Immunomodulatory Effects of Curcumin in Rheumatoid Arthritis: Evidence from Molecular Mechanisms to Clinical Outcomes.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder characterized by the destruction of the joint and bone resorption. The production of pro-inflammatory cytokines and chemokines, dysregulated functions of three important subtypes of T helper (TH) cells including TH1, TH17, and regulator T (Treg) cells are major causes of the initiation and development of RA. Moreover, B cells as a source of the production of several autoantibodies play key roles in the pathogenesis of RA. The last decades have seen increasingly rapid advances in the field of immunopharmacology using natural origin compounds for the management of various inflammatory diseases. Curcumin, a main active polyphenol compound isolated from turmeric, curcuma longa, possesses a wide range of pharmacologic properties for the treatment of several diseases. This review comprehensively will assess beneficial immunomodulatory effects of curcumin on the production of pro-inflammatory cytokines and also dysregulated functions of immune cells including TH1, TH17, Treg, and B cells in RA. We also seek the clinical efficacy of curcumin for the treatment of RA in several recent clinical trials. In conclusion, curcumin has been found to ameliorate RA complications through modulating inflammatory and autoreactive responses in immune cells and synovial fibroblast cells via inhibiting the expression or function of pro-inflammatory mediators, such as nuclear factor-κB (NF-κB), activated protein-1 (AP-1), and mitogen-activated protein kinases (MAPKs). Of note, curcumin treatment without any adverse effects can attenuate the clinical symptoms of RA patients and, therefore, has therapeutic potential for the treatment of the diseases.

Evaluating the effect of LPS from periodontal pathogenic bacteria on the expression of senescence-related genes in human dental pulp stem cells.

The human dental pulp stem cells (hDPSCs) are one of the readily available sources of multipotent mesenchymal stem cells (MSCs) and can be considered as a type of tool cells for cell-based therapies. However, the main limitation in the clinical use of these cells is DPSC senescence, which can be induced by lipopolysaccharide (LPS) of oral pathogenic bacteria. Up to now, far little attention has been paid to exploring the molecular mechanisms of senescence in DPSCs. So, the current study aimed to investigate the underlying molecular mechanism of senescence in hDPSCs stimulated with Porphyromonas gingivalis (P. gingivalis) and Escherichia coli (E. coli)-derived LPSs, by evaluating both mRNA and protein expression of four important senescence-related genes, including TP53, CDKN1A, CDKN2A and SIRT1. To this purpose, hDPSCs were stimulated with different LPSs for 6, 24 and 48 h and then the gene expression was evaluated using quantitative real-time polymerase chain reaction (qPCR) and western blotting. Following stimulation with P. gingivalis and E. coli-derived LPSs, the relative mRNA and protein expression of all genes were significantly up-regulated in a time-dependent manner, as compared with unstimulated hDPSCs. Moreover, the hDPSCs stimulated with P. gingivalis LPS for 6 and 24 h had the highest mRNA expression of CDKN1A and SIRT1, respectively (p < 0.0001), whereas the highest mRNA expression of CDKN2A and TP53 was seen in hDPSCs stimulated with E. coli LPS for 48 h (p < 0.0001). In summary, because DPSCs have been reported to have therapeutic potential for several cell-based therapies, targeting molecular mechanisms aiming at preventing DPSC senescence could be considered a valuable strategy.

Gene expression analysis of intestinal IL-8, IL-17 A and IL-10 in patients with celiac and inflammatory bowel diseases.

BACKGROUND: Celiac disease (CeD) and inflammatory bowel disease (IBD) are accompanied by impaired immune responses. To study the immune regulation of these diseases, we evaluated the expression levels of pro-inflammatory (IL-8 and IL-17 A) and anti-inflammatory (IL-10) cytokines in intestinal biopsy specimens of CeD and IBD patients in comparison to healthy subjects. METHODS AND RESULTS: Intestinal biopsies were collected from 33 patients with IBD, 47 patients with CeD, and 20 healthy individuals. Total RNA was extracted and mRNA expression levels of IL-8, IL-17 A and IL-10 were assessed by qPCR. P-value < 0.05 was considered statistically significant. The expression levels of IL-8 and IL-17 A were higher in biopsies of IBD (UC and CD) and CeD patients compared to the control group (P < 0.05). IBD patients (UC and CD) had higher IL-8 intestinal level than CeD patients (P < 0.0001 and P = 0.0007, respectively). The expression of IL-10 was significantly down-regulated in intestinal biopsies of CeD and IBD patients compared with controls (P < 0.001). In addition, the expression level of this cytokine was significantly lower in IBD patients (P < 0.001 for UC patients and P < 0.0001 for CD patients) than CeD group. CONCLUSIONS: The three selected pro- and anti-inflammatory cytokines showed a similar expression pattern in both IBD and CeD patients. As IBD and CeD are immune-mediated disorders and are accompanied by inflammatory events, the understanding of the similarities and differences among them can help researchers to find out useful candidate therapeutic protocols. We suggest that larger cohort studies be organized to achieve more insights into this regulation.

Designing new nanoliposomal formulations and evaluating their effects on myeloid-derived suppressor cells and regulatory T cells in a colon cancer model aiming to develop an efficient delivery system for cancer treatment; an in vitro and in vivo study.

Regulfatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are common immunosuppressive cells in the tumor microenvironment. These cells, through various mechanisms, inhibit antitumor immune responses and impede effective therapies. Therefore, designing an efficient protocol for inducing immune surveillance in tumors is highly recommended. Recently, nanoliposomes have provided broad-spectrum and state-of-the-art vehicles to deliver antigens or immune system compartments in immunotherapies. It has been shown that different lipids in the structure of liposomes and various liposomal formulations can affect immune responses in the tumor microenvironment. This study was aimed to evaluate the effects of four different liposomal formulations on MDSCs and Tregs in C26 tumor-bearing mice. To this end, after preparing liposomes, they were injected into tumor-inoculated mice and analyzed MDSC and Treg population and functions in spleen and tumor tissues. Results showed that 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-containing liposomes reduced MDSC population and activity in the spleen, but not tumor, compared with other groups significantly (p < 0.05 and p < 0.01, respectively). Moreover, DOTAP-containing liposomes reduced the expression of S100A8 and arginase-1 genes in splenic MDSCs (p < 0.05). In conclusion, we provided evidence that DOTAP-containing liposomes contributed to stimulating immune responses and provided a situation to inhibit immunosuppression in the tumor microenvironment.

Berberine as a promising natural compound for the treatment of periodontal disease: A focus on anti-inflammatory properties.

Accumulating evidence during the last two decades has addressed the potential anti-inflammatory properties of berberine (BBR), a bioactive alkaloid compound isolated from Coptidis rhizoma, in controlling or treating several inflammatory diseases. Periodontitis is one of the most common chronic and serious inflammatory diseases, in which uncontrolled and unabated host immune responses against periodontopathic pathogens play critical and crucial roles in the disease pathogenesis. Hence, regulating inflammatory responses in periodontitis has a valuable approach and holds promise in treating periodontitis. For the first time, this paper reviews the evidence from in vitro and in vivo experimental models to explore the anti-inflammatory effects of BBR in periodontitis and exhibits that BBR has the high potency to exert anti-inflammatory effects by reducing expression and secretion of pro-inflammatory mediators including TNF-α, IL-1ß, IL-17, RANKL, MMP-2, MMP-9 and MCP-1. The BBR-mediated anti-inflammatory actions could translate into the inhibition of the periodontal tissues and alveolar bone destruction and the control of the disease in vivo. As the second aim of this paper, we also paid attention to the therapeutic potential of BBR in treating human diseases regarding its anti-inflammatory properties.

CXC chemokine ligand 16: a Swiss army knife chemokine in cancer.

Today, cancer is one of the leading causes of death worldwide. Lately, cytokine and chemokine imbalances have gained attention amongst different involved pathways in cancer development and attracted much consideration in cancer research. CXCL16, as a member of the CXC subgroup of chemokines, has been attributed to be responsible for immune cell infiltration into the tumour microenvironment. The aberrant expression of CXCL16 has been observed in various cancers. This chemokine has been shown to play a conflicting role in tumour development through inducing pro-inflammatory conditions. The infiltration of various immune and non-immune cells such as lymphocytes, cancer-associated fibroblasts and myeloid-derived suppressor cells by CXCL16 into the tumour microenvironment has complicated the tumour fate. Given this diverse role of CXCL16 in cancer, a better understanding of its function might build-up our knowledge about tumour biology. Hence, this study aimed to review the impact of CXCL16 in cancer and explored its therapeutic application. Consideration of these findings might provide opportunities to achieve novel approaches in cancer treatment and its prognosis.

Assessment of the protective effect of KN-93 drug in systemic epilepsy disorders induced by pilocarpine in male rat.

BACKGROUND AND AIMS: Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN-93 by blocking Ca2+ /calmodulin-dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN-93 in systemic epilepsy disorders induced by pilocarpine. MATERIALS AND METHODS: In this animal study, male rats were divided into five groups including treatment group (KN-93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN-93 group (received 5 mM KN-93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Pretreatment with KN-93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF-α and IL-1ß were observed in hippocampus supernatant of KN-93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN-93 improved neuronal density and attenuated the seizure activity and behavior. CONCLUSIONS: Overall, our findings suggest that KN-93 can effectively suppress oxidative stress and inflammation. Furthermore, KN-93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.

Immunoliposomes bearing lymphocyte activation gene 3 fusion protein and P5 peptide: A novel vaccine for breast cancer.

LAG3-Ig as an immune adjuvant has elicited potent anti-tumor immune responses in several preclinical and clinical studies, but the full potential immunostimulatory of LAG3-Ig has yet to be achieved. We hypothesized that by anchoring LAG3-Ig to the surface of liposomes, the adjuvant activity of LAG3-Ig could be improved. We also investigated the immunotherapy by co-delivery of liposome-coupled LAG3-Ig and P5 tumor antigen in mice model of TUBO breast cancer. We prepared and characterized novel PEGylated liposomes bearing surface conjugated LAG3-Ig and P5. Consistent with our hypothesis, liposomes-conjugated LAG3-Ig via multivalent binding to MHC class II molecules exerted immunostimulatory of LAG3-Ig and markedly induced maturation of dendritic cells more efficiently than free LAG3-Ig. LAG3-Ig-P5-immunoliposomes effectively elicited protective anti-tumor responses more than locally injected soluble LAG3-Ig + P5. The higher percentage of CD4+ and CD8+ T cells in the spleen and more rapid and pronounced infiltration of these effector cells into the site of the tumor were seen following immunoliposome therapy. Finally, anti-tumor immunity induced by LAG3-Ig-P5-immunoliposomes translated into the more tumor regression and prolonged survival of treated mice, compared to soluble immunotherapy. Taken together, our findings suggest that LAG3-Ig-P5-immunoliposomes can be considered as a valuable candidate for developing a liposome-based therapeutic cancer vaccine in treating HER2/ neu+ breast cancer patients.

Curcumin and cancer; are long non-coding RNAs missing link?

Despite significant signs of progress in cancer treatment over the past decade, either cancer prevalence or mortality continuously grow worldwide. Current anti-cancer agents show insignificant effectiveness, followed by serious side effects. It is important to find new, highly efficient pharmacological agents to increase cancer patients' clinical outcomes. Curcumin, a polyphenolic compound, has gained growing attention because of its anti-cancer properties. Curcumin can hinder the development, migration, and metastasis of cancer cells. The anti-cancer effects of curcumin are principally attributed to the regulation of several cellular signaling pathways, including MAPK/PI3K/Akt, Wnt/ß-catenin, JAK/STAT, and NF-ĸB signaling pathways. Furthermore, curcumin can affect the expression and function of tumor-suppressive and oncogenic long non-coding RNAs (lncRNAs). In this study, we briefly reviewed the modulatory effect of curcumin on dysregulated tumor-supportive and tumor-suppressive lncRNAs in several cancers. It is hoped that a better understanding of curcumin's anti-cancer properties would pave the way for the development of a therapeutic approach in cancer.

Serum Level of Soluble Lymphocyte-Activation Gene 3 Is Increased in Patients with Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is described as a systemic and chronic autoimmune disease characterized by inflammatory polyarthritis. Lymphocyte-activation gene 3 (LAG3) is a membrane glycoprotein expressed on activated, exhausted, and regulatory T cells. LAG3 plays a major role in the function of Treg cells. LAG3 also has a soluble form (sLAG3) with a controversial role. OBJECTIVE: To evaluate the serum level of sLAG3 in rheumatoid arthritis patients in comparison with healthy subjects and assess its association with the disease activity. METHODS: This cross-sectional study was performed on 105 patients with RA referred to Ghaem hospital of Mashhad, Iran. We divided the participants into four groups: 1) 35 untreated patients with newly diagnosed RA, 2) 35 active RA patients, 3) 35 patients in the remission phase of the disease, and 4) 35 healthy individuals matched in terms of age and sex. After completing the interview and questionnaire, the sLAG3 was evaluated by commercial ELISA. RESULTS: The serum level of sLAG3 significantly increased in RA patients (76.78 ng/ml) as compared with the healthy participants (51.67, p=0.002). However, there was no significant difference between RA patients in the remission phase of the disease (114.11 ng/ml) and those with moderate to high disease activity (63.06 ng/ml, p=0.076). CONCLUSION: This study provided insights into the role of sLAG3 in the immunopathogenesis of RA disease, but further investigations are also warranted.

Modulatory effects of curcumin on the atherogenic activities of inflammatory monocytes: Evidence from in vitro and animal models of human atherosclerosis.

Atherosclerosis is a complex and long-lasting disorder characterized by chronic inflammation of arteries that leads to the initiation and progression of lipid-rich plaques, in which monocytes/macrophages play the central role in endothelial inflammation and taking up these lipids. Circulating monocytes can adopt a long-term proinflammatory phenotype leading to their atherogenic activities. During atherogenic condition, inflammatory monocytes adhere to the surface of the activated endothelial cells and then transmigrate across the endothelial monolayer into the intima, where they proliferate and differentiate into macrophages and take up the lipoproteins, forming foam cells that derive atherosclerosis progression. Therefore, modulating the atherogenic activities of inflammatory monocytes can provide a valuable therapeutic approach for atherosclerosis prevention and treatment. Curcumin is a naturally occurring polyphenolic compound with numerous pharmacological activities and shows protective effects against atherosclerosis; however, underlying mechanisms are not clearly known yet. In the present review, on the basis of a growing body of evidence, we show that curcumin can exert antiatherosclerotic effect through inhibiting the atherogenic properties of monocytes, including inflammatory cytokine production, adhesion, and transendothelial migration, as well as intracellular cholesterol accumulation.

Production and Characterization of Monoclonal Antibody against Vit v1: A Grape Allergen Belonging to Lipid Transfer Protein Family.

Allergy to non-specific lipidtransfer protein (nsLTP), the major allergen of grape (Vit v1), is considered as one of the most common fruit allergies in Iran. Therefore, a specific monoclonal antibody (mAb) can be used for the characterization and assessment of. Accordingly, this study aimed to generate and characterize a mAb against Vit v1 with a diagnostic purpose. To this end, Vit v1 allergen (9 kDa) was extracted using a modified Bjorksten extraction method. Natural Vit v1-immunized mouse splenocytes were fused with SP2/0Ag-14 myeloma cells for generating hybridoma cells. Specific antibody-secreting Hybridoma cells were selected using ELISA. Finally, anti-Vit v1 mAb was characterized by western blotting, ELISA, and isotyping methods. In the current study, a 9 kDa (Vit v1) protein was attained fromcrude and fresh juice of grape extracts and the isotype of desired anti-Vit v1 mAb was determined as IgM with k light chain. In addition, The ELISA results demonstrated that anti-Vit v1 mAb was specified against natural Vit v1 in the grape cultivar and related LTP allergens, such as Pla or 3 (p<0.0001). In the present study, a specific mAb was produced for detecting the LTP allergen. This mAb with a confirmed specificity can be utilized for evaluating the LTP allergens and their allergenicity in different grape cultivars.