Search results for: in vivo biomarkers

Authors: Allison Herlene Du Plessis, Dalena (R.M.) Van Rooyen, Wilma Ten Ham-Baloyi, Sihaam Jardien-Baboo

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Introduction: Women die in pregnancy and childbirth for five main reasons—severe bleeding, infections, unsafe abortions, hypertensive disorders (pre-eclampsia and eclampsia), and medical complications including cardiac disease, diabetes, or HIV/AIDS complicated by pregnancy. In 2015, WHO classified sepsis as the third highest cause for maternal mortalities in the world. Chorioamnionitis is a clinical syndrome of intrauterine infection during any stage of the pregnancy and it refers to ascending bacteria from the vaginal canal up into the uterus, causing infection. While the incidence rates for chorioamnionitis are not well documented, complications related to chorioamnionitis are well documented and midwives still struggle to identify this condition in time due to its complex nature. Few diagnostic methods are available in public health services, due to escalated laboratory costs. Often the affordable biomarkers, such as C-reactive protein CRP, full blood count (FBC) and WBC, have low significance in diagnosing chorioamnionitis. A lack of screening impacts on effective and timeous management of chorioamnionitis, and early identification and management of risks could help to prevent neonatal complications and reduce the subsequent series of morbidities and healthcare costs of infants who are health foci of perinatal infections. Objective: This integrative literature review provides an overview of current best research evidence on the screening of women at risk for chorioamnionitis. Design: An integrative literature review was conducted using a systematic electronic literature search through EBSCOhost, Cochrane Online, Wiley Online, PubMed, Scopus and Google. Guidelines, research studies, and reports in English related to chorioamnionitis from 2008 up until 2020 were included in the study. Findings: After critical appraisal, 31 articles were included. More than one third (67%) of the literature included ranked on the three highest levels of evidence (Level I, II and III). Data extracted regarding screening for chorioamnionitis was synthesized into four themes, namely: screening by clinical signs and symptoms, screening by causative factors of chorioamnionitis, screening of obstetric history, and essential biomarkers to diagnose chorioamnionitis. Key conclusions: There are factors that can be used by midwives to identify women at risk for chorioamnionitis. However, there are a paucity of established sociological, epidemiological and behavioral factors to screen this population. Several biomarkers are available to diagnose chorioamnionitis. Increased Interleukin-6 in amniotic fluid is the better indicator and strongest predictor of histological chorioamnionitis, whereas the available rapid matrix-metalloproteinase-8 test requires further testing. Maternal white blood cells count (WBC) has shown poor selectivity and sensitivity, and C-reactive protein (CRP) thresholds varied among studies and are not ideal for conclusive diagnosis of subclinical chorioamnionitis. Implications for practice: Screening of women at risk for chorioamnionitis by health care providers providing care for pregnant women, including midwives, is important for diagnosis and management before complications arise, particularly in resource-constraint settings.

Keywords: chorioamnionitis, guidelines, best evidence, screening, diagnosis, pregnant women

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Authors: L. Kashyap, S. Jha, D. Shende, V. K. Mohan, P. Khanna, A. Aravindan, S. Kashyap, L. Singh, S. Aggarwal

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Obesity is associated with a chronic inflammatory state. During surgery, there is an interplay between anaesthetic and surgical stress vis-a-vis the already present complex immune state. Moreover, the postoperative period is dictated by inflammation, which is crucial for wound healing and regeneration. An excess of inflammatory response might hamper recovery besides increasing the risk for infection and complications. There is definite evidence of the immunosuppressive role of inhaled anaesthetic agents. This immune modulation may be brought into effect directly by influencing the innate and adaptive immunity cells. The effects of propofol on immune mechanisms in has been widely elucidated because of its popularity. It reduces superoxide generation, elastase release, and chemotaxis. However, there is no unequivocal proof of one’s superiority over the other. Hence, an anaesthetic regimen with lesser inflammatory potential and specific to the obese patient is needed. OBESITA trial protocol (2019) by Sousa and co-workers in progress aims to test the hypothesis that anaesthesia with sevoflurane results in a weaker proinflammatory response compared to propofol, as evidenced by lower IL-6 and other biomarkers and an increased macrophage differentiation into M2 phenotype in adipose tissue. IL-6 was used as the objective parameter to evaluate inflammation as it is regulated by both surgery and anesthesia. It is the most sensitive marker of the inflammatory response to tissue damage since it is released within minutes by blood leukocytes. We hypothesized that maintenance of anaesthesia with propofol would lead to less inflammation than that with desflurane. Aims: The effect of two anaesthetic techniques, total intravenous anaesthesia (TIVA) with propofol and desflurane, on surgical stress response was evaluated. The primary objective was to compare serum interleukin-6 (IL-6) levels before and after surgery. Methods: In this prospective single-blinded randomized controlled trial undertaken, 30 obese patients (BMI>30 kg/m2) undergoing laparoscopic bariatric surgery under general anaesthesia were recruited. Patients were randomized to receive desflurane or TIVA using a target-controlled infusion for maintenance of anaesthesia. As a marker of inflammation, pre-and post-surgery IL-6 levels were compared. Results: After surgery, IL-6 levels increased significantly in both groups. The rise in IL-6 was less with TIVA than with desflurane; however, it did not reach significance. IL-6 rise post-surgery correlated positively with the complexity of procedure and duration of surgery and anaesthesia, rather than anaesthetic technique. Both groups did not differ in terms of intra-operative hemodynamic and respiratory variables, time to awakening, postoperative pulmonary complications, and duration of hospital stay. The incidence of nausea was significantly higher with desflurane than with TIVA. Conclusion: Inflammatory response did not differ as a function of anaesthetic technique when propofol and desflurane were compared. Also, patient and surgical variables dictated post-operative inflammation more than the anaesthetic factors. Further, larger sample size is needed to confirm or refute these findings.

Keywords: bariatric, biomarkers, inflammation, laparoscopy

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Authors: C. Sancho Salvatierra, J. M. Martinez Nieto, R. García Gonzalez-Gordon, M. I. Martinez Bellido

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Introduction: Nature could act as an asset for human health protecting against possible diseases and promoting the state of both physical and mental health. Goals: This paper aims to determine which natural elements present evidence that show positive influence on human health, on which particular aspects and how. It also aims to determine the best biomarkers to measure such influence. Method: A systematic literature review was carried out. First, a general free text search was performed in databases, such as Scopus, PubMed or PsychInfo. Secondly, a specific search was performed combining keywords in order of increasing complexity. Also the Snowballing technique was used and it was consulted in the CSIC’s (The Spanish National Research Council). Databases: Of the 130 articles obtained and reviewed, 80 referred to natural elements that influenced health. These 80 articles were classified and tabulated according to the nature elements found, the health aspects studied, the health measurement parameters used and the measurement techniques used. In this classification the results of the studies were codified according to whether they were positive, negative or neutral both for the elements of nature and for the aspects of health studied. Finally, the results of the 80 selected studies were summarized and categorized according to the elements of nature that showed the greatest positive influence on health and the biomarkers that had shown greater reliability to measure said influence. Results: Of the 80 articles studied, 24 (30.0%) were reviews and 56 (70.0%) were original research articles. Among the 24 reviews, 18 (75%) found positive results of natural elements on health, and 6 (25%) both positive and negative effects. Of the 56 original articles, 47 (83.9%) showed positive results, 3 (5.4%) both positive and negative, 4 (7.1%) negative effects, and 2 (3.6%) found no effects. The results reflect positive effects of different elements of nature on the following pathologies: diabetes, high blood pressure, stress, attention deficit hyperactivity disorder, psychotic, anxiety and affective disorders. They also show positive effects on the following areas: immune system, social interaction, recovery after illness, mood, decreased aggressiveness, concentrated attention, cognitive performance, restful sleep, vitality and sense of well-being. Among the elements of nature studied, those that show the greatest positive influence on health are forest immersion, natural views, daylight, outdoor physical activity, active transport, vegetation biodiversity, natural sounds and the green residences. As for the biomarkers used that show greater reliability to measure the effects of natural elements are the levels of cortisol (both in blood and saliva), vitamin D levels, serotonin and melatonin, blood pressure, heart rate, muscle tension and skin conductance. Conclusions: Nature is an asset for health, well-being and quality of life. Awareness programs, education and health promotion are needed based on the elements that nature brings us, which in turn generate proactive attitudes in the population towards the protection and conservation of nature. The studies related to this subject in Spain are very scarce. Aknowledgements. This study has been promoted and partially financed by the Environmental Foundation Jaime González-Gordon.

Keywords: health, green areas, nature, well-being

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Authors: Elena Maria Scalisi, Roberta Pecoraro, Martina Contino, Sara Ignoto, Carmelo Iaria, Santi Concetto Pavone, Gino Sorbello, Loreto Di Donato, Maria Violetta Brundo

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5G Technology is evolving to satisfy a variety of service requirements that may allow high data-rate connections (1Gbps) and lower latency times than current (<1ms). In order to support a high data transmission speed and a high traffic service for eMBB (enhanced mobile broadband) use cases, 5G systems have the characteristic of using different frequency bands of the radio wave spectrum (700 MHz, 3.6-3.8 GHz and 26.5-27.5 GHz), thus taking advantage of higher frequencies than previous mobile radio generations (1G-4G). However, waves at higher frequencies have a lower capacity to propagate in free space and therefore, in order to guarantee the capillary coverage of the territory for high reliability applications, it will be necessary to install a large number of repeaters. Following the introduction of this new technology, there has been growing concern over the past few months about possible harmful effects on human health. The aim of this preliminary study is to evaluate possible short term effects induced by 5G-millimeter waves on embryonic development and early life stages of Danio rerio by Z-FET. We exposed developing zebrafish at frequency of 27 GHz, with a standard pyramidal horn antenna placed at 15 cm far from the samples holder ensuring an incident power density of 10 mW/cm2. During the exposure cycle, from 6 h post fertilization (hpf) to 96 hpf, we measured a different morphological endpoints every 24 hours. Zebrafish embryo toxicity test (Z-FET) is a short term test, carried out on fertilized eggs of zebrafish and it represents an effective alternative to acute test with adult fish (OECD, 2013). We have observed that 5G did not reveal significant impacts on mortality nor on morphology because exposed larvae showed a normal detachment of the tail, presence of heartbeat, well-organized somites, therefore hatching rate was lower than untreated larvae even at 48 h of exposure. Moreover, the immunohistochemical analysis performed on larvae showed a negativity to the HSP-70 expression used as a biomarkers. This is a preliminary study on evaluation of potential toxicity induced by 5G and it seems appropriate to underline the importance that further studies would take, aimed at clarifying the probable real risk of exposure to electromagnetic fields.

Keywords: Biomarker of exposure, embryonic development, 5G waves, zebrafish embryo toxicity test

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Authors: Pornrut Rabintossaporn, Suphaket Saenthaweesuk, Amornnat Thuppia, Nuntiya Somparn

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Several dietary and herbal plants have been shown to possess cytoprotective and antioxidant effects with various mechanisms of action. The aim of this study was to determine the antioxidant effects and its mechanism of aqueous leaves extract of Ocimum americanum (OA), commonly known as American basil or 'hoary basil', in rat. The extract was screened for its phytochemical contents and antioxidant activity in vitro. Moreover, the extract was studied in rats to evaluate its effects in vivo. Rats were orally administered with the extract at the dose of 100, 200 and 400 mg/kg for 28 days. Phytochemical screening of plant extracts revealed the presence of alkaloid, cardiac glycosides, tannin and steroid compounds. The extract contained phenolic compounds 36.91 ± 0.66 mg of gallic acid equivalents per gram OA extract. The free radical scavenging activity assessed by DPPH assay gave IC50 of 41.27 ± 1.86 µg/mL, which is relatively lower than that of BHT with IC50 of 12.34 ± 1.14µg/mL. In the animals, the extract was well tolerated by the animals throughout the 28 days of study as shown by normal serum levels AST, ALP, ALT, BUN and Cr as well as normal histology of liver and pancreatic and kidney tissue. The protein expression of antioxidant enzymes, γ-glutamylcysteine ligase (γ-GCL) in liver was significantly increased compared with normal control. Consistent with the induction of γ-GCL protein expression significantly reduction of serum oxidative stress marker malondialdehyde (MDA) was found in rat treated with OA extract compared with control. Taken together, this study provides evidence that Ocimum americanum exhibits direct antioxidant properties and can induce cytoprotective enzyme in vivo.

Keywords: antioxidant, γ-glutamylcysteine ligase, MDA, Ocimum americanum

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Authors: Gyati Shilakari Asthana, Abhay Asthana

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Purpose: The therapeutic potential of oligonucleotide (ODN) is primarily dependent upon its safe and efficient delivery to specific cells overcoming degradation and maximizing cellular uptake in vivo. The present study is focused to design low molecular weight chitosan nanoconstructs to meet the requirements of safe and effectual delivery of ODNs. LMW-chitosan is a biodegradable, water soluble, biocompatible polymer and is useful as a non-viral vector for gene delivery due to its better stability in water. Methods: LMW chitosan ODN nanoparticles (CHODN NPs) were formulated by self assembled method using various N/P ratios (moles ratio of amine groups of CH to phosphate moieties of ODNs; 0.5:1, 1:1, 3:1, 5:1 and 7:1) of CH to ODN. The developed CHODN NPs were evaluated with respect to gel retardation assay, particle size, zeta potential and cytotoxicity and transfection efficiency. Results: Complete complexation of CH/ODN was achieved at the charge ratio of 0.5:1 or above and CHODN NPs displayed resistance against DNase I. On increasing the N/P ratio of CH/ODN, particle size of the NPs decreased whereas zeta potential (ZV) value increased. No significant toxicity was observed at all CH concentrations. The transfection efficiency was increased on increasing N/P ratio from 1:1 to 3:1, whereas it was decreased with further increment in N/P ratio upto 7:1. Maximum transfection of CHODN NPs with both the cell lines (Raw 267.4 cells and Hela cells) was achieved at N/P ratio of 3:1. The results suggest that transfection efficiency of CHODN NPs is dependent on N/P ratio. Conclusion: Thus the present study states that LMW chitosan nanoparticulate carriers would be acceptable choice to improve transfection efficiency in vitro as well as in vivo delivery of oligonucleotide.

Keywords: LMW-chitosan, chitosan nanoparticles, biocompatibility, cytotoxicity study, transfection efficiency, oligonucleotide

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Authors: Macie Matta, Ahmad Jabri, Stephanie Jackson

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Introduction: In the absence of hypotension, pulmonary embolism (PE) causing right ventricular dysfunction or strain, whether confirmed by imaging or cardiac biomarkers, is deemed to be an intermediate-risk category. Urgent treatment of intermediate-risk PE can prevent progression to hemodynamic instability and death. Management options include thrombolysis, thrombectomy, or systemic anticoagulation. We aim to evaluate the short-term outcomes of a half-dose tissue plasminogen activator (tPA) for the management of intermediate-risk PE. Methods: We retrospectively identified adult patients diagnosed with intermediate-risk PE between the years 2000 and 2021. Demographic data, lab values, imaging, treatment choice, and outcomes were all obtained through chart review. Primary outcomes measured include major bleeding events and in-hospital mortality. Patients on standard systemic anticoagulation without receiving thrombolysis or thrombectomy served as controls. Patient data were analyzed using SAS®️ Software (version 9.4; Cary, NC) to compare individuals that received half-dose tPA with controls, and statistical significance was set at a p-value of 0.05. Results: We included 57 patients in our final analysis, with 19 receiving tPA. Patient characteristics and comorbidities were comparable between both groups. There was a significant difference between PE location, presence of acute deep vein thrombosis, and peak troponin level between both groups. The thrombolytic cohort was more likely to demonstrate a 60/60 sign and thrombus in transit finding on echocardiography than controls. The thrombolytic group was more likely to have major bleeding (17% vs 7.9%, p= 0.4) and in-hospital mortality (5.3% vs 0%, p=0.3); however, this was not statistically significant. Patients who received half-dose tPA had non-significantly higher rates of major bleeding and in-hospital mortality. Larger scale, randomized control trials are needed to establish the benefit and safety of thrombolytics in patients with intermediate-risk PE.

Keywords: pulmonary embolism, half dose thrombolysis, tissue plasminogen activator, cardiac biomarkers, echocardiographic findings, major bleeding event

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Authors: Tamer M. Shehata, Heba S. Elsewedy, Mashel Al Dosary, Alaa Elshehry, Mohamed A. Khedr, Maged E. Mohamed

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Objective: 2,4-Dichlorophenoxy acetic acid (2,4-D) is a well-known herbicide widely used as a weed killer. Recently, 2,4-D was rediscovered as a new anti-inflammatory agent through in silico as well as in-vivo experiments. However, poor solubility of 2,4-D could represent a problems during pharmaceutical development in addition to lower bioavailability. Solid dispersion (SD) refers to a group of solid products consisting of at least two different components, usually a hydrophobic drug and hydrophilic matrix. It is well known technique for enhancing drug solubility. Therefore, selecting SD as a tool for enhancing 2,4-D could be of great interest to the formulator. Method: In our project, several polymers were investigated (such as PEG, HPMC, citric acid and others) in addition to drug polymer ratios and its effect on solubility. Evaluation of drug polymer interaction was investigated through both Fourier Transform Infrared (FTIR) and Differential Scanning Calorimetry (DSC). Finally, in-vivo evaluation was performed for the best selected preparation through inflammatory response of rat induce hind paw. Results: Results indicated that, citric acid 2,4-D and in ratio of 0.75 : 1 showed modified the dissolution profile of the drug. The FTIR resltes indicated no significant chemical interaction, however DSC showed shifting of the drug melting point. Finally, Carragenan induced rat hind paw edema showed significant reduction of the drug solid dispersion in comparison to the pure drug, indicating rapid and complete absorption of the drug in solid dispersion form. Conclusion: Solid dispersion technology can be utilized efficiently to enhance the solubility of 2,4-D.

Keywords: solid dispersion, 2, 4-D solubility, carragenan induced edema

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Authors: Christina Williams, Mehari Weldemariam, Ann M. Farese, Thomas J. MacVittie, Maureen A. Kane

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Radiation exposure results in dose-dependent and time-dependent multi-organ damage. Drug development of medical countermeasures (MCM) for radiation-induced injury occurs under the FDA Animal Rule because human efficacy studies are not ethical or feasible. The FDA Animal Rule requires the representation of both sexes and describes several uses for biomarkers in MCM drug development studies. Currently, MCMs are limited and there is no FDA-approved biomarker for any radiation injury. Sex as a variable is essential to identifying biomarkers and developing effective MCMs for acute radiation exposure (ARS) and delayed effects of acute radiation exposure (DEARE). These studies aim to address the death of information on sex differences that have not been determined by studies that included only male, single-sex cohorts. Studies have reported differences in radiosensitivity according to sex. As such, biomarker discovery for radiation-induced damage must consider sex as a variable. This study evaluated the plasma proteomic profile of Rhesus macaque non-human primates after different exposures and doses, as well as time points after radiation. Exposures and doses included total body irradiation between 5-7.5 Gy and partial body irradiation with 5% bone marrow sparing at 9, 9.5 and 10 Gy. Timepoints after irradiation included days 1, 3, 60, and 180, which encompassed both acute radiation syndromes and delayed effects of acute radiation exposure. Bottom-up proteomic analyses of plasma included equal numbers of males and females. In the control animals, few proteomic differences are observed between the sexes. In the irradiated animals, there are a few sex differences, with changes mostly consisting of proteins upregulated in the female animals. Multiple canonical pathways were upregulated in irradiated animals relative to the control animals when subjected to pathway analysis, but differential responses between the sexes are limited. These data provide critical baseline differences according to sex and establish sex differences in non-human primate models relevant to drug development of MCM under the FDA Animal Rule.

Keywords: ionizing radiation, sex differences, plasma proteomics, biomarker discovery

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Authors: Robnier Reyes, Andrew J. P. Marques, Joel Ramjist, Chris R. Pasarikovski, Victor X. D. Yang

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Over the past three decades, surgical robotic systems have demonstrated their ability to improve surgical outcomes. The LBR Med is a collaborative robotic arm that is meant to work with a surgeon to streamline surgical workflow. It has 7 degrees of freedom and thus can be easily oriented. Position and torque sensors at each joint allow it to maintain a position accuracy of 150 µm with real-time force and torque feedback, making it ideal for complex surgical procedures. Spinal fusion procedures involve the placement of as many as 20 pedicle screws, requiring a great deal of accuracy due to proximity to the spinal canal and surrounding vessels. Any deviation from intended path can lead to major surgical complications. Assistive surgical robotic systems are meant to serve as collaborative devices easing the workload of the surgeon, thereby improving pedicle screw placement by mitigating fatigue related inaccuracies. Moreover, robotic spinal systems have shown marked improvements over conventional freehanded techniques in both screw placement accuracy and fusion quality and have greatly reduced the need for screw revision, intraoperatively and post-operatively. However, current assistive spinal fusion robots, such as the ROSA Spine, are limited in functionality to positioning surgical instruments. While they offer a small degree of improvement in pedicle screw placement accuracy, they do not alleviate surgeon fatigue, nor do they provide real-time force and torque feedback during screw insertion. We propose a semi-autonomous surgical robot workflow for spinal fusion where the surgeon guides the robot to its initial position and orientation, and the robot drives the pedicle screw accurately into the vertebra. Here, we demonstrate feasibility by inserting pedicle screws into ex-vivo bovine rib bone. The robot monitors position, force and torque with respect to predefined values selected by the surgeon to ensure the highest possible spinal fusion quality. The workflow alleviates the strain on the surgeon by having the robot perform the screw placement while the ability to monitor the process in real-time keeps the surgeon in the system loop. The approach we have taken in terms of level autonomy for the robot reflects its ability to safely collaborate with the surgeon in the operating room without external navigation systems.

Keywords: ex vivo bovine bone, pedicle screw, surgical robot, surgical workflow

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Authors: Fisseha Shiferie (Bpharm, Mpharm)

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Diarrhea is a common gastrointestinal disorder characterized by an increase in stool frequency and a change in stool consistency. Inspite of the availability of many drugs as antidiarrheal agents, the search for a drug with affordable cost and better efficacy is essential to overcome diarrheal problems. The root extract of Echinops kebericho, is used by traditional practitioners for the treatment of diarrhea. However, the scientific basis for this usage has not been yet established. The purpose of the present study was to evaluate the antidiarrheal and spasmolytic activities of the aqueous extract of the roots of E. kebericho in rodents and isolated guinea-pig ileum preparations. In the castor oil induced intestinal transit test, E. kebericho produced a significant (p < 0.01) dose dependent decrease in propulsion with peristaltic index values of 45.05±3.3, 42.71±2.25 and 33.17±3.3%, respectively at doses of 100, 200 and 400 mg/kg compared with 63.43±7.3% for control. In the castor oil-induced diarrhea test, the mean defecation was reduced from 1.81±0.18 to 0.99 ± 0.21 compared with 2.59 ±0.81 for control. The extract (at doses stated above) significantly decreased the volume of intestinal fluid secretion induced by castor oil (2.31±0.1 to 2.01±0.2) in relation to 3.28±0.3 for control. When tested on a guinea-pig ileum, root extract of Echinops kebericho exhibited a dose dependent spasmolytic effect, 23.07 % being its highest inhibitory effect. The results obtained in this study give some scientific support to the use of Echinops kebericho as an antidiarrheal agent due to its inhibitory effects on the different diarrheal parameters used in this study.

Keywords: antidiarrheal activity, E. kebericho, traditional medicine, diarrhea, enteropooling, and intestinal transit

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Authors: M. Gowri, E. K. Girija, V. Ganesh

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Background and Significance: Among the dental infections, inflammation and infection of the root canal are common among all age groups. Currently, the management of root canal infections involves cleaning the canal with powerful irrigants followed by intracanal medicament application. Though these treatments have been in vogue for a long time, root canal failures do occur. Treatment for root canal infections is limited due to the anatomical complexity in terms of small micrometer volumes and poor penetration of drugs. Thus, infections of the root canal seem to be a challenge that demands development of new agents that can eradicate C. albicans. Methodology: In the present study, we synthesized and screened silver-curcumin nanoparticle against Candida albicans. Detailed molecular studies were carried out with silver-curcumin nanoparticle on C. albicans pathogenicity. Morphological cell damage and antibiofilm activity of silver-curcumin nanoparticle on C. albicans was studied using scanning electron microscopy (SEM). Biochemical evidence for membrane damage was studied using flow cytometry. Further, the antifungal activity of silver-curcumin nanoparticle was evaluated in an ex vivo dentinal tubule infection model. Results: Screening data showed that silver-curcumin nanoparticle was active against C. albicans. Silver-curcumin nanoparticle exerted time kill effect and post antifungal effect. When used in combination with fluconazole or nystatin, silver-curcumin nanoparticle revealed a minimum inhibitory concentration (MIC) decrease for both drugs used. In-depth molecular studies with silver-curcumin nanoparticle on C. albicans showed that silver-curcumin nanoparticle inhibited yeast to hyphae (Y-H) conversion. Further, SEM images of C. albicans showed that silver-curcumin nanoparticle caused membrane damage and inhibited biofilm formation. Biochemical evidence for membrane damage was confirmed by increased propidium iodide (PI) uptake in flow cytometry. Further, the antifungal activity of silver-curcumin nanoparticle was evaluated in an ex vivo dentinal tubule infection model, which mimics human tooth root canal infection. Confocal laser scanning microscopy studies showed eradication of C. albicans and reduction in colony forming unit (CFU) after 24 h treatment in the infected tooth samples in this model. Conclusion: The results of this study can pave the way for developing new antifungal agents with well deciphered mechanisms of action and can be a promising antifungal agent or medicament against root canal infection.

Keywords: C. albicans, ex vivo dentine model, inhibition of biofilm formation, root canal infection, yeast to hyphae conversion inhibition

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Authors: Jie Gao

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The combination of chemotherapy with gene therapy is highly effective in cancer therapy. To achieve combined therapeutic effects in human gastric cancer over expressing EGFR, we developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab’ for co-delivery of doxorubicin (DOX) and ribonucleotide reductase M2 (RRM2) siRNA (DOX-RRM2-TLPD). The results showed that EGFR was over expressed in several gastric cancer cell lines and gastric cancer tissues. Gene Expression Omnibus (GEO) results showed that RRM2 expression was significantly higher in gastric cancer than in non-gastric cancer tissue, and RRM2 siRNA inhibited the proliferation of several gastric cancer cells, indicating that RRM2 is a candidate target for gastric cancer therapy. Confocal studies and flow cytometry showed that DOX-RRM2-TLPD delivered DOX and RRM2 siRNA to EGFR over expressing gastric cancer cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity and apoptosis) compared with single-drug loaded or non-targeted controls, including DOX-NC-TLPD (targeted LPD co-delivering DOX and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and DOX-RRM2-NTLPD (non-targeted LPD co-delivering DOX and RRM2 siRNA). The in vivo antitumor assay showed that the average weight of the gastric cancer in mice treated with DOX-RRM2-TLPD was significantly lighter than that of mice treated with other controls. DOX-RRM2-TLPD represents an effective approach for combined therapy of gastric cancer over expressing EGFR.

Keywords: gene therapy, chemotherapy, immunoliposomes, gastric cancer

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Authors: Javier Enciso-Benavides, Fredy Fabian, Carlos Castaneda, Luis Alfaro, Alex Choque, Aparicio Aguilar, Javier Enciso

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Background: The use of biomarkers in breast cancer diagnosis, therapy, and prognosis has gained increasing interest. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and may cause relapse. Therefore, due to the importance of diagnosis, therapy, and prognosis, several biomarkers that characterize CSCs have been identified; however, in treatment-naïve triple-negative breast tumors, there is an urgent need to identify new biomarkers and therapeutic targets. According to this, the aim of this study was to identify serum proteins associated with cancer stem cells and pluripotency in women with triple-negative breast tumors in order to subsequently identify a biomarker for this type of breast tumor. Material and Methods: Whole blood samples from 12 women with histopathologically diagnosed triple-negative breast tumors were used after obtaining informed consent from the patient. Blood serum was obtained by conventional procedure and frozen at -80ºC. Identification of cancer stem cell-associated proteins was performed by matrix-assisted laser desorption/ionisation-assisted laser desorption/ionisation mass spectrometry (MALDI-TOF MS), protein analysis was obtained using the AB Sciex TOF/TOF™ 5800 system (AB Sciex, USA). Sequences not aligned by ProteinPilot™ software were analyzed by Protein BLAST. Results: The following proteins related to pluripotency and cancer stem cells were identified by MALDI TOF/TOF mass spectrometry: A-chain, Serpin A12 [Homo sapiens], AIEBP [Homo sapiens], Alpha-one antitrypsin, AT {internal fragment} [human, partial peptide, 20 aa] [Homo sapiens], collagen alpha 1 chain precursor variant [Homo sapiens], retinoblastoma-associated protein variant [Homo sapiens], insulin receptor, CRA_c isoform [Homo sapiens], Hydroxyisourate hydrolase [Streptomyces scopuliridis], MUCIN-6 [Macaca mulatta], Alpha-actinin-3 [Chrysochloris asiatica], Polyprotein M, CRA_d isoform, partial [Homo sapiens], Transcription factor SOX-12 [Homo sapiens]. Recommendations: The serum proteins identified in this study should be investigated in the exosome of triple-negative breast cancer stem cells and in the blood serum of women without breast cancer. Subsequently, proteins found only in the blood serum of women with triple-negative breast cancer should be identified in situ in triple-negative breast cancer tissue in order to identify a biomarker to study the evolution of this type of cancer, or that could be a therapeutic target. Conclusions: Eleven cancer stem cell-related serum proteins were identified in 12 women with triple-negative breast cancer, of which MUCIN-6, retinoblastoma-associated protein variant, transcription factor SOX-12, and collagen alpha 1 chain are the most representative and have not been studied so far in this type of breast tumor. Acknowledgement: This work was supported by Proyecto CONCYTEC–Banco Mundial “Mejoramiento y Ampliacion de los Servicios del Sistema Nacional de Ciencia Tecnología e Innovacion Tecnologica” 8682-PE (104-2018-FONDECYT-BM-IADT-AV).

Keywords: triple-negative breast cancer, MALDI TOF/TOF MS, serum proteins, cancer stem cells

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Authors: Mohammad K. Parvez, Ahmed H. Arbab, Mohammed S. Al-Dosari, Adnan J. Al-Rehaily

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We investigated ex vivo and in vivo antioxidative and hepatoprotective effect of Aerva javanica. Total ethanol extract of A. javanica aerial parts was prepared, and tested on DCFH-toxicated HepG2 cell in CCl4-injured Wistar rats. MTT-assay was used to determine cell viability, and serum biochemical markers of liver injury as well as histopathology were performed. In vitro DPPH and β-carotene free-radical scavenging assay and phytochemical screening of the extract was done. Furthermore, A. javanica total extract was standardized and validated by HPTLC method. While DCFH-injured cells were recovered to about 56.7% by 100 microg/ml of the extract, a 200 microg/ml dose resulted in hepatocytes recovery by about 90.2%. Oral administration of the extract (100 and 200 mg/kg.bw/day) significantly normalized the serum SGOT, SGPT, GGT, ALP, bilirubin, cholesterol, HDL, LDL, VLDL, TG and MDA levels, including tissue NP-SH and TP in CCl4-injured rats. In addition, the histopathology of dissected liver also revealed that A. javanica cured the tissue lesion compared to reference drug, Silymarin. In vitro assays revealed strong free-radical scavenging ability of the extract and presence of alkaloids, flavonoids, tannins, sterols and saponins where Rutin, a well-known antioxidant flavonoid was identified. Our finding therefore, suggests the therapeutic potential of A. javanica in various liver diseases. However, isolation of the active principles, their mechanism of action and other therapeutic contribution remain to be addressed.

Keywords: Aerva javanica, antioxidant, hepatoprotection, rutin

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Authors: Sudhir Kumar, V. R. Sinha

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Water in oil topical microemulsions of 5-FU were developed and optimized using face centered central composite design. Topical w/o microemulsion of 5-FU were prepared using sorbitan monooleate (Span 80), polysorbate 80 (Tween 80), with different oils such as oleic acid (OA), triacetin (TA), and isopropyl myristate (IPM). The ternary phase diagrams designated the microemulsion region and face centered central composite design helped in determining the effects of selected variables viz. type of oil, smix ratio and water concentration on responses like drug content, globule size and viscosity of microemulsions. The CCD design exhibited that the factors have statistically significant effects (p<0.01) on the selected responses. The actual responses showed excellent agreement with the predicted values as suggested by the CCD with lower residual standard error. Similarly, the optimized values were found within the range as predicted by the model. Furthermore, other characteristics of microemulsions like pH, conductivity were investigated. For the optimized microemulsion batch, ex-vivo skin flux, skin irritation and retention studies were performed and compared with marketed 5-FU formulation. In ex vivo skin permeation studies, higher skin retention of drug and minimal flux was achieved for optimized microemulsion batch then the marketed cream. Results confirmed the actual responses to be in agreement with predicted ones with least residual standard errors. Controlled release of drug was achieved for the optimized batch with higher skin retention of 5-FU, which can further be utilized for the treatment of many dermatological disorders.

Keywords: 5-FU, central composite design, microemulsion, ternanry phase diagram

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Authors: Majid Afkhami, Maryam Ehsanpour, Reza Khoshnood, Zahra Khoshnood, Rastin Afkhami

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Marine pollution is a global environmental problem. Different human activities on land, in the water and in the air contribute to the contamination of seawater, sediments and organisms with potentially toxic substances. Contaminants can be natural substances or artificially produced compounds. After discharge into the sea, contaminants can stay in the water in dissolved form or they can be removed from the water column through sedimentation to the bottom sediments. Histopathological alterations can be used as indicators for the effects of various anthropogenic pollutants on organisms and are a reflection of the overall health of the entire population in the ecosystem. These histo pathological biomarkers are closely related to other biomarkers of stress since many pollutants have to undergo metabolic activation in order to be able to provoke cellular change in the affected organism. In order to make evaluation of the effects of oil pollution, some heavy metals bioaccumulation and explore their histopathological effects on hepatocytes of Oriental sole (Euryglossa orientalis) and Deep flounder (Psettodes erumei), fishes caught from two areas of north coast of the Persian Gulf: Bandar Abbass and Bandar Lengeh. Concentrations of Ni and V in liver of both species in two sampling regions were in following order: Bandar abbass Bandar lengeh; also between two species, these quantities were higher in P. erumei than E. orientalis in both sampling regions. Histopathology of the liver shows some cellular alterations including: degeneration, necrosis and tissue disruption, and histopathological effects were severe in P. erumei than E. orientalis. Results showed that Bandar Abbass region was more polluted than Bandar Lengeh, and because Ni and V were oil pollution indicators, and two flat fishes were benthic, they can receive considerable amount of oil pollution through their biological activities like feeding. Also higher amounts of heavy metal concentrations and major histopathological effects in E. orientalis showed strong relationship between benthic habitat of the fish and amounts of received pollutants from water and sediments, because E. orientalis is more related to the bottom than P. erumei.

Keywords: heavy metals, flatfishes, Persian Gulf, oil pollution

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Authors: S. N. T. I. Sampath, J. M. S. Jayasinghe, A. P. Attanayake, V. Karunaratne

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Diabetes mellitus is one of the major public health posers throughout the world today that incidence and associated with increasing mortality. Insufficient regulation of the blood glucose level might be serious effects for health and its necessity to identify new therapeutics that have ability to reduce hyperglycaemic condition in the human body. Even though synthetic antidiabetic drugs are more effective to control diabetes mellitus, there are considerable side effects have been reported. Thus, there is an increasing demand for searching new natural products having high antidiabetic activity with lesser side effects. The purposes of the present study were to evaluate different physical parameters and in-vitro and in-vivo antidiabetic potential of the selected combined medicinal plant extracts mixture composed of leaves of Murraya koenigii, cloves of Allium sativum, fruits of Garcinia queasita and seeds of Piper nigrum. The selected plants parts were mixed and ground together and extracted sequentially into the hexane, ethyl acetate and methanol. Solvents were evaporated and they were further dried by freeze-drying to obtain a fine powder of each extract. Various physical parameters such as moisture, total ash, acid insoluble ash and water soluble ash were evaluated using standard test procedures. In-vitro antidiabetic activity of combined plant extracts mixture was screened using enzyme assays such as α-amylase inhibition assay and α-glucosidase inhibition assay. The acute anti-hyperglycaemic activity was performed using oral glucose tolerance test for the streptozotocin induced diabetic Wistar rats to find out in-vivo antidiabetic activity of combined plant extracts mixture and it was assessed through total oral glucose tolerance curve (TAUC) values. The percentage of moisture content, total ash content, acid insoluble ash content and water soluble ash content were ranged of 7.6-17.8, 8.1-11.78, 0.019-0.134 and 6.2-9.2 respectively for the plant extracts and those values were less than standard values except the methanol extract. The hexane and ethyl acetate extracts exhibited highest α-amylase (IC50 = 25.7 ±0.6; 27.1 ±1.2 ppm) and α-glucosidase (IC50 = 22.4 ±0.1; 33.7 ±0.2 ppm) inhibitory activities than methanol extract (IC50 = 360.2 ±0.6; 179.6 ±0.9 ppm) when compared with the acarbose positive control (IC50 = 5.7 ±0.4; 17.1 ±0.6 ppm). The TAUC values for hexane, ethyl acetate, and methanol extracts and glibenclamide (positive control) treated rats were 8.01 ±0.66; 8.05 ±1.07; 8.40±0.50; 5.87 ±0.93 mmol/L.h respectively, whereas in diabetic control rats the TAUC value was 13.22 ±1.07 mmol/L.h. Administration of plant extracts treated rats significantly suppressed (p<0.05) the rise in plasma blood glucose levels compared to control rats but less significant than glibenclamide. The obtained results from in-vivo and in-vitro antidiabetic study showed that the hexane and ethyl acetate extracts of selected combined plant mixture might be considered as a potential source to isolate natural antidiabetic agents and physical parameters of hexane and ethyl acetate extracts will helpful to develop antidiabetic drug with further standardize properties.

Keywords: diabetes mellitus, in-vitro antidiabetic assays, medicinal plants, standardization

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Authors: Iván Castelló, Georgiana Stoica, Emilio Palomares, Fernando Bravo

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We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. The system proved to be a faster (minutes) method, with two times higher sensitivity than the state-of-the-art biomarkers based sensors for cystic fibrosis (CF), allowing the quantification of trypsin concentrations in a wide range (0-350 mg/L). Furthermore, as trypsin is directly related to the development of cystic fibrosis, different human genotypes, i.e. healthy homozygotic (> 80 mg/L), CF homozygotic (< 50 mg/L), and heterozygotic (> 50 mg/L), respectively, can be determined using our 2nanoSi nanospheres.

Keywords: cystic fibrosis, trypsin, quantum dots, biomarker, homozygote, heterozygote

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Authors: Gyati Shilakari Asthana, Abhay Asthana, Dharm Veer Kohli, Suresh Prasad Vyas

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Purpose: The therapeutic potential of oligonucleotide (ODN) is primarily dependent upon its safe and efficient delivery to specific cells overcoming degradation and maximizing cellular uptake in vivo. The present study is focused to design low molecular weight chitosan nanoconstructs to meet the requirements of safe and effectual delivery of ODNs. LMW-chitosan is a biodegradable, water soluble, biocompatible polymer and is useful as a non-viral vector for gene delivery due to its better stability in water. Methods: LMW chitosan ODN nanoparticles (CHODN NPs) were formulated by self-assembled method using various N/P ratios (moles ratio of amine groups of CH to phosphate moieties of ODNs; 0.5:1, 1:1, 3:1, 5:1, and 7:1) of CH to ODN. The developed CHODN NPs were evaluated with respect to gel retardation assay, particle size, zeta potential and cytotoxicity and transfection efficiency. Results: Complete complexation of CH/ODN was achieved at the charge ratio of 0.5:1 or above and CHODN NPs displayed resistance against DNase I. On increasing the N/P ratio of CH/ODN, the particle size of the NPs decreased whereas zeta potential (ZV) value increased. No significant toxicity was observed at all CH concentrations. The transfection efficiency was increased on increasing N/P ratio from 1:1 to 3:1, whereas it was decreased with further increment in N/P ratio upto 7:1. Maximum transfection of CHODN NPs with both the cell lines (Raw 267.4 cells and Hela cells) was achieved at N/P ratio of 3:1. The results suggest that transfection efficiency of CHODN NPs is dependent on N/P ratio. Conclusion: Thus the present study states that LMW chitosan nanoparticulate carriers would be acceptable choice to improve transfection efficiency in vitro as well as in vivo delivery of oligonucleotide.

Keywords: LMW-chitosan, chitosan nanoparticles, biocompatibility, cytotoxicity study, transfection efficiency, oligonucleotide

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Authors: Harukuni Tokuda, Takanari Arai, Xu FengHao, Nobutaka Suzuki

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In our continuous search for anti-tumor promoting, chemopreventive active potency from natural source material, a kind of healthy tea, Gromwell seed (Coix lachryma-jobi) ext., and including compounds Monoolein and Trilinolein have been screened using the in vitro synergistic assay indicated by inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by TPA. In assay, Gromwell seed aqueous extract and hot aqueous extract exhibited the potential inhibitory effects on EBV-EA activation without strong cytotoxicity on Raji cells. In our experimental system, the inhibitory effects of both Gromwell extracts and compounds were greater than that of beta-carotene, which is known anti-tumor promoting agent and/or chemopreventive agent. These compounds were evaluated for their in vitro inhibitory effect on EBV-EA activation induced by TPA. The percentages of the inhibition of TPA-induced EBV-EA activation for these materials were 60% and 30% at concentration 100 μg. Based on the results obtained in vitro, we studied the inhibitory effect of compounds, in an in vivo two-stage carcinogenesis test of mouse skin papilloma using DMBA as an initiator and TPA as a potential promoter. The control animals showed a 100% incidence of papilloma at 20 weeks after DMBA-TPA tumor promotion, while treatment with compounds reduced the percentage of number of tumor to 60 % after 20 weeks. Results from in vitro and in vivo studies showing chemopreventive activity against TPA promoting stage and these data support the effective potency of carcinogenic stage in clinical evaluation of integrative oncology.

Keywords: gromwell seed, medicinal plant, chemoprevention, pharmaceutical medicine

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Authors: Taraneh Estedlal

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The objective of this study was to review in-vivo and in-vitro studies to compare the effectiveness of bulk-fill and conventional resin composites with regard to marginal adaptation, polymerization shrinkage, and other mechanical properties.PubMed and Scopus databases was investigated for in-vitro studies and randomized clinical trials comparing incidence of fractures, color stability, marginal adaptation, pain and discomfort, recurrent caries, occlusion, pulpal reaction, and proper proximal contacts of restorations made with conventional and bulk resins. The failure rate of conventional and flowable bulk-fill resin composites was not significantly different to sculptable bulk-fill resin composites. The objective of this study was to review in-vivo and in-vitro studies to compare the effectiveness of bulk-fill and conventional resin composites with regard to marginal adaptation, polymerization shrinkage, and other mechanical properties. PubMed and Scopus databases was investigated for in-vitro studies and randomized clinical trials comparing one of the pearlier mentioned properties between bulk-fill and control composites. Despite differences in physical and in-vitro properties, failure rate of conventional and flowable bulk-fill resin composites was not significantly different to sculptable bulk-fill resin composites.

Keywords: polymerization shrinkage, color stability, marginal adaptation, recurrent caries, occlusion, pulpal reaction

Procedia PDF Downloads 127

Authors: Iñaki Iturria, Pasquale Russo, Montserrat Nacher-Vázquez, Giuseppe Spano, Paloma López, Miguel Angel Pardo

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Introduction: It is known that some Lactic Acid Bacteria (LAB) present an interesting probiotic effect. Probiotic bacteria stimulate host resistance to microbial pathogens and thereby aid in immune response, and modulate the host's immune responses to antigens with a potential to down-regulate hypersensitivity reactions. Therefore, probiotic therapy is valuable against intestinal infections and may be beneficial in the treatment of Inflammatory Bowel Disease (IBD). Several in vitro tests are available to evaluate the probiotic potential of a LAB strain. However, an in vivo model is required to understand the interaction between the host immune system and the bacteria. During the last few years, zebrafish (Danio rerio) has gained interest as a promising vertebrate model in this field. This organism has been extensively used to study the interaction between the host and the microbiota, as well as the host immune response under several microbial infections. In this work, we report on the use of the zebrafish model to investigate in vivo the colonizing ability and the immunomodulatory effect of probiotic LAB. Methods: Lactobacillus strains belonging to different LAB species were fluorescently tagged and used to colonize germ-free zebrafish larvae gastrointestinal tract (GIT). Some of the strains had a well-documented probiotic effect (L. acidophilus LA5); while others presented an exopolysaccharide (EPS) producing phenotype, thus allowing evaluating the influence of EPS in the colonization and immunomodulatory effect. Bacteria colonization was monitored for 72 h by direct observation in real time using fluorescent microscopy. CFU count per larva was also evaluated at different times. The immunomodulatory effect was assessed analysing the differential expression of several innate immune system genes (MyD88, NF-κB, Tlr4, Il1β and Il10) by qRT- PCR. The anti-inflammatory effect was evaluated using a chemical enterocolitis zebrafish model. The protective effect against a pathogen was also studied. To that end, a challenge test was developed using a fluorescently tagged pathogen (Vibrio anguillarum-GFP+). The progression of the infection was monitored up to 3 days using a fluorescent stereomicroscope. Mortality rates and CFU counts were also registered. Results and conclusions: Larvae exposed to EPS-producing bacteria showed a higher fluorescence and CFU count than those colonized with no-EPS phenotype LAB. In the same way, qRT-PCR results revealed an immunomodulatory effect on the host after the administration of the strains with probiotic activity. A downregulation of proinflammatory cytoquines as well as other cellular mediators of inflammation was observed. The anti-inflammatory effect was found to be particularly marked following exposure to LA% strain, as well as EPS producing strains. Furthermore, the challenge test revealed a protective effect of probiotic administration. As a matter of fact, larvae fed with probiotics showed a decrease in the mortality rate ranging from 20 to 35%. Discussion: In this work, we developed a promising model, based on the use of gnotobiotic zebrafish coupled with a bacterial fluorescent tagging in order to evaluate the probiotic potential of different LAB strains. We have successfully used this system to monitor in real time the colonization and persistence of exogenous LAB within the gut of zebrafish larvae, to evaluate their immunomodulatory effect and for in vivo competition assays. This approach could bring further insights into the complex microbial-host interactions at intestinal level.

Keywords: gnotobiotic, immune system, lactic acid bacteria, probiotics, zebrafish

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Authors: Adegoke Yinka Adebayo

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An understanding of the critical product attributes that impact on in vivo performance is key to the production of safe and effective medicines. Thus, a key driver for our research is the development of new basic science and technology underpinning the development of new pharmaceutical products. Research includes the structure and properties of drugs and excipients, biopharmaceutical characterisation, pharmaceutical processing and technology and formulation and analysis.

Keywords: drug discovery, drug development, drug delivery

Procedia PDF Downloads 461

Authors: Ramin Mehdiabadi

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Background: Breast cancer remains the most prevalent cancer diagnosis and the leading cause of cancer death among women globally, representing 11.7% of new cases and 6.9% of deaths. While the incidence and mortality of major cancers are declining in developed regions like the United States and Western Europe, underdeveloped and developing countries exhibit an increasing trend, attributed to lifestyle factors such as smoking, physical inactivity, and high-calorie diets. Objective: This study explores the intricate relationship between the mammalian transcription factor forkhead box (FoxM1) and the microRNA miR-216b-5p in various subtypes of breast cancer, aiming to deepen the understanding of their roles in tumorigenesis, metastasis, and drug resistance. Methods: Breast cancer subtypes were categorized based on key biomarkers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. These include luminal A, luminal B, HER2 enriched, triple-negative, and normal-like subtypes. We focused on analyzing the expression levels of FoxM1 and miR-216b-5p, given the known role of FoxM1 in cell proliferation and its implications in cancer pathologies such as lung, gastric, and breast cancers. Concurrently, miR-216b-5p's function as a tumor suppressor was evaluated to ascertain its regulatory effects on FoxM1. Results: Preliminary data indicate a nuanced interplay between FoxM1 and miR-216b-5p, suggesting a potential inverse relationship that varies across breast cancer subtypes. This relationship underscores the dual role of these biomarkers in modulating cancer progression and response to treatments. Conclusion: The findings advocate for the potential of miR-216b-5p to serve as a prognostic biomarker and a therapeutic target, particularly in subtypes where FoxM1 is prominently expressed. Understanding these molecular interactions provides crucial insights into the personalized treatment strategies and could lead to more effective therapeutic interventions in breast cancer management. Implications: The study highlights the importance of molecular profiling in breast cancer treatment and emphasizes the need for targeted therapeutic approaches in managing diverse cancer subtypes, particularly in varying global contexts where lifestyle factors significantly impact cancer dynamics.

Keywords: breast cancer, gene expression, FoxM1, microRNA

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Authors: Alex Kiselyov, Suehyun Cho, Darrell Harrington; Florent Cros, Olin Palmer, John Caputo, Michael Kardosh, Eran Oren, William Loudon, Michael Shpigelmacher

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Despite the most aggressive surgical and adjuvant therapeutic strategies, treatment of both pediatric and adult brainstem tumors remains problematic. Novel strategies, including targeted biologics, immunotherapy, and specialized delivery systems such as convection-enhanced delivery (CED), have been proposed. While some of these novel treatments are entering phase I trials, the field is still in need of treatment(s) that exhibits dramatically enhanced potency with optimal therapeutic ratio. Bionaut Labs has developed a modular microrobotic platform for performing localized delivery of diverse therapeutics in vivo. Our biocompatible particles (Bionauts™) are externally propelled and visualized in real-time. Bionauts™ are specifically designed to enhance the effect of radiation therapy via anatomically precise delivery of a radiosensitizing agent, as exemplified by temozolomide (TMZ) and Avastin™ to the brainstem gliomas of diverse origin. The treatment protocol is designed to furnish a better therapeutic outcome due to the localized (vs systemic) delivery of the drug to the neoplastic lesion(s) for use as a synergistic combination of radiation and radiosensitizing agent. In addition, the procedure is minimally invasive and is expected to be appropriate for both adult and pediatric patients. Current progress, including platform optimization, selection of the lead radiosensitizer as well as in vivo safety studies of the Bionauts™ in large animals, specifically the spine and the brain of porcine and ovine models, will be discussed.

Keywords: Bionaut, brainstem, glioma, local delivery, micro-robot, radiosensitizer

Procedia PDF Downloads 147

Authors: Austin Jiang, Richard M. Salmon, Nicholas W. Morrell, Wei Li

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BMP10 is highly expressed in the developing heart and plays essential roles in cardiogenesis. BMP10 deletion in mice results in embryonic lethality due to impaired cardiac development. In adults, BMP10 expression is restricted to the right atrium, though ventricular hypertrophy is accompanied by increased BMP10 expression in a rat hypertension model. However, reports of BMP10 activity in the circulation are inconclusive. In particular it is not known whether in vivo secreted BMP10 is active or whether additional factors are required to achieve its bioactivity. It has been shown that high-affinity binding of the BMP10 prodomain to the mature ligand inhibits BMP10 signaling activity in C2C12 cells, and it was proposed that prodomain-bound BMP10 (pBMP10) complex is latent. In this study, we demonstrated that the BMP10 prodomain did not inhibit BMP10 signaling activity in multiple endothelial cells, and that recombinant human pBMP10 complex, expressed in mammalian cells and purified under native conditions, was fully active. In addition, both BMP10 in human plasma and BMP10 secreted from the mouse right atrium were fully active. Finally, we confirmed that active BMP10 secreted from mouse right atrium was in the prodomain-bound form. Our data suggest that circulating BMP10 in adults is fully active and that the reported vascular quiescence function of BMP10 in vivo is due to the direct activity of pBMP10 and does not require an additional activation step. Moreover, being an active ligand, recombinant pBMP10 may have therapeutic potential as an endothelial-selective BMP ligand, in conditions characterized by loss of BMP9/10 signaling.

Keywords: bone morphogenetic protein 10 (BMP10), endothelial cell, signal transduction, transforming growth factor beta (TGF-B)

Procedia PDF Downloads 249

Authors: M. Dieb, T. Hodairi

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In the Southwest Libya area, the Palaeozoic deposits are an important petroleum system, with Silurian shale considered a hydrocarbon source rock and Cambro-Ordovician recognized as a good reservoir. The Palaeozoic petroleum system has the greatest potential for conventional and is thought to represent the significant prospect of unconventional petroleum resources in Southwest Libya. Until now, the lateral and vertical heterogeneity of the source rock was not well evaluated, and oil-source correlation is still a matter of debate. One source rock, which is considered the main source potential in Marzuq Basin, was investigated for its uranium contents using gamma-ray logs, rock-eval pyrolysis, and organic petrography for their bulk kinetic characteristics to determine the petroleum potential qualitatively and quantitatively. Thirty source rock samples and fifteen oil samples from the Tannezzuft source rock were analyzed by Rock-Eval Pyrolysis, microscopely investigation, GC, and GC-MS to detect acyclic isoprenoids and aliphatic, aromatic, and NSO biomarkers. Geochemistry tools were applied to screen source and age-significant biomarkers to high-spot genetic relationships. A grating heterogeneity exists among source rock zones from different levels of depth with varying uranium contents according to gamma-ray logs, rock-eval pyrolysis results, and kinetic features. The uranium-rich Tannezzuft Formations (Hot Shales) produce oils and oil-to-gas hydrocarbons based on their richness, kerogen type, and thermal maturity. Biomarker results such as C₂₇, C₂₈, and C₂₉ steranes concentrations and C₂₄ tetracyclic terpane/C₂₉ tricyclic terpane ratios, with sterane and hopane ratios, are considered the most promising biomarker information in differentiating within the Silurian Shale Tannezzuft Formation and in correlating with its expelled oils. The Tannezzuft Hot Shale is considered the main source rock for oil and gas accumulations in the Cambro-Ordovician reservoirs within the Marzuq Basin. Migration of the generated and expelled oil and gas from the Tannezzuft source rock to the reservoirs of the Cambro-Ordovician petroleum system was interpreted to have occurred along vertical and lateral pathways along the faults in the Palaeozoic Strata. The Upper Tannezzuft Formation (cold shale) is considered the primary seal in the Marzuq Basin.

Keywords: heterogeneity, hot shale, kerogen, Silurian, uranium

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Authors: Farhan Sohail, Gul Shahnaz Irshad Hussain, Shoaib Sarwar, Ibrahim Javed, Zajif Hussain, Akhtar Nadhman

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The present study was aimed to develop a hybrid nanocarrier (NC) system with enhanced membrane permeability, bioavailability and targeted delivery of Docetaxel (DTX) in breast cancer. Hybrid NC’s based on folic acid (FA) grafted thiolated chitosan (TCS) enveloped liposomes were prepared with DTX and evaluated in-vitro and in-vivo for their enhanced permeability and bioavailability. Physicochemical characterization of NC’s including particle size, morphology, zeta potential, FTIR, DSC, PXRD, encapsulation efficiency and drug release from NC’s was determined in vitro. Permeation enhancement and p-gp inhibition were performed through everted sac method on freshly excised rat intestine which indicated that permeation was enhanced 5 times as compared to pure DTX and the hybrid NC’s were strongly able to inhibit the p-gp activity as well. In-vitro cytotoxicity and tumor targeting was done using MDA-MB-231 cell line. The stability study of the formulations performed for 3 months showed the improved stability of FA-TCS enveloped liposomes in terms of its particles size, zeta potential and encapsulation efficiency as compared to TCS NP’s and liposomes. The pharmacokinetic study was performed in vivo using rabbits. The oral bioavailability and AUC0-96 was increased 10.07 folds with hybrid NC’s as compared to positive control. Half-life (t1/2) was increased 4 times (58.76 hrs) as compared to positive control (17.72 hrs). Conclusively, it is suggested that FA-TCS enveloped liposomes have strong potential to enhance permeability and bioavailability of hydrophobic drugs after oral administration and tumor targeting.

Keywords: docetaxel, coated liposome, permeation enhancement, oral bioavailability

Procedia PDF Downloads 378

Authors: Soroosh Torabi, Brad Berron, Ren Xu, Christine Trinkle

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Microfluidics integrated with 3D cell culture is a powerful technology to mimic cellular environment, and can be used to study cell activities such as proliferation, migration and response to drugs. This technology has gained more attention in cancer studies over the past years, and many organ-on-a-chip systems have been developed to study cancer cell behaviors in an ex-vivo tumor microenvironment. However, there are still some barriers to adoption which include low throughput, complexity in 3D cell culture integration and limitations on non-optical analysis of cells. In this study, a user-friendly microfluidic multi-well plate was developed to mimic the in vivo tumor microenvironment. The microfluidic platform feeds multiple 3D cell culture sites at the same time which enhances the throughput of the system. The platform uses hydrophobic Cassie-Baxter surfaces created by microchannels to enable convenient loading of hydrogel/cell suspensions into the device, while providing barrier free placement of the hydrogel and cells adjacent to the fluidic path. The microchannels support convective flow and diffusion of nutrients to the cells and a removable lid is used to enable further chemical and physiological analysis on the cells. Different breast cancer cell lines were cultured in the device and then monitored to characterize nutrient delivery to the cells as well as cell invasion and proliferation. In addition, the drug response of breast cancer cell lines cultured in the device was compared to the response in xenograft models to the same drugs to analyze relevance of this platform for use in future drug-response studies.

Keywords: microfluidics, multi-well 3d cell culture, tumor microenvironment, tumor-on-a-chip

Procedia PDF Downloads 238