Exosomes released by oxidative stress-induced mesenchymal stem cells promote murine mammary tumor progression through activating the STAT3 signaling pathway.

Mesenchymal stem cells (MSCs) may play a pivotal role in shaping the tumor microenvironment (TME), influencing tumor growth. Nonetheless, conflicting evidence exists regarding the distinct impacts of MSCs on tumor progression, with some studies suggesting promotion while others indicate suppression of tumor cell growth. Considering that oxidative stress is implicated in the dynamic interaction between components of the TME and tumor cells, we investigated the contribution of exosomes released by hydrogen peroxide (H2O2)-treated MSCs to murine mammary tumor growth and progression. Additionally, we aimed to identify the underlying mechanism through which MSC-derived exosomes affect breast tumor growth and angiogenesis. Our findings demonstrated that exosomes released by H2O2-treated, stress-induced MSCs (St-MSC Exo) promoted breast cancer cell progression by inducing the expression of vascular endothelial growth factor (VEGF) and markers associated with epithelial-to-mesenchymal transition. Further clarification revealed that the promoting effect of St-MSC Exo on VEGF expression may, in part, depend on activating STAT3 signaling in BC cells. In contrast, exosomes derived from untreated MSCs retarded JAK1/STAT3 phosphorylation and reduced VEGF expression. Additionally, our observations revealed that the activation of the transcription factor NF-κB in BC cells, stimulated with St-MSC Exo, occurs concurrently with an increase in intracellular ROS production. Moreover, we observed that the increase in VEGF secretion into the conditioned media of 4T1 BC, mediated by St-MSC Exo, positively influenced endothelial cell proliferation, migration, and vascular behavior in vitro. In turn, our in vivo studies confirmed that St-MSC Exo, but not exosomes derived from untreated MSCs, exhibited a significant promoting effect on breast tumorigenicity. Collectively, our findings provide new insights into how MSCs may contribute to modulating the TME. We propose a novel mechanism through which exosomes derived from oxidative stress-induced MSCs may contribute to tumor progression and angiogenesis.

The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors.

Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.

The investigation of Pulse-Modulated GSM-900 MHz electromagnetic field effects on the electrochemotherapy mechanisms in vivo.

Electrochemotherapy (ECT) as a tumor treatment modality is approved for cutaneous and subcutaneous tumors. The purpose of the present study was to examine the effect of 900 MHz radiofrequency (RF) pulse-modulated by 217 Hz EMFs similar to those emitted by mobile phones on the mechanisms of ECT in vivo including: tumor hypoxia and immune system response, and on tumor volume.4 T1 cells were injected subcutaneously into the right flank of Balb/c mice. The mice were exposed to RF fields at specific absorption rate (SAR) 2 W/kg for 10 min/day and then treated with ECT. Two protocols of ECT were used: ((70 V/cm-5 kHz) and 70 V/cm-4 kHz)). Tumor hypoxia was analyzed through HIF-1α immuonohistochemistry assay. Interleukin 4 (IL-4) and IFN-γ levels were estimated by enzyme-linked immunosorbent assay (ELISA) technique to evaluate immune system response. Also, tumors volume changes were measured for 24 days following the treatment. The results showed that pulse-modulated RF fields could increase hypoxia induced by ECT, significantly (about 13% in ECT (70 V/cm-5 kHz) and 11% in ECT (70 V/cm-4 kHz)). However, these fields did not have significant effect on immune system response (the levels of IL-4 and IFN-γ) and tumor volume changes induced by ECT. Our results indicated that pulse-modulated RF fields could not affect tumor volume changes in ECT with the frequency of 5 kHz and voltage of 70 V/cm efficacy in vivo. However, investigating the role of other environmental intervening factors on this protocol of ECT is recommended in further studies.

Hyaluronic acid optimises therapeutic effects of hydrogen peroxide-induced oxidative stress on breast cancer.

Distinguishing the multiple effects of reactive oxygen species (ROS) on cancer cells is important to understand their role in tumour biology. On one side, ROS can be oncogenic by promoting hypoxic conditions, genomic instability and tumorigenesis. Conversely, elevated levels of ROS-induced oxidative stress can induce cancer cell death. This is evidenced by the conflicting results of research using antioxidant therapy, which in some cases promoted tumour growth and metastasis. However, some antioxidative or ROS-mediated oxidative therapies have also yielded beneficial effects. To better define the effects of oxidative stress, in vitro experiments were conducted on 4T1 and splenic mononuclear cells (MNCs) under hypoxic and normoxic conditions. Furthermore, hydrogen peroxide (H2 O2 ; 10-1,000 µM) was used as an ROS source alone or in combination with hyaluronic acid (HA), which is frequently used as drug delivery vehicle. Our result indicated that the treatment of cancer cells with H2 O2 + HA was significantly more effective than H2 O2 alone. In addition, treatment with H2 O2 + HA led to increased apoptosis, decreased proliferation, and multiphase cell cycle arrest in 4T1 cells in a dose-dependent manner under normoxic or hypoxic conditions. As a result, migratory tendency and the messenger RNA levels of vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), and MMP-9 were significantly decreased in 4T1 cells. Of note, HA treatment combined with 100-1,000 µM H2 O2 caused more damage to MNCs as compared to treatment with lower concentrations (10-50 µM). Based on these results, we propose to administer high-dose H2 O2 + HA (100-1000 µM) for intratumoural injection and low doses for systemic administration. Intratumoural route could have toxic and inhibitory effects not only on the tumour but also on residential myeloid cells defending it, whereas systemic treatment could stimulate peripheral immune responses against the tumour. More in vivo research is required to confirm this hypothesis.

The effect of 900 MHz electromagnetic fields on biological pathways induced by electrochemotherapy.

Electrochemotherapy (ECT) is a new and promising treatment strategy for cancer treatment. The aim of this work is to investigate the effect of 900 MHz radiofrequency electromagnetic fields (RF-EMFs) on the mechanisms of ECT (low voltage, high frequency) including cell permeability in vitro, and tumor hypoxia, immune system response in vivo, and on volume of tumors treated with ECT (70 V/cm, 5 kHz). The 4T1 cells were exposed to RF-EMFs at 17, 162, or 349 µW/cm2 power densities, using GSM900 simulator, 10 min. The cells were then put in individual groups, comprising of no treatment, chemotherapy, electric pulses (EPs), or ECT. The cell viability was evaluated. The mice with 4T1 tumor cells were exposed to RF field 10 min/day until the tumor volume reached about 8 mm. Then, the mice tumors were treated with ECT. Tumor hypoxia and immune system response was analyzed through immunohistochemistry (IHC) assay and ELISA technique, respectively. The volume of tumors was also calculated for 24 days following the treatment. The results showed that RF fields at 349 µW/cm2 could increase tumor hypoxia induced by ECT and cause a significant increase of Interferon-gamma (IFN-γ) in comparison with group ECT alone. However, 900 MHz radiations did not affect the volume of tumors treated to ECT (70 V/cm, 5 kHz) significantly. In this study, 900 MHz EMF could improve some biological pathways induced by ECT. Such a positive effect could utilize in some other treatments to increase efficacy, which should be investigated in further research.

Comparative immunomodulatory properties of mesenchymal stem cells derived from human breast tumor and normal breast adipose tissue.

OBJECTIVE: Mesenchymal stem cells (MSCs), one of the most important stromal cells in the tumor microenvironment, play a major role in the immunomodulation and development of tumors. In contrast to immunomodulatory effects of bone marrow-derived MSCs, resident MSCs were not well studied in tumor. The aim of this study was to compare the immunomodulatory properties and protein secretion profiles of MSCs isolated from breast tumor (T-MSC) and normal breast adipose tissue (N-MSC). MATERIALS AND METHODS: T-MSCs and N-MSCs were isolated by the explant culture method and characterized, and their immunomodulatory function was assessed on peripheral blood lymphocytes (PBLs) by evaluating the effects of MSC conditioned media on the proliferation and induction of some cytokines and regulatory T cells (Tregs) by BrdU assay, ELISA, and flow cytometry. In addition, we compared the secretion of indoleamine 2,3-dioxygenase (IDO), vascular endothelial growth factor (VEGF), matrix metallopeptidase (MMP)-2, MMP-9, and Galectin-1. RESULTS: T-MSCs showed a higher secretion of transforming growth factor beta (TGF-ß), prostaglandin E2 (PGE2), IDO, and VEGF and lower secretion of MMP-2 and MMP-9 compared with N-MSCs. However, no significant difference was found in the secretion of interferon gamma (IFN-γ), interleukin 10 (IL10), IL4, IL17, and Galectin-1 in T-MSCs and N-MSCs. The immunomodulatory effect of soluble factors on PBLs showed that T-MSCs, in contrast to N-MSCs, stimulate PBL proliferation. Importantly, the ability of T-MSCs to induce IL10, TGF-ß, IFN-γ, and PGE2 was higher than that of N-MSCs. In addition, T-MSCs and N-MSCs exhibited no significant difference in Treg induction. CONCLUSION: MSCs educated in stage II breast cancer and normal breast adipose tissue, although sharing a similar morphology and immunophenotype, exhibited a clearly different profile in some immunomodulatory functions and protein secretions.

Measurement of oxidized albumin: An opportunity for diagnoses or treatment of COVID-19.

Human serum albumin (HSA) as the most abundant protein in human blood plasma, can be a good indicator for evaluating severity of some diseases in the clinic. HSA can be find in two forms: reduced albumin (human mercaptalbumin (HMA)) and oxidized albumin (human non-mercaptalbumin (HNA)). The rate of oxidized albumin to total albumin can be enhanced in multiple diseases. Increase in HNA level have been demonstrated in liver, diabetes plus fatigue and coronary artery diseases. In liver patients, this enhancement can reach to 50-200 percent which can then lead to bacterial/viral infections and eventually death in severe conditions. Due to the induction of cytokine storm, we can say that the level of HNA in serum of coronavirus disease 2019 (COVID-19) patients may be a positive predictor of mortality, especially in patients with underlying diseases such as cardiovascular disease (CVD), diabetes, aging and other inflammatory diseases. We suggest that checking oxidized albumin in COVID-19 patients may provide new therapeutic and diagnostic opportunities to better combat COVID-19.

Investigating the route of administration and efficacy of adipose tissue-derived mesenchymal stem cells and conditioned medium in type 1 diabetic mice.

Type 1 diabetes (T1D) is a chronic autoimmune disease destroying the insulin-producing beta cells. Recently, stem cell therapy has been tested to treat T1D. In the present study, we aim to investigate the effects of intraperitoneal and intravenous infusion of multipotent mesenchymal stem/stromal cells (MSCs) and MSC-conditioned medium (MSC-CM) in an experimental model of diabetes, induced by multiple injections of Streptozotocin (STZ). The adipose tissue-derived MSC and MSC-CM were isolated from C57Bl/6 male mice and characterized. Later, MSC and MSC-CM were injected intraperitoneally or intravenously into mice. The blood glucose, urinary glucose, and body weight were measured, and the percentages of CD4+ CD25+ FOXP3+ T cells as well as the levels of IFN-γ, TGF-ß, IL-4, IL-17, and IL-10 were evaluated. Our results showed that both intraperitoneal and intravenous infusions of MSC and MSC-CM could decrease the blood glucose, recover pancreatic islets, and increase the levels of insulin-producing cells. Furthermore, the percentage of CD4+ CD25+ FOXP3+ T cells was increased after intraperitoneal injection of MSC or MSC-CM and intravenous injection of MSCs. After intraperitoneal injection of the MSC and MSC-CM, the levels of inflammatory cytokines reduced, while the levels of anti-inflammatory cytokines increased. Together current data showed that although both intraperitoneal and intravenous administration had beneficial effects on T1D animal model, but intraperitoneal injection of AD-MSC and AD-MSC-CM was more effective than systemic administration.

The role of 217-Hz ELF magnetic fields emitted from GSM mobile phones on electrochemotherapy mechanisms.

Electrochemotherapy (ECT), the combination of electric pulses (EPs) and an anticancer drug, is a type of cancer treatment method. We investigated the effect of 217-Hz magnetic fields (MFs) similar to that generated by GSM900 mobile phones, as intervening factors, on proposed mechanisms of ECT including permeability, tumor hypoxia and immune system response. The 4T1 cells were exposed to extremely low-frequency (ELF)-MFs at 93, 120 or 159 µT intensities, generated by Helmholtz coils 10 min, and then put in individual groups, comprising no treatment, chemotherapy, EPs or ECT. The cell viability was evaluated. Then, two treatment protocols were selected for in vivo experiments. The mice with 4T1 tumor cells were exposed to ELF-MFs 10 min/day until the day their tumors reached 8 mm in diameter. Then, the tumors were treated to ECT. Tumor hypoxia and immune system response were analyzed through immunohistochemistry assay and enzyme-linked immunosorbent assay technique, respectively. The results in vitro indicated a significant decreased ECT efficacy of 60 V/cm, 5 kHz at the flux density of 93 µT. The results in vivo showed that pre-exposure to ELF-MFs could increase tumor hypoxia induced by ECT. In addition, exposure to ELF-MFs before ECT caused a significant increase in interferon-γ/interleukin-4 in comparison with ECT alone. More studies, including studies on the effect of ELF-MFs emitted from mobile phones on tumor volume changes induced by ECT, are needed to elucidate how the process of ECT is influenced by the MFs.

microRNA modified tumor-derived exosomes as novel tools for maturation of dendritic cells.

Tumor-derived exosomes (TEX) are known by their immune suppression effects as well as initiation mediators in cancer progression and metastasis. Meanwhile, they are appropriate sources to induce immunity against tumor cells, as consist of tumor specific and associated antigens. The aim of the current study is modifying TEX with microRNA miR-155, miR-142, and let-7i, to enhance their immune stimulation ability and induce potent dendritic cells (DC). For this, exosomes were isolated from mouse mammalian breast cancer cell line; 4T1, and subjected to miR-155, miR-142, and let-7i by electroporation. Immature DCs were generated from mouse bone marrow in the presence of interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF). To mature DCs, lipopolysaccharide (LPS), TEX, and modified TEX were used. The expression level of miRNAs and their target genes (IL-6, IL-17, IL-1b, TGFß, SOCS1, KLRK1, IFNγ, and TLR4) was determined. TEX were nanovesicles with spheroid morphology which expressed CD81, CD63, and TSG101, as exosome markers, at protein level. MHCII, CD80, and CD40 as maturation markers were assessed by flow cytometry. Overexpression of miRNAs were confirmed in exosomes and mDCs. Up and downregulation of target genes confirmed the gene network in DC maturation. We found that Let-7i could efficiently induce the DC maturation, as well as miR-142 and miR-155 have enhancing effects. These findings reveal that the modified TEX would be a hopeful cell-free vaccine for the cancer treatment.

The anti-neoplastic effects of metformin modulate the acquired phenotype of fibroblast cells in the breast cancer-normal fibroblast co-culture system.

Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation, growth, and therapy resistance. The hallmarks of cancer-fibroblast interactions, consisting of caveolin 1 (Cav1) and mono-carboxylate transporter 4 (MCT4) (metabolic coupling markers), along with IL-6, TGFß, and lactate secretion, are considered robust biomarkers predicting recurrence and metastasis. In order to promote a novel phenotype in normal fibroblasts, we predicted that breast cancer cells could be able to cause loss of Cav1 and increase of MCT4, as well as elevate IL-6 and TGFß in nearby normal fibroblasts. We created a co-culture model using breast cancer (4T1) and normal fibroblast (NIH3T3) cell lines cultured under specific experimental conditions in order to directly test our theory. Moreover, we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cav1 and gain of MCT4 in adjacent fibroblasts and increase lactate secretion. These results were validated using the monoculture of each group separately as a control. In this system, we show that metformin inhibits IL-6 and TGFß secretion and re-expresses Cav1 in both cells. However, MCT4 and lactate stayed high after treatment with metformin. In conclusion, our work shows that co-culture with breast cancer cells may cause significant alterations in the phenotype and secretion of normal fibroblasts. Metformin, however, may change this state and affect fibroblasts' acquired phenotypes. Moreover, mitochondrial inhibition by metformin after 8 days of treatment, significantly hinders tumor growth in mouse model of breast cancer.

Comparative immunomodulatory properties of adipose-derived mesenchymal stem cells conditioned media from BALB/c, C57BL/6, and DBA mouse strains.

Adipose tissue-derived mesenchymal stem cells (AD-MSCs) have been shown to be capable of differentiating into multiple cell type and exert immunomodulatory effects. Since the selection of ideal stem cell is apparently crucial for the outcome of experimental stem cell therapies, therefore, in this study we compared AD-MSCs conditioned media (CM) from BALB/c, C57BL/6, and DBA mouse strains. No significant difference was found in the morphology, cell surface markers, in vitro differentiation and proliferation potentials of AD-MSCs isolated from C57BL/6, BALB/c, and DBA mice. The immunological assays showed some variation among the strains in the cytokines, nitric oxide (NO), and indoleamine 2,3-dioxygenase (IDO) production and immunomodulatory effects on splenocytes functions. Our results indicated a suppression of splenocytes proliferation in the presence of AD-MSC CM from the three inbred mouse strains. However, BALB/c CM exerted a higher suppression of splenocytes proliferation. AD-MSCs isolated from C57BL/6 and BALB/c mice produced higher levels of TGF-ß than those from DBA mice. Furthermore, IL-17 and IDO production was higher in AD-MSCs isolated from BALB/c mice. Our results indicated an increased production of TGF-ß, IL-4, IL-10, NO, and IDO by splenocytes in response to CM from BALB/c AD-MSCs. In conclusion, our results showed that the immunomodulatory properties of mouse AD-MSCs is strain-dependent and this variation should be considered during selection of appropriate stem cell source for in vivo experiments and stem cell therapy strategies.

In vitro immunomodulatory properties of osteogenic and adipogenic differentiated mesenchymal stem cells isolated from three inbred mouse strains.

Mesenchymal stem cells (MSCs) are used for cell-based therapies because of their immunomodulatory properties. The immunomodulatory properties of adipogenic (AD) and osteogenic (OS) differentiated adipose tissue-derived MSCs (AD-MSCs) isolated from BALB/c, C57BL/6, and DBA mice were compared. Splenocytes proliferation was suppressed in the presence of AD-MSCs conditioned media in all mice. After OS differentiation, BALB/c AD-MSCs produced higher levels of TGF-ß and IL-17 and lower levels of NO than AD-MSCs isolated from C57BL/6 and DBA mice. In addition, OS differentiated AD-MSCs isolated from DBA mice produced lower levels of IL-10 than AD-MSCs isolated from C57BL/6 and DBA mice. After in vitro AD and OD differentiation, AD-MSCs isolated from each mouse produced higher levels of NO and IDO than undifferentiated cells. Additionally, AD-MSCs isolated from C57BL/6 and DBA mice produced higher levels of NO than AD-MSCs isolated from BALB/c mice. Adipose tissue-derived MSCs thus retain their immunomodulatory properties after in vitro OS and AD differentiation in a strain-dependent manner.

Cloning, Expression, Purification and Toxicity Evaluation of Helicobacter pylori Outer Inflammatory Protein A.

The Helicobacter pylori outer membrane proteins play an important role in pathogenesis; the outer inflammatory protein A (OipA) is one of these proteins which play the main role in the development of inflammation. In this study, purification of recombinant H. pylori OipA was performed by Ni-NTA affinity chromatography. Gastric carcinoma epithelial cells (AGS cell) were treated by different concentrations of recombinant OipA for various lengths of time and cell viability was evaluated by the viability assay. Statistical analysis showed that OipA had toxic effects on AGS cells in a concentration of 500 ng/ml after 24 and 48 h, and this toxic dose was 256 ng/ml after 72 h. OipA had direct toxic effects on gastric epithelial cells and the toxicity was observed to depend on time and dose of H. pylori exposure. Attachment of H. pylori to gastric epithelial cells is a key part in the pathogenesis and enables H. pylori to damage the epithelial cells with OipA.

Short exposure to collagenase and coculture with mouse embryonic pancreas improve human dermal fibroblast culture.

The dermal fibroblast as a major component of connective tissue has attracted much attention in the past few years, and application of these very fast growing cells in several fields has been intensively studied. Isolating dermal fibroblasts is an appropriate way to expand these fast growing cells in vitro. Although using a dissociated fibroblast culture method is more convenient than skin explant culture, its enzymatic digestion is critical because a large number of cells can be lost over prolonged exposure to collagenase. This study was performed to increase the number of viable cells after digestion of fresh human foreskin of donors aged from 1 to 3 months with collagenase and also by to design a coculture system for resuscitation of the injured fibroblast. Our results demonstrate that we can maximize cell yield while maintaining cell viability by cutting the specimens into very small pieces (1-2 mm³) after removing the epidermal layer with dispase II and also by collecting released cells every 20 Min subsequent to digesting the dermal layer with collagenase. Moreover, our data strongly indicate that coculturing of isolated fibroblasts with embryonic pancreas explants can enhance the rate of proliferation in cultured fibroblasts.

Long-term ocular consequences of sulfur mustard in lung-injured war veterans.

PURPOSE: Ocular and pulmonary involvement are the most important complications of sulfur mustard (SM) that may happen many years after exposure. This study aims to evaluate the severity of ocular involvement and the correlation between late ocular and lung complications in patients exposed to SM. METHODS: This descriptive cross-sectional study was conducted on SM lung-injured war veterans. Status of pulmonary involvement was categorized into normal, mild, moderate, and severe based on the "Forced Expiratory Volume in first second (FEV1)".Status of ocular involvement was also categorized into normal, mild, moderate, and severe, based on the slit lamp findings. Correlation between pulmonary and ocular involvements was evaluated by Spearman rank correlation test. RESULTS: Totally, 292 war veterans with clinical pulmonary involvement were included in the study. Status of pulmonary involvement was 3.8% normal, 11.2% mild, 16.1% moderate, and 68.9% severe. Status of the ocular involvement was 68.2% normal, 13.8% mild, 5.4% moderate, and 12.6% severe. Among all patients, 96.3% had pulmonary involvement and 32.5% had ocular involvement. There was a positive correlation between the severity of ocular and pulmonary involvements (p = 0.049 and r = 0.122). CONCLUSION: The results of this study showed that although there was a positive correlation between the severity of pulmonary and ocular involvement, this correlation was weak. This might be due to the nature of the studied population or differences in the tissue susceptibilities, gas types, or exposure patterns.

Synthesis of Artemether-Loaded Albumin Nanoparticles and Measurement of Their Anti-Cancer Effects.

Colorectal cancer is the third most common cancer in the world. Due to the side effects of common treatments such as chemotherapy and radiotherapy, the use of herbal medicines has received much attention. Artemether (ARM) is an herbal medicine derived from artemisinin, which has many anti-tumor properties. However, factors such as low solubility and short half-life have limited the use of artemether in clinical practice. In this study, we aimed to reduce these limitations by encapsulating artemether in human serum albumin (HSA). The hydrodynamic diameter and the zeta potential value of ARM-ALB nanoparticles (NPs) were 171.3 ± 5.88 nm and -19.1 ± 0.82 mV, respectively. Comparison of the effect of free and encapsulated artemether on CT 26 cell line showed that the use of artemether in capsulated form can reduce the effective concentration of the drug. Additionally, in vivo studies have also shown that albumin-artemether nanoparticles can control tumor growth by increasing the production of cytokine IFN-γ and decreasing the production of IL4. Therefore, ARM-ALB nanoparticles have greater anti-tumor effects than free artemether.

New Paradigm in Cell Therapy Using Sperm Head to Restore Brain Function and Structure in Animal Model of Alzheimer's Disease: Support for Boosting Constructive Inflammation vs. Anti-Inflammatory Approach.

Alzheimer's is characterized by accumulation of amyloid-ß (Aß) associated with insufficient clearance of toxicants from the brain establishing a chronic inflammation and other abnormalities in the brain. Inflammatory microglia and astrocytes along with abnormal lymphatics associated with insufficient clearance of Aß and other toxicants from the brain establish a chronic inflammation. This causes abnormal choroid plexus, leukocyte trafficking, and hypoxic condition along with high levels of regulatory T cells (Tregs). There is no consensus among researchers regarding decreasing or increasing Tregs to achieve therapeutic effects. Different opposing studies tried to suppress or boost inflammation to treat AD. Based on reproductive immunology, sperm induces constructive inflammatory response and seminal-vesicle-fluid (SVF) suppresses inflammation leading to uterus remodeling. It prompted us to compare therapeutic efficiency of inflammatory or anti-inflammatory approaches in AD model based on reproductive immunology. To do so, SVF, sperm, or sperm head (from Wistar rat) was administered via intra-cerebro-ventricular route to Sprague Dawley rat AD model. Behavioral and histological examination were made and treatment groups were compared with control AD model and normal groups. Therapeutic efficacy was in the order of sperm head>sperm>SVF. Sperm head returned learning memory, Aß, lymphatics, neural growth factors, choroid plexus function, Iba-1/GFAP, MHC II/CD86/CD40, CD38/IL-10, and hypoxia levels back to normal level. However, SVF just partially ameliorated the disease. Immunologic properties of sperm/sperm head to elicit constructive inflammation can be extended to organs other than reproductive. This nature-based approach overcomes genetic difference as an important obstacle and limitation in cell therapy, and is expected to be safe or with least side effects.

Circular RNAs play roles in regulatory networks of cell signaling pathways in human cancers.

AIMS: Circular RNAs (circRNAs) are endogenous covalently closed non-coding RNAs produced by reverse splicing of linear RNA. These molecules are highly expressed in mammalian cells and show cell/tissue-specific expression patterns. They are also significantly dysregulated in various cancers and function as oncogenes or tumor suppressors. Emerging evidence reveals that circRNAs contribute to cancer progression via modulating different cell signaling pathways. Nevertheless, the functional significance of circRNAs in cell signaling pathways regulation is still largely elusive. Considering this, shedding light on the multi-pathway effects of circRNAs may improve our understanding of targeted cancer therapy. Here, we discuss how circRNAs regulate the major cell signaling pathways in human cancers. MATERIALS AND METHODS: We adopted a systematic search in PubMed using the following MeSH terms: circRNAs, non-coding RNAs, lncRNAs, exosomal circRNAs, cancer, and cell signaling. KEY FINDINGS: We discussed different roles of circRNAs during tumorigenesis in which circRNAs affect tumor development through activating or inactivating certain cell signaling pathways via molecular interactions using various signaling pathways. We also discussed how crosstalk between circRNAs and lncRNAs modulate tumorigenesis and provides a resource for the identification of cancer therapeutic targets. SIGNIFICANCE: We here elucidated how circRNAs can modulate different cell signaling pathways and play roles in cancer. This can broaden our horizons toward introducing promising prognostic, diagnostic, and therapeutic targets.

Cimetidine and Ibuprofen Modulate T Cell Responses in a Mouse Model of Breast Cancer.

Cimetidine and ibuprofen exhibit immunomodulatory effects as an antagonist of histamine H2 receptor, and a cyclooxygenase inhibitor, respectively. Here, the effects of cimetidine and ibuprofen on some effector T cell-related parameters were investigated using a breast cancer (BC) model. BC was established in Balb/c mice using the 4T1 cell line. On day 10 after tumor induction, the BC-bearing mice were classified into four groups and treated with PBS, cimetidine (20 mg/kg), ibuprofen (20 mg/kg) or a combination of "cimetidine + ibuprofen" via intraperitoneal injection (daily from days 11 to 30). The mice were sacrificed on day 31 and the frequency of splenic Th1 and Treg cells, plasma IFN-γ and TGF-ß levels, and intra-tumoral T-bet, GATA3, FOXP3 and RORγt expressions were detected using flowcytometry, ELISA and real-time-PCR, respectively. In untreated cancerous mice, the percentage of splenic Th1 cells and plasma IFN-γ levels were lower (P<0.003 and P<0.01, respectively), whereas the percentage of splenic Treg cells and plasma TGF-ß levels were higher than in healthy mice (P<0.04 and P<0.005, respectively). Treatment of BC-bearing mice with cimetidine, ibuprofen or both drugs promoted the frequency of Th1 cells (P<0.05, P<0.007 and P<0.005, respectively) as well as IFN-γ levels (P<0.004, P<0.0001 and P<0.03, respectively), while reduced the frequencies of Treg cells (P<0.02, P<0.03 and P<0.01, respectively), TGF-ß levels (P<0.006, P<0.02 and P<0.002, respectively), intra-tumoral expression of FOXP3 (P<0.006, P<0.005 and P<0.005, respectively), and intra-tumoral expression of RORγt (P<0.04, P<0.03 and P<0.05, respectively) compared with untreated BC mice. The "cimetidine + ibuprofen"-treated mice displayed greater T-bet expression than the un-treated mice (P<0.006). Cimetidine and/or ibuprofen-treated BC-bearing mice exhibited reduced intra-tumoral expression of GATA3 compared with the untreated BC mice, but the differences were not significant. Cimetidine and ibuprofen correct some effector T cell-related parameters in cancerous mice. Immunotherapeutic potentials cimetidine and ibuprofen in cancers need investigations.