular dystrophy (DMD) is caused by an X linked mutation in the dystrophin gene; lack of dystrophin causes a progressive muscle necrosis which leads to a progressive decrease in mobility in those suffering from the disease. The MDX mouse, a mutant mouse model which displays a frank dystrophinopathy, is currently widely employed in pre clinical efficacy models for treatments and therapies aimed at DMD. In general the end-points examined within this model have been based on invasive histopathology of muscles and serum biochemical measures like measurement of serum creatine kinase (sCK). It is established that a “critical period” between 4 and 6 weeks exists in the MDX mouse when there is extensive muscle damage that is largely sub clinical but evident with sCK measurements and histopathological staining. However, a full characterization of the MDX model remains largely incomplete especially with respect to the ability to aggravate of the muscle damage beyond the critical period. The purpose of this study was to attempt to aggravate the muscle damage in the MDX mouse and to create a wider, more readily translatable and discernible, therapeutic window for the testing of potential therapies for DMD. The study consisted of subjecting 15 male mutant MDX mice and 15 male wild-type mice to an intense chronic exercise regime that consisted of bi-weekly (two times per week) treadmill sessions over a 12 month period. Each session was 30 minutes in duration and the treadmill speed was gradually built up to 14m/min for the entire session. Baseline plasma creatine kinase (pCK), treadmill training performance and locomotor activity were measured after the “critical period” at around 10 weeks of age and again at 14 weeks of age, 6 months, 9 months and 12 months of age. In addition, kinematic gait analysis was employed using a novel analysis algorithm in order to compare changes in gait and fine motor skills in diseased exercised MDX mice compared to exercised wild type mice and non exercised MDX mice. In addition, a morphological and metabolic profile (including lipid profile), from the muscles most severely affected, the gastrocnemius muscle and the tibialis anterior muscle, was also measured at the same time intervals. Results indicate that by aggravating or exacerbating the underlying muscle damage in the MDX mouse by exercise a more pronounced and severe phenotype in comes to light and this can be picked up earlier by kinematic gait analysis. A reduction in mobility as measured by open field is not apparent at younger ages nor during the critical period, but changes in gait are apparent in the mutant MDX mice. These gait changes coincide with pronounced morphological and metabolic changes by non-invasive anatomical MRI and proton spectroscopy (1H-MRS) we have reported elsewhere. Evidence of a progressive asymmetric pathology in imaging parameters as well as in the kinematic gait analysis was found. Taken together, the data show that chronic exercise regime exacerbates the muscle damage beyond the critical period and the ability to measure through non-invasive means are important factors to consider when performing preclinical efficacy studies in the MDX mouse.

Keywords: Gait, muscular dystrophy, Kinematic analysis, neuromuscular disease

Procedia PDF Downloads 264

Authors: Md. Abu Sufian, Robiqul Islam, Imam Hossain Shajid, Mahesh Hanumanthu, Jarasree Varadarajan, Md. Sipon Miah, Mingbo Niu

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Coronary Heart Disease (CHD) remains a principal cause of global morbidity and mortality, characterized by atherosclerosis—the build-up of fatty deposits inside the arteries. The study introduces an innovative methodology that leverages cloud-based platforms like AWS Live Streaming and Artificial Intelligence (AI) to early detect and prevent CHD symptoms in web applications. By employing novel simulation processes and AI algorithms, this research aims to significantly mitigate the health and societal impacts of CHD. Methodology: This study introduces a novel simulation process alongside a multi-phased model development strategy. Initially, health-related data, including heart rate variability, blood pressure, lipid profiles, and ECG readings, were collected through user interactions with web-based applications as well as API Integration. The novel simulation process involved creating synthetic datasets that mimic early-stage CHD symptoms, allowing for the refinement and training of AI algorithms under controlled conditions without compromising patient privacy. AWS Live Streaming was utilized to capture real-time health data, which was then processed and analysed using advanced AI techniques. The novel aspect of our methodology lies in the simulation of CHD symptom progression, which provides a dynamic training environment for our AI models enhancing their predictive accuracy and robustness. Model Development: it developed a machine learning model trained on both real and simulated datasets. Incorporating a variety of algorithms including neural networks and ensemble learning model to identify early signs of CHD. The model's continuous learning mechanism allows it to evolve adapting to new data inputs and improving its predictive performance over time. Results and Findings: The deployment of our model yielded promising results. In the validation phase, it achieved an accuracy of 92% in predicting early CHD symptoms surpassing existing models. The precision and recall metrics stood at 89% and 91% respectively, indicating a high level of reliability in identifying at-risk individuals. These results underscore the effectiveness of combining live data streaming with AI in the early detection of CHD. Societal Implications: The implementation of cloud-based AI for CHD symptom detection represents a significant step forward in preventive healthcare. By facilitating early intervention, this approach has the potential to reduce the incidence of CHD-related complications, decrease healthcare costs, and improve patient outcomes. Moreover, the accessibility and scalability of cloud-based solutions democratize advanced health monitoring, making it available to a broader population. This study illustrates the transformative potential of integrating technology and healthcare, setting a new standard for the early detection and management of chronic diseases.

Keywords: coronary heart disease, cloud-based ai, machine learning, novel simulation techniques, early detection, preventive healthcare

Procedia PDF Downloads 46

Authors: Kelsi Hagerty, Ami Rosen, Aaliyah Heyward, Nadia Ali, Emily Brown, Erin Demo, Yue Guan, Modele Ogunniyi, Brianna McDaniels, Alanna Morris, Kunal Bhatt

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Hereditary transthyretin amyloidosis (hATTR) is a progressive, multi-systemic, and life-threatening disease caused by a disruption in the TTR protein that delivers thyroxine and retinol to the liver. This disruption causes the protein to misfold into amyloid fibrils, leading to the accumulation of the amyloid fibrils in the heart, nerves, and GI tract. Over 130 variants in the TTR gene are known to cause hATTR. The Val122Ile variant is the most common in the United States and is seen almost exclusively in people of African descent. TTR variants are inherited in an autosomal dominant fashion and have incomplete penetrance and variable expressivity. Individuals with hATTR may exhibit symptoms from as early as 30 years to as late as 80 years of age. hATTR is characterized by a wide range of clinical symptoms such as cardiomyopathy, neuropathy, carpal tunnel syndrome, and GI complications. Without treatment, hATTR leads to progressive disease and can ultimately lead to heart failure. hATTR disproportionately affects individuals of African descent; the estimated prevalence of hATTR among Black individuals in the US is 3.4%. Unfortunately, hATTR is often underdiagnosed and misdiagnosed because many symptoms of the disease overlap with other cardiac conditions. Due to the progressive nature of the disease, multi-systemic manifestations that can lead to a shortened lifespan, and the availability of free genetic testing and promising FDA-approved therapies that enhance treatability, early identification of individuals with a pathogenic hATTR variant is important, as this can significantly impact medical management for patients and their relatives. Furthermore, recent literature suggests that TTR genetic testing should be performed in all patients with suspicion of TTR-related cardiomyopathy, regardless of age, and that follow-up with genetic counseling services is recommended. Relatives of patients with hATTR benefit from genetic testing because testing can identify carriers early and allow relatives to receive regular screening and management. Despite the striking prevalence of hATTR among Black individuals, hATTR remains underdiagnosed in this patient population, and germline genetic testing for hATTR in Black individuals seems to be underrepresented, though the reasons for this have not yet been brought to light. Historically, Black patients experience a number of barriers to seeking healthcare that has been hypothesized to perpetuate the underdiagnosis of hATTR, such as lack of access and mistrust of healthcare professionals. Prior research has described a myriad of factors that shape an individual’s decision about whether to pursue presymptomatic genetic testing for a familial pathogenic variant, such as family closeness and communication, family dynamics, and a desire to inform other family members about potential health risks. This study explores these factors through 10 in-depth interviews with patients with hATTR about what factors may be contributing to the underdiagnosis of hATTR in the Black population. Participants were selected from the Emory University Amyloidosis clinic based on having a molecular diagnosis of hATTR. Interviews were recorded and transcribed verbatim, then coded using MAXQDA software. Thematic analysis was completed to draw commonalities between participants. Upon preliminary analysis, several themes have emerged. Barriers identified include i) Misdiagnosis and a prolonged diagnostic odyssey, ii) Family communication and dynamics surrounding health issues, iii) Perceptions of healthcare and one’s own health risks, and iv) The need for more intimate provider-patient relationships and communication. Overall, this study gleaned valuable insight from members of the Black community about possible factors contributing to the underdiagnosis of hATTR, as well as potential solutions to go about resolving this issue.

Keywords: cardiac amyloidosis, heart failure, TTR, genetic testing

Procedia PDF Downloads 82

Authors: Imdad Ullah Khan, Yongseok Yoon, Kyeung Uk Choi, Kwang Rae Jo, Namyul Kim, Eunbee Lee, Wan Hee Kim, Oh-Kyeong Kweon

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The primary spinal cord injury (SCI) causes mechanical damage to the neurons and blood vessels. It leads to secondary SCI, which activates multiple pathological pathways, which expand neuronal damage at the injury site. It is characterized by vascular disruption, ischemia, excitotoxicity, oxidation, inflammation, and apoptotic cell death. It causes nerve demyelination and disruption of axons, which perpetuate a loss of impulse conduction through the injured spinal cord. It also leads to the production of myelin inhibitory molecules, which with a concomitant formation of an astroglial scar, impede axonal regeneration. The pivotal role regarding the neuronal necrosis is played by oxidation and inflammation. During an early stage of spinal cord injury, there occurs an abundant expression of reactive oxygen species (ROS) due to defective mitochondrial metabolism and abundant migration of phagocytes (macrophages, neutrophils). ROS cause lipid peroxidation of the cell membrane, and cell death. Abundant migration of neutrophils, macrophages, and lymphocytes collectively produce pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1β), matrix metalloproteinase, superoxide dismutase, and myeloperoxidases which synergize neuronal apoptosis. Therefore, it is crucial to control inflammation and oxidation injury to minimize the nerve cell death during secondary spinal cord injury. Therefore, in response to oxidation and inflammation, heme oxygenase-1 (HO-1) is induced by the resident cells to ameliorate the milieu. In the meanwhile, neurotrophic factors are induced to promote neuroregeneration. However, it seems that anti-stress enzyme (HO-1) and neurotrophic factor (BDNF) do not significantly combat the pathological events during secondary spinal cord injury. Therefore, optimum healing can be induced if anti-inflammatory and neurotrophic factors are administered in a higher amount through an exogenous source. During the first experiment, the inflammation and neuroregeneration were selectively targeted. HO-1 expressing MSCs (HO-1 MSCs) and BDNF expressing MSCs (BDNF MSC) were co-transplanted in one group (combination group) of dogs with subacute spinal cord injury to selectively control the expression of inflammatory cytokines by HO-1 and induce neuroregeneration by BDNF. We compared the combination group with the HO-1 MSCs group, BDNF MSCs group, and GFP MSCs group. We found that the combination group showed significant improvement in functional recovery. It showed increased expression of neural markers and growth-associated proteins (GAP-43) than in other groups, which depicts enhanced neuroregeneration/neural sparing due to reduced expression of pro-inflammatory cytokines such as TNF-alpha, IL-6 and COX-2; and increased expression of anti-inflammatory markers such as IL-10 and HO-1. Histopathological study revealed reduced intra-parenchymal fibrosis in the injured spinal cord segment in the combination group than in other groups. Thus it was concluded that selectively targeting the inflammation and neuronal growth with the combined use of HO-1 MSCs and BDNF MSCs more favorably promote healing of the SCI. HO-1 MSCs play a role in controlling the inflammation, which favors the BDNF induced neuroregeneration at the injured spinal cord segment of dogs.

Keywords: HO-1 MSCs, BDNF MSCs, neuroregeneration, inflammation, anti-inflammation, spinal cord injury, dogs

Procedia PDF Downloads 107

Authors: Pedro M. Rodrigues, Claudia Raposo, Denise Schrama, Marco Cerqueira

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Farmed fish welfare is a very recent concept, widely discussed among the scientific community. Consumers’ interest regarding farmed animal welfare standards has significantly increased in the last years posing a huge challenge to producers in order to maintain an equilibrium between good welfare principles and productivity, while simultaneously achieve public acceptance. The major bottleneck of standard aquaculture is to impair considerably fish welfare throughout the production cycle and with this, the quality of fish protein. Welfare assessment in farmed fish is undertaken through the evaluation of fish stress responses. Primary and secondary stress responses include release of cortisol and glucose and lactate to the blood stream, respectively, which are currently the most commonly used indicators of stress exposure. However, the reliability of these indicators is highly dubious, due to a high variability of fish responses to an acute stress and the adaptation of the animal to a repetitive chronic stress. Our objective is to use comparative proteomics to identify and validate a fingerprint of proteins that can present an more reliable alternative to the already established welfare indicators. In this way, the culture conditions will improve and there will be a higher perception of mechanisms and metabolic pathway involved in the produced organism’s welfare. Due to its high economical importance in Portuguese aquaculture Gilthead seabream will be the elected species for this study. Protein extracts from Gilthead Seabream fish muscle, liver and plasma, reared for a 3 month period under optimized culture conditions (control) and induced stress conditions (Handling, high densities, and Hipoxia) are collected and used to identify a putative fish welfare protein markers fingerprint using a proteomics approach. Three tanks per condition and 3 biological replicates per tank are used for each analisys. Briefly, proteins from target tissue/fluid are extracted using standard established protocols. Protein extracts are then separated using 2D-DIGE (Difference gel electrophoresis). Proteins differentially expressed between control and induced stress conditions will be identified by mass spectrometry (LC-Ms/Ms) using NCBInr (taxonomic level - Actinopterygii) databank and Mascot search engine. The statistical analysis is performed using the R software environment, having used a one-tailed Mann-Whitney U-test (p < 0.05) to assess which proteins were differentially expressed in a statistically significant way. Validation of these proteins will be done by comparison of the RT-qPCR (Quantitative reverse transcription polymerase chain reaction) expressed genes pattern with the proteomic profile. Cortisol, glucose, and lactate are also measured in order to confirm or refute the reliability of these indicators. The identified liver proteins under handling and high densities induced stress conditions are responsible and involved in several metabolic pathways like primary metabolism (i.e. glycolysis, gluconeogenesis), ammonia metabolism, cytoskeleton proteins, signalizing proteins, lipid transport. Validition of these proteins as well as identical analysis in muscle and plasma are underway. Proteomics is a promising high-throughput technique that can be successfully applied to identify putative welfare protein biomarkers in farmed fish.

Keywords: aquaculture, fish welfare, proteomics, welfare biomarkers

Procedia PDF Downloads 136

Authors: Ikele Chika Bright, Mgbenka Bernard Obialo, Ikele Chioma Faith

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Icthyophthiriasis is a prevalent protozoan (ectoparasite) mostly affecting cultured and aquarium fishes. The majority of the chemotherapeutants lack efficacy for completely eliminating Ich parasite without affecting the environment and they are not safe for human health. The present work is focused on the evaluating different immersion treatments of African catfish (Clarias gariepinus) infected with ichthyophthiriasis and treated with a non-chemical and environmental friendly parasiticides Moringa oleifera. A total number of 800 apparently healthy parasites free (examined) post juvenile catfish were obtained from a reputable farm, disinfected with potassium permanganate in a quarantine tank to remove any possible external parasites. The fish were further challenged with approximately 44,000 infective stages of theronts which were obtained through serial passages by cohabitation. Seven groups (A-G) of post Juvenile were used for the experiment which was carried out into three stages; Dips (60minutes), short term treatment (24-96h) and prolong bath treatment (0-15 days). The concentrations selected were dependent on the outcome of the LC50 of the plant material from which dose-dependent factors were used to select various concentrations of the treatment. In Dips treatment, group D-G were treated with 1,500mg/L, 2500mg/L., 3500mg/L and 4500mg/L, short-term treatment was treated with 150mg/L, 250mg/L, 350mg/L and 450mg/L and prolong bath was treated with 15mg/L, 25mg/L, 35mg/L and 45mg/L of the plant extract whereas group A, B and C were normal control, Ich- infested not treated and Ich- infested treated with standard drug (Acriflavin), respectively. The various types of treatment applied with corresponding concentrations showed almost complete elimination of the adult parasites (trophonts) both in the gills and the body smear, thereby making M. oleifera a potential parasiticides. There were serious pathological alterations in the skin and gills which are usually the main point for Ich parasites invasion but no significant morphological characteristics was noted among the treated groups subjected to different immersion treatment patterns. Epitheliocystis, aneurysm, oedema, hemorrhage, and localization of the adult parasite in the gills were the overall common observations made in the gills whereas degeneration of muscle fibre, dermatitis, hemorrhage, oedema, abscess formation and keratinisation were observed in the skin. However, there are no pathological changes in the control group. Moreover, biochemical parameters such as urea, creatinine, albumin., globulin, total protein, ALT, AST), blood chemistry (sodium, chloride, potassium, bicarbonate), antioxidants (CAT, SOD, GPx, LPO), enzymatic activities (myeloperoxidase, thioreadoxin reductase), Inflammatory response (C-reactive protein), Stress markers (lactate dehydrogenase), heamatological parameters (RBC, PCV, WBC, HB and differential count), lipid profile (total cholesterol, tryglycerides , high density lipoprotein and low density lipoprotein) all showed various significant (P<0.05) and no significant (P>0.05) responses among the Ich-infested fish treated under three immersion treatments. It is suggested that M. oleifera may serve as an alternatives to chemotherapeutants for control of Ichthyophthiriasis in African catfish Clarias gariepinus.

Keywords: Icthyophthirius multifilis, immersion treatment, pathophysiology, African catfish

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Authors: Mohammadjavad Sotoudeheian, Navid Farahmandian

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Kawasaki disease (KD) is the primary cause of acquired pediatric heart disease as an acute vasculitis. In children with prolonged fever, rash, and inflammation of the mucosa KD must be considered as a clinical diagnosis. There is a persuasive suggestion of immune-mediated damage as the pathophysiologic cascade of KD. For example, the invasion of cytotoxic T-cells supports a viral etiology and the inflammasome of the innate immune system is a critical component in the vasculitis formation in KD. Animal models of KD propose the cytokine profiles, such as increased IL-1 and GM-CSF, which cause vascular damage. CRP and IFN-γ elevated expression and the upregulation of IL-6, and IL-10 production are also described in previous studies. Untreated KD is a critical risk factor for coronary artery diseases and myocardial infarction. Vascular damage may encompass amplified T-cell activity. SMAD3 is an essential molecule in down-regulating T-cells and increasing expression of FoxP3. It has a critical effect in the differentiation of regulatory T-cells. The discrepancy of regulatory T-cells and pro-inflammatory Th17 has been studied in acute coronary syndrome during KD. However in the coronary artery damaged lymphocytes and IgA plasma cells are seen at the lesion locations, the major immune cells in the coronary lesions are monocytes/macrophages and neutrophils. These cells secrete TNF-α, and activates matrix metalloprotease (MMP)-9, reducing the integrity of vessels and prompting patients to arise aneurysm. MMPs can break down the components of the extracellular matrix and assist immune cell movement. IVIG as an effective form of treatment clarified the role of the immune system, which may target pathogenic antigens and regulate cytokine production. Several reports have revealed that in the coronary arteries, high expression of MMP-9 in monocyte/macrophage results in pathologic cascades. Curcumin is a potent antioxidant and anti-inflammatory molecule. Curcumin decreases the production of reactive oxygen and nitrogen species and inhibits transcription factors like AP-1 and NF-κB. Curcumin also contains the characteristics of inhibitory effects on MMPs, especially MMP-9. The upregulation of MMP-9 is an important cellular response. Curcumin treatment caused a reverse effect and down-regulates MMP-9 gene expression which may fund the anti-inflammatory effect. Curcumin inhibits MMP-9 expression via PKC and AMPK-dependent pathways in Human monocytes cells. Elevated expression and activity of MMP-9 are correlated with advanced vascular lesions. AMPK controls lipid metabolism and oxidation, and protein synthesis. AMPK is also necessary for the MMP-9 activity and THP-1 cell adhesion to endothelial cells. Curcumin was shown to inhibit the activation of AMPKα. Compound C (AMPK inhibitor) inhibits MMP-9 expression level. Therefore, through inactivating AMPKs and PKC, curcumin decreases the MMP-9 level, which results in inhibiting monocyte/macrophage differentiation. Compound C also suppress the phosphorylation of three major classes of MAP kinase signaling, suggesting that curcumin may suppress MMP-9 level by inactivation of MAPK pathways. MAPK cascades are activated to induce the expression of MMP-9. Curcumin inhibits MAPKs phosphorylation, which contributes to the down-regulation of MMP-9. This study demonstrated that the potential inhibitory properties of curcumin over MMP-9 lead to a therapeutic strategy to reduce the risk of coronary artery involvement during KD.

Keywords: MMP-9, coronary artery aneurysm, Kawasaki’s disease, curcumin, AMPK, immune system, NF-κB, MAPK

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Authors: Andreia Garrido, Artur Conde, Ana Cunha, Ric De Vos

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Climate changes predictions point to increases in abiotic stress for crop plants in Portugal, like pronounced temperature variation and decreased precipitation, which will have negative impact on grapevine physiology and consequently, on grape berry and wine quality. Short-term mitigation strategies have, therefore, been implemented to alleviate the impacts caused by adverse climatic periods. These strategies include foliar application of kaolin, an inert mineral, which has radiation reflection proprieties that decreases stress from excessive heat/radiation absorbed by its leaves, as well as smart irrigation strategies to avoid water stress. However, little is known about the influence of these mitigation measures on grape berries, neither on the photosynthetic activity nor on the photosynthesis-related metabolic profiles of its various tissues. Moreover, the role of fruit photosynthesis on berry quality is poorly understood. The main objective of our work was to assess the effects of kaolin and irrigation treatments on the photosynthetic activity of grape berry tissues (exocarp and seeds) and on their global metabolic profile, also investigating their possible relationship. We therefore collected berries of field-grown plants of the white grape variety Alvarinho from two distinct microclimates, i.e. from clusters exposed to high light (HL, 150 µmol photons m⁻² s⁻¹) and low light (LL, 50 µmol photons m⁻² s⁻¹), from both kaolin and non-kaolin (control) treated plants at three fruit developmental stages (green, véraison and mature). Plant irrigation was applied after harvesting the green berries, which also enabled comparison of véraison and mature berries from irrigated and non-irrigated growth conditions. Photosynthesis was assessed by pulse amplitude modulated chlorophyll fluorescence imaging analysis, and the metabolite profile of both tissues was assessed by complementary metabolomics approaches. Foliar kaolin application resulted in, for instance, an increased photosynthetic activity of the exocarp of LL-grown berries at green developmental stage, as compared to the control non-kaolin treatment, with a concomitant increase in the levels of several lipid-soluble isoprenoids (chlorophylls, carotenoids, and tocopherols). The exocarp of mature berries grown at HL microclimate on kaolin-sprayed non-irrigated plants had higher total sugar levels content than all other treatments, suggesting that foliar application of this mineral results in an increased accumulation of photoassimilates in mature berries. Unbiased liquid chromatography-mass spectrometry-based profiling of semi-polar compounds followed by ASCA (ANOVA simultaneous component analysis) and ANOVA statistical analysis indicated that kaolin had no or inconsistent effect on the flavonoid and phenylpropanoid composition in both seed and exocarp at any developmental stage; in contrast, both microclimate and irrigation influenced the level of several of these compounds depending on berry ripening stage. Overall, our study provides more insight into the effects of mitigation strategies on berry tissue photosynthesis and phytochemistry, under contrasting conditions of cluster light microclimate. We hope that this may contribute to develop sustainable management in vineyards and to maintain grape berries and wines with high quality even at increasing abiotic stress challenges.

Keywords: climate change, grape berry tissues, metabolomics, mitigation strategies

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Authors: M. H. Pazandeh, M. Doudi, S. Barahimi, L. Rahimzadeh Torabi

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The use of antibiotics is essential in reducing the occurrence of adverse effects and inhibiting the emergence of antibiotic resistance in microbial populations. The necessity for a novel methodology concerning local administration of antibiotics has arisen, with particular focus on dealing with localized infections prompted by bacterial colonization of medical devices or implant materials. Bioactive glasses (BG) are extensively employed in the field of regenerative medicine, encompassing a diverse range of materials utilized for drug delivery systems. In the present investigation, various drug carriers for imipenem and tetracycline, namely single systems BG/SnO2, BG/NiO with varying proportions of metal oxide, and nanocomposite BG/SnO2/NiO, were synthesized through the sol-gel technique. The antibacterial efficacy of the synthesized samples was assessed through the utilization of the disk diffusion method with the aim of neutralizing Staphylococcus aureus as the bacterial model. The current study involved the examination of the bioactivity of two samples, namely BG10SnO2/10NiO and BG20SnO2, which were chosen based on their heightened bacterial inactivation properties. This evaluation entailed the employment of two techniques: the measurement of the pH of simulated body fluid (SBF) solution and the analysis of the sample tablets through X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared (FTIR) spectroscopy. The sample tablets were submerged in SBF for varying durations of 7, 14, and 28 days. The bioactivity of the composite bioactive glass sample was assessed through characterization of alterations in its surface morphology, structure, and chemical composition. This evaluation was performed using scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, and X-ray diffraction spectroscopy. Subsequently, the sample was immersed in simulated liquids to simulate its behavior in biological environments. The specific body fat percentage (SBF) was assessed over a 28-day period. The confirmation of the formation of a hydroxyapatite surface layer serves as a distinct indicator of bioactivity. The infusion of antibiotics into the composite bioactive glass specimen was done separately, and then the release kinetics of tetracycline and imipenem were tested in simulated body fluid (SBF). Antimicrobial effectiveness against various bacterial strains have been proven in numerous instances using both melt and sol-gel techniques to create multiple bioactive glass compositions. An elevated concentration of calcium ions within a solution has been observed to cause an increase in the pH level. In aqueous suspensions, bioactive glass particles manifest a significant antimicrobial impact. The composite bioactive glass specimen exhibits a gradual and uninterrupted release, which is highly desirable for a drug delivery system over a span of 72 hours. The reduction in absorption, which signals the loss of a portion of the antibiotic during the loading process from the initial phosphate-buffered saline solution, indicates the successful bonding of the two antibiotics to the surfaces of the bioactive glass samples. The sample denoted as BG/10SnO2/10NiO exhibits a higher loading of particles compared to the sample designated as BG/20SnO2 in the context of bioactive glass. The enriched sample demonstrates a heightened bactericidal impact on the bacteria under investigation while concurrently preserving its antibacterial characteristics. Tailored bioactive glass that incorporates hydroxyapatite, with a regulated and efficient release of drugs targeting bacterial infections, holds promise as a potential framework for bone implant scaffolds following rigorous clinical evaluation, thereby establishing potential future biomedical uses. During the modification process, the introduction of metal oxides into bioactive glass resulted in improved antibacterial characteristics, particularly in the composite bioactive glass sample that displayed the highest level of efficiency.

Keywords: antibacterial, bioactive glasses, implant infections, multi drug resistant

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Authors: Shikha Rani, Neeta Sehgal, Vipin Kumar Verma, Om Prakash

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Introduction: Fish is an important protein source for humans and has great economic value. Fish cultures are affected due to various anthropogenic activities that lead to bacterial and viral infections. Aeromonas hydrophila is a fish pathogenic bacterium that causes several aquaculture outbreaks throughout the world and leads to huge mortalities. In this study, plants of no commercial value were used to investigate their immunostimulatory, antioxidant, anti-inflammatory, anti-bacterial, and disease resistance potential in fish against Aeromonas hydrophila, through fish feed fortification. Methods: The plant was dried at room temperature in the shade, dissolved in methanol, and analysed for biological compounds through GC-MS/MS. DPPH, FRAP, Phenolic, and flavonoids were estimated following standardized protocols. In silico molecular docking was also performed to validate its broad-spectrum activities based on binding affinity with specific proteins. Fish were divided into four groups (n=6; total 30 in a group): Group 1, non-challenged fish (fed on a non-supplemented diet); Group 2, fish challenged with bacteria (fed on a non-supplemented diet); Group 3 and 4, fish challenged with bacteria (A. hydrophila) and fed on plant supplemented feed at 2.5% and 5%. Blood was collected from the fish on 0, 7th, 14th, 21st, and 28th days. Serum was separated for glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase assay (ALP), lysozyme activity assay, superoxide dismutase assay (SOD), lipid peroxidation assay (LPO) and molecular parameters (including cytokine levels) were estimated through ELISA. The phagocytic activity of macrophages from the spleen and head kidney, along with quantitative analysis of immune-related genes, were analysed in different tissue samples. The digestive enzymes (Pepsin, Trypsin, and Chymotrypsin) were also measured to evaluate the effect of plant-supplemented feed on freshwater fish. Results and Discussion: GC-MS/MS analysis of a methanolic extract of plant validated the presence of key compounds having antioxidant, anti-inflammatory, anti-bacterial, anti-inflammatory, and immunomodulatory activities along with disease resistance properties. From biochemical investigations like ABTS, DPPH, and FRAP, the amount of total flavonoids, phenols, and promising binding affinities towards different proteins in molecular docking analysis helped us to realize the potential of this plant that can be used for investigation in the supplemented feed of fish. Measurement liver function tests, ALPs, oxidation-antioxidant enzyme concentrations, and immunoglobulin concentrations in the experimental groups (3 and 4) showed significant improvement as compared to the positive control group. The histopathological evaluation of the liver, spleen, and head kidney supports the biochemical findings. The isolated macrophages from the group fed on supplemented feed showed a higher percentage of phagocytosis and a phagocytic index, indicating an enhanced cell-mediated immune response. Significant improvements in digestive enzymes were also observed in fish fed on supplemented feed, even after weekly challenges with bacteria. Hence, the plant-fortified feed can be recommended as a regular feed to enhance fish immunity and disease resistance against the Aeromonas hydrophila infection after confirmation from the field trial.

Keywords: immunostimulation, antipathogen, plant fortified feed, macrophages, GC-MS/MS, in silico molecular docking

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Authors: Mary-Ann N. Jallad, Dalal F. Jaber, Alexander M. Abdelnoor

Abstract:

Introduction: Current evidence confirms that both innate and adaptive immune systems are capable of recognizing and abolishing malignant cells. The emergence of cancerous tumors in patients is, therefore, an indication that certain cancer cells can resist elimination by the immune system through a process known as “immune evasion”. In fact, cancer cells often exploit regulatory mechanisms to escape immunity. Such mechanisms normally exist to control the immune responses and prohibit exaggerated or autoimmune reactions. Recently, immunotherapies have shown promising yet limited results. Therefore this study investigates several immunotherapeutic combinations and devises a triple immunotherapy which harnesses the innate and acquired immune responses towards the annihilation of malignant cells through overcoming their ability of immune evasion, consequently hampering malignant progression and eliminating established tumors. The aims of the study are to rule out acute/chronic toxic effects of the proposed treatment combinations, to assess the effect of these combinations on tumor growth and survival rates, and to investigate potential mechanisms underlying the phenotypic results through analyzing serum levels of anti-tumor cytokines, angiogenic factors and tumor progression indicator, and the tumor-infiltrating immune-cells populations. Methodology: For toxicity analysis, cancer-free C57BL/6 mice are randomized into 9 groups: Group 1 untreated, group 2 treated with sterile saline (solvent of used treatments), group 3 treated with Monophosphoryl-lipid-A, group 4 with anti-CTLA4-antibodies, group 5 with 1-Methyl-Tryptophan (Indolamine-Dioxygenase-1 inhibitor), group 6 with both MPLA and anti-CTLA4-antibodies, group 7 with both MPLA and 1-MT, group 8 with both anti-CTLA4-antibodies and 1-MT, and group 9 with all three: MPLA, anti-CTLA4-antibodies and 1-MT. Mice are monitored throughout the treatment period and for three following months. At that point, histological sections from their main organs are assessed. For tumor progression and survival analysis, a murine melanoma model is generated by injecting analogous mice with B16F10 melanoma cells. These mice are segregated into the listed nine groups. Their tumor size and survival are monitored. For a depiction of underlying mechanisms, melanoma-bearing mice from each group are sacrificed at several time-points. Sera are tested to assess the levels of Interleukin-12 (IL-12), Vascular-Endothelial-Growth Factor (VEGF), and S100B. Furthermore, tumors are excised for analysis of infiltrated immune cell populations including T-cells, macrophages, natural killer cells and immune-regulatory cells. Results: Toxicity analysis shows that all treated groups present no signs of neither acute nor chronic toxicity. Their appearance and weights were comparable to those of control groups throughout the treatment period and for the following 3 months. Moreover, histological sections from their hearts, kidneys, lungs, and livers were normal. Work is ongoing for completion of the remaining study aims. Conclusion: Toxicity was the major concern for the success of the proposed comprehensive combinational therapy. Data generated so far ruled out any acute or chronic toxic effects. Consequently, ongoing work is quite promising and may significantly contribute to the development of more effective immunotherapeutic strategies for the treatment of cancer patients.

Keywords: cancer immunotherapy, check-point blockade, combination therapy, melanoma

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Authors: Jana Chakrabarti, Madhushrita Das, Ankhi Haldar, Roshni Chatterjee, Tanmoy Dey, Pubali Dhar

Abstract:

High incidences of Protein Energy Malnutrition as a consequence of low protein intake are quite prevalent among the children in developing countries. Thus prevention of under-nutrition has emerged as a critical challenge to India’s developmental Planners in recent times. Increase in population over the last decade has led to greater pressure on the existing animal protein sources. But these resources are currently declining due to persistent drought, diseases, natural disasters, high-cost of feed, and low productivity of local breeds and this decline in productivity is most evident in some developing countries. So the need of the hour is to search for efficient utilization of unconventional low-cost animal protein resources. Molluscs, as a group is regarded as under-exploited source of health-benefit molecules. Bivalve is the second largest class of phylum Mollusca. Annual harvests of bivalves for human consumption represent about 5% by weight of the total world harvest of aquatic resources. The freshwater mussel Lamellidens marginalis is widely distributed in ponds and large bodies of perennial waters in the Indian sub-continent and well accepted as food all over India. Moreover, ethno-medicinal uses of the flesh of Lamellidens among the rural people to treat hypertension have been documented. Present investigation thus attempts to evaluate the potential of Lamellidens marginalis as functional food. Mussels were collected from freshwater ponds and brought to the laboratory two days before experimentation for acclimatization in laboratory conditions. Shells were removed and fleshes were preserved at- 20oC until analysis. Tissue homogenate was prepared for proximate studies. Fatty acids and amino acids composition were analyzed. Vitamins, Minerals and Heavy metal contents were also studied. Mussel Protein hydrolysate was prepared using Alcalase 2.4 L and degree of hydrolysis was evaluated to analyze its Functional properties. Ferric Reducing Antioxidant Power (FRAP) and DPPH Antioxidant assays were performed. Anti-hypertensive property was evaluated by measuring Angiotensin Converting Enzyme (ACE) inhibition assay. Proximate analysis indicates that mussel meat contains moderate amount of protein (8.30±0.67%), carbohydrate (8.01±0.38%) and reducing sugar (4.75±0.07%), but less amount of fat (1.02±0.20%). Moisture content is quite high but ash content is very low. Phospholipid content is significantly high (19.43 %). Lipid constitutes, substantial amount of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which have proven prophylactic values. Trace elements are found present in substantial amount. Comparative study of proximate nutrients between Labeo rohita, Lamellidens and cow’s milk indicates that mussel meat can be used as complementary food source. Functionality analyses of protein hydrolysate show increase in Fat absorption, Emulsification, Foaming capacity and Protein solubility. Progressive anti-oxidant and anti-hypertensive properties have also been documented. Lamellidens marginalis can thus be regarded as a functional food source as this may combine effectively with other food components for providing essential elements to the body. Moreover, mussel protein hydrolysate provides opportunities for utilizing it in various food formulations and pharmaceuticals. The observations presented herein should be viewed as a prelude to what future holds.

Keywords: functional food, functional properties, Lamellidens marginalis, protein hydrolysate

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Authors: Sajeli A. Begum, Ameer Basha, Kirti Hira, Rukaiyya Khan

Abstract:

Cyclic dipeptides are simple diketopiperazine derivatives being investigated by several scientists for their biological effects which include anticancer, antimicrobial, haematological, anticonvulsant, immunomodulatory effect, etc. They are potentially active microbial metabolites having been synthesized too, for developing into drug candidates. Cultures of Pseudomonas species have earlier been reported to produce cyclic dipeptides, helping in quorum sensing signals and bacterial–host colonization phenomena during infections, causing cell anti-proliferation and immunosuppression. Fluorescing Pseudomonas species have been identified to secrete lipid derivatives, peptides, pyrroles, phenazines, indoles, aminoacids, pterines, pseudomonic acids and some antibiotics. In the present work, results of investigation on the cyclic dipeptide metabolites secreted by the culture broth of Pseudomonas species as potent pro-inflammatory cytokine inhibitors are discussed. The bacterial strain was isolated from the rhizospheric soil of groundnut crop and identified as Pseudomonas aeruginosa by 16S rDNA sequence (GenBank Accession No. KT625586). Culture broth of this strain was prepared by inoculating into King’s B broth and incubating at 30 ºC for 7 days. The ethyl acetate extract of culture broth was prepared and lyophilized to get a dry residue (EEPA). Lipopolysaccharide (LPS)-induced ELISA assay proved the inhibition of tumor necrosis factor-alpha (TNF-α) secretion in culture supernatant of RAW 264.7 cells by EEPA (IC50 38.8 μg/mL). The effect of oral administration of EEPA on plasma TNF-α level in rats was tested by ELISA kit. The LPS mediated plasma TNF-α level was reduced to 45% with 125 mg/kg dose of EEPA. Isolation of the chemical constituents of EEPA through column chromatography yielded ten cyclic dipeptides, which were characterized using nuclear magnetic resonance and mass spectroscopic techniques. These cyclic dipeptides are biosynthesized in microorganisms by multifunctional assembly of non-ribosomal peptide synthases and cyclic dipeptide synthase. Cyclo (Gly-L-Pro) was found to be more potentially (IC50 value 4.5 μg/mL) inhibiting TNF-α production followed by cyclo (trans-4-hydroxy-L-Pro-L-Phe) (IC50 value 14.2 μg/mL) and the effect was equal to that of standard immunosuppressant drug, prednisolone. Further, the effect was analyzed by determining mRNA expression of TNF-α in LPS-stimulated RAW 264.7 macrophages using quantitative real-time reverse transcription polymerase chain reaction. EEPA and isolated cyclic dipeptides demonstrated diminution of TNF-α mRNA expression levels in a dose-dependent manner under the tested conditions. Also, they were found to control the expression of other pro-inflammatory cytokines like IL-1β and IL-6, when tested through their mRNA expression levels in LPS-stimulated RAW 264.7 macrophages under LPS-stimulated conditions. In addition, significant inhibition effect was found on Nitric oxide production. Further all the compounds exhibited weak toxicity to LPS-induced RAW 264.7 cells. Thus the outcome of the study disclosed the effectiveness of EEPA and the isolated cyclic dipeptides in down-regulating key cytokines involved in pathophysiology of autoimmune diseases.In another study led by the investigators, microbial cyclic dipeptides were found to exhibit excellent antimicrobial effect against Fusarium moniliforme which is an important causative agent of Sorghum grain mold disease. Thus, cyclic dipeptides are emerging small molecular drug candidates for various autoimmune diseases.

Keywords: cyclic dipeptides, cytokines, Fusarium moniliforme, Pseudomonas, TNF-alpha

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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