Candidiasis in breast cancer: Tumor progression or not?

Candida albicans is an "opportunistic fungal agent" in cancer patients that can become colonized in both mucosal and deep tissues and cause severe infections. Most evidence has shown that C. albicans can enhance the progress of different cancers by several mechanisms such as generating virulence factors, participation in endogenous production of pro-inflammatory mediators, and stimulating a wide range of immune cells in the host. The main idea of this review is to describe a range of Candida-used mechanisms that are important in candidiasis-associated malignant processes and cancer development, particularly breast cancer. This review intends to provide a detailed discussion on different regulatory mechanisms of C. albicans that undoubtedly help to open new therapeutic horizons of cancer therapy in patients with fungal infection. The current therapeutic approach is not fully effective in immunocompromised and cancer patients, and further studies are required to find new products with effective antifungal properties and minimal side effects to increase the susceptibility of opportunistic fungal infections to conventional antifungal agents. So, in this situation, a special therapy should be considered to control the infection and simultaneously have the most therapeutic index on tumor patients.

Activin A-Targeted Therapy in Cancer: An Updated Review on Challenges and Opportunities in Clinical Translation.

Activin A (ActA) is a cytokine from the TGF-ß superfamily that mediates a vast number of physiological mechanisms, mainly through the SMAD signaling pathway. Growing evidence indicates that ActA overexpression is also correlated with poor prognosis in cancer patients and several tumor characteristics, including cancer proliferation, metastasis, immunosuppression, drug resistance, cachexia, and cancer-associated fibroblast activation. As such, ActA-targeted therapy has been viewed as a potential adjuvant therapy alongside other anti-cancer modalities that may result in more efficient anti-cancer effects, such as stronger immune responses, overcoming drug resistance, reversing cachexia, etc. However, despite its interesting concept, targeting ActA is not without certain challenges and considerations. Indeed, ActA has unexpectedly shown anti-tumor effects in some cases, which might be explained by differences in the expression levels of different ActA receptors on the cell surface, activation of non-SMAD pathways, and imbalance in ActA levels. Besides, many of the current ActA antagonists lack enough specificity and, as a result, bind to non-ActA receptors as well. Furthermore, ubiquitous expression of ActA in the body can cause serious adverse effects following systemic administration. Furthermore, to address these issues, anti-ActA monoclonal antibodies and nanoparticle drug delivery systems have recently been suggested to target ActA with better precision in the affected area. In this review, first, we provide the different implications of ActA in cancer. Then, we discuss the recent insights into targeting ActA signaling as an adjuvant therapy alongside other anti-cancer modalities, as well as the possible challenges and novel opportunities on the path of clinical translation.

Inactivated herpes simplex virus-1 vaccine formulated in aqueous and alcoholic extracts of propolis boosts cellular and IgG responses.

Objectives: In this study, the adjuvant activity of aqueous and alcoholic extracts of propolis was examined on the inactivated herpes simplex virus-1 (HSV-1). Materials and Methods: BALB/C mice were administered with inactivated (HSV-1; the KOS strain) plus alcoholic and aqueous extracts, followed by assessment of the cellular and humoral immune responses. Results: Alcoholic and aqueous extracts, as an adjuvant, revealed a significant increase in lymphocyte proliferation and cytotoxic T lymphocyte (CTL) responses versus the HSV-1 group. In addition, HSV-1 plus alcoholic extract showed a remarkable increase in IFN-γ cytokine and IFN-γ/IL-4 ratio. On the other hand, both alcoholic and aqueous extracts in the HSV-1 vaccine suppressed the IL-4 cytokine response as compared with the HSV-1 vaccine. In addition, HSV-1 plus alcoholic extract showed a significant increment in IgG1, IgG2a, and IgG2b isotypes as compared with the HSV-1 vaccine. Conclusion: Propolis extracts seem to modulate the immune response against inactivated HSV-1 model and can be used as a suitable vaccine adjuvant or a component of a complex adjuvant against infectious diseases.

Immunologic Mechanisms of BCc1 Nanomedicine Synthesized by Nanochelating Technology in Breast Tumor-bearing Mice: Immunomodulation and Tumor Suppression.

INTRODUCTION: The side effects of anti-cancer chemotherapy remain a concern for patients. So, designing alternative medications seems inevitable. In this research, the immunological mechanisms of BCc1 nanomedicine on tumor-bearing mice were investigated. METHODS: BALB/c mice underwent tumor transplantation and were assigned into four groups. Group 1 was orally administered with PBS buffer, Group 2 was orally administered BCc1 10 mg/kg, and Group 3 was orally administered BCc1 40 mg/kg daily, respectively. In addition, a group of mice was administered Cyclophosphamide, 20 mg/kg daily. The weight and tumor volume of mice were evaluated bi-weekly. After 24 days of treatment, cytokines and CTL assay in the spleen cell and the tumor were assessed. Furthermore, the spleen, liver, kidney, lung, gut, and uterine tissue were stained with hematoxylin and eosin. Finally, the tumor samples were stained and analyzed for FOXP3. The survival rate of mice was recorded. RESULTS: The results confirmed the histological safety of BCc1. This nanomedicine, especially BCc1 10 mg/kg, led to a strong IFN-γ response and suppressed TGF-ß cytokine. The frequency of Treg in the tumor tissue of BCc1 nanomedicine groups was decreased. In addition, nanomedicine repressed tumor volume and tumor weight significantly, which was comparable to Cyclophosphamide. These immunologic events increased the survival rate of BCc1-treated groups. The results indicate that BCc1 nanomedicine can suppress tumor growth and thereby increase the survival rate of experimental mice. CONCLUSION: It seems a modulation in the tumor microenvironment and polarization toward a Th1 response may be involved. So, BCc1 nanomedicine is efficient for human cancer therapy.

Targeted drug delivery using nanobodies to deliver effective molecules to breast cancer cells: the most attractive application of nanobodies.

Targeted drug delivery is one of the attractive ways in which cancer treatment can significantly reduce side effects. In the last two decades, the use of antibodies as a tool for accurate detection of cancer has been noted. On the other hand, the binding of drugs and carriers containing drugs to the specific antibodies of cancer cells can specifically target only these cells. However, the use of whole antibodies brings challenges, including their large size, the complexity of conjugation, the high cost of production, and the creation of immunogenic reactions in the body. The use of nanobodies, or VHHs, which are a small part of camel heavy chain antibodies, is very popular due to their small size, high craftsmanship, and low production cost. In this article, in addition to a brief overview of the structure and characteristics of nanobodies, the use of this molecule in the targeted drug delivery of breast cancer has been reviewed.

Beneficial effects of the combination of BCc1 and Hep-S nanochelating-based medicines on IL-6 in hospitalized moderate COVID-19 adult patients: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: In the severe forms of COVID-19 and many other infectious diseases, the patients develop a cytokine storm syndrome (CSS) where pro-inflammatory cytokines such as IL-6 and TNF-α play a key role in the development of this serious process. Selenium and iron are two important trace minerals, and their metabolism is tightly connected to immune system function. Numerous studies highlight the role of selenium and iron metabolism changes in the procedure of COVID-19 inflammation. The immunomodulator effect of nanomedicines that are synthesized based on nanochelating technology has been proved in previous studies. In the present study, the effects of the combination of BCc1(with iron-chelating property) and Hep-S (containing selenium) nanomedicines on mentioned cytokines levels in hospitalized moderate COVID-19 patients were evaluated. METHODS: Laboratory-confirmed moderate COVID-19 patients were enrolled to participate in a randomized, double-blind, placebo-controlled study in two separate groups: combination of BCc1 and Hep-S (N = 62) (treatment) or placebo (N = 60) (placebo). The blood samples were taken before medications on day zero, at discharge, and 28 days after consumption to measure hematological and biochemical parameters and cytokine levels. The clinical symptoms of all the patients were recorded according to an assessment questionnaire before the start of the treatment and on days 3 and discharge day. RESULTS: The results revealed that consumption of the nanomedicines led to a significant decrease in the mean level of IL-6 cytokine, and at the end of the study, there was a 77% downward trend in IL-6 in the nanomedicine group, while an 18% increase in the placebo group (p < 0.05). In addition, the patients in the nanomedicines group had lower TNF-α levels; accordingly, there was a 21% decrease in TNF-α level in the treatment group, while a 31% increase in this cytokine level in the placebo was observed (p > 0.05). On the other hand, in nanomedicines treated groups, clinical scores of coughing, fatigue, and need for oxygen therapy improved. CONCLUSIONS: In conclusion, the combination of BCc1 and Hep-S inhibits IL-6 as a highly important and well-known cytokine in COVID-19 pathophysiology and presents a promising view for immunomodulation that can manage CSS. TRIAL REGISTRATION: Iranian Registry of Clinical Trials RCT20170731035423N2 . Registered on June 12, 2020.

Nanoadjuvants Produced by Advanced Nanochelating Technology in the Inactivated-Severe Acute Respiratory Syndrome Coronavirus-2 Vaccine Formulation: Preliminary Results on Cytokines and IgG Responses.

Despite the great success of vaccines in various infectious diseases, most current vaccines are not effective enough, and on the contrary, clinically approved alum adjuvants cannot induce sufficient immune responses, including a potent cellular immune response to confer protection. In this study, we used Nanochelating Technology to develop novel nanoadjuvants to boost the potency of the alum-adjuvanted inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. BALB/c mice were immunized twice over 2 weeks with different doses of adjuvanted-vaccine formulations and immune responses were assessed. The analysis results of IFN-γ and IL-17 cytokines demonstrated the effectiveness of the nanoadjuvants produced by the Nanochelating Technology in shifting the alum-based vaccine toward a stronger Th1 pattern. In addition, these nanoadjuvants improved IL-2 cytokine response, which shows the efficacy of these novel formulations in inducing specific T lymphocyte proliferation. Using these nanoadjuvants increased IL-10 cytokine secretion that may be representative of a better immunoregulatory impact and may also potentially prevent immunopathology responses. Moreover, specific IgG titer analysis revealed the potency of these nanoadjuvants in improving humoral immune responses. The enzyme-linked immunosorbent assay of receptor-binding domain (RBD)-specific IgG response showed that the developed novel formulations induced strong IgG responses against this protein. This study shows that the nanostructures produced by the Advanced Nanochelating Technology have potent adjuvant effects on alum-based SARS-CoV-2 vaccines to not only compensate for alum weakness in inducing the cellular immune responses by smart regulation of the immune system but also significantly improve the humoral and cellular immune responses simultaneously.

Different Formulations of Inactivated SARS-CoV-2 Vaccine Candidates in Human Compatible Adjuvants: Potency Studies in Mice Showed Different Platforms of Immune Responses.

Several inactivated SARS-CoV-2 vaccines have been approved for human use, but are not highly potent. In this study, different formulations of the inactivated SARS-CoV-2 virus were developed in Alum, Montanide 51VG, and Montanide ISA720VG adjuvants, followed by assessment of immune responses. The SARS-CoV-2 virus was inactivated with formalin and formulated in the adjuvants. BALB/c mice were immunized subcutaneously with 4 µg of vaccines on days 0 and 14; (IL-4) and (IFN-g), cytotoxic T lymphocyte (CTL) activity, and specific immunoglobulin G (IgG) titer and IgG1, IgG2a, and IgG2a/IgG1 ratio, and anti-receptor-binding domain (RBD) IgG response were assessed 2 weeks after the final immunization. Immunization with SARS-CoV-2-Montanide ISA51VG showed a significant increase in the IFN-γ cytokine versus SARS-CoV-2-Alum, SARS-CoV-2-Montanide ISA720VG, and control groups (p < 0.0033). Cytokine IL-4 response in SARS-CoV-2-Alum group showed a significant increase compared with SARS-CoV-2-Montanide ISA51VG, SARS-CoV-2-Montanide ISA720VG, and control groups (p < 0.0206). In addition, SARS-CoV-2-Montanide ISA51VG vaccine induced the highest IFN-γ/IL-4 cytokine ratio versus other groups (p < 0.0004). CTL activity in SARS-CoV-2-Montanide ISA51VG and SARS-CoV-2-Montanide ISA720VG groups showed a significant increase compared with SARS-CoV-2-Alum and control groups (p < 0.0075). Specific IgG titer in SARS-CoV-2-Montanide ISA51 VG and SARS-CoV-2-Montanide ISA720VG showed a significant increase compared with SARS-CoV-2-Alum and control groups (p < 0.0143). Results from specific IgG1and IgG2a in SARS-CoV-2-Alum, SARS-CoV-2-Montanide ISA51VG, and SARS-CoV-2-Montanide ISA720VG vaccine showed a significant increase compared with phosphate buffer saline (PBS) group (p < 0.0001), but SARS-CoV-2-Montanide ISA51VG and SARS-CoV-2-Montanide ISA 720VG groups showed the highest IgG2a/IgG1 ratio and a significant increase compared with SARS-CoV-2-Alum group (p < 0.0379). Moreover, inactivated SARS-CoV-2+Alum and SARS-CoV-2-Montanide ISA 720VG groups demonstrated a significant increase in anti-RBD IgG response versus the SARS-CoV-2-Montanide ISA51VG group. It seems that the type of vaccine formulation is a critical parameter, influencing the immunologic pattern and vaccine potency and human-compatible oil-based adjuvants were more potent than Alum adjuvant in the vaccine formulation.

Improvement of the inactivated SARS-CoV-2 vaccine potency through formulation in alum/naloxone adjuvant; Robust T cell and anti-RBD IgG responses.

Objectives: SARS-CoV-2, emerging as a major threat to public health, has to be controlled through vaccination. Naloxone (NLX), an opioid receptor antagonist, demonstrated its adjuvant activity for microbial vaccines. In this study, inactivated SARS-CoV-2 was developed in the Alum/NLX adjuvant to increase the potency of the inactivated SARS-CoV-2 vaccine. Materials and Methods: BALB/c mice were immunized on days 0 and 14 with inactivated SARS-CoV-2-Alum, -Alum + NLX 3 mg/kg, -Alum + NLX 10 mg/kg, and -Freund adjuvant, as well as PBS. IFN-γ and IL-4 cytokines and Granzyme-B release were assessed with ELISA. In addition, specific total IgG, IgG1/IgG2a isotypes, and ratio as well as anti-RBD IgG responses were assessed with an optimized ELISA. Results: SARS-CoV-2-Alum-NLX10 group showed a significant increase in the IFN-γ cytokine response versus SARS-CoV-2-Alum, SARS-CoV-2-Alum-NLX3, and PBS groups. The SARS-CoV-2-Alum-NLX3 group exhibited a significant decrease in IL-4 cytokine versus SARS-CoV-2-Alum. The mice immunized with SARS-CoV-2-Alum-NLX10 showed a significant increase in CTL activity versus SARS-CoV-2-Alum and PBS. In addition, mice immunized with SARS-CoV-2-Alum-NLX3, SARS-CoV-2-Alum-NLX10 and SARS-CoV-2-Freund demonstrated an increase in IgG response, as compared with SARS-CoV-2-Alum and PBS group. Furthermore, all formulations of SARS-CoV-2 vaccines could induce both IgG1 and IgG2a isotypes. But, the IgG2a/IgG1 ratio in SARS-CoV-2-Freund and SARS-CoV-2-Alum-NLX10 revealed an increase as compared with that of the SARS-CoV-2-Alum group. Anti-RBD IgG response in the SARS-CoV-2-Alum-NLX10 group showed a significant increase as compared with the Alum-based vaccine. Conclusion: Formulation of inactivated SARS-CoV-2 virus in NLX/alum adjuvant improved the potency of humoral and, especially, cellular responses.

Immunomodulatory Effects of α-Tocopherol on the H1N1 Influenza Vaccine: Improving the Potency and Efficacy of the Influenza Vaccine in Aged Mice.

Declined immune response is the main cause of decreased potency of the influenza vaccine in the elderly, regardless of virus mutations. Herein, we hypothesized that the addition of α-tocopherol to the influenza vaccine formulation might increase vaccine potency and efficacy. Hemagglutinin of the H1N1 virus was formulated in Alum and α-tocopherol, and then aged (16-20-month-old) and young (6-8-week-old) mice were immunized subcutaneously two times with 2-week intervals with 5 µg of different vaccine formulations. Two weeks after the final boosting, IFN-γ and IL-4 cytokines were assessed by using ELISA. Humoral immune responses were assessed by hemagglutination inhibition (HI). In addition, vaccine efficacy was determined by intranasal viral challenge of mice using mouse-adapted H1N1 virus. Our results showed that the new vaccine formulation improved IFN-γ and IL-4 responses in the experimental mice. However, the increase was evident mainly in the aged group and, to some extent, in the young group. Results from the HI assay showed that α-tocopherol in the vaccine formulation could increase HI activity in both young and aged mice. Furthermore, α-tocopherol, as an adjuvant, increased the protectivity of the influenza vaccine in both aged and young groups through the decreased lung viral load and increased survival rate of the experimental mice. In conclusion, it seems that α-tocopherol can not only be used as an appropriate adjuvant for aged people, but also empower old and worn out cells to increase the effectiveness of the vaccine in the elderly.

Pharmaceutical, cosmeceutical, and traditional applications of marine carbohydrates.

Marine carbohydrates are most important organic molecules made by photosynthetic organisms. It is very essential for humankind: the role in being an energy source for the organism and they are considered as an important dissolve organic compound (DOC) in marine environment's sediments. Carbohydrates found in different marine environments in different concentrations. Polysaccharides of carbohydrates play an important role in various fields such as pharmaceutical, food production, cosmeceutical, and so on. Marine organisms are good resources of nutrients, and they are rich carbohydrate in sulfated polysaccharide. Seaweeds (marine microalgae) are used in different pharmaceutical industries, especially in pharmaceutical compound production. Seaweeds have a significant amount of sulfated polysaccharides, which are used in cosmeceutical industry, besides based on the biological applications. Since then, traditional people, cosmetics products, and pharmaceutical applications consider many types of seaweed as an important organism used in food process. Sulfated polysaccharides containing seaweed have potential uses in the blood coagulation system, antiviral activity, antioxidant activity, anticancer activity, immunomodulating activity, antilipidepic activity, etc. Some species of marine organisms are rich in polysaccharides such as sulfated galactans. Various polysaccharides such as agar and alginates, which are extracted from marine organisms, have several applications in food production and cosmeceutical industries. Due to their high health benefits, compound-derived extracts of marine polysaccharides have various applications and traditional people were using them since long time ago. In the future, much attention is supposed to be paid to unraveling the structural, compositional, and sequential properties of marine carbohydrate as well.