Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges.

Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.

Use of antioxidant nanoparticles to reduce oxidative stress in blood storage.

Oxidative damage by free radicals has a negative effect on blood quality during storage. Antioxidant nanoparticles can prevent oxidative stress. We use SOD-CAT-Alb-PEG-PLGA- nanoparticles to reduce the effects of oxidative stress in blood storage. Electrospray was employed to prepare nanoparticles. Nanoparticles entered the test bags and were kept for 35 days from the time of donation under standard conditions. On target days, experiments were performed on the samples taken. The examination included blood smear, red blood cells count, hemoglobin, hematocrit, K, Fe, glutathione peroxidase, glutathion reductase, glucose-6-phosphate dehydrogenase, prooxidant-antioxidant balance, malondialdehyde, and flow cytometric assay for phosphatidylserine. The repeated measures analysis was performed on samples every week. Morphological changes were less in the test group compared to the control. The quantitative hemolysis profile test showed significant changes in the test and control groups (p < 0.05) in consecutive weeks except for K and Fe. Oxidative stress parameters too showed a significant change during the target days of the examination (p < 0.05). Also, the phosphatidylserine expression was increased in control groups more than test in consecutive weeks (p < 0.05). It seems that the use of antioxidant nanoparticles improves the quality of stored red blood cells and can prevent posttransfusion complications and blood loss by reducing oxidative stress.

Reduced Serum Levels of Zinc and Superoxide Dismutase in Obese Individuals.

The oxidant-stress (OS) has an essential role to play in the pathogenesis and progression of many diseases. OS is the outcome when the level of free-radical-formation is increased or protective-antioxidant-mechanisms are compromised. Its value is expected to increase, although its emerging roles have not been conclusive in different studies. The objective of this study was to explore the level of zinc, copper, and antioxidant in response to obesity-related-stress by measuring superoxide-dismutase (SOD) levels as a key antioxidant-enzyme in 706 individuals with/without obesity. Anthropometric/biochemical parameters including total-cholesterol (TC), fasting-blood-glucose, high-density-lipoprotein (HDL), low-density-lipoprotein, and triglycerides were determined. The activity of SOD was measured followed by the measurement of Cu and Zn levels. Obese subjects had a significantly higher level of body mass index (BMI) and TC, while the level of HDL was lower in the obese group, as compared to the related values in control subjects. The level of Zn was significantly decreased in the obese group, while the level of Cu and Cu/Zn ratio increased. Additionally, we observed that the SOD level was less in obese subjects when compared to that in the non-obese subjects. In addition to the complications of high BMI, low level of Zn and SOD in obesity can be considered a risk factor, resulting in a reduced antioxidant response, supporting the need for identifying a suitable treatment option for this group.

Effect of Phytosterols on Serum Levels of C-Reactive Protein: A Time- and Dose-Response Meta-analysis of Randomized Controlled Trial.

INTRODUCTION: Phytosterols are recognized for their cholesterol-reducing effects and are commonly used as dietary supplements or added to foods due to their potential cardiovascular benefits. However, evidence regarding the impact of phytosterol supplementation on inflammatory markers remains inconclusive. AIM: This systematic review and meta-analysis aim to evaluate the effect of phytosterols in reducing levels of C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP). METHODS: A systematic literature search of the primary databases was conducted up to May 2024 to identify eligible studies. The measurement of effect sizes was determined using WMD (weighted mean difference) and 95% CI. RESULTS: For the meta-analysis, 14 publications (19 study arms) for hs-CRP and 10 publications (16 study arms) for CRP were included. The pooled analysis showed that the administration of phytosterol did not significantly reduce CRP compared to control with WMD= -0.04 mg/l (95% CI: -0.28 to 0.20, P = 0.74). However, phytosterol supplementation significantly decreased the hs-CRP level compared to the control group with WMD of -0.25 mg/l (95% CI: -0.42 to -0.07, P = 0.006). The WMD for hs-CRP reduction was - 0.36 mg/l (95% CI: -0.53 to -0.18, P < 0.001) for supplementation with a phytosterol dose ≥ 2000 mg/day compared to the control group. CONCLUSIONS: Phytosterol supplementation may be effective in reducing hs-CRP levels.

Antifungal activity of Fe3O4@SiO2/Schiff-base/Cu(II) magnetic nanoparticles against pathogenic Candida species.

The antifungal efficacy and cytotoxicity of a novel nano-antifungal agent, the Fe3O4@SiO2/Schiff-base complex of Cu(II) magnetic nanoparticles (MNPs), have been assessed for targeting drug-resistant Candida species. Due to the rising issue of fungal infections, especially candidiasis, and resistance to traditional antifungals, there is an urgent need for new therapeutic strategies. Utilizing Schiff-base ligands known for their broad-spectrum antimicrobial activity, the Fe3O4@SiO2/Schiff-base/Cu(II) MNPs have been synthesized. The Fe3O4@SiO2/Schiff-base/Cu(II) MNPs was characterized by Fourier Transform-Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), Energy-dispersive X-ray (EDX), Vibrating Sample Magnetometer (VSM), and Thermogravimetric analysis (TGA), demonstrating successful synthesis. The antifungal potential was evaluated against six Candida species (C. dubliniensis, C. krusei, C. tropicalis, C. parapsilosis, C. glabrata, and C. albicans) using the broth microdilution method. The results indicated strong antifungal activity in the range of 8-64 µg/mL with the lowest MIC (8 µg/mL) observed against C. parapsilosis. The result showed the MIC of 32 µg/mL against C. albicans as the most common infection source. The antifungal mechanism is likely due to the disruption of the fungal cell wall and membrane, along with increased reactive oxygen species (ROS) generation leading to cell death. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay for cytotoxicity on mouse L929 fibroblastic cells suggested low toxicity and even enhanced cell proliferation at certain concentrations. This study demonstrates the promise of Fe3O4@SiO2/Schiff-base/Cu(II) MNPs as a potent antifungal agent with potential applications in the treatment of life-threatening fungal infections, healthcare-associated infections, and beyond.

Cytidine deaminase enzyme activity is a predictive biomarker in gemcitabine-treated cancer patients.

BACKGROUND: Gemcitabine is a chemotherapeutic agent, widely used for the treatment of many types of cancer. Cytidine deaminase (CDA) enzyme plays an important role in the metabolism of gemcitabine. This study aimed to assess the power of serum CDA residual activity in predicting drug efficacy and toxicity in gemcitabine-treated cancer patients. METHODS: This prospective observational study enrolled 63 patients with different types of malignancies who received gemcitabine chemotherapy between May 2019 and January 2022. Blood samples were obtained before the initiation of chemotherapy and serum CDA residual activity was determined using a modification of the Berthelot assay. The patients were followed up for at least 12 months up to 41 months. Overall survival was recorded and treatment-related toxicities were documented according to National Cancer Institute Common Terminology Criteria. RESULTS: Kaplan-Meier analysis showed that patients with a lower than median CDA value (≤ 8.06 U/mg protein) had a significantly longer survival compared to patients with higher CDA values (> 8.06 U/mg, P ˂ 0.005). Among several potentially involved factors, a significant association between CDA activity and overall survival was observed in univariate analysis (HR = 4.219, 95% CI 1.40-12.74, P = 0.011). On the other hand, the rate of anemia was significantly higher in low-CDA patients compared to high-CDA individuals (P < 0.05). CONCLUSION: These findings suggest that CDA activity could be a promising biomarker to predict survival and the occurrence of anemia in cancer patients treated with gemcitabine.

A COVID-19 Patient Presenting with Pneumothorax.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus that has affected millions of individuals across the world. It was officially declared as a pandemic on March 11, 2020. Although most patients with COVID-19 manifest as viral pneumonia characterized by symptoms such as fever, dyspnea, and cough, atypical presentations such as acute respiratory distress syndrome (ARDS) and acute kidney or cardiac injury have been reported amongst COVID-19 patients. Bilateral and peripheral ground-glass and opacities are the hallmarks of COVID-19 infection on imaging exams. Herein, we aim to describe a COVID-19 patient who presented with shortness of breath, neck pain, chest pain, and bilateral pneumothorax in his imaging exam.

Dose-dependent efficacy of antioxidant nanoparticles on red blood cells storage.

BACKGROUND: Transfusion of healthy red blood cells (RBCs) after storage is important. One of the storage lesions on blood bags is oxidative stress. One way to prevent increased oxidative stress is to use antioxidant nanoparticles (NPs). Superoxide dismutase (SOD) and catalase (CAT) play an important role in antioxidant defense on RBC. poly lactic-co-glycolic acid (PLGA) is a nontoxic biodegradable polymer that is approved by the Food and Drug Administration for drug delivery. This study aimed to assess dose-dependent efficacy of SOD-CAT-polyethylene glycol -PLGA on RBCs storage. MATERIALS AND METHODS: Using a descriptive study, during 1 month, twenty donors from Bojnourd Blood Donation Center were selected. NPs with different concentrations were injected into the satellite bags after directing blood to them. On target days, experiments were performed on the samples taken. Electrospray was employed to prepare SOD-CAT-PLGA NPs. Twenty packed RBCs were isolated from the whole blood bags by the mechanical method, and certain amount of product was transferred to the satellite bags. On days 1, 7, 14, 21, 28, and 35, bags were sampled. Malondialdehyde (MDA), prooxidant-antioxidant balance (PAB), and Annexin V were performed on the samples taken. The repeated measures analysis with the help of SPSS software version 20 was performed on samples. RESULTS: MDA increased in both groups. The maximum increase in test group was seen in concentration 12 mg (MDA Day 14, test [1.93 ± 0.3], [P MDA < 0.001]). Maximum increase in PAB was seen in concentration 12 mg (from 444 ± 1.7 to 563 ± 2.5) (P PAB = 0.000). Furthermore, PS expression increased in the concentration of 12 mg greater than other concentration in consecutive (from 5.00 ± 0.8 to 22.26 ± 1.7, [P < 0.001]). CONCLUSION: Evaluation of dose dependency showed that different concentrations of antioxidant NPs affect RBC. This effect can be changed oxidative stress and apoptosis. Using both changes to evaluate functional and toxicity can be helpful.

Small interfering RNA (siRNA) to target genes and molecular pathways in glioblastoma therapy: Current status with an emphasis on delivery systems.

Glioblastoma multiforme (GBM) is one of the worst brain tumors arising from glial cells, causing many deaths annually. Surgery, chemotherapy, radiotherapy and immunotherapy are used for GBM treatment. However, GBM is still an incurable disease, and new approaches are required for its successful treatment. Because mutations and amplifications occurring in several genes are responsible for the progression and aggressive behavior of GBM cells, genetic approaches are of great importance in its treatment. Small interfering RNA (siRNA) is a new emerging tool to silence the genes responsible for disease progression, particularly cancer. SiRNA can be used for GBM treatment by down-regulating genes such as VEGF, STAT3, ELTD1 or EGFR. Furthermore, the use of siRNA can promote the chemosensitivity of GBM cells. However, the efficiency of siRNA in GBM is limited via its degradation by enzymes, and its off-targeting effects. SiRNA-loaded carriers, especially nanovehicles that are ligand-functionalized by CXCR4 or angiopep-2, can be used for the protection and targeted delivery of siRNA. Nanostructures can provide a platform for co-delivery of siRNA plus anti-tumor drugs as another benefit. The prepared nanovehicles should be stable and biocompatible in order to be tested in human studies.

A Gaussian-based model for early detection of mild cognitive impairment using multimodal neuroimaging.

BACKGROUND: Diagnosis of early mild cognitive impairment (EMCI) as a prodromal stage of Alzheimer's disease (AD) with its delineation from the cognitively normal (CN) group remains a challenging but essential step for the planning of early treatment. Although several studies have focused on the MCI diagnosis, this study introduces the early stage of MCI to assess more thoroughly the earliest signs of disease manifestation and progression. NEW METHOD: We used random forest feature selection model with a Gaussian-based algorithm to perform method evaluation. This integrated method serves to define multivariate normal distributions in order to classify different stages of AD, with the focus placed on detecting EMCI subjects in the most challenging classification of CN vs. EMCI. RESULTS: Using 896 participants classified into the four categories of CN, EMCI, late mild cognitive impairment (LMCI) and AD, the results show that the EMCI group can be delineated from the CN group with a relatively high accuracy of 78.8% and sensitivity of 81.3%. COMPARISON WITH EXISTING METHOD(S): The feature selection model and classifier are compared with some other prominent algorithms. Although higher accuracy has been achieved using the Gaussian process (GP) model (78.8%) over the SVM classifier (75.6%) for CN vs. EMCI classification, with 0.05 being the cutoff for significance, and based on student's t-test, it was determined that the differences for accuracy, sensitivity, specificity between the GP method and support vector machine (SVM) are not statistically significant. CONCLUSION: Addressing the challenging classification of CN vs. EMCI provides useful information to help clinicians and researchers determine essential measures that can help in the early detection of AD.

A survey on applications and analysis methods of functional magnetic resonance imaging for Alzheimer's disease.

BACKGROUND: Functional magnetic resonance imaging (fMRI) is an MRI-based neuroimaging technique that measures brain activity on the basis of blood oxygenation level. This study reviews the main fMRI methods reported in the literature and their related applications in clinical and preclinical studies, focusing on relating functional brain networks in the prodromal stages of Alzheimer's disease (AD), with a focus on the transition phases from cognitively normal (CN) to mild cognitive impairment (MCI) and from MCI to AD. NEW METHOD: The purpose of this study is to present and compare different approaches of supervised and unsupervised fMRI analyses and to highlight the different applications of fMRI in the diagnosis of MCI and AD. RESULTS: Survey article asserts that brain network disruptions of a given dysfunction or in relation to disease prone areas of the brain in neurodegenerative dementias could be extremely useful in ascertaining the extent of cognitive deficits at the different stages of the disease. Identifying the earliest changes in these activity patterns is essential for the early planning of treatment and therapeutic protocols. COMPARISON WITH EXISTING METHODS: Analysis methods such as independent component analysis (ICA) and graph theory-based approaches are strong analytical techniques most suitable for functional connectivity investigations. However, graph theory-based approaches have received more attention due to the higher performance they achieve in both functional and effective connectivity studies. CONCLUSION: This article shows that the disruption of brain connectivity patterns of MCI and AD could be associated with cognitive decline, an interesting finding that could augment the prospects for early diagnosis. More importantly, results reveal that changes in functional connectivity as obtained through fMRI precede detection of cortical thinning in structural MRI and amyloid deposition in positron emission tomography (PET). However, a major challenge in using fMRI as a single imaging modality, like all other imaging modalities used in isolation, is in relating a particular disruption in functional connectivity in relation to a specific disease. This is a challenge that requires more thorough investigation, and one that could perhaps be overcome through multimodal neuroimaging by consolidating the strengths of these individual imaging modalities.

Serum Oxidative Stress Markers in Patients with Senile Cataract and Healthy Controls.

OBJECTIVE: To investigate the role of oxidative stress in patients with senile cataract. STUDY DESIGN: Case-control study. PLACE AND DURATION OF STUDY: North Khorasan University of Medical Sciences, Bojnurd, Iran, from 2014 to 2015. METHODOLOGY: Non-randomised sampling was conducted on 74 patients with senile cataract and 79 healthy people. The oxidative stress level, glutathione peroxidase (GPx) and superoxide dismutase (SOD) enzymes were measured in serum. The results were analysed using SPSS software and followed by t-test analysis. P<0.05 was considered to be significant. RESULTS: The median activity of GPx and SOD antioxidant enzymes in patients with cataract, was higher than healthy people (p=0.018 and p<0.0001, respectively). Peroxide-antioxidant (PAB) levels in patients with cataract was significantly higher than in healthy people (p<0.0001). CONCLUSION: This study showed that despite the high level of oxidative stress in patients, the activity rate of GPx and SOD enzymes also increased.

Neural adaptive observer-based sensor and actuator fault detection in nonlinear systems: Application in UAV.

A new online detection strategy is developed to detect faults in sensors and actuators of unmanned aerial vehicle (UAV) systems. In this design, the weighting parameters of the Neural Network (NN) are updated by using the Extended Kalman Filter (EKF). Online adaptation of these weighting parameters helps to detect abrupt, intermittent, and incipient faults accurately. We apply the proposed fault detection system to a nonlinear dynamic model of the WVU YF-22 unmanned aircraft for its evaluation. The simulation results show that the new method has better performance in comparison with conventional recurrent neural network-based fault detection strategies.