Correlation of PTEN signaling pathway and miRNA in breast cancer.

Breast cancer (BC) is one of the most common cancers among women and can be fatal if not diagnosed and treated on time. Various genetic and environmental factors play a significant role in the development and progression of BC. Within the body, different signaling pathways have been identified that contribute to cancer progression, or conversely, cancer prevention. Phosphatase and tensin homolog (PTEN) is one of the proteins that prevent cancer by inhibiting the oncogenic PI3K/Akt/mTOR signaling pathway. MicroRNAs (miRNAs) are molecules with about 18 to 28 base pairs, which regulate about 30% of human genes after transcription. miRNAs play a key role in the progression or prevention of cancer through different signaling pathway and mechanisms, e.g., apoptosis, angiogenesis, and proliferation. miRNAs, which are upstream mediators of PTEN, can reinforce or suppress the effect of PTEN signaling on BC cells, and suppressing the PTEN signaling, linked to weakness of the cancer cells to chemotherapeutic drugs. However, the precise mechanism and function of miRNAs on PTEN in BC are not yet fully understood. Therefore, in the present study, has been focused on miRNAs regulating PTEN function in BC.

Plant-derived VLP: a worthy platform to produce vaccine against SARS-CoV-2.

After its emergence in late 2019 SARS-CoV-2 was declared a pandemic by the World Health Organization on 11 March 2020 and has claimed more than 2.8 million lives. There has been a massive global effort to develop vaccines against SARS-CoV-2 and the rapid and low cost production of large quantities of vaccine is urgently needed to ensure adequate supply to both developed and developing countries. Virus-like particles (VLPs) are composed of viral antigens that self-assemble into structures that mimic the structure of native viruses but lack the viral genome. Thus they are not only a safer alternative to attenuated or inactivated vaccines but are also able to induce potent cellular and humoral immune responses and can be manufactured recombinantly in expression systems that do not require viral replication. VLPs have successfully been produced in bacteria, yeast, insect and mammalian cell cultures, each production platform with its own advantages and limitations. Plants offer a number of advantages in one production platform, including proper eukaryotic protein modification and assembly, increased safety, low cost, high scalability as well as rapid production speed, a critical factor needed to control outbreaks of potential pandemics. Plant-based VLP-based viral vaccines currently in clinical trials include, amongst others, Hepatitis B virus, Influenza virus and SARS-CoV-2 vaccines. Here we discuss the importance of plants as a next generation expression system for the fast, scalable and low cost production of VLP-based vaccines.

The benefits of Vitamin D in the COVID-19 pandemic: biochemical and immunological mechanisms.

In December 2019, a new infectious complication called CoronaVirus Infectious Disease-19, briefly COVID-19, caused by SARS-COV-2, is identified in Wuhan, China. It spread all over the world and became a pandemic. In many individuals who had suffered SARS-COV-2 infection, cytokine storm starts through cytokine overproduction and leads to Acute Respiratory Syndrome (ARS), organ failure, and death. According to the obtained evidence, Vitamin D (VitD) enhances the ACE2/Ang(1-7)/MasR pathway activity, and it also reduces cytokine storms and the ARS risk. Therefore, VitD intake may be beneficial for patients with SARS-COV-2 infection exposed to cytokine storm but do not suffer hypotension. In the present review, we have explained the effects of VitD on the renin-angiotensin system (RAS) function and angiotensin-converting enzyme2 (ACE2) expression. Furthermore, we have reviewed the biochemical and immunological effects of VitD on immune function in the underlying diseases and its role in the COVID-19 pandemic.

Cancer Drug Resistance Reduction via Co-treatment with Oxaliplatin and Nitazoxanide: Targeting the ABC Transporters.

OBJECTS: Shortly after cancer is diagnosed, a phenomenon develops in cancer cells called multidrug resistance (MDR), in which cell sensitivity against anti-cancer drugs is significantly reduced. The present investigation aimed to assess the effects of nitazoxanide (NTZ), a safe drug, on LS174T/OXP-resistant cells. METHODS: In the current in vitro research, the effects of NTZ and oxaliplatin (OXP) on the viability of LS174T and LS174T/OXP cell lines were evaluated through MTT assay. Then, the changes in expression levels of MDR1, MRP1, BCRP, and LRP genes and proteins were measured by RT-qPCR and western blotting methods, respectively. Lastly, the apoptosis status was assessed by annexin V-FITC/PI staining flow cytometry assay. RESULTS: The IC50 values for cells resistant or sensitive to OXP were revealed (11567 nM vs. 1745 nM; p <0.05 for 24 h incubation, and 5161 nM vs. 882.2 nM; p <0.05 for 48 h incubation). Moreover, NTZ plus OXP led to a leftward shift in the cytotoxicity curve (2004 nM; p = 0.007). This co-treatment significantly decreased the expression of all genes and proteins (p <0.05). Finally, the combination of NTZ and OXP induced a significant increase in apoptosis (p <0.001). CONCLUSION: The data showed that NTZ treatment could increase the sensitivity of LS174T/OXP cell line to the OXP cytotoxic effects. Thus, NTZ may be efficient in reducing drug resistance in clinics by means of the negative regulation of ATP-binding cassette (ABC) transporters. However, further studies are necessary to explain the exact mechanisms of NTZ.

Nitazoxanide and Cancer Drug Resistance: Targeting Wnt/ß-catenin Signaling Pathway.

OBJECTIVES: One of the most important complications that lead to unsuccessful treatment of cancer is resistance against chemotherapy agents, so called multidrug resistance (MDR). Thus, identification of the novel medications with low side effects and high efficacy to reverse MDR is highly required. Accordingly, the current study was performed to investigate the molecular mechanism of MDR in LS174T and LS174T/Oxaliplatin (OXP) cell lines during treatment with Nitazoxanide (NTZ) in combination with OXP. MATERIALS AND METHODS: In the present in vitro study, we evaluated the effects of NTZ on the cytotoxicity of OXP using Thiazolyl Blue Tetrazolium Blue (MTT) assay in LS174T and LS174T/OXP cell lines when treated with OXP and NTZ, alone or in combination, for 24 and 48 h incubation. Then, we assessed the changes in the expression level of CTNNB1, ABCB1, c-Myc, and cyclin D1 genes in different treated groups. RESULTS: Exposure of LS174T/OXP cells to NTZ led to the elevation of cell sensitivity to OXP and induced caspase-3/7 activity, which results in apoptosis. Furthermore, NTZ downregulated Wnt/ß-catenin signaling pathway through significant decrease of CTNNB1, c-Myc, ABCB1, and cyclin D1 genes and resulted in drug resistance reversal and inhibition of cell proliferation. CONCLUSION: These results indicate that Wnt/ß-catenin pathway is important in developing cancer and MDR. In this regard, NTZ could reverse MDR in colorectal cancer (CRC) cells by downregulation of Wnt/ß-catenin signaling pathway, suggesting that NTZ should be more considered in future studies as a potent adjuvant in CRC chemotherapy.

Blockage of Wnt/ß-catenin Signaling Pathway in Colorectal Cancer Resistant Cells by Nitazoxanide Effects on Peptidylarginine Deiminases Expression.

BACKGROUND: Multidrug resistance (MDR) is a major cause of unsuccessful cancer treatment in which drugs are not effective. Therefore, it is necessary to identify the critical mechanisms of the development of MDR and target those with novel compounds. Accordingly, the current study is the first to investigate the combination effect and molecular mechanism of nitazoxanide (NTZ) and oxaliplatin (OXP) on LS174T/OXP-resistant cells. METHODS: The effect of NTZ on OXP cytotoxicity in LS174T and LS174T/OXP cell lines was evaluated by MTT assay. Changes in expression levels of MDR1, MRP1, CTNNB1, peptidylarginine deiminase (PAD)2, and PAD4 genes and proteins were evaluated by RT-qPCR and western blotting methods, respectively. Lastly, the apoptosis assay was performed by flow cytometer. RESULTS: OXP resistant and sensitive cells were identified based on the IC50 values (11567 nM vs. 1745 nM, p<0.05 for 24 h treatment; and 5161 nM vs. 882 nM, p<0.05 for 48 h incubation). The combination of NTZ and OXP for 48 h led to a reduction in IC50 values in resistant cells (2154 nM, p<0.05). The effect of NTZ plus OXP significantly decreased the expression of MDR1 (p<0.001), MRP1 (p<0.05), and CTNNB1 (p<0.001), while PAD2 and PAD4 expression was significantly increased (p<0.001). This combination therapy enhanced the percentage of the sub-G1 population (apoptosed) compared to other groups. CONCLUSION: The results showed that NTZ leads to notable upregulation of PAD2 and PAD4, which can disrupt the Wnt/ß-catenin signaling pathway and reverse the MDR by reducing MDR1 and MRP1 expression.

Serum Copper and Zinc Levels Among Iranian Vitiligo Patients.

Introduction: Vitiligo is a chronic skin disease, which its etiopathogenesis is not fully understood. Numerous studies have suggested that oxidative stress may play a role in the pathophysiology of vitiligo. There are controversial reports as to the changes of serum trace elements, copper (Cu) and zinc (Zn) levels in vitiligo patients. Objectives: We evaluated the alterations in the level of serum Cu and Zn among a group of Iranian vitiligo patients. Methods: The levels of serum Cu and Zn were compared between 117 vitiligo patients and 137 healthy controls using atomic absorption spectrophotometry. Results: The mean Cu and Zn levels in the cases (113.57 ± 59.43 and 95.01 ± 58.95 µg/dl, respectively) were significantly lower than those of the controls (138.90 ± 38.14 and 121.83 ± 33.80 µg/dl, respectively) (P = 0.00). We also observed significantly lower serum Cu and Zn concentrations in young (< 50 years) than the elderly (≥ 50 years) patients (P = 0.00). The mean Cu and Zn levels in the patients with generalized vitiligo (111.63±54.18 and 93.11±59.33 µg/dl, respectively) were significantly lower than patients with localized vitiligo (120.74 ±71.64 and 98.69±58.63 µg/dl, respectively) and those in the control (P = 0.00). The serum Cu/Zn ratio obtained in the young and male patients was higher than those in their matched controls (P = 0.01). Conclusions: The current study has shown that the disturbance of serum Cu and Zn levels is associated with vitiligo, and may play an important role in the disease development of Iranian patients.

Fertility preservation in women with ovarian cancer: Finding new pathways: A case-control study.

BACKGROUND: Surgery and chemotherapy are the two most common treatments for cancers, including ovarian cancer. Although most ovarian cancers occur over the age of 45 yr, it may involve younger women and affect their reproductive ability. OBJECTIVE: To assess the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), Forkhead Box O1 (FOXO1), and miR-340 genes in the ovarian cancer tissues as well as ovarian cancer cell lines. MATERIALS AND METHODS: In this case-control study, 30 ovarian cancer samples (with the average age of 37 ± 2.5 years) coupled with their non-tumor marginal tissue (as a control) were collected. Proliferated cell lines were treated with several concentrations of cisplatin, and the half maximal inhibitory concentration (IC50) of cisplatin was quantified by MTT-assay. After RNA extraction, cDNA synthesis and qRT-PCR were done. Finally, the results were analyzed. RESULTS: While the expression levels of miR-340 and FOXO1 genes in tumor samples displayed a significant reduction (p ≤ 0.001), the LGR5 gene presented a significant increase in expression (p ≤ 0.0001). However, conversely, the expression levels of miR-340 and FOXO1 genes in cisplatin-sensitive cell lines, after 24, 48, and 72 hr of cisplatin treatment, indicated a significant increase (p ≤ 0.001) while the expression of LGR5 gene showed a significant decrease in the cisplatin-sensitive cell line (p < 0.05). CONCLUSION: The LGR5, FOXO1, and miR-340 genes can be targeted for early diagnosis and more accurate treatment of ovarian cancer and may prevent some of the ovarian cancer complications such as infertility.

Serum lipid profile of Parkinson's disease patients: A study from the Northwest of Iran.

BACKGROUND: Parkinson's disease (PD) is defined as a long-lasting, neurological illness. Low levels of serum lipid fractions are related with a high risk of PD. Current investigation was designed to evaluate the concentration blood lipid fractions in patients suffering from PD and compared with healthy subjects. METHODS: This case-control study was conducted from February 2016 to September 2018 in Tabriz University of Medical Sciences, Tabriz, Iran. The present investigation consisted of 75 persons who had PD and 75 normal people. The blood levels of lipid fractions were measured by concentrations of total cholesterol (TC), serum triglycerides (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), and total cholesterol. The results were analyzed with SPSS software using Kolmogorov-Smirnov, chi-square, and student's t-test. RESULTS: Serum level of TG was remarkably lower in patients with PD (111.92±8.75 mg/dL) compared with healthy subjects (123.64±9.97 mg/dL, P=0.008). Furthermore, we saw an important difference in the level of LDL-C (P=0.001) and TC (P=0.004) between the two groups. However, there was not any observed meaningful difference in the serum concentrations of HDL-C between the studied groups (P=0.135). CONCLUSION: Our results showed that the serum concentration of TG, LDL-C, and TC are noticeably lower in the PD suffering patients. Further investigations are needed to provide comprehensive information on the participants' cognitive layout and subsequent actions.

The Association between Serum Oxidative Stress Indexes and Pathogenesis of Parkinson's Disease in the Northwest of Iran.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Oxidative stress is a main modulator in the advancement of PD. This investigation aimed to evaluate the relations between serum trace elements, vitamin C, ferritin, transferrin, Nitrite Oxide (NOx) and Peroxynitrite (PrN) concentrations and clinical parameters in patients with PD. METHODS: Serum concentrations of variables were measured in 75 PD patients and 75 healthy subjects from Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran between Feb 2016 and Sep 2018. Receiver Operating Characteristic (ROC) analysis was performed to examine incremental diagnostic value of vitamin C, NOx, and PrN in the study groups. RESULTS: Mean serum NOx (35.81±5.16 vs. 11.27±3.59 mol/L, P<0.001) and PrN (15.78±4.23 vs. 9.62±4.57 mol/L, P= 0.004) were markedly higher in patient group versus healthy individuals. Significant differences were also observed in the serum levels of vitamin C (P<0.001), copper (Cu) (P<0.001), Iron (Fe) (P=0.003), and Zinc (Zn) (P<0.001) between patients with PD and healthy subjects. Nevertheless, the serum levels of Se (P=0.515), ferritin (P=0.103), and transferrin (P=0.372) were not statistically significant between the study groups. ROC analysis has revealed a diagnostic ability of serum vitamin C levels for PD with an area under ROC curve of ≥0.7 (P<0.05) and relatively high sensitivity and specificity. CONCLUSION: Serum levels of NOx and PrN are significantly higher in patients with PD. In additions, serum vitamin C levels have a diagnostic value as a biomarker. Further studies are required with larger sample size to provide more detailed information about the cognitive profile of participants and the outcome measures.

Preparation and characterization of functional sodium caseinate/guar gum/TiO2/cumin essential oil composite film.

Eco-friendly functional bionanocomposite films were prepared using sodium caseinate (SC) and guar gum (GG) as the polymer matrix and TiO2 and cumin essential oil (CEO) as functional fillers. 0.2 vol% GG selected for the preparation of SC/GG composite film and various amount of TiO2 and CEO (1 and 2 wt% based on SC) were incorporated into the SC/GG film either individually or in combination. The addition of TiO2 and CEO significantly improved the water permeability and sensitivity properties and mechanical characteristics such as the strength (TS), stiffness (YM), and flexibility (EB) of the composite films. Also, the SC/GG films incorporated with TiO2 and CEO exhibited remarkable antibacterial activity against both Gram-positive (L. monocytogenes and S. aureus) and Gram-negative (E. coli O157: H7 and S. enteritidis) bacteria. All the film properties were varied not only on the concentration of TiO2 and CEO, but also increased synergistically when they were added together.

Mysterious Virus: A Review on Behavior and Treatment Approaches of the Novel Coronavirus, 2019-nCoV.

At the end of the year 2019, the novel coronavirus (2019-nCoV) was spreading in Wuhan, China, and the outbreak process has a high speed. It was recognized as a pandemic by the World Health Organization (WHO) on 11 March 2020. Coronaviruses are enveloped and single-stranded RNA that have several families including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The pathogenesis mechanism and disease outcomes of SARS and MERS are now clear to some extent, but little information is available for 2019-nCoV. This newly identified corona virus infection represents flu-like symptoms, but usually the first symptoms are fever and dry cough. There has been no specific treatment against 2019-nCoV up to now, and physicians only apply supportive therapy. In the present article, we made an attempt to review the behavior of the virus around the world, epidemiology, a pathway for influx into the host cells, clinical presentation, as well as the treatments currently in use and future approaches; nitazoxanide may be our dream drug. We hope that this review has a positive impact on public knowledge for helping to deal with the 2019-nCoV and move one step forward toward its treatment in the near future.

Dysregulation of body antioxidant content is related to initiation and progression of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative illness. It has been believed that oxidative stress (OS) is an important factor in the advancement of PD. This investigation attempts to evaluate the relations between blood trace elements, ferritin, and transferrin concentrations as well as the levels of protein and gene expression of ceruloplasmin (CP), Nrf-2, and HO-1 in patients suffering PD. METHODS: The serum concentrations of variables were assessed in 110 PD patients group and 110 normal subjects. Furthermore, we applied qRT-PCR as well as western blot (WB) analysis to measure the levels of gene and protein, respectively. RESULTS: Considerable differences were detected in the serum concentrations of copper (Cu), iron (Fe), and zinc (Zn), when healthy and patient groups were compared. Nevertheless, the levels of Se, ferritin, and transferrin were not significantly different between the two groups. qRT-PCR and WB data analysis revealed significant differences of CP, Nrf-2, and HO-1at genes expression and protein levels when comparing the two PD patients and control groups. CONCLUSION: The results of the current work revealed that blood levels of Cu, Fe, and Zn were significantly higher in subjects who had PD. In addition, it was found that the levels of protein and gene expression CP, Nrf-2, and HO-1 were markedly higher in PD group than in non-PD subjects. Indeed, in this study, the results showed that the antioxidant content of the body can be linked to PD.

Oxidative stress and Parkinson's disease: conflict of oxidant-antioxidant systems.

Parkinson's disease (PD) is defined as a chronic neurodegenerative disorder which is diagnosed mostly by its clinical manifestations. Reactive oxygen species (ROS) are considered as key modulators in the development of PD. Despite the intensive investigations, antioxidant-dependent molecular mechanisms of initiation and development of PD are controversial. Free radicals cause serious damage and death of dopamine producing cells when antioxidant capacity of the cells is reduced against oxidative stress (OxS). Many intracellular reactions create ROS, including activation of NADPH oxidase (NOX), mitochondrial dysfunction, and hydrogen peroxide (H2O2) decomposition. On the contrary, natural antioxidants, vitamins, proteins, and antioxidant signaling pathways are major factors to neutralize ROS and its destructive effects. The functional role of nuclear factor E2-related factor 2, Heme oxygenase-1, and selenium against ROS-dependent initiation and progression of PD is elucidated. In this review, we collected multiple factors that play the main role in the initiation, development, and pathogenesis of PD and we discussed their function in the PD.

Micheliolide Protects Against Doxorubicin-Induced Cardiotoxicity in Mice by Regulating PI3K/Akt/NF-kB Signaling Pathway.

Micheliolide (MCL) is a naturally derived anti-inflammatory agent. In the present investigation, we examined the protective potential of MCL against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were injected with a single 15-mg/kg intraperitoneal dose of DOX at day 1 and the study groups received daily 12.5, 25, and 50 mg/kg doses of MCL for 7 days. Cardiac histopathology, cardiac function, serum markers of cardiac injury, and tissue markers of inflammation, and oxidative stress were examined. MCL decreased serum levels of creatinine kinase MB (CK-MB) and cardiac troponin I (cTnI) levels, ameliorated cardiac tissue architecture, and improved cardiac stroke volume. Apart from reducing the activities of NF-kB p65 subunit, MCL attenuated the cardiac levels of PI3K, phosphorylated (p)-Akt, p-Bad, and caspase-3 levels and simultaneously elevated p-PTEN levels. While the gene expressions of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) were decreased, the tissue activities of superoxide dismutase (SOD) as well as gene expressions of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase-1 (NQO1) were increased after treatment with MCL. Furthermore, tissue levels of malondialdehyde (MDA) were also decreased. Collectively, these findings point to the protective effects of MCL against DOX-induced cardiotoxicity by regulating PI3K/Akt/NF-kB signaling pathway in mice.

Candidate biomarkers for Parkinson's disease.

Parkinson's disease (PD) is one of the most common diseases associated with neurodegenerative disorders. It affects 3% to 4% of the population over the age of 65 years. The neuropathological dominant symptoms of PD include the destruction of neurons in the substantia nigra, thus causing striatal dopamine deficiency and the presence of intracellular inclusions that contain aggregates of α­synuclein. The premature form of PD is familial and is known as early onset PD (EOPD). It involves a small portion of patients with PD, displaying symptoms before the age of 60 years. Although individuals who are suffering from the EOPD may have genetic changes, the molecular mechanisms that differentiate between EOPD and late onset PD (LOPD) remain unclear. Owing to the complexity of discriminating between the different forms, treatment, and management of PD, the identification of biomarkers for early diagnosis seems necessary. For this purpose, many studies have been undertaken for the introduction of several biological molecules through various techniques as potential biomarkers. The main focus of these studies was on α-synuclein. However, there are other molecules that are potential biomarkers, such as microRNAs and peptoids. In this article, we tried to review some of these studies.

Dysregulation of serum NADPH oxidase1 and ferritin levels provides insights into diagnosis of Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) is a common neurodegenerative disease. Oxidative stress is considered as a key modulator in the development of PD. This study aimed to investigate associations between serum NOX1 (NADPH oxidase1), ferritin, selenium (Se), and uric acid (UA) levels and clinical parameters in patients with PD. DESIGN AND METHODS: Serum levels of NOX1, ferritin, Se, and UA were measured in 40 PD patients and 40 healthy individuals. Receiver operating characteristic (ROC) analysis was performed to investigate incremental diagnostic value of each factor in the study groups. RESULTS: Mean serum NOX1 levels were markedly higher in patient group (22.36±5.80ng/mL) versus healthy individuals (8.89±2.37ng/mL) (p<0.001). Significant differences were also observed in the serum concentrations of ferritin (p=0.005) and Se (p=0.001) between patients with PD and healthy individuals. However, the serum concentrations of UA were not statistically significant between the study groups (p=0.560). ROC analysis revealed a diagnostic ability of serum NOX1 and ferritin levels for PD with an area under ROC curve of ≥0.7 (p<0.05) and relatively high sensitivity and specificity. Combination of serum NOX1 and Se along with ferritin and UA levels increased the sensitivity up to 85%, specificity up to 97% and area under the ROC curve up to 0.94 (95% confidence interval (95% CI): 0.89 to 0.99, p<0.001). CONCLUSION: Our findings indicated that serum concentrations of NOX1, ferritin, and Se are significantly higher in the patients with PD. Therefore, these factors can be considered as potential diagnostic biomarkers for diagnosis and monitoring of PD patients. Further studies are required with larger sample size to provide more detailed information about the cognitive profile of participants and the outcome measures.