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Objective(s): Breast cancer is one of the most common cancers among women, and current treatments are inadequate due to unwarranted side effects and lack of specificity resulting in off target consequences. Artesunate is a synthetic anti-malarial drug that exerts inhibitory effects on cancer cell lines via apoptosis and has been used treating some cancers. This study investigated the anticancer effects of Fe3O4 magnetic nanoparticles conjugated with chitosan, polyethylene glycol, folic acid, and artesunate in vivo and in vitro. Materials and Methods: Nanoparticles were synthesized by co-precipitation; morphology and size were determined by scanning electron microscopy (SEM), and the presence of the components was verified by nanoscale Fourier transform infrared spectroscopy (FTIR). 4T1 murine mammary tumor cells were treated with nanoparticles, and cell viability was determined by MTT assay. 4T1 cells were also subcutaneously injected into BALB/c mice, and magnetic resonance imaging was carried out two weeks later to determine tumor size among the groups. Interferon gamma (IFN-γ) and IL-4 levels (in splenocytes culture supernatant) were measured by ELISA, and tumors, surrounding tissues, and mouse livers were histopathologically studied. Results: The nanoparticle made in this article had good anticancer effects and caused apoptosis in cancer cells in breast cancer, and also strengthened the cellular immune system and further increased interferon gamma and increased the half-life of mice with cancer, while this nanoparticle It did not have the side effects of chemotherapy drugs. Conclusion: Artesunate-containing nanoparticles decreased 4T1 cell viability and increased apoptosis to a greater extent than nanoparticles without the drug. In vivo, artesunate nanoparticles showed no toxicity and were more effective in decreasing tumor size than control. They were also associated with increased survival, increased IFN-γ, and decreased IL-4 levels in the spleen. The findings show the drug targets cancer cells effectively with minimal side effects due to its herbal nature and targeted nano delivery. [ABSTRACT FROM AUTHOR]

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, TGFβ, 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 TGFβ 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 TGFβ 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. [ABSTRACT FROM AUTHOR]

Objectives The use of shark cartilage as a supplementary treatment has a long yet unresolved history in the realm of complementary-alternative medicine. This study aimed to investigate the impact of concentrated and purified extracts from Persian Gulf shark cartilage (PGSC) on oral cavity squamous cell carcinoma (SCC) (specifically, the KB cell line) induced in an animal model. Methods Ectopic tumors of oral cavity SCC were induced in eight nude mice through the heterotransplantation of the KB cell line. Once the tumor volume reached 100 mm3, the mice were randomly divided into two groups: treatment and control. The treatment group received shark cartilage at a dosage of 50 mg/kg body weight, while the control group received a phosphate buffer. The drug was administered daily for four days via the intraperitoneal route. Following this, the drug administration was halted for a period of five days before resuming (as per the NCI protocol). After 54 days, the animals were sacrificed, and their tumors were sent for immunohistochemical evaluation using Ki-67 and CD34 markers. Results The findings revealed a significant reduction in intratumoral blood vessels in the treatment group compared to the control group (P-value = 0.001). While there was a decrease in both the size of the tumor and the proliferation of tumor cells, this reduction was not statistically significant. The average proliferation index was 13.33% for the treatment group and 33.33% for the control group. Conclusion Significant decrease in intra-tumoral vascularity can control tumor spreading and metastasis, potentially playing an important role in cancer management of oral cavity SCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Several vaccine candidates for COVID-19 have been developed, and few vaccines received emergency approval with an acceptable level of efficacy and safety. We herein report the development of the first recombinant protein-based vaccine in Iran based on the recombinant SARS-CoV-2 spike protein in its monomeric (encompassing amino acid 1-674 for S1 and 685-1211 for S2 subunits) and trimer form (S-Trimer) formulated in the oil-in-water adjuvant system RAS-01 (Razi Adjuvant System-01). The safety and immunity of the candidate vaccine, referred to as RAZI-COV PARS, were evaluated in Syrian hamster, BALB/c mice, Pirbright guinea pig, and New Zeeland white (NZW) rabbit. All vaccinated animals received two intramuscular (IM) and one intranasal (IN) candidate vaccine at 3-week intervals (days 0, 21, and 51). The challenge study was performed intranasally with 5×106 pfu of SARS-CoV-2 35 days post-vaccination. None of the vaccinated mice, hamsters, guinea pigs, or rabbits showed any changes in general clinical observations; body weight and food intake, clinical indicators, hematology examination, blood chemistry, and pathological examination of vital organs. Safety of vaccine after the administration of single and repeated dose was also established. Three different doses of candidate vaccine stimulated remarkable titers of neutralizing antibodies, S1, Receptor-Binding Domain (RBD), and N-terminal domain (NTD) specific IgG antibodies as well as IgA antibodies compared to placebo and control groups (P<0.01). Middle and high doses of RAZI-COV PARS vaccine significantly induced a robust and quick immune response from the third-week post-immunization. Histopathological studies on vaccinated hamsters showed that the challenge with SARS-CoV-2 did not induce any modifications in the lungs. The protection of the hamster was documented by the absence of lung pathology, the decreased virus load in the lung, rapid clearance of the virus from the lung, and strong humoral and cellular immune response. These findings confirm the immunogenicity and efficacy of the RAZI-COV PARS vaccine. Of the three tested vaccine regimens, the middle dose of the vaccine showed the best protective immune parameters. This vaccine with heterologous prime-boost vaccination method can be a good candidate to control the viral infection and its spread by stimulating central and mucosal immunity. [ABSTRACT FROM AUTHOR]

Alzheimer's is characterized by accumulation of amyloid-β (Aβ) 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 Aβ 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, Aβ, 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. [ABSTRACT FROM AUTHOR]

Alzheimer's is characterized by accumulation of amyloid-β (Aβ) 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 Aβ 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, Aβ, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metformin, cimetidine, and ibuprofen separately exhibit immunomodulatory and anti-tumorigenic effects. Herein, the impacts of metformin alone and in combination with cimetidine/ibuprofen on some Th1- and regulatory T (Treg) cell-related parameters were evaluated using a breast cancer (BC) model. For establishing the BC model, four groups of Balb/c mice were challenged with the carcinoma cell line. After 11-30 days post-induction, they were treated intraperitoneally (with metformin (200 mg/kg), "metformin plus cimetidine (20 mg/kg)"; "metformin plus ibuprofen (20 mg/kg)", or with all three drugs in mentioned doses. Untreated BC and without tumor mice were enrolled as control groups. On day 31, splenic Th1 and Treg cell frequencies, serum interferon-gamma (IFN-γ), and transforming growth factor-beta (TGF-β) concentration, and intra-tumoral T-bet, TGF-β, and forkhead box protein P3 (FOXP3) expression were measured; using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and real-time-PCR, respectively. Treatment of the BC mice with metformin alone and in combination with cimetidine and/or ibuprofen enhanced the frequency of Th1 cells, and IFN-γ concentration, while it resulted in a decrease in the frequency of Treg cells, serum TGF-β concentration, and the expression of FOXP3 and TGF-β compared with un-treated BC mice. FOXP3 expression in the metformin-treated group was lower in mice who received combination therapy. Survival rate and body weight were increased, while tumor size and spleen index were reduced in mice treated with metformin alone and its combination with cimetidine and/or ibuprofen. No remarkable differences were found between metformin-treated mice and those who received combination therapies regarding Th1 and Treg cell percentages, TGF-β expression, body weight, tumor size, and spleen index. The benefits of combinational therapy may be largely attributed to metformin. Immunotherapeutic potentials of metformin in cancers need further considerations. [ABSTRACT FROM AUTHOR]

The potent anti-tumorigenic effects were attributed to ginger and there are some reports regarding the anti-cancer and immunomodulatory properties ginger-derived components. This study aimed to investigate the effects of zingerone on some immune-related parameters in an animal model of breast cancer. The breast cancer was established in female BALB/c mice using a carcinogenic 4T1 cell line. At day 10 after cancer induction, tumor-bearing mice were divided into five groups and treated intraperitoneal (daily from days 11–30) with saline or zingerone (at doses 10, 20, 50 and 100 mg/kg/day). The mice were sacrificed on day 31 and the number of splenic Th1- and Treg cells, the expression of IFN-γ and TGF-β in the blood mononuclear cells, the antibody production against sheep red blood cell (SRBC) were determined using flow cytometry, real time-PCR and a standard hemagglutination assay, respectively. Zingerone at doses 50 and 100 mg/kg enhanced the number of splenic Th1 cells (p<0.03 and 0.007, respectively); at doses 10, 20, 50 and 100 mg/kg reduced the number of splenic Treg cells (p<0.02, 0.01, and 0.01, respectively), at doses 50 and 100 mg/kg enhanced the expression of IFN-γ (p<0.03), at doses 50 and 100 mg/kg reduced the expression of TGF-β, at doses 50 mg/kg reduced the titer of anti-SRBC antibody (p<0.05). Zingerone improve the T cell-mediated and antibody responses in a mouse model of breast cancer. The immunotherapeutic potentials of zingerone in cancers need more considerations. [ABSTRACT FROM AUTHOR]

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 (H2O2; 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 H2O2 + HA was significantly more effective than H2O2 alone. In addition, treatment with H2O2 + 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 H2O2 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 H2O2 + 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The T-cell immunoglobulin and mucin-3 (TIM-3)/galectin-9 (Gal-9) autocrine loop is an indispensable signaling in acute myeloid leukemia (AML) cells, which induces their self-renewal through activation of nuclear factor-kappa b (NF-kB) and β-catenin pathways. In this study, we evaluated the effects of oridonin and doxorubicin on the TIM-3/Gal-9 autocrine loop. We also evaluated oridonin anti-inflammatory and anti-cancer properties on U937 cells, as an AML cell line in comparison to doxorubicin as a common anthracycline drug for AML treatment. Cell counting kit-8 (CCK-8) was applied to evaluate the cytotoxicity of oridonin and doxorubicin on U937 cells and also to determine the impact of galectin-9 (Gal-9) on their proliferation. The effects of oridonin and doxorubicin on Gal-9, TIM-3, and interleukin-1β (IL-1β) gene expression were determined by real-time polymerase chain reaction (RT-PCR). The Gal-9 secretion level was measured by enzyme-linked immunosorbent assay (ELISA) and activation of NF-kB pathway was assessed by western blotting. In a dose-dependent manner, oridonin and doxorubicin were capable to eradicate U937 cells while Gal-9 expanded them. Following the treatment of U937 cells with oridonin, the expression of Gal-9, TIM-3, and IL-1β genes was down-regulated, and the Gal-9 secretion and NF-kB phosphorylation were diminished, whereas doxorubicin increased all of these factors. Doxorubicin is a common treatment agent in AML, but it may induce inflammation and upregulate the TIM3/Gal-9 autocrine loop, consequently can enhance the possibility of disease relapse. Meanwhile, oridonin is capable to inhibit the essential signaling pathways in AML cells and reduce the inflammation and expansion of tumor cells and postpone AML recurrence. [ABSTRACT FROM AUTHOR]

No Abstract. [ABSTRACT FROM AUTHOR]