Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM ...multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR.
A dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance.
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In this paper, an efficient optimization technique called Chaotic Harris Hawks optimization (CHHO) is proposed and applied for estimating the accurate operating parameters of proton exchange membrane ...fuel cell (PEMFC), which simulate and mimic its electrical performance. The conventional Harris Hawks optimization (HHO) is a recent optimization technique that is based on the hunting approach of Harris hawks. In this proposed optimization technique, ten chaotic functions are applied for tackling with the studied optimization problem. The CHHO is proposed to enhance the search capability of conventional HHO and avoid its trapping into local optima. The sum of squared errors (SSE) between the experimentally measured output voltage and the corresponding simulated ones is adopted as the objective function. The developed CHHO technique is tested on four various commercial PEMFC stacks to assess and validate its effectiveness compared with other well-known optimization techniques. A statistical study is performed to appreciate the stability and reliability of the proposed CHHO technique. However, the results show the effectiveness and superiority of proposed CHHO compared with the conventional HHO and other competitive metaheuristic optimization algorithms under the same study cases.
Although, pre-operative inspiratory muscle training has been investigated and reported to be an effective strategy to reduce postoperative pulmonary complications, the efficacy of postoperative ...inspiratory muscle training as well as the proper load, frequency, and duration necessary to reduce the postoperative pulmonary complications has not been fully investigated. This study was designed to investigate the effect of postoperative high-load long-duration inspiratory muscle training on pulmonary function, inspiratory muscle strength, and functional capacity after mitral valve replacement surgeries.
Prospective randomized controlled trial.
A total of one hundred patients (mean age 38.3±3.29years) underwent mitral valve replacement surgery were randomized into experimental (n = 50) and control (n = 50) groups. The control group received conventional physiotherapy care, while experimental group received conventional care in addition to inspiratory muscle training, with 40% of the baseline maximal inspiratory pressure targeting a load of 80% by the end of the 8 weeks intervention protocol. Inspiratory muscle training started on the patient's first day in the inpatient ward. Lung functions, inspiratory muscle strength, and functional capacity were evaluated using a computer-based spirometry system, maximal inspiratory pressure measurement and 6MWT respectively at 5 time points and a follow-up assessment was performed 6 months after surgery. Repeated measure ANOVA and post-hoc analyses were used (p <0.05).
Group-time interactions were detected for all the studied variables (p<0.001). Between-group analysis revealed statistically significant postoperative improvements in all studied variables in the experimental group compared to the control group (p <0.001) with large effect size of η2 ˃0.14. Within-group analysis indicated substantial improvements in lung function, inspiratory pressure and functional capacity in the experimental group (p <0.05) over time, and these improvements were maintained at follow-up.
High intensity, long-duration postoperative inspiratory muscle training is highly effective in improving lung function, inspiratory muscle strength, and functional capacity after mitral valve replacement surgeries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). ...Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.
Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer’s and Parkinson’s diseases. Vilda‘s ...effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington’s disease (HD). However, Vilda’s role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (
p
Y458/199)-PI3K,
p
S473-Akt. Together, it boosted striatal neurotrophic factors and receptor;
p
S133-CREB, BDNF,
p
Y515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.
Recently, extracting the precise values of unknown parameters of the polymer electrolyte membrane fuel cell (PEMFC) is considered one of the most widely nonlinear and semi-empirical optimization ...problems. This paper proposes and applies a Modified Artificial Ecosystem Optimization (MAEO) algorithm to solve the problem of PEMFC parameters extraction. The conventional AEO is a novel optimization technique that is inspired by the energy flow in a natural ecosystem which is defined as abiotic, which includes non-living bodies and elements such as light, water and air. The proposed optimization algorithm, MAEO, is used to enhance the performance of conventional AEO and provide faster convergence rate as well as to be far away from falling into the local optima. In the proposed MAEO, an operator is suggested to improve the balance between exploitation and Exploration phases. The accurate estimation of PEMFC unknown parameters leads to develop a precise mathematical model which simulates the electrochemical and electrical characteristics of PEMFC. The objective function of the studied optimization problem is formulated as the sum of squared errors (SSE) between the measured and simulated stack voltages. To prove the reliability and capability of the proposed MAEO algorithm in solving this problem compared with other recent algorithms, it is tested on four different PEMFC stack models, namely, BCS-500W, SR-12 500W, 250W and Temasek 1 kW stacks. Moreover, statistical measures are performed to assess the superiority and robustness of the proposed algorithm. In addition, the accuracy of optimized parameters is assessed through the dynamic characteristics of PEMFCs under varying the reactants' pressures and temperature of the cell. However, the simulation results confirm that the proposed MAEO algorithm has high accuracy and reliability in extracting the PEMFC optimal parameters compared with the conventional AEO and other effective algorithms.
Apart from endoscopic interventions, readily attainable cost-effective biomarkers for ulcerative colitis (UC) assessment are required. For this purpose, we evaluated differential leucocytic ratio, ...mainly neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) as simple available indicators of disease activity in patients with ulcerative colitis.
Study conducted on 80 UC patients who were classified into two groups of 40 each according to Mayo score and colonoscopic findings. Group 1 (active UC) and group 2 (inactive UC). Another 40 group-matched healthy participants were enrolled. White blood cell count, NLR, LMR, C-reactive protein, and Erythrocyte sedimentation rate were measured and recorded.
Significant elevation of NLR was observed in active UC group compared to inactive UC and controls (2.63 ± 0.43, 1.64 ± 0.25, 1.44 ± 0.19 respectively; p < 0.0001). The optimal NLR cut-off value for active UC was > 1.91, with a sensitivity and a specificity of 90% and 90% respectively. The mean LMRs of active UC was significantly lower compared with inactive UC patients and controls (2.25 ± 0.51, 3.58 ± 0.76, 3.64 ± 0.49 respectively; p < 0.0001). The cut-off value of LMR for determining the disease activity was ≤ 2.88 with a sensitivity of 90% and a specificity of 90%. NLR, LMR, and CRP were found to be significant independent markers for discriminating disease activity (p = 0.000). Besides, NLR was significantly higher in patients with pancolitis and positively correlated with endoscopically severe disease.
NLRs and LMRs are simple non-invasive affordable independent markers of disease activity in UC.
The levels of messenger RNA (mRNA) transcription of FOXP3, IFN-γ, TNF, IL-6 and COX-2 from both COVID-19 infected and control subjects were evaluated using SYBRTM green real-time polymerase chain ...reaction (RT-PCR). Severe/critical cases showed significantly lower lymphocyte counts and higher neutrophil counts than the mild or moderate cases. There were significantly lower levels of mRNA expressions of IFN-γ, TNFα and FOXP3 in COVID-19 patients than in the control group. On the other hand, IL-6 and COX-2 expressions were significantly higher in patients suffering from severe disease. FOXP3 expressions were correlated with the severities of hypoxia and were excellent in predicting the disease severity. This was followed by the IL-6, COX-2 and TNFα expressions. FOXP3 expression was the only biomarker to show a significant correlation with patient mortality. It was concluded that SARS-CoV-2 infection is associated with the downregulation of FOXP3 and upregulations of IL-6 and COX-2.
•The immunological response to SARS-CoV-2 infection is still obscure.•Low mRNA expressions of IFN-γ, TNFα and FOXP3 were detected in COVID-19 patients.•IL-6 and COX-2 are highly expressed in patients suffering from severe COVID-19.•FOXP3 can be used as a potential biomarker for predicting disease severity.•COVID-19 coincides with downregulation of FOXP3 and upregulations of IL-6 and COX-2.
•Proton exchange membrane fuel cells.•An improved Salp Swarm Algorithm (SSA) is proposed to enhance the conventional SSA.•The proposed ISSA has been utilized for identifying the unknown parameter ...values.•The Sum of Squared Errors (SSE) is adopted as the objective function.•Statistical analysis of proposed ISSA compared with the conventional SSA is carried out.
Recently, Proton Exchange Membrane Fuel Cells (PEMFCs) become one of the most promising friendly renewable energy sources. Therefore, developing a mathematical model for the PEMFC is an urgent necessity for simulation and evaluation of the processes occurring inside the fuel cell (FC) stack. In this paper, a precis model, which can stimulate the electrical and electrochemical phenomenon of the PEMFC is introduced. Improved salp swarm algorithm (ISSA) is proposed to enhance the performance of the conventional SSA and avoid getting stuck on local optimum. The proposed ISSA has been utilized for identifying the unknown parameter values of PEMFC stack models. The proposed ISSA is validated on four different FC stacks and a comparison between the computed and measured results has been accomplished. The Sum of Squared Errors (SSE) between experimental and estimated voltages is adopted as the objective function which has to be minimized. For validating the goodness of the ISSA, the generated values of the unknown parameters and the value of SSE using the ISSA-based PEMFC model are compared with the corresponding ones obtained by other optimization techniques. Furthermore, statistical analysis of proposed ISSA compared with the conventional SSA is carried out for all the PEMFC stacks involved in this work. The simulation results under various conditions of operation and the statistical results proved the stability and reliability of ISSA in comparison with recently utilized algorithms.
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