Search results for: therapeutic horseback riding

Authors: Sergio D’Ambrosioa, Azza Dobousa, Chiara Schiraldia, Donatella Ciminib

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Probiotics are living microorganisms that give beneficial effects while consumed. Lactic acid bacteria and bifidobacteria are among the most representative strains assessed as probiotics and exploited as food supplements. Numerous studies demonstrated their potential as a therapeutic candidate for a variety of diseases (restoring gut flora, lowering cholesterol, immune response-enhancing, anti-inflammation and anti-oxidation activities). These beneficial actions are also due to biomolecules produced by probiotics, such as exopolysaccharides (EPSs), that demonstrate plenty of beneficial properties such as antimicrobial, antitumor, anti-biofilm, antiviral and immunomodulatory activities. Limosilactobacillus fermentum is a widely studied member of probiotics; however, few data are available on the development of fermentation and downstream processes for the production of viable biomasses for potential industrial applications. However, few data are available on the development of fermentation processes for the large-scale production of probiotics biomass for industrial applications and for purification processes of EPSs at an industrial scale. For this purpose, L. fermentum strain was isolated from buffalo milk and used as a test example for biotechnological process development. The strain was able to produce up to 109 CFU/mL on a (glucose-based) semi-defined medium deprived of animal-derived raw materials up to the pilot scale (150 L), demonstrating improved results compared to commonly used, although industrially not suitable, media-rich of casein and beef extract. Biomass concentration via microfiltration on hollow fibers, and subsequent spray-drying allowed to recover of about 5.7 × 1010CFU/gpowder of viable cells, indicating strain resistance to harsh processing conditions. Overall, these data demonstrate the possibility of obtaining and maintaining adequate levels of viable L. fermentum cells by using a simple approach that is potentially suitable for industrial development. A downstream EPS purification protocol based on ultrafiltration, precipitation and activated charcoal treatments showed a purity of the recovered polysaccharides of about 70-80%.

Keywords: probiotics, fermentation, exopolysaccharides (EPSs), purification

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Authors: Mrinal Gupta, Mohammad Rumman, Babita Singh Abbas Ali Mahdi, Shivani Pandey

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Introduction: Berberine (BBR), a bioactive compound isolated from Coptidis Rhizoma, possesses diverse pharmacological activities, including anti-bacterial, anti-inflammatory, antitumor, hypolipidemic, and anti-diabetic. However, its role as an anti-diabetic agent in animal models of dexamethasone (Dex)-induced diabetes remains unknown. Studies have shown that natural compounds, including aloe, caper, cinnamon, cocoa, green and black tea, and turmeric, can be used for treating Type 2 diabetes mellitus (DM). Compared to conventional drugs, natural compounds have fewer side effects and are easily available. Herein, we studied the anti-diabetic effects of BBR in a mice model of Dex-induced diabetes. Methods: HepG2 cell line was used for glucose release and glycogen synthesis studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. For animal studies, mice were treated with Dex (2 mg/kg, i.m.) for 30 days and the effect of BBR at the doses 100, 200, and 500 mg/kg (p.o.) was analyzed. Glucose, insulin, and pyruvate tests were performed to evaluate the development of the diabetic model. An echo MRI was performed to assess the fat mass. Further, to elucidate the mechanism of action of BBR, mRNA expression of genes regulating gluconeogenesis, glucose uptake, and glycolysis were analyzed. Results: In vitro BBR had no impact on cell viability up to a concentration of 50μM. Moreover, BBR suppressed the hepatic glucose release and improved glucose tolerance in HepG2 cells. In vivo, BBR improved glucose homeostasis in diabetic mice, as evidenced by enhanced glucose clearance, increased glycolysis, elevated glucose uptake, and decreased gluconeogenesis. Further, Dex treatment increased the total fat mass in mice, which was ameliorated by BBR treatment. Conclusion: BBR improves glucose tolerance by increasing glucose clearance, inhibiting hepatic glucose release, and decreasing obesity. Thus, BBR may become a potential therapeutic agent for treating glucocorticoid-induced diabetes and obesity in the future.

Keywords: glucocorticoid, hyperglycemia, berberine, HepG2 cells, insulin resistance, glucose

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Authors: Michela Terlizzi, Chiara Colarusso, Aldo Pinto, Rosalinda Sorrentino

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Sphingosine-1-phosphate (S1P) is a membrane-derived bioactive phospholipid exerting a multitude of effects on respiratory cell physiology and pathology through five S1P receptors (S1PR1-5). Higher levels of S1P have been registered in a broad range of respiratory diseases, including inflammatory disorders and cancer, although its exact role is still elusive. Based on our previous study in which we found that S1P/S1PR3 is involved in an inflammatory pattern via the activation of Toll-like Receptor 9 (TLR9), highly expressed on lung cancer cells, the main goal of the current study was to better understand the involvement of S1P/S1PR3 pathway/signaling during lung carcinogenesis, taking advantage of a mouse model of first-hand smoke exposure and of carcinogen-induced lung cancer. We used human samples of Non-Small Cell Lung Cancer (NSCLC), a mouse model of first-hand smoking, and of Benzo(a)pyrene (BaP)-induced tumor-bearing mice and A549 lung adenocarcinoma cells. We found that the intranuclear, but not the membrane, localization of S1PR3 was associated to the proliferation of lung adenocarcinoma cells, the mechanism that was correlated to human and mouse samples of smoke-exposure and carcinogen-induced lung cancer, which were characterized by higher utilization of S1P. Indeed, the inhibition of the membrane S1PR3 did not alter tumor cell proliferation after TLR9 activation. Instead, according to the nuclear localization of sphingosine kinase (SPHK) II, the enzyme responsible for the catalysis of the S1P last step synthesis, the inhibition of the kinase completely blocked the endogenous S1P-induced tumor cell proliferation. These results prove that the endogenous TLR9-induced S1P can on one side favor pro-inflammatory mechanisms in the tumor microenvironment via the activation of cell surface receptors, but on the other tumor progression via the nuclear S1PR3/SPHK II axis, highlighting a novel molecular mechanism that identifies S1P as one of the crucial mediators for lung carcinogenesis-associated inflammatory processes and that could provide differential therapeutic approaches especially in non-responsive lung cancer patients.

Keywords: sphingosine-1-phosphate (S1P), S1P Receptor 3 (S1PR3), smoking-mice, lung inflammation, lung cancer

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Authors: Paulina Zavistanaviciute, Vita Krungleviciute, Elena Bartkiene

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Lactic acid bacteria (LAB) are microbial supplements that increase the nutritional, therapeutic, and safety value of food and feed. Often LAB strains are incubated in an expensive commercially available de Man-Rogosa-Sharpe (MRS) medium; the cultures are centrifuged, and the cells are washing with sterile water. Potato juice and apple juice industry bio-products are industrial wastes which may constitute a source of digestible nutrients for microorganisms. Due to their low cost and good chemical composition, potato juice and apple juice production bio- products could have a potential application in LAB encapsulation. In this study, pure LAB (P. acidilactici and P. pentosaceus) were multiplied in a crushed potato juice and apple juice industry bio-products medium. Before using, bio-products were sterilized and filtered. No additives were added to mass, except apple juice industry bioproducts were diluted with sterile water (1/5; v/v). The tap of sterilised mass, and LAB cell suspension (5 mL), containing of 8.9 log10 colony-forming units (cfu) per mL of the P. acidilactici and P. pentosaceus was used to multiply the LAB for 72 h. The final colony number in the potato juice and apple juice bio- products substrate was on average 9.60 log10 cfu/g. In order to stabilize the LAB, several methods of dehydration have been tested: lyophilisation (MilrockKieffer Lane, Kingston, USA) and dehydration in spray drying system (SD-06, Keison, Great Britain). Into the spray drying system multiplied LAB in a crushed potato juice and apple juice bio-products medium was injected in peristaltic way (inlet temperature +60 °C, inlet air temperature +150° C, outgoing air temperature +80 °C, air flow 200 m3/h). After lyophilisation (-48 °C) and spray drying (+150 °C) the viable cell concentration in the fermented potato juice powder was 9.18 ± 0.09 log10 cfu/g and 9.04 ± 0.07 log10 cfu/g, respectively, and in apple mass powder 8.03 ± 0.04 log10 cfu/g and 7.03 ± 0.03 log10 cfu/g, respectively. Results indicated that during the storage (after 12 months) at room temperature (22 +/- 2 ºC) LAB count in dehydrated products was 5.18 log10 cfu/g and 7.00 log10 cfu/g (in spray dried and lyophilized potato juice powder, respectively), and 3.05 log10 cfu/g and 4.10 log10 cfu/g (in spray dried and lyophilized apple juice industry bio-products powder, respectively). According to obtained results, potato juice could be used as alternative substrate for P. acidilactici and P. pentosaceus cultivation, and by drying received powders can be used in food/feed industry as the LAB starters. Therefore, apple juice industry by- products before spray drying and lyophilisation should be modified (i. e. by using different starches) in order to improve its encapsulation.

Keywords: bio-products, encapsulation, lactic acid bacteria, sustainability

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Authors: Li Chun Zhao, Zhi Chao Hu, Xi Qiang Liu, Man Lai Lee, Chak Shing Yeung, Man Fei Xu, Yuen Yee Kwan, Alan H. M. Ho, Nickie W. K. Chan, Bin Deng, Zhong Zhen Zhao, Min Xu

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Background: Chuangxiong Rhizoma (Chuangxion, CX) is one of the most frequently used herbs in Chinese medicine because of its wide therapeutic effects such as vasorelaxation and anti-inflammation. Aim: The purposes of this study are (1) to perform non-targeted / targeted analyses of CX methanol extract and water extract, and compare the present data with previously LC-MS or GC-MS fingerprints; (2) to examine the difference between CX methanol extract and water extract for preliminarily evaluating whether current compound markers of methanol extract from crude CX materials could be suitable for quality control of CX water extract. Method: CX methanol extract was prepared according to the Hong Kong Chinese Materia Medica Standards. DG water extract was prepared by boiling with pure water for three times (one hour each). UHPLC-Q-TOF-MS/MS fingerprint analysis was performed by C18 column (1.7 µm, 2.1 × 100 mm) with Agilent 1290 Infinity system. Experimental data were analyzed by Agilent MassHunter Software. A database was established based on 13 published LC-MS and GC-MS CX fingerprint analyses. Total 18 targeted compounds in database were selected as markers to compare present data with previous data, and these markers also used to compare CX methanol extract and water extract. Result: (1) Non-targeted analysis indicated that there were 133 compounds identified in CX methanol extract, while 325 compounds in CX water extract that was more than double of CX methanol extract. (2) Targeted analysis further indicated that 9 in 18 targeted compounds were identified in CX methanol extract, while 12 in 18 targeted compounds in CX water extract that showed a lower lose-rate of water extract when compared with methanol extract. (3) By comparing CX methanol extract and water extract, Senkyunolide A (+1578%), Ferulic acid (+529%) and Senkyunolide H (+169%) were significantly higher in water extract when compared with methanol extract. (4) Other bioactive compounds such as Tetramethylpyrazine were only found in CX water extract. Conclusion: Many new compounds in both CX methanol and water extracts were found by using UHPLC Q-TOF MS/MS analysis when compared with previous published reports. A new standard reference including non-targeted compound profiling and targeted markers functioned especially for quality control of CX water extract (herbal decoction) should be established in future. (This project was supported by Hong Kong Baptist University (FRG2/14-15/109) & Natural Science Foundation of Guangdong Province (2014A030313414)).

Keywords: Chuanxiong rhizoma, fingerprint analysis, targeted analysis, quality control

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Authors: Shaimaa Eltanani, Thangal Yumnamcha, Ahmed S. Ibrahim

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Purpose: Mitochondria dysfunction is central to breaking the barrier integrity of retinal endothelial cells (RECs) in various blinding eye diseases such as diabetic retinopathy and retinopathy of prematurity. Therefore, we aimed to dissect the role of different mitochondrial components, specifically, those of oxidative phosphorylation (OxPhos), in maintaining the barrier function of RECs. Methods: Electric cell-substrate impedance sensing (ECIS) technology was used to assess in real-time the role of different mitochondrial components in the total impedance (Z) of human RECs (HRECs) and its components; the capacitance (C) and the total resistance (R). HRECs were treated with specific mitochondrial inhibitors that target different steps in OxPhos: Rotenone for complex I; Oligomycin for ATP synthase; and FCCP for uncoupling OxPhos. Furthermore, data were modeled to investigate the effects of these inhibitors on the three parameters that govern the total resistance of cells: cell-cell interactions (Rb), cell-matrix interactions (α), and cell membrane permeability (Cm). Results: Rotenone (1 µM) produced the greatest reduction in the Z, followed by FCCP (1 µM), whereas no reduction in the Z was observed after the treatment with Oligomycin (1 µM). Following this further, we deconvoluted the effect of these inhibitors on Rb, α, and Cm. Firstly, rotenone (1 µM) completely abolished the resistance contribution of Rb, as the Rb became zero immediately after the treatment. Secondly, FCCP (1 µM) eliminated the resistance contribution of Rb only after 2.5 hours and increased Cm without considerable effect on α. Lastly, Oligomycin had the lowest impact among these inhibitors on Rb, which became similar to the control group at the end of the experiment without noticeable effects on Cm or α. Conclusion: These results demonstrate differential roles for complex I, complex V, and coupling of OxPhos in maintaining the barrier functionality of HRECs, in which complex I being the most important component in regulating the barrier functionality and the spreading behavior of HRECs. Such differences can be used in investigating gene expression as well as for screening selective agents that improve the functionality of complex I to be used in the therapeutic approach for treating REC-related retinal diseases.

Keywords: human retinal endothelial cells (hrecs), rotenone, oligomycin, fccp, oxidative phosphorylation, oxphos, capacitance, impedance, ecis modeling, rb resistance, α resistance, and barrier integrity

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Authors: Deeba N. Baig, Ateeqa Ijaz, Saloome Rafiq

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Camel is a religious and culturally significant animal in Asian and African regions. In Pakistan Dromedary and Bactrian are common camel breeds. Other than the transportation use, it is a pivotal source of milk and meat. The quality of its milk and meat is predominantly dependent on the geographical location and variety of vegetation available for the diet. Camel milk (CM) is highly nutritious because of its reduced cholesterol and sugar contents along with enhanced minerals and vitamins level. The absence of beta-lactoglobulin (like human milk), makes CM a safer alternative for infants and children having Cow Milk Allergy (CMA). In addition to this, it has a unique probiotic profile both in raw and fermented form. Number of Lactic acid bacteria (LAB) including lactococcus, lactobacillus, enterococcus, streptococcus, weissella, pediococcus and many other bacteria have been detected. From these LAB Lactobacilli, Bifidobacterium and Enterococcus are widely used commercially for fermentation purpose. CM has high therapeutic value as its effectiveness is known against various ailments like fever, arthritis, asthma, gastritis, hepatitis, Jaundice, constipation, postpartum care of women, anti-venom, dropsy etc. It also has anti-diabetic, anti-microbial, antitumor potential along with its robust efficacy in the treatment of auto-immune disorders. Recently, the role of CM has been explored in brain-gut axis for the therapeutics of neurodevelopmental disorders. In this connection, a lot of grey area was available to explore the probiotics and therapeutics latent in the CM available in Pakistan. Thus, current study was designed to explore the predominant probiotic flora and antimicrobial potential of CM from different local breeds of Pakistan. The probiotics have been identified through biochemical, physiological and ribo-typing methods. In addition to this, bacteriocins (antimicrobial-agents) were screened through PCR-based approach. Results of this study revealed that CM from different breeds of camel depicted a number of similar probiotic candidates along with the range of limited variability. However, the nucleotide sequence analysis of selected anti-listerial bacteriocins exposed least variability. As a conclusion, the CM has sufficient probiotic availability and significant anti-microbial potential.

Keywords: bacteriocins, camel milk, probiotics potential, therapeutics

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Authors: Ledi Neçaj

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Introduction: Cardio-respiratory rehabilitation is the set of coordinated interventions needed to provide the best physical, psychological, and social conditions so that patients with chronic or post-acute cardiopulmonary disease, with their efforts, maintain or resume optimal functioning in society through improved health behaviors. Purpose: To study the effectiveness of the application of Cardio-Respiratory Rehabilitation in the typology of patients with chronic or post-acute cardiomyopathy and chronic respiratory diseases in order to facilitate their therapeutic use and to improve the overall quality of life. Material and Method: This is a prospective study including patients with COPD and cardiac disease who were included in the rehabilitation program during the period January 2019 - November 2021. The study was conducted at the University Hospital Center "Mother Teresa" in Tirana, University Hospital "SHEFQET NDROQI", AMERICAN Hospital, HYGEA Hospital, and "Our Lady of Good Counsel, Tirana". An individual chart was used to collect sociodemographic, physical, clinical, and functional examinations for each patient. Results: The study included 253 patients, with a mean age of 62.1 (± 7.9) years, ranging from 48 to 82 years. (67.6%) of the patients were males, and (32.4%) female. Male patients predominated in all age groups, with a statistically significant difference with females (p<0.01). The most common cardiac pathologies are coronary artery bypass (24%), cerebral stroke (9%), myocardial infarction (17%), Stent placement (8%) (p<0.01). Correlation matrix of risk factors found a significant correlation of alcohol consumption with diabetes, smoking, dyslipidemia, sedentary life, obesity, AVC, and hypertension. Functional capacity estimated by change in metabolic equivalents (MET) improved by 46% from 4. ±2.2 to 7.2± .8 METs (p<0.01). Duration of exercise after rehabilitation was increased by 21% compared to baseline (p<0.01). The mean score of all three subscales of the questionnaire: symptoms (p=0.03), activity (p<0.01), and impact (p<0.01) after rehabilitation, was lower compared to pre-rehabilitation. Conclusions: The rehabilitation program has impacted on improving the quality of life, reducing symptoms, reducing the impact of negative factors on daily life, and reducing dyspnea during daily activities.

Keywords: cardio-respiratory rehabilitation, physical exercise, quality of life, diseases

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Authors: Deepthy Ann Joy, N. Sreedevi

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Hearing impairment (HI) at an early age, identified before the onset of language development can reduce the negative effect on speech and language development of children. Early rehabilitation is very important in the improvement of speech production in children with HI. Other than conventional hearing aids, Cochlear Implants are being used in the rehabilitation of children with HI. However, delay in acquisition of speech and language milestones persist in children with Cochlear Implant (CI). Delay in speech milestones are reflected through speech sound errors. These errors reflect the temporal and spectral characteristics of speech. Hence, acoustical analysis of the speech sounds will provide a better representation of speech production skills in children with CI. The present study aimed at investigating the acoustic characteristics of vowels in Malayalam speaking children with a cochlear implant. The participants of the study consisted of 20 Malayalam speaking children in the age range of four and seven years. The experimental group consisted of 10 children with CI, and the control group consisted of 10 typically developing children. Acoustic analysis was carried out for 5 short (/a/, /i/, /u/, /e/, /o/) and 5 long vowels (/a:/, /i:/, /u:/, /e:/, /o:/) in word-initial position. The responses were recorded and analyzed for acoustic parameters such as Vowel duration, Ratio of the duration of a short and long vowel, Formant frequencies (F₁ and F₂) and Formant Centralization Ratio (FCR) computed using the formula (F₂u+F₂a+F₁i+F₁u)/(F₂i+F₁a). Findings of the present study indicated that the values for vowel duration were higher in experimental group compared to the control group for all the vowels except for /u/. Ratio of duration of short and long vowel was also found to be higher in experimental group compared to control group except for /i/. Further F₁ for all vowels was found to be higher in experimental group with variability noticed in F₂ values. FCR was found be higher in experimental group, indicating vowel centralization. Further, the results of independent t-test revealed no significant difference across the parameters in both the groups. It was found that the spectral and temporal measures in children with CI moved towards normal range. The result emphasizes the significance of early rehabilitation in children with hearing impairment. The role of rehabilitation related aspects are also discussed in detail which can be clinically incorporated for the betterment of speech therapeutic services in children with CI.

Keywords: acoustics, cochlear implant, Malayalam, vowels

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Authors: Ayesha Waqar Khan, Mariam Altaf, Jamil Ahmad, Shaheen Shahzad

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Kidney fibrosis is an anticipated outcome of possibly all types of progressive chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) signaling pathway is responsible for production of matrix-producing fibroblasts and myofibroblasts in diseased kidney. In this study, a discrete model of TGF-beta (transforming growth factor) and CTGF (connective tissue growth factor) was constructed using Rene Thomas formalism to investigate renal fibrosis turn over. The kinetic logic proposed by Rene Thomas is a renowned approach for modeling of Biological Regulatory Networks (BRNs). This modeling approach uses a set of constraints which represents the dynamics of the BRN thus analyzing the pathway and predicting critical trajectories that lead to a normal or diseased state. The molecular connection between TGF-beta, Smad 2/3 (transcription factor) phosphorylation and CTGF is modeled using GenoTech. The order of BRN is CTGF, TGF-B, and SMAD3 respectively. The predicted cycle depicts activation of TGF-B (TGF-β) via cleavage of its own pro-domain (0,1,0) and presentation to TGFR-II receptor phosphorylating SMAD3 (Smad2/3) in the state (0,1,1). Later TGF-B is turned off (0,0,1) thereby activating SMAD3 that further stimulates the expression of CTGF in the state (1,0,1) and itself turns off in (1,0,0). Elevated CTGF expression reactivates TGF-B (1,1,0) and the cycle continues. The predicted model has generated one cycle and two steady states. Cyclic behavior in this study represents the diseased state in which all three proteins contribute to renal fibrosis. The proposed model is in accordance with the experimental findings of the existing diseased state. Extended cycle results in enhanced CTGF expression through Smad2/3 and Smad4 translocation in the nucleus. The results suggest that the system converges towards organ fibrogenesis if CTGF remains constructively active along with Smad2/3 and Smad 4 that plays an important role in kidney fibrosis. Therefore, modeling regulatory pathways of kidney fibrosis will escort to the progress of therapeutic tools and real-world useful applications such as predictive and preventive medicine.

Keywords: CTGF, renal fibrosis signaling pathway, system biology, qualitative modeling

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Authors: Sophio Kobauri, David Tugushi, Vladimir P. Torchilin, Ramaz Katsarava

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Hydrophobic / hydrophilically modified functional polymers are of high interest in modern biomedicine due to their ability to solubilize water-insoluble / poorly soluble (hydrophobic) drugs. Among the many approaches that are being developed in this direction, one of the most effective methods is the use of polymeric micelles (PMs) (micelles formed by amphiphilic block-copolymers) for solubilization of hydrophobic biologicals. For therapeutic purposes, PMs are required to be stable and biodegradable, although quite a few amphiphilic block-copolymers are described capable of forming stable micelles with good solubilization properties. For obtaining micelle-forming block-copolymers, polyethylene glycol (PEG) derivatives are desirable to use as hydrophilic shell because it represents the most popular biocompatible hydrophilic block and various hydrophobic blocks (polymers) can be attached to it. Although the construction of the hydrophobic core, due to the complex requirements and micelles structure development, is the very actual and the main problem for nanobioengineers. Considering the above, our research goal was obtaining biodegradable micelles for the solubilization of hydrophobic drugs and biologicals. For this purpose, we used biodegradable polymers– pseudo-proteins (PPs)(synthesized with naturally occurring amino acids and other non-toxic building blocks, such as fatty diols and dicarboxylic acids) as hydrophobic core since these polymers showed reasonable biodegradation rates and excellent biocompatibility. In the present study, we used the hydrophobic amino acid – L-phenylalanine (MW 4000-8000Da) instead of L-leucine. Amino-PEG (MW 2000Da) was used as hydrophilic fragments for constructing the suitable micelles. The molecular weight of PP (the hydrophobic core of micelle) was regulated by variation of used monomers ratios. Micelles were obtained by dissolving of synthesized amphiphilic polymer in water. The micelle-forming property was tested using dynamic light scattering (Malvern zetasizer NanoZSZEN3600). The study showed that obtaining amphiphilic block-copolymer form stable neutral micelles 100 ± 7 nm in size at 10mg/mL concentration, which is considered as an optimal range for pharmaceutical micelles. The obtained preliminary data allow us to conclude that the obtained micelles are suitable for the delivery of poorly water-soluble drugs and biologicals.

Keywords: amino acid – L-phenylalanine, pseudo-proteins, amphiphilic block-copolymers, biodegradable micelles

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Authors: Nigatu Tadesse, Ying Liu, Juan Li, Hong Ming Liu

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Gastric carcinogenesis is a lengthy process of histopathological transition from normal to atrophic gastritis (AG) to intestinal metaplasia (GIM), dysplasia toward gastric cancer (GC). The stage of GIM identified as precancerous lesions with resistance to H-pylori eradication and recurrence after endoscopic surgical resection therapies. GIM divided in to two morphologically distinct phenotypes such as complete GIM bearing intestinal type morphology whereas the incomplete type has colonic type morphology. The incomplete type GIM considered to be the greatest risk factor for the development of GC. Studies indicated the expression of the caudal type homeobox 2 (CDX2) gene is responsible for the development of complete GIM but its progressive downregulation from incomplete metaplasia toward advanced GC identified as the risk for IM progression and neoplastic transformation. The downregulation of CDX2 gene have promoted cell growth and proliferation in gastric and colon cancers and ascribed in chemo-treatment inefficacies. CDX2 downregulated through promoter region hypermethylation in which the methylation frequency positively correlated with the dietary history of the patients, suggesting the role of diet as methyl carbon donor sources such as methionine. However, the metabolism of exogenous methionine is yet unclear. Targeting exogenous methionine metabolism has become a promising approach to limits tumor cell growth, proliferation and progression and increase treatment outcome. This review article discusses molecular alterations that could shed light on the potential of exogenous methionine metabolisms, such as gut microbiota alteration as sources of methionine to host cells, metabolic pathway signaling via PI3K/AKt/mTORC1-c-MYC to rewire exogenous methionine and signature of increased gene methylation index, cell growth and proliferation in GIM, with insights to new treatment avenue via targeting methionine metabolism, and the need for future integrated studies on molecular alterations and metabolomics to uncover altered methionine metabolism and characterization of CDX2 methylation in gastric intestinal metaplasia for potential therapeutic exploitation.

Keywords: altered methionine metabolism, Intestinal metaplesia, CDX2 gene, gastric cancer

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Authors: J. Wozniak-Holecka, T. Holecki, P. Romaniuk

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Spa facilities are being perceived as the ways of healing treatment in Poland and are guaranteed within the public financing. The universal health insurance (National Health Fund, NFZ), and the disability prevention programme held by Social Insurance Institution (ZUS) are the main sources of financing spa facilities. The dominant public payer of spa services is the NFZ. The Social Insurance Institution covers the cost of health treatment realized in spa facilities as medical rehabilitation, in the field of disability prevention. Health services delivered in the spa resorts are characterized by complexity, and the combination of various methods, typical for health prevention, education, balneotherapy, and physiotherapy. Healing with natural methods, believed to enhance the therapeutic effect, is also involved in health spa treatment. Regardless of the type of facility, each form of spa treatment includes health promotion, health education, prevention at all levels, including rehabilitation. The aim of the study was to determine the optimal organization of health education process. Its efficiency strongly depends on the type of service provider and the funding institution (NFZ vs ZUS). It results from the use of different measures of the effectiveness, the quality and the evaluation of the process being assessed by funding institutions. The methods of the study include a comparative and descriptive quantitative and qualitative analysis. In the empirical part, a questionnaire had been developed. It was then distributed among spa personnel, responsible directly for the health promotion, and among patients who are beneficiaries of health services in spa centers. The quantitative part of the study was based on interviews carried with the use of the online survey (CAWI: Computer-Assisted Web Interview), telephone survey (CATI: Computer-Assisted Telephone Interview) and a conventional questionnaire (PAPI: Paper over Pencil Interview). As a result of the conducted research, it was found that the effectiveness of health education activities in spa resort facilities in Poland is higher when the services are organized using structured tools for managerial control. This applies to formalized procedures implemented by one of the dominant payers covering costs of services (ZUS) and involves the application of health education as one of the mandatory elements of treatment, subjected to the process of control during the course of spa therapy and evaluation after it is completed.

Keywords: effectiveness, health education, public health system, spa treatment

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Authors: Shouta Sora, Shizuki Kuriu, Radhika Mishra, Ariunbuyan Sukhbaatar, Maya Sakamoto, Shiro Mori, Tetsuya Kodama

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Lymph node (LN) metastasis accounts for 20 - 30 % of all deaths in patients with head and neck cancer. Therefore, the control of metastatic lymph nodes (MLNs) is necessary to improve the life prognosis of patients with cancer. In a classical metastatic theory, tumor cells are thought to metastasize hematogenously through a bead-like network of lymph nodes. Recently, a lymph node-mediated hematogenous metastasis theory has been proposed, in which sentinel LNs are regarded as a source of distant metastasis. Therefore, the treatment of MLNs at the early stage is essential to prevent distant metastasis. Radiation therapy is one of the primary therapeutic modalities in cancer treatment. In addition, total body irradiation (TBI) has been reported to act as activation of natural killer cells and increase of infiltration of CD4+ T-cells to tumor tissues. However, the treatment effect of TBI for MLNs remains unclear. This study evaluated the possibilities of low-dose total body irradiation (L-TBI) and middle-dose total body irradiation (M-TBI) for the treatment of MLNs. Mouse breast cancer FM3A-Luc cells were injected into subiliac lymph node (SiLN) of MXH10/Mo/LPR mice to induce the metastasis to the proper axillary lymph node (PALN) and lung. Mice were irradiated for the whole body on 4 days after tumor injection. The L-TBI and M-TBI were defined as irradiations to the whole body at 0.2 Gy and 1.0 Gy, respectively. Tumor growth was evaluated by in vivo bioluminescence imaging system. In the non-irradiated group, tumor activities on SiLN and PALN significantly increased over time, and the metastasis to the lung from LNs was confirmed 28 days after tumor injection. The L-TBI led to a tumor growth delay in PALN but did not control tumor growth in SiLN and metastasis to the lung. In contrast, it was found that the M-TBI significantly delayed the tumor growth of both SiLN and PALN and controlled the distant metastasis to the lung compared with non-irradiated and L-TBI groups. These results suggest that the M-TBI is an effective treatment method for MLNs in the early stage and distant metastasis from lymph nodes via blood vessels connected with LNs.

Keywords: metastatic lymph node, lung metastasis, radiation therapy, total body irradiation, lymphatic system

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Authors: S. D. Kadir

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Background: Antibiotics have always been at the centrum of the revolution of modern microbiology. Micro-organisms and its pathogenicity, resistant organisms, inappropriate or over usage of various types of antibiotic agents are fuelled multidrug-resistant pathogenic organisms. Our present time review report mainly focuses on the therapeutic condition of antibiotic resistance and the possible roots behind the development of antibiotic resistance in Bangladesh in 2019. Methodology: The systemic review has progressed through a series of research analyses on various manuscripts published on Google Scholar, PubMed, Research Gate, and collected relevant information from established popular healthcare and diagnostic center and its subdivisions all over Bangladesh. Our research analysis on the possible assurance of antibiotic resistance been ensured by the selective medical reports and on random assay on the extent of individual antibiotic in 2019. Results: 5 research articles, 50 medical report summary, and around 5 patients have been interviewed while going through the estimation process. We have prioritized research articles where the research analysis been performed by the appropriate use of the Kirby-Bauer method. Kirby-Bauer technique is preferred as it provides greater efficiency, ensures lower performance expenditure, and supplies greater convenience and simplification in the application. In most of the reviews, clinical and laboratory standards institute guidelines were strictly followed. Most of our reports indicate significant resistance shown by the Beta-lactam drugs. Specifically by the derivatives of Penicillin's, Cephalosporin's (rare use of the first generation Cephalosporin and overuse of the second and third generation of Cephalosporin and misuse of the fourth generation of Cephalosporin), which are responsible for almost 67 percent of the bacterial resistance. Moreover, approximately 20 percent of the resistance was due to the fact of drug pumping from the bacterial cell by tetracycline and sulphonamides and their derivatives. Conclusion: 90 percent of the approximate antibiotic resistance is due to the usage of relative and true broad-spectrum antibiotics. The environment has been created by the following circumstances where; the excessive usage of broad-spectrum antibiotics had led to a condition where the disruption of native bacteria and a series of anti-microbial resistance causing a disturbance of the surrounding environments in medium, leading to a state of super-infection.

Keywords: antibiotics, antibiotic resistance, Kirby Bauer method, microbiology

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Authors: Rabah Iratni, Husain El Hasasna, Khawlah Athamneh, Halima Al Sameri, Nehla Benhalilou, Asma Al Rashedi

Abstract:

Background: Cancer therapies have witnessed great advances in the recent past, however, cancer continues to be a leading cause of death, with colorectal cancer being the fourth cause of cancer-related deaths. Colorectal cancer affects both sexes equally with poor survival rate once it metastasizes. Phytochemicals, which are plant derived compounds, have been on a steady rise as anti-cancer drugs due to the accumulation of evidences that support their potential. Here, we investigated the anticancer effect of Rhus coriaria on colon cancer cells. Material and Method: Human colon cancer HT-29 cell line was used. Protein expression and protein phosphorylation were examined using Western blotting. Transcription activity was measure using Quantitative RT-PCR. Human tumoral clonogenic assay was used to assess cell survival. Senescence was assessed by the senescence-associated beta-galactosidase assay. Results: Rhus coriaria extract (RCE) was found to significantly inhibit the viability and colony growth of human HT-29 colon cancer cells. RCE induced senescence and cell cycle arrest at G1 phase. These changes were concomitant with upregulation of p21, p16, downregulation of cyclin D1, p27, c-myc and expression of Senescence-associated-β-Galactosidase activity. Moreover, RCE induced non-canonical beclin-1independent autophagy and subsequent apoptotic cell death through activation of activation caspase 8 and caspase 7. The blocking of autophagy by 3-methyladenine (3-MA) or chloroquine (CQ) reduced RCE-induced cell death. Further, RCE induced DNA damage, reduced mutant p53 protein level and downregulated phospho-AKT and phospho-mTOR, events that preceded autophagy. Mechanistically, we found that RCE inhibited the AKT and mTOR pathway, a regulator of autophagy, by promoting the proteasome-dependent degradation of both AKT and mTOR proteins. Conclusion: Our findings provide strong evidence that Rhus coriaria possesses strong anti-colon cancer activity through induction of senescence and autophagic cell death, making it a promising alternative or adjunct therapeutic candidate against colon cancer.

Keywords: autophagy, proteasome degradation, senescence, mTOR, apoptosis, Beclin-1

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Authors: Shujun Xie, Shirong Zhang, Shenglin Ma

Abstract:

Background: Chronic inflammation might lead to many malignancies, and inadequate resolution could play a crucial role in tumor invasion, progression, and metastases. A randomised, double-blind, placebo-controlled trial shows that IL-1β inhibition with canakinumab could reduce incident lung cancer and lung cancer mortality in patients with atherosclerosis. The process and secretion of proinflammatory cytokine IL-1β are controlled by the inflammasome. Here we showed the correlation of the innate immune system and afatinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) in non-small cell lung cancer. Methods: Murine Bone marrow derived macrophages (BMDMs), peritoneal macrophages (PMs) and THP-1 were used to check the effect of afatinib on the activation of NLRP3 inflammasome. The assembly of NLRP3 inflammasome was check by co-immunoprecipitation of NLRP3 and apoptosis-associated speck-like protein containing CARD (ASC), disuccinimidyl suberate (DSS)-cross link of ASC. Lipopolysaccharide (LPS)-induced sepsis and Alum-induced peritonitis were conducted to confirm that afatinib could inhibit the activation of NLRP3 in vivo. Peripheral blood mononuclear cells (PBMCs) from non-small cell lung cancer (NSCLC) patients before or after taking afatinib were used to check that afatinib inhibits inflammation in NSCLC therapy. Results: Our data showed that afatinib could inhibit the secretion of IL-1β in a dose-dependent manner in macrophage. Moreover, afatinib could inhibit the maturation of IL-1β and caspase-1 without affecting the precursors of IL-1β and caspase-1. Next, we found that afatinib could block the assembly of NLRP3 inflammasome and the ASC speck by blocking the interaction of the sensor protein NLRP3 and the adaptor protein ASC. We also found that afatinib was able to alleviate the LPS-induced sepsis in vivo. Conclusion: Our study found that afatinib could inhibit the activation of NLRP3 inflammasome in macrophage, providing new evidence that afatinib could target the innate immune system to control chronic inflammation. These investigations will provide significant experimental evidence in afatinib as therapeutic drug for non-small cell lung cancer or other tumors and NLRP3-related diseases and will explore new targets for afatinib.

Keywords: inflammasome, afatinib, inflammation, tyrosine kinase inhibitor

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Authors: Reshu Saxena, R. K. Tripathi

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HIV-1 transmission and spread involves significant host-virus interaction. Potential targets for prevention of HIV-1 lies at the site of mucosal barriers. Thus a better understanding of how HIV-1 infects target cells at such sites and lead their invasion is required, with prime focus on the host determinants regulating HIV-1 spread. HIV-1 Nef is important for viral infectivity and pathogenicity. It promotes HIV-1 replication, facilitating immune evasion by interacting with various host factors and altering cellular pathways via multiple protein-protein interactions. In this study nef was sequenced from HIV-1 patients, and showed specific mutations revealing sequence variability in nef. To explore the difference in Nef functionality based on sequence variability we have studied the effects of HIV-1 Nef in human SupT1 T cell line and (THP-1) monocyte-macrophage cell lines through proteomics approach. 2D-Gel Electrophoresis in control and Nef-transfected SupT1 cells demonstrated several differentially expressed proteins with significant modulation of alpha-enolase. Through further studies, effects of Nef on alpha-enolase regulation were found to be cell lineage-specific, being stimulatory in macrophages/monocytes, inhibitory in T cells and without effect in HEK-293 cells. Cell migration and invasion studies were employed to determine biological function affected by Nef mediated regulation of alpha-enolase. Cell invasion was enhanced in THP-1 cells but was inhibited in SupT1 cells by wildtype nef. In addition, the modulation of enolase and cell invasion remained unaffected by a unique nef variant. These results indicated that regulation of alpha-enolase expression and invasive property of host cells by Nef is sequence specific, suggesting involvement of a particular motif of Nef. To precisely determine this site, we designed a heptapeptide including the suggested alpha-enolase regulating sequence of nef and a nef mutant with deletion of this site. Macrophages/monocytes being the major cells affected by HIV-1 at mucosal barriers, were particularly investigated by the nef mutant and peptide. Both the nef mutant and heptapeptide led to inhibition of enhanced enolase expression and increased invasiveness in THP-1 cells. Together, these findings suggest a possible mechanism of host invasion by HIV-1 through Nef mediated regulation of alpha-enolase and identifies a potential therapeutic target for HIV-1 entry at mucosal barriers.

Keywords: HIV-1 Nef, nef variants, host-virus interaction, tissue invasion

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Authors: Naira Sahakyan, Margarit Petrosyan, Armen Trchounian

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One of the tasks in contemporary biotechnology, pharmacology and other fields of human activities is to obtain biologically active substances from plants. They are very essential in the treatment of many diseases due to their actually high therapeutic value without visible side effects. However, sometimes the possibility of obtaining the metabolites is limited due to the reduction of wild-growing plants. That is why the plant cell cultures are of great interest as alternative sources of biologically active substances. Besides, during the monitored cultivation, it is possible to obtain substances that are not synthesized by plants in nature. Isolated culture of Ajuga genevensis with high growth activity and ability of regeneration was obtained using MS nutrient medium. The agar-diffusion method showed that aqueous extracts of callus culture revealed high antimicrobial activity towards various gram-positive (Bacillus subtilis A1WT; B. mesentericus WDCM 1873; Staphylococcus aureus WDCM 5233; Staph. citreus WT) and gram-negative (Escherichia coli WKPM M-17; Salmonella typhimurium TA 100) microorganisms. The broth dilution method revealed that the minimal and half maximal inhibitory concentration values against E. coli corresponded to the 70 μg/mL and 140 μg/mL concentration of the extract respectively. According to the photochemiluminescent analysis, callus tissue extracts of leaf and root origin showed higher antioxidant activity than the same quantity of A. genevensis intact plant extract. A. genevensis intact plant and callus culture extracts showed no cytotoxic effect on K-562 suspension cell line of human chronic myeloid leukemia. The GC-MS analysis showed deep differences between the qualitative and quantitative composition of callus culture and intact plant extracts. Hexacosane (11.17%); n-hexadecanoic acid (9.33%); and 2-methoxy-4-vinylphenol (4.28%) were the main components of intact plant extracts. 10-Methylnonadecane (57.0%); methoxyacetic acid, 2-tetradecyl ester (17.75%) and 1-Bromopentadecane (14.55%) were the main components of A. genevensis callus culture extracts. Obtained data indicate that callus culture of A. genevensis can be used as an alternative source of biologically active substances.

Keywords: Ajuga genevensis, antibacterial activity, antioxidant activity, callus cultures

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Authors: Philip Friedlander, John Rutledge, Jason Suh

Abstract:

Inhibition of programmed death-1 (PD-1) or its ligand PD-L1 confers therapeutic efficacy in a wide range of solid tumor malignancies. Primary or acquired resistance can develop through activation of immunosuppressive immune cells such as tumor-associated macrophages. The renin angiotensin system (RAS) systemically regulates fluid and sodium hemodynamics, but components are expressed on and regulate the activity of immune cells, particularly of myeloid lineage. We hypothesized that inhibition of RAS would improve the efficacy of PD-1/PD-L-1 treatment. A retrospective analysis was performed through a chart review of patients with solid metastatic malignancies treated with a PD-1/PD-L1 inhibitor between 1/2013 and 6/2019 at Valley Hospital, a community hospital in New Jersey, USA. Efficacy was determined by medical oncologist documentation of clinical benefit in visit notes and by the duration of time on immunotherapy treatment. The primary endpoint was the determination of efficacy differences in patients treated with an inhibitor of RAS ( ace inhibitor, ACEi, or angiotensin blocker, ARB) compared to patients not treated with these inhibitors. To control for broader antihypertensive effects, efficacy as a function of treatment with beta blockers was assessed. 173 patients treated with PD-1/PD-L-1 inhibitors were identified of whom 52 were also treated with an ACEi or ARB. Chi-square testing revealed a statistically significant relationship between being on an ACEi or ARB and efficacy to PD-1/PD-L-1 therapy (p=0.001). No statistically significant relationship was seen between patients taking or not taking beta blocker antihypertensives (p= 0.33). Kaplan-Meier analysis showed statistically significant improvement in the duration of therapy favoring patients concomitantly treated with ACEi or ARB compared to patients not exposed to antihypertensives and to those treated with beta blockers. Logistic regression analysis revealed that age, gender, and cancer type did not have significant effects on the odds of experiencing clinical benefit (p=0.74, p=0.75, and p=0.81, respectively). We conclude that retrospective analysis of the treatment of patients with solid metastatic tumors with anti-PD-1/PD-L1 in a community setting demonstrates greater clinical benefit in the context of concomitant ACEi or ARB inhibition, irrespective of gender or age. This data supports the development of prospective assessment through randomized clinical trials.

Keywords: angiotensin, cancer, immunotherapy, PD-1, efficacy

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Authors: Sadeq Al Yaari, Muhammad Alkhunayn, Sajedah Al Yaari, Adham Al Yaari, Ayman Al Yaari, Montaha Al Yaari, Ayah Al Yaari, Fatehi Eissa

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Dysgraphia is a neurological disorder of written expression that impairs writing ability and fine motor skills, resulting primarily in problems relating not only to handwriting but also to writing coherence and cohesion. We investigate the properties of smart writing technology to highlight some unique features of the effects they cause on the academic performance of pupils with dysgraphia. In Amis, dysgraphics undergo writing problems to express their ideas due to ordinary writing aids, as the default strategy. The Amis data suggests a possible connection between available writing aids and pupils’ writing improvement; therefore, texts’ expression and comprehension. A group of thirteen dysgraphic pupils were placed in a regular classroom of primary school, with twenty-one pupils being recruited in the study as a control group. To ensure validity, reliability and accountability to the research, both groups studied writing courses for two semesters, of which the first was equipped with smart writing aids while the second took place in an ordinary classroom. Two pre-tests were undertaken at the beginning of the first two semesters, and two post-tests were administered at the end of both semesters. Tests examined pupils’ ability to write coherent, cohesive and expressive texts. The dysgraphic group received the treatment of a writing course in the first semester in classes with smart technology and produced significantly greater increases in writing expression than in an ordinary classroom, and their performance was better than that of the control group in the second semester. The current study concludes that using smart teaching aids is a ‘MUST’, both for teaching and learning dysgraphia. Furthermore, it is demonstrated that for young dysgraphia, expressive tasks are more challenging than coherent and cohesive tasks. The study, therefore, supports the literature suggesting a role for smart educational aids in writing and that smart writing techniques may be an efficient addition to regular educational practices, notably in special educational institutions and speech-language therapeutic facilities. However, further research is needed to prompt the adults with dysgraphia more often than is done to the older adults without dysgraphia in order to get them to finish the other productive and/or written skills tasks.

Keywords: smart technology, writing aids, pupils with dysgraphia, hands’ movement

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Authors: Luís R. Silva, Ana C. Gonçalves, Catarina Bento, Fábio Jesus, Branca M. Silva

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Prunus avium Linnaeus, more known as sweet cherry, is one of the most appreciated fruit worldwide. Most of these quantities are produced in Fundão region, being Saco the cultivar most produced. Saco is very rich in bioactive compounds, especially phenolics, and presents great antioxidant capacity. The purpose of the present study was to investigate the chemical profile and biological potential, concerning antioxidant, anti-diabetic activity and protective effects towards erythrocytes by Saco sweet cherry collected from Fundão region (Portugal). The hydroethanolic extracts were prepared and passed through a C18 solid-phase extraction column. The phenolic profile analyzed by LC-DAD method allowed to the identification of 22 phenolic compounds, being 16 non-phenolics and 6 anthocyanins. In respect to non-coloured phenolics, 3-O-caffeoylquinic and ρ-coumaroylquinic acids were the main ones. Concerning to anthocyanins, cyanidin-3-O-rutinoside was found in higher amounts. Relatively to biological potential, Saco showed great antioxidant potential, through DPPH and NO radical assays, with IC50 =16.24 ± 0.46 µg/mL and IC50 = 176.69 ± 3.35 µg/mL for DPPH and NO, respectively. These results were similar to those obtained for ascorbic acid control (IC50 = 16.92 ± 0.69 and IC50 = 162.66 ± 1.31 μg/mL for DPPH and NO, respectively). In respect to antidiabetic potential, Saco revealed capacity to inhibit α-glucosidase in a dose-dependent manner (IC50 = 10.79 ± 0.40 µg/mL), being much active than positive control acarbose (IC50 = 306.66 ± 0.84 μg/mL). Additionally, Saco extracts revealed protective effects against ROO•-mediated toxicity generated by AAPH in human blood erythrocytes, inhibiting hemoglobin oxidation (IC50 = 38.57 ± 0.96 μg/mL) and hemolysis (IC50 = 73.03 ± 1.48 μg/mL), in a concentration-dependent manner. However, Saco extracts were less effective than quercetin control (IC50 = 3.10 μg/mL and IC50 = 0.7 μg/mL for inhibition of hemoglobin oxidation and hemolysis, respectively). The results obtained showed that Saco is an excellent source of phenolic compounds. These ones are natural antioxidant substances, which easily capture reactive species. This work presents new insights regarding sweet cherry antioxidant properties which may be useful for the future development of new therapeutic strategies for preventing or attenuating oxidative-related disorders.

Keywords: antioxidant capacity, health benefits, phenolic compounds, saco

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Authors: Jee-Young Lee, Joaquim J. Ferreira, Hyeo-il Ma, José-Francisco Rocha, Beomseok Jeon

Abstract:

The effective management of wearing-off is a key driver of medication changes for patients with Parkinson’s disease (PD) treated with levodopa (L-DOPA). While L-DOPA is well tolerated and efficacious, its clinical utility over time is often limited by the development of complications such as dyskinesia. Still, common first-line option includes adjusting the daily L-DOPA dose followed by adjunctive therapies usually counting for the L-DOPA equivalent daily dose (LEDD). The LEDD conversion formulae are a tool used to compare the equivalence of anti-PD medications. The aim of this work is to compare the effects of opicapone (OPC) 50 mg, a catechol-O-methyltransferase (COMT) inhibitor, and an additional 100 mg dose of L-DOPA in reducing the off time in PD patients with early motor fluctuations receiving different daily L-DOPA doses. OPC was found to be well tolerated and efficacious in advanced PD population. This work utilized patients' home diary data from a 4-week Phase 2 pharmacokinetics clinical study. The Korean ADOPTION study randomized (1:1) patients with PD and early motor fluctuations treated with up to 600 mg of L-DOPA given 3–4 times daily. The main endpoint was change from baseline in off time in the subgroup of patients receiving 300–400 mg/day L-DOPA at baseline plus OPC 50 mg and in the subgroup receiving >300 mg/day L-DOPA at baseline plus an additional dose of L-DOPA 100 mg. Of the 86 patients included in this subgroup analysis, 39 received OPC 50 mg and 47 L-DOPA 100 mg. At baseline, both L-DOPA total daily dose and LEDD were lower in the L-DOPA 300–400 mg/day plus OPC 50 mg group than in the L-DOPA >300 mg/day plus L-DOPA 100 mg. However, at Week 4, LEDD was similar between the two groups. The mean (±standard error) reduction in off time was approximately three-fold greater for the OPC 50 mg than for the L-DOPA 100 mg group, being -63.0 (14.6) minutes for patients treated with L-DOPA 300–400 mg/day plus OPC 50 mg, and -22.1 (9.3) minutes for those receiving L-DOPA >300 mg/day plus L-DOPA 100 mg. In conclusion, despite similar LEDD, OPC demonstrated a significantly greater reduction in off time when compared to an additional 100 mg L-DOPA dose. The effect of OPC appears to be LEDD independent, suggesting that caution should be exercised when employing LEDD to guide treatment decisions as this does not take into account the timing of each dose, onset, duration of therapeutic effect and individual responsiveness. Additionally, OPC could be used for keeping the L-DOPA dose as low as possible for as long as possible to avoid the development of motor complications which are a significant source of disability.

Keywords: opicapone, levodopa, pharmacokinetics, off-time

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Authors: Masome Moeni, Roya Abedizadeh, Elham Aram, Hamid Sadeghi-Abandansari, Davood Sabour, Robert Menzel, Ali Hassanpour

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Significant number of studies and preclinical research in formulation of cancer nano-pharmaceutics have led to an improvement in cancer care. Nonetheless, the antineoplastic agents have ‘failed to live up to its promise’ since their clinical performance is moderately low. For almost ninety years, iron oxide nanoparticles (IONPS) have managed to keep its reputation in clinical application due to their low toxicity, versatility and multi-modal capabilities. Drug Administration approved utilization of IONPs for diagnosis of cancer as contrast media in magnetic resonance imaging, as heat mediator in magnetic hyperthermia and for the treatment of iron deficiency. Furthermore, IONPs have high drug-loading capacity, which makes them good candidates as therapeutic agent transporters. There are yet challenges to overcome for successful clinical application of IONPs, including stability of drug and poor delivery, which might lead to (i) drug resistance, (ii) shorter blood circulation time, and (iii) rapid elimination and adverse side effects from the system. In this study, highly stable and super paramagnetic IONPs were prepared for efficient and targeted drug delivery in cancer treatment. The synthesis procedure was briefly involved the production of IONPs via co-precipitation followed by coating with tetraethyl orthosilicate and 3-aminopropylethoxysilane and grafting with folic acid for stability targeted purposes and controlled drug release. Physiochemical and morphological properties of modified IONPs were characterised using different analytical techniques. The resultant IONPs exhibited clusters of 10 nm spherical shape crystals with less than 100 nm size suitable for drug delivery. The functionalized IONP showed mesoporous features, high stability, dispersibility and crystallinity. Subsequently, the functionalized IONPs were successfully loaded with oxaliplatin, a chemotherapeutic agent, for a controlled drug release in an actively targeting cancer cells. FT-IR observations confirmed presence of oxaliplatin functional groups, while ICP-MS results verified the drug loading was ~ 1.3%.

Keywords: cancer treatment, chemotherapeutic agent, drug delivery, iron oxide, multi-functional nanoparticle

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Authors: Olubukayo-Opeyemi Oyetayo, Oscar Mendez-Lucio, Andreas Bender, Hans Kiefer

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The thermal melting curve of a protein provides information on its conformational stability and could provide cues on its aggregation behavior. Naturally-occurring osmolytes have been shown to improve the thermal stability of most proteins in a concentration-dependent manner. They are therefore commonly employed as additives in therapeutic protein purification and formulation. A number of intertwined and seemingly conflicting mechanisms have been put forward to explain the observed stabilizing effects, the most prominent being the preferential exclusion mechanism. We attempted to probe and summarize molecular mechanisms for thermal stabilization of a monoclonal antibody (mAb) by developing quantitative structure-activity relationships using a rationally-selected library of 120 osmolyte-like compounds in the polyhydric alcohols, amino acids and methylamines classes. Thermal stabilization potencies were experimentally determined by thermal shift assays based on differential scanning fluorimetry. The cross-validated QSAR model was developed by partial least squares regression using descriptors generated from Molecular Operating Environment software. Careful evaluation of the results with the use of variable importance in projection parameter (VIP) and regression coefficients guided the selection of the most relevant descriptors influencing mAb thermal stability. For the mAb studied and at pH 7, the thermal stabilization effects of tested compounds correlated positively with their fractional polar surface area and inversely with their fractional hydrophobic surface area. We cannot claim that the observed trends are universal for osmolyte-protein interactions because of protein-specific effects, however this approach should guide the quick selection of (de)stabilizing compounds for a protein from a chemical library. Further work with a large variety of proteins and at different pH values would help the derivation of a solid explanation as to the nature of favorable osmolyte-protein interactions for improved thermal stability. This approach may be beneficial in the design of novel protein stabilizers with optimal property values, especially when the influence of solution conditions like the pH and buffer species and the protein properties are factored in.

Keywords: thermal stability, monoclonal antibodies, quantitative structure-activity relationships, osmolytes

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Authors: Seyedahmad Hosseini, Mohammadjavad Sotoudeheian

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Introduction: Allergic asthma is a heterogeneous immuno-inflammatory disease based on Th-2-mediated inflammation. Histopathologic abnormalities of the airways characteristic of asthma include epithelial damage and subepithelial collagen deposition. Objectives: Human bronchial epithelial cell genome expression of TNF‑α, IL‑6, ICAM‑1, VCAM‑1, nuclear factor (NF)‑κB signaling pathways up-regulate during inflammatory cascades. Moreover, immunofluorescence assays confirmed the nuclear translocation of NF‑κB p65 during inflammatory responses. An absolute LDH leakage assays suggestedLPS-inducedcells injury, and the associated mechanisms are co-incident events. LPS-induced phosphorylation of ERKand JNK causes inflammation in epithelial cells through inhibition of ERK and JNK activation and NF-κB signaling pathway. Furthermore, the inhibition of NF-κB mRNA expression and the nuclear translocation of NF-κB lead to anti-inflammatory events. Likewise, activation of SUMF2 which inhibits IL-13 and reduces Th2-cytokines, NF-κB, and IgE levels to ameliorate asthma. On the other hand, TNFα-induced mucus production reduced NF-κB activation through inhibition of the activation status of Rac1 and IκBα phosphorylation. In addition, bradykinin B2 receptor (B2R), which mediates airway remodeling, regulates through NF-κB. Bronchial B2R expression is constitutively elevated in allergic asthma. In addition, certain NF-κB -dependent chemokines function to recruit eosinophils in the airway. Besides, bromodomain containing 4 (BRD4) plays a significant role in mediating innate immune response in human small airway epithelial cells as well as transglutaminase 2 (TG2), which is detectable in saliva. So, the guanine nucleotide-binding regulatory protein α-subunit, Gα16, expresses a κB-driven luciferase reporter. This response was accompanied by phosphorylation of IκBα. Furthermore, expression of Gα16 in saliva markedly enhanced TNF-α-induced κB reporter activity. Methods: The applied method to form NF-κB activation is the electromobility shift assay (EMSA). Also, B2R-BRD4-TG2 complex detection by immunoassay method within saliva with EMSA of NF-κB activation may be a novel biomarker for asthma diagnosis and follow up. Conclusion: This concept introduces NF-κB signaling pathway as potential asthma biomarkers and promising targets for the development of new therapeutic strategies against asthma.

Keywords: NF-κB, asthma, saliva, T-helper

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Authors: Pravina Gurjar, Bothiraja Pour, Vijay Kumbhar, Ganesh Dama

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Andrographolide (AG), a bioactive phytoconstituent, has a wider range of pharmacological action. However, due to the intestinal degradation, shows low oral bioavailability. The aim of the present work was to develop Floating In-situ gelling Gastro retentive System (FISGS) for AG in order to enhance its site specific absorption and minimize pH dependent hydrolysis in alkaline environment. Further to increase its therapeutic efficacy for peptic ulcer disease caused by H. pyroli. Gellan based floating in situ gelling system of AG were prepared by using sodium citrate and calcium carbonate. The 32 factorial designs was used to study the effect of gellan and calcium carbonate concentration (independent variables) on dependent variable such as viscosity, floating lag time and drug release. Developed system was evaluated for drug content, floating lag time, viscosity, and drug release studies. Drug content, viscosity, and floating lag time was found to be 81-99%, 67-117 Cps, and 3-5 sec, respectively. The obtained system showed good in vitro floating ability for more than 12 h using 0.1 N HCl as dissolution medium with initial burst release followed by the controlled zero order drug release up to 24 hrs. In vivo testing of FISGS of AG to rats demonstrated significant antiulcer activity that were evaluated by various parameters like pH, volume, total acidity, millimole equivalent of H+ ions/30 min, and protein content of gastric content. The densities of all the formulation batches were found to be near about 0.9 and floating duration above 12 hr. It was observed that with the increase in conc. of gellan there was increase in the viscosity of formulation but all formulations were in optimum range. The drug content of optimized batch was found to be 99.23. In histopathology study of stomach, the villi at the mucosal surface, the intercellular junction, the intestinal lumen were intact; no destruction of the epithelium, and submucosal gland in formulation treated and control group animals as compared to pure drug AG and standard ranitidine. Gellan-based in situ gastro retentive floating system could be advantageous in terms of increased bioavailability of AG to maintain an effective drug conc. in gastric fluid as well as in serum for longer period of time.

Keywords: andrographolide, floating drug delivery, in situ gelling system, gastroretentive system

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Authors: Varsha Salian, Shama Rao, N. Narendra, B. Mohana Kumar

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Evolving evidence proposes the existence of a highly tumorigenic subpopulation of undifferentiated, self-renewing cancer stem cells, responsible for exhibiting resistance to conventional anti-cancer therapy, recurrence, metastasis and heterogeneous tumor formation. Importantly, the mechanisms exploited by cancer stem cells to resist chemotherapy are very less understood. Oral squamous cell carcinoma (OSCC) is one of the most regularly diagnosed cancer types in India and is associated commonly with alcohol and tobacco use. Therefore, the isolation and in vitro characterization of cancer stem-like cells from patients with OSCC is a critical step to advance the understanding of the chemoresistance processes and for designing therapeutic strategies. With this, the present study aimed to establish and characterize cancer stem-like cells in vitro from OSCC. The primary cultures of cancer stem-like cell lines were established from the tissue biopsies of patients with clinical evidence of an ulceroproliferative lesion and histopathological confirmation of OSCC. The viability of cells assessed by trypan blue exclusion assay showed more than 95% at passage 1 (P1), P2 and P3. Replication rate was performed by plating cells in 12-well plate and counting them at various time points of culture. Cells had a more marked proliferative activity and the average doubling time was less than 20 hrs. After being cultured for 10 to 14 days, cancer stem-like cells gradually aggregated and formed sphere-like bodies. More spheroid bodies were observed when cultured in DMEM/F-12 under low serum conditions. Interestingly, cells with higher proliferative activity had a tendency to form more sphere-like bodies. Expression of specific markers, including membrane proteins or cell enzymes, such as CD24, CD29, CD44, CD133, and aldehyde dehydrogenase 1 (ALDH1) is being explored for further characterization of cancer stem-like cells. To summarize the findings, the establishment of OSCC derived cancer stem-like cells may provide scope for better understanding the cause for recurrence and metastasis in oral epithelial malignancies. Particularly, identification and characterization studies on cancer stem-like cells in Indian population seem to be lacking thus provoking the need for such studies in a population where alcohol consumption and tobacco chewing are major risk habits.

Keywords: cancer stem-like cells, characterization, in vitro, oral squamous cell carcinoma

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

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The Dandy-Walker malformation (DWM) represents a clinical syndrome manifesting as a combination of posterior fossa cyst, hypoplasia of the cerebellar vermis, and obstructive hydrocephalus. Anatomic hallmarks include hypoplasia of the cerebellar vermis, enlargement of the posterior fossa, and cystic dilatation of the fourth ventricle. Current treatments of DWM, including shunting of the cerebral spinal fluid ventricular system and endoscopic third ventriculostomy (ETV), are frequently clinically insufficient, require additional surgical interventions, and carry risks of infections and neurological deficits. Bionaut Labs develops an alternative way to treat Dandy-Walker Malformation (DWM) associated with non-communicating hydrocephalus. We utilize our discreet microsurgical Bionaut™ particles that are controlled externally and remotely to perform safe, accurate, effective fenestration of the Dandy-Walker cyst, specifically in the posterior fossa of the brain, to directly normalize intracranial pressure. Bionaut™ allows for complex non-linear trajectories not feasible by any conventional surgical techniques. The microsurgical particle safely reaches targets in the lower occipital section of the brain. Bionaut™ offers a minimally invasive surgical alternative to highly involved posterior craniotomy or shunts via direct fenestration of the fourth ventricular cyst at the locus defined by the individual anatomy. Our approach offers significant advantages over the current standards of care in patients exhibiting anatomical challenge(s) as a manifestation of DWM, and therefore, is intended to replace conventional therapeutic strategies. Current progress, including platform optimization, Bionaut™ control, and real-time imaging and in vivo safety studies of the Bionauts™ in large animals, specifically the spine and the brain of ovine models, will be discussed.

Keywords: Bionaut™, cerebral spinal fluid, CSF, cyst, Dandy-Walker, fenestration, hydrocephalus, micro-robot

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Authors: Klazina T. Havinga, Hilde R. H. de Geus

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Introduction: Pre-operative coagulation management of Apixaban prescribed patients, a new oral anticoagulant (a factor Xa inhibitor), is difficult, especially when chronic kidney disease (CKD) causes drug overdose. Apixaban is not dialyzable due to its high level of protein binding. An antidote, Andexanet α, is available but expensive and has an unfavorable short half-life. We report the successful extracorporeal removal of Apixaban prior to emergency surgery with the CytoSorb® Hemoadsorption device. Methods: A 89-year-old woman with CKD, with an Apixaban prescription for atrial fibrillation, was presented at the ER with traumatic rib fractures, a flail chest, and an unstable spinal fracture (T12) for which emergency surgery was indicated. However, due to very high Apixaban levels, this surgery had to be postponed. Based on the Apixaban-specific anti-factor Xa activity (AFXaA) measurements at admission and 10 hours later, complete clearance was expected after 48 hours. In order to enhance the Apixaban removal and reduce the time to operation, and therefore reduce pulmonary complications, CRRT with CytoSorb® cartridge was initiated. Apixaban-specific anti-factor Xa activity (AFXaA) was measured frequently as a substitute for Apixaban drug concentrations, pre- and post adsorber, in order to calculate the adsorber-related clearance. Results: The admission AFXaA concentration, as a substitute for Apixaban drug levels, was 218 ng/ml, which decreased to 157 ng/ml after ten hours. Due to sustained anticoagulation effects, surgery was again postponed. However, the AFXaA levels decreased quickly to sub-therapeutic levels after CRRT (Multifiltrate Pro, Fresenius Medical Care, Blood flow 200 ml/min, Dialysate Flow 4000 ml/h, Prescribed renal dose 51 ml-kg-h) with Cytosorb® connected in series into the circuit was initiated (within 5 hours). The adsorber-related (indirect) Apixaban clearance was calculated every half hour (Cl=Qe * (AFXaA pre- AFXaA post/ AFXaA pre) with Qe=plasma flow rate calculated with Ht=0.38 and system blood flow rate 200 ml-min): 100 ml/min, 72 ml/min and 57 ml/min. Although, as expected, the adsorber-related clearance decreased quickly due to saturation of the beads, still the reduction rate achieved resulted in a very rapid decrease in AFXaA levels. Surgery was ordered and possible within 5 hours after Cytosorb initiation. Conclusion: The CytoSorb® Hemoadsorption device enabled rapid correction of Apixaban associated anticoagulation.

Keywords: Apixaban, CytoSorb, emergency surgery, Hemoadsorption

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