Exploring the immune-modulating properties of boswellic acid in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a condition where the central nervous system loses its myelin coating due to autoimmune inflammation. The experimental autoimmune encephalomyelitis (EAE) simulates some aspects of human MS. Boswellic acids are natural compounds derived from frankincense extract, known for their anti-inflammatory properties. The purpose of this research was to investigate therapeutic potential of boswellic acids. Mice were divided into three groups: low-dose (LD), high-dose (HD), and control groups (CTRL). Following EAE induction, the mice received daily doses of boswellic acid for 25 days. Brain tissue damage, clinical symptoms, and levels of TGF-ß, IFN-γ, and IL-17 cytokines in cell cultured supernatant of lymphocytes were assessed. Gene expression of transcription factors in brain was measured using real-time PCR. The levels of brain demyelination were significantly lower in the treatment groups compared to the CTRL group. Boswellic acid reduced the severity and duration of EAE symptoms. Furthermore, boswellic acid decreased the amounts of IFN-γ and IL-17, also the expression of T-bet and ROR-γt in brain. On the contrary, it increased the levels of TGF-ß and the expression FoxP3 and GATA3. Our findings suggest that boswellic acids possess therapeutic potential for EAE by modulating the immune response and reducing inflammation.

Therapeutic potential of lipid-lowering probiotics on the atherosclerosis development.

Hypercholesterolemia is a critical risk factor for atherosclerosis, mostly attributed to lifestyle behavior such as diet. Recent advances have emphasized the critical effects of gastrointestinal bacteria in the pathology of hypercholesterolemia and atherosclerosis, suggesting that the gastrointestinal microbiome can therefore provide efficient therapeutic targets for preventing and treating atherosclerosis. Thus, interventions, such as probiotic therapy, aimed at altering the bacterial composition introduce a promising therapeutic procedure. In the current review, we will provide an overview of anti-atherogenic probiotics contributing to lipid-lowering, inhibiting atherosclerotic inflammation, and suppressing bacterial atherogenic metabolites.

Tolerogenic probiotics Lactobacillus delbrueckii and Lactobacillus rhamnosus promote anti-inflammatory profile of macrophages-derived monocytes of newly diagnosed patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is known as an autoimmune disorder that is characterized by the breakdown of self-tolerance, resulting in disease onset and progression. Macrophages have been implicated as a factor in the development of SLE through faulty phagocytosis of dead cells or an imbalanced M1/M2 ratio. The study aimed to investigate the immunomodulatory effects of Lactobacillus delbrueckii and Lactobacillus rhamnosus on M1 and M2 macrophages in new case lupus patients. For this purpose, blood monocytes were collected from lupus patients and healthy people and were cultured for 5 days to produce macrophages. For 48 h, the macrophages were then cocultured with either probiotics or lipopolysaccharides (LPS). Flow cytometry and real-time polymerase chain reaction were then used to analyze the expression of cluster of differentiation (CD) 14, CD80, and human leukocyte antigen - DR (HLADR) markers, as well as cytokine expression (interleukin [IL]1-ß, IL-12, tumor necrosis factor α [TNF-α], IL-10, and transforming growth factor beta [TGF-ß]). The results indicated three distinct macrophage populations, M0, M1, and M2. In both control and patient-derived macrophage-derived monocytes (MDMs), the probiotic groups showed a decrease in CD14, CD80, and HLADR expression compared to the LPS group. This decrease was particularly evident in M0 and M2 macrophages from lupus patients and M1 macrophages from healthy subjects. In addition, the probiotic groups showed increased levels of IL-10 and TGF-ß and decreased levels of IL-12, IL1-ß, and TNF-α in MDMs from both healthy and lupus subjects compared to the LPS groups. Although there was a higher expression of pro-inflammatory cytokines in lupus patients, there was a higher expression of anti-inflammatory cytokines in healthy subjects. In general, L. delbrueckii and L. rhamnosus could induce anti-inflammatory effects on MDMs from both healthy and lupus subjects.

Investigation of IL-6 serum level in COVID-19 patients with positive COVID-19 IgG/IgM antibody titers to check inflammation and disease progression.

OBJECTIVE: The SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), leads to severe pathogenicity and high mortality among different communities around the world. Therefore, it is important to understand the mechanisms of virus pathogenesis and the immune system's response to prevent the further spread of this virus. This study was aimed to evaluate the relationship between the serum level of interleukin 6 and positive IgG and IgM antibody levels in patients with COVID-19 to investigate inflammation and disease progression. METHODS & MATERIALS: In this study, 10 ml of EDTA blood samples were taken from 414 COVID-19 patients. Then, the plasma was separated and the levels of IgM and IgG antibodies and interleukin 6 cytokine were evaluated by ELISA and chemiluminescence methods, respectively. All data were analyzed by SPSS 22 and GraphPad prism 9 software at the significance level of P < 0.05. RESULTS: The results of this study showed that there was no significant difference in the expression of IgM and IgG antibodies between men and women. Also, a significant increase in the mean expression of IL-6 was observed only in the high concentration range (100-〉1000 pg/ml) in men compared to women (P < 0.001). In addition, in the female population, all three concentration ranges (negative, medium, and high) of IL-6 have the highest correlation with high titers (>10 U/ml) of IgM and IgG antibodies. While, in men, all three concentration ranges of IL-6 had the highest correlation with > 10 U/ml IgM antibody titers, but in the case of IgG, the highest correlation between different concentrations of IL-6 was observed with the negative or moderate titers of this antibody and there was an inverse relationship with the high titers of IgG (>10 U/ml). CONCLUSION: As a result, the relationship between different serum levels of cytokine IL-6 with different titers of IgM and IgG antibodies was observed in both male and female populations. In general, it can be concluded that the correlation between different concentrations of IL-6 with different IgM titers was similar in both men and women, but in the case of different IgG titers, this correlation was higher in women than men.

Berberine: A natural modulator of immune cells in multiple sclerosis.

Berberine is a benzylisoquinoline alkaloid found in such plants as Berberis vulgaris, Berberis aristata, and others, revealing a variety of pharmacological properties as a result of interacting with different cellular and molecular targets. Recent studies have shown the immunomodulatory effects of Berberine which result from its impacts on immune cells and immune response mediators such as diverse T lymphocyte subsets, dendritic cells (DCs), and different inflammatory cytokines. Multiple sclerosis (MS) is a chronic disabling and neurodegenerative disease of the central nervous system (CNS) characterized by the recruitment of autoreactive T cells into the CNS causing demyelination, axonal damage, and oligodendrocyte loss. There have been considerable changes discovered in MS regards to the function and frequency of T cell subsets such as Th1 cells, Th17 cells, Th2 cells, Treg cells, and DCs. In the current research, we reviewed the outcomes of in vitro, experimental, and clinical investigations concerning the modulatory effects that Berberine provides on the function and numbers of T cell subsets and DCs, as well as important cytokines that are involved in MS.

Lactobacillus rhamnosus and Lactobacillus delbrueckii Ameliorate the Expression of miR-125a and miR-146a in Systemic Lupus Erythematosus Patients.

The microRNAs are non-coding RNA molecules involved in physiological and pathological processes, causing autoimmune diseases such as systemic lupus erythematosus (SLE). Probiotics are living microorganisms that possess beneficial effects on the host immune system and modulate it. The effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii on the expression of miR-125a and miR-146a was studied in peripheral blood mononuclear cells (PBMCs) from newly diagnosed lupus patients in this in vitro study. During this study, 20 recently diagnosed SLE patients and 20 healthy individuals participated. Ficoll method was used to isolate the PBMCs from whole blood, which were cultured for 48 h with Lactobacillus rhamnosus and Lactobacillus delbrueckii. In the next step, total RNA containing microRNA was extracted. cDNA was synthesized for miR-125a and miR-146a genes and analyzed by real-time PCR. Results were presented as fold changes. As compared to healthy controls, SLE patients expressed lower levels of miR-125a and miR-146a. PBMCs treated with Lactobacillus rhamnosus, Lactobacillus delbrueckii, or both probiotics had significantly higher levels of miR-125a and miR-146a compared to the untreated group. Treatment of PBMCs with both L. rhamnosus and L. delbrueckii upregulated the expression of miR-125a and miR-146a in treated cells compared with untreated cells in SLE patients (p = 0.02, p = 0.001). Lactobacillus rhamnosus and Lactobacillus delbrueckii modify lupus patients' immune responses and disease effects by regulating miR-125a and miR-146a.

Thymoquinone improves experimental autoimmune encephalomyelitis by regulating both pro-inflammatory and anti-inflammatory cytokines.

Introduction Multiple sclerosis (MS) is an autoimmune condition marked by inflammation and the loss of myelin in the central nervous system (CNS). The aim of this research was to understand how Thymoquinone regulate the molecular and cellular processes involved in controlling experimental autoimmune encephalomyelitis (EAE), which is an animal model often used to study MS. Methods Female C57BL/6 mice were split into different groups receiving different doses (low, medium, and high) of Thymoquinone simultaneously with EAE induction. Clinical scores and other measurements were observed daily throughout the 25-day post immunization. We assessed lymphocyte infiltration and demyelination in the spinal cord through histological staining, analyzed T-cell profiles using ELISA, and quantified the expression levels of transcription factors in the CNS using Real-time PCR. Results Thymoquinone prevented the development of EAE. Histological experiments revealed only a small degree of leukocyte infiltration into the CNS. Thymoquinone resulted in a notable reduction in the generation of IFN-γ, IL-17, and IL-6, while simultaneously increasing the production of IL-4, IL-10, and TGF-ß in Th2 and Treg cells. Results from Real-time PCR suggested Treatment with Thymoquinone decreased the expression of T-bet and ROR-γt while increasing the expression of Foxp3 and GATA3. Conclusion These findings showed that Thymoquinone could decrease both disease incidence and severity.

A glance on the role of IL-35 in systemic lupus erythematosus (SLE).

It is well known that systemic lupus erythematosus (SLE) is an auto-inflammatory disease that is characterized by chronic and widespread inflammation. The exact pathogenesis of SLE is still a matter of debate. However, it has been suggested that the binding of autoantibodies to autoantigens forms immune complexes (ICs), activators of the immune response, in SLE patients. Ultimately, all of these responses lead to an imbalance between anti-inflammatory and pro-inflammatory cytokines, resulting in cumulative inflammation. IL-35, the newest member of the IL-12 family, is an immunosuppressive and anti-inflammatory cytokine secreted mainly by regulatory cells. Structurally, IL-35 is a heterodimeric cytokine, composed of Epstein-Barr virus-induced gene 3 (EBI3) and p35. IL-35 appears to hold therapeutic and diagnostic potential in cancer and autoimmune diseases. In this review, we summarized the most recent associations between IL and 35 and SLE. Unfortunately, the comparative review of IL-35 in SLE indicates many differences and contradictions, which make it difficult to generalize the use of IL-35 in the treatment of SLE. With the available information, it is not possible to talk about targeting this cytokine for the lupus treatment. So, further studies would be needed to establish the clear and exact levels of this cytokine and its related receptors in people with lupus to provide IL-35 as a preferential therapeutic or diagnostic candidate in SLE management.

Curcumin and Berberine Arrest Maturation and Activation of Dendritic Cells Derived from Lupus Erythematosus Patients.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disease recognized by elevated activity of autoimmune cells, loss of tolerance, and decreased regulatory T cells producing inhibitory cytokines. Despite many efforts, the definitive treatment for lupus has not been fully understood. Curcumin (CUR) and berberine (BBR) have significant immunomodulatory roles and anti-inflammatory properties that have been demonstrated in various studies. This study aimed to investigate the anti-inflammatory properties of CUR and BBR on human monocyte-derived dendritic cells (DCs) with an special focus on the maturation and activation of DCs. METHODS: Human monocytes were isolated from the heparinized blood of SLE patients and healthy individuals, which were then exposed to cytokines (IL-4 and GM-CSF) for five days to produce immature DCs. Then, the obtained DCs were characterized by FITC-uptake assay and then cultured in the presence of CUR, BBR, or lipopolysaccharide (LPS) for 48 h. Finally, the maturation of DCs was analyzed by the level of maturation using flow cytometry or real-time PCR methods. RESULTS: The results showed promising anti-inflammatory effects of CUR and BBR in comparison with LPS, supported by a significant reduction of not only co-stimulatory and antigen-presenting factors such as CD80, CD86, CD83, CD1a, CD14, and HLA-DR but also inflammatory cytokines such as IL-12. CONCLUSION: CUR and BBR could arrest DC maturation and develop a tolerogenic DC phenotype that subsequently promoted the expression of inhibitory cytokines and reduced the secretion of proinflammatory markers.

A better understanding of the role of the CTLA-CD80/86 axis in the treatment of autoimmune diseases.

Autoimmune diseases are diseases in which the regulatory mechanisms of the immune response are disturbed. As a result, the body loses self-tolerance. Since one of the main regulatory mechanisms of the immune response is the CTLA4-CD80/86 axis, this hypothesis suggests that autoimmune diseases potentially share a similar molecular basis of pathogenesis. Hence, investigating the CTLA4-CD80/86 axis may be helpful in finding an appropriate treatment strategy. Therefore, this study aims to investigate the molecular basis of the CTLA4-CD80/86 axis in the regulation of the immune response, and then its role in developing some autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. As well, the main therapeutic strategies affecting the CTLA4-CD80/86 axis have been summarized to highlight the importance of this axis in management of autoimmune diseases.

Lupus mice derived mesenchymal stromal cells: Beneficial or detrimental on SLE disease outcome.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear genes, deposition of immune complexes, and autoimmune T cells, through which, tissue damage would ultimately occur. Furthermore, loss of immune tolerance and imbalance of Th1/Th2 cells in addition to Th17/Treg are contributed to the pathogenesis of SLE. Mesenchymal stromal cells (MSCs) infusion is a potential therapy for SLE disease. Despite a majority of SLE patients achieving clinical remission after allogeneic MSC infusion from healthy individuals, SLE patients have less benefited from autologous MSC infusion, justifying the probable compromised function of SLE patients-derived MSCs. In this study, we aim to further investigate the potential immunoregulatory mechanisms in which mesenchymal stromal cells derived from pristane-induced lupus mice, following injection into healthy and lupus mice, exert their possible effects on the lupus process. METHOD: 40 female Balb/c mice aged 3 weeks were purchased and randomly divided into six groups. First, lupus disease was induced into the lupus groups by intraperitoneal injection of pristane and then the mice were surveyed for 6 months. The body weight, anti-dsDNA autoantibody levels, serum creatinine, and Blood Urea Nitrogen (BUN) levels were measured in two-month intervals. After 6 months, the group of lupus mice was sacrificed, and lupus MSCs were isolated. Two months later, cultured lupus MSCs were intravenously injected into two groups of healthy and lupus mice. After two months, the mice were euthanized and the kidneys of each group were examined histologically by hematoxylin & eosin (H&E) staining and the immunofluorescence method was also performed to evaluate IgG and C3 deposition. The frequency of splenic Th1, Th2, Th17, and Treg cells was measured by flow cytometry. Moreover, the cytokine levels of IFN-γ, IL-4, IL-17, and TGF-ß in sera were measured by ELISA method. RESULTS: Our results showed that the induction of lupus disease by pristane in Balb/c mice caused the formation of lipogranuloma, increased levels of anti-dsDNA autoantibodies, and impaired renal function in all pristane-induced lupus groups. In addition, the injection of lupus mesenchymal stromal cells (L-MSC) into healthy and lupus mice led to a further rise in anti-dsDNA serum levels, IgG and C3 deposition, and further dysfunction of mice renal tissue. Also, the flow cytometry results implicated that compared to the control groups, splenic Th1, Th2, and Th17 inflammatory cell subtypes and their secreted cytokines (IFN-γ, IL-4, and IL-17) in the sera of healthy and lupus mice were increased after the intake of L-MSC. Additionally, the splenic Treg cells were also significantly increased in the lupus mice receiving L-MSC. However, a decrease in serum levels of TGF-ß cytokine was observed in healthy and lupus mice following L-MSC injection. In contrast, the lupus mice receiving healthy mesenchymal stem cells (H-MSC) manifested opposite results. CONCLUSION: In a nutshell, our results suggest that although allogeneic MSCs are encouraging candidates for SLE treatment, syngeneic MSCs may not be eligible for treating SLE patients due to their defects in regulating the immune system in addition to their capability in promoting inflammation which would consequently worsen the SLE disease status.

A new generation of mesenchymal stromal/stem cells differentially trained by immunoregulatory probiotics in a lupus microenvironment.

BACKGROUND: Increasing evidence suggests that multipotent mesenchymal stem/stromal cells (MSCs) are a promising intervention strategy in treating autoimmune inflammatory diseases. It should be stated that systemic immunoregulation is increasingly recognized among the beneficial effects of MSCs and probiotics in treating morbid autoimmune disorders such as lupus. This study aimed to determine if immunoregulatory probiotics L. rhamnosus or L. delbrueckii can change the immunomodulatory effects of MSCs in lupus-like disease. METHODS: Pristane-induced lupus (PIL) mice model was created via intraperitoneal injection of Pristane and then confirmed. Naïve MSCs (N-MSCs) were coincubated with two Lactobacillus strains, rhamnosus (R-MSCs) or delbrueckii (D-MSCs), and/or a combination of both (DR-MSCs) for 48 h, then administrated intravenously in separate groups. Negative (PBS-treated normal mice) and positive control groups (PBS-treated lupus mice) were also investigated. At the end of the study, flow cytometry and enzyme-linked immunosorbent assay (ELISA) analysis were used to determine the percentage of Th cell subpopulations in splenocytes and the level of their master cytokines in sera, respectively. Moreover, lupus nephritis was investigated and compared. Analysis of variance (ANOVA) was used for multiple comparisons. RESULTS: Abnormalities in serum levels of anti-dsDNA antibodies, creatinine, and urine proteinuria were significantly suppressed by MSCs transplantation, whereas engrafted MSCs coincubation with both L. strains did a lesser effect on anti-dsDNA antibodies. L. rhamnosus significantly escalated the ability of MSCs to scale down the inflammatory cytokines (IFN-É£, IL-17), while L. delbrueckii significantly elevated the capacity of MSCs to scale down the percentage of Th cell subpopulations. However, incubation with both strains induced MSCs with augmented capacity in introducing inflammatory cytokines (IFN-É£, IL-17). Strikingly, R-MSCs directly restored the serum level of TGF-ß more effectively and showed more significant improvement in disease parameters than N-MSCs. These results suggest that R-MSCs significantly attenuate lupus disease by further skew the immune phenotype of MSCs toward increased immunoregulation. CONCLUSIONS: Results demonstrated that Lactobacillus strains showed different capabilities in training/inducing new abilities in MSCs, in such a way that pretreated MSCs with L. rhamnosus might benefit the treatment of lupus-like symptoms, given their desirable properties.

The potential role of miRNA in regulating macrophage polarization.

Macrophage polarization is a dynamic process determining the outcome of various physiological and pathological situations through inducing pro-inflammatory responses or resolving inflammation via exerting anti-inflammatory effects. The miRNAs are epigenetic regulators of different biologic pathways that target transcription factors and signaling molecules to promote macrophage phenotype transition and regulate immune responses. Modulating the macrophage activation, differentiation, and polarization by miRNAs is crucial for immune responses in response to microenvironmental signals and under various physiological and pathological conditions. In term of clinical significance, regulating macrophage polarization via miRNAs could be utilized for inflammation control. Also, understanding the role of miRNAs in macrophage polarization can provide insights into diagnostic strategies associated with dysregulated miRNAs and for developing macrophage-centered therapeutic methods. In this case, targeting miRNAs to further regulate of macrophage polarization may become an efficient strategy for treating immune-associated disorders. The current review investigated and categorized various miRNAs directly or indirectly involved in macrophage polarization by targeting different transcription factors and signaling pathways. In addition, prospects for regulating macrophage polarization via miRNA as a therapeutic choice that could be implicated in various pathological conditions, including cancer or inflammation-mediated injuries, were discussed.

Melittin as a safe compound to BALB/c mice immune system; a tiered approach immunotoxicity screening.

BACKGROUND: Maintenance of immune system integrity is a vital requirement to protect human body against pathogens/cancers. Natural compounds have long been used due to their benefits for the immune system. One of which is bee venom that contains a peptide called melittin having antimicrobial and anticancer effects. Since a limited number of studies regarding the effects of melittin on the immune system have been carried out, we aimed to evaluate the effects of melittin on BALB/c mice immune system parameters. METHODS: Female BALB /c mice were treated intraperitoneally (i.p) with 0.75 and 1.5 mg/kg doses of melittin for 14 days (5 doses per week). The negative control group received i.p normal saline whereas the positive controls received i.p 20 mg/kg cyclophosphamide (CYP). Immunological parameters such as hematological parameters, delayed-type hypersensitivity (DTH), hemagglutination titer (HA), spleen cellularity, splenocytes proliferation, as well as spleen and bone marrow histopathological assessment were evaluated. RESULTS: Our findings showed that melittin has no gross pathological effect on the spleen and bone marrow. It was also demonstrated that melittin has no any significant effect on hematological parameters. Melittin did not cause any significant changes to proliferation response of splenocytes to PHA and LPS, spleen cellularity, DTH response, as well as the production of anti-SRBC antibodies. According to our results, melittin at 0.75 and 1.5 mg/kg doses could not induce significant changes on immune parameters and as a result, melittin was found to be safe for the mice immune system.

Curcumin's spice-infused therapeutic promise: disease severity alleviation in a mouse model of multiple sclerosis via modulation of immune responses.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune central nervous system (CNS) disorder indicated by demyelination, chronic inflammation, and neuronal destruction. Regional demyelination, inflammation responses, scar development, and various axonal damage are pathological characteristics of MS. Curcumin is a hydrophobic polyphenol extracted from the rhizome of the turmeric plant. In addition to anti-inflammatory effects, beneficial therapeutic effects such as antioxidant, anti-cancer and nerve protection have also been seen from this compound. The purpose of the current investigation was to provide light on the potential benefits of Curcumin in treating experimental autoimmune encephalomyelitis (EAE), the animal model of MS. METHODS AND RESULTS: in Female C57BL/6 mice were used to induce EAE through myelin oligodendroglial glycoprotein (MOG). Curcumin doses of 100 and 200 mg/kg were administered orally in the treatment groups starting on the first day of EAE induction. Brains and splenocytes were extracted from euthanized animals on day 25 following EAE induction. Demyelination and leukocyte infiltration, proliferation, cytokine, and gene expression profiles were assessed. Our findings demonstrate that both low and high doses of Curcumin decreased the progression of EAE. Histological analyses revealed low infiltration of leukocytes into the CNS. Curcumin therapy enhanced Th2 and Treg cell secretion of IL-4, IL-10, and TGF-ß although considerably decreasing IFN-γ and TNF-α. Curcumin-induced Th2 and Treg cell cytokine production and transcription factor gene expression (IL-13, GATA3, STAT6 and IL-35, CTLA4, Foxp3) and anti-inflammatory cytokines (IL-27, IL-33). CONCLUSION: Overall, these findings provide additional evidence that Curcumin can slow disease development and alleviate symptoms in EAE through stimulating Treg and Th2 cell polarization. They support Curcumin's potential therapeutic role in MS.

Regulatory NK cells in autoimmune disease.

NK cells are defined as the major components of the immunological network which exerts defense against tumors and viral infections as well as regulation of innate and adaptive immunity, shaped through interaction with other cells like T cells. According to the surface markers, NK cells can be divided into CD56dim NK and CD56bright NK subsets. CD56bright NK cells usually are known as regulatory NK cells. Once the immune system loses its self-tolerance, autoimmune diseases develop. NK cells and their subsets can be altered during autoimmune diseases, indicative of their prominent regulatory roles and even pathological and protective functions in autoimmune disorders. In this regard, activation of CD56bright NK cells can suppress activated autologous CD4+ T cells and subsequently prevent the initiation of autoimmunity. In this review article, we summarize the roles of regulatory NK cells in autoimmune disease occurrence which needs more research to uncover their exact related mechanism. It seems that targeting NK cells can be a promising therapeutic platform against autoimmune diseases.

The Effects of Clove Oil on The Biochemical and Histological Parameters, and Autophagy Markers in Polycystic Ovary Syndrome-Model Rats.

BACKGROUND: This study aimed to determine whether syzygium aromaticum (clove) could help polycystic ovary syndrome (PCOS) rats. MATERIALS AND METHODS: In this experimental study, forty adult female Wistar rats (weighing 250 ± 10 g) were divided randomly into five groups; G1: control, G2: PCOS group, G3: PCOS+clove (30 mg/kg/ orally/daily) group, G4: PCOS+clove (60 mg/kg/orally/daily) group, and G5: PCOS+gonadectomy group. The PCOS was induced by a single dose injection of estradiol valerate (16 mg/kg/IM). Following PCOS induction, the rats were treated for 14 days. Histological parameters, follicle apoptosis, mRNA expression of autophagy markers (Lc3, Beclin1), oxidative stress markers, insulin and blood glucose levels, as well as serum levels of aromatase and testosterone were evaluated in these rats. Finally, the ratio of serum luteinizing hormone (LH) to follicle-stimulating hormone (FSH) levels was also calculated. RESULTS: The autophagy markers (Lc3, Beclin1), histological parameters, oxidative stress, insulin, and hormone levels changed significantly in the PCOS rats (G2). In G3 and G5 groups, it was observed that the levels of LH/FSH and testosterone decreased significantly in comparison to the PCOS group, and inhibition of autophagy was also observed in these groups. Treatment with cloves in the G3 group significantly improved oxidative stress, histological parameters, and insulin levels. CONCLUSION: These findings demonstrated that oxidative stress, apoptosis, and excessive autophagy could be improved by treatment with low doses of clove and gonadectomy. Cloves may help to improve these parameters by regulating and inhibiting excessive autophagy. However, discovering the direct role of this extract in regulating the parameters such as oxidative stress, insulin, and androgens requires further investigation. In the present study, P<0.05 was considered statistically significant.

Implications of IL-21 in solid tumor therapy.

Cancer, the most deadly disease, is known as a recent dilemma worldwide. Presently different treatments are used for curing cancers, especially solid cancers. Because of the immune-enhancing functions of cytokine, IL-21 as a cytokine may have new possibilities to manipulate the immune system in disease conditions, as it stimulates NK and CTL functions and drives IgG antibody production. Indeed, IL-21 has been revealed to elicit antitumor-immune responses in several tumor models. Combining IL-21 with other agents, which target tumor cells, immune-regulatory circuits, or other immune-enhancing molecules enhances this activity. The exciting breakthrough in the results obtained in pre-clinical situations has led to the early outset of present developing clinical trials in cancer patients. In the paper, we have reviewed the function of IL-21 in solid tumor immunotherapy.

Impacts of Porphyromonas gingivalis periodontitis on rheumatoid arthritis autoimmunity.

In RA patients' synovial sites, citrullinated RA-related antigens such as type II collagens, fibrin (ogen), vimentin, and α-enolase could be targeted by ACCPAs. Since ACCPA production can be initiated a long time before RA sign appearance, primary auto-immunization against these citrullinated proteins can be originated from extra-articular sites. It has been shown that there is a significant association between P. gingivalis periodontitis, anti- P. gingivalis antibodies, and RA. P. gingivalis gingipains (Rgp, Kgp) can degrade proteins such as fibrin and α-enolase into some peptides in the form of Arg in the C-terminal which is converted to citrulline by PPAD. Also, PPAD can citrullinate type II collagen and vimentins (SA antigen). P. gingivalis induces inflammation and chemoattraction of immune cells such as neutrophils and macrophages through the increase of C5a (gingipain C5 convertase-like activity) and SCFA secretion. Besides, this microorganism stimulates anoikis, a special type of apoptosis, and NETosis, an antimicrobial form of neutrophil death, leading to the release of PAD1-4, α-enolase, and vimentin from apoptotic cells into the periodontal site. In addition, gingipains can degrade macrophages CD14 and decrease their ability in apoptotic cell removal. Gingipains also can cleave IgGs in the Fc region and transform them into rheumatoid factor (RF) antigens. In the present study, the effects of P. gingivalis on rheumatoid arthritis autoimmune response have been reviewed, which could attract practical insight both in bench and clinic.

The Evaluation of the Effect of Tolerogenic Probiotics on the Maturation of Healthy Dendritic Cells versus Immature Dendritic Cells.

Background: Dendritic cells, (DCs) as one of the important immune cell populations, are responsible for the initiation, development, and control of acquired immune responses. Myeloid dendritic cells can be used as a vaccine for several autoimmune diseases and cancers. Tolerogenic probiotics with regulatory properties can affect the maturation and development of immature dendritic cells (IDC) into mature DCs with certain immunomodulatory effects. Objective: To assess the immunomodulatory effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii, as two tolerogenic probiotics, in the differentiation and maturation of myeloid dendritic cells. Methods: The IDCs were derived from the healthy donors in GM-CSF and IL 4 medium. Mature DCs (MDC) were produced with L. delbrueckii, L. rhamnosus, and LPS from IDCs. Real-Time PCR and flow cytometry were used to confirm the DC maturation and to determine DC markers as well as IDO, IL10, and IL12 expression levels, respectively. Results: Probiotic-derived DCs showed a significant reduction in the level of HLA-DR (P≤0.05), CD86 (P≤0.05), CD80 (P≤0.001), CD83 (P≤0.001), and CD1a. Also, the expression of IDO (P≤0.001) and IL10 increased while IL12 expression decreased (P≤0.001). Conclusion: Our findings revealed that tolerogenic probiotics could induce regulatory DCs by reducing co-stimulatory molecules along with increasing the expression of IDO and IL10 during the differentiation process. Therefore, the induced regulatory DCs probably can be used in the treatment of various inflammatory diseases.