Generation of immune cells from induced pluripotent stem cells (iPSCs): Their potential for adoptive cell therapy.

Advances in human stem cell technologies enable induced pluripotent stem cells (iPSCs) to be explored as potent candidates for treating various diseases, such as malignancies, autoimmunity, immunodeficiencies, and allergic reactions. iPSCs with infinite self-renewal ability can be derived from different types of somatic cells without the ethical issues associated with embryonic stem cells. To date, numerous cell types, including various immune cell subsets [CD4+ and CD8+ T cells, gamma delta T (γδ T) cells, regulatory T cells, dendritic cells, natural killer cells, macrophages, and neutrophils] have successfully been generated from iPSCs paving the way for effective adoptive cell transfer therapy, drug development, and disease modeling. Herein, we review various iPSC-derived immune cells and their possible application in immunotherapy.

The Interplay Between Helicobacter pylori and Suppressors of Cytokine Signaling (SOCS) Molecules in the Development of Gastric Cancer and Induction of Immune Response.

Helicobacter pylori (H. pylori) colonizes the stomach and leads to the secretion of a vast range of cytokines by infiltrated leukocytes directing immune/inflammatory response against the bacterium. To regulate immune/inflammatory responses, suppressors of cytokine signaling (SOCS) proteins bind to multiple signaling components located downstream of cytokine receptors, such as Janus kinase (JAK), signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune cells may facilitate the immune evasion of H. pylori, allowing the bacteria to induce chronic inflammation. Dysregulation of SOCS expression and function can contribute to the sustained H. pylori-mediated gastric inflammation which can lead to gastric cancer (GC) development. Among SOCS molecules, dysregulated expression of SOCS1, SOCS2, SOCS3, and SOCS6 were indicated in H. pylori-infected individuals as well as in GC tissues and cells. H. pylori-induced SOCS1, SOCS2, SOCS3, and SOCS6 dysregulation can contribute to the GC development. The expression of SOCS molecules can be influenced by various factors, such as epigenetic DNA methylation, noncoding RNAs, and gene polymorphisms. Modulation of the expression of SOCS molecules in gastric epithelial cells and immune cells can be considered to control gastric carcinogenesis as well as regulate antitumor immune responses, respectively. This review aimed to explain the interplay between H. pylori and SOCS molecules in GC development and immune response induction as well as to provide insights regarding potential therapeutic strategies modulating SOCS molecules.

Human Gut Microbiome Before and After Bariatric Surgery in Obese Patients with and Without Type 2 Diabetes.

BACKGROUND: Bariatric surgery, a significant intervention for obesity, may influence weight loss through changes in gut microbiota, particularly the Firmicutes and Bacteroidetes. This study explores these potential shifts and their metabolic implications. MATERIALS: We conducted a cross-sectional study involving patients who had undergone bariatric surgery. Stool samples were collected at baseline, 3 months, and 6 months post-operation. We performed DNA extraction and quantified the bacterial phyla Firmicutes and Bacteroidetes to assess changes in the gut microbiota over time. RESULTS: Our research revealed a significant alteration in the gut microbiota following bariatric surgery. In diabetic individuals, there was a marked increase in the average number of Firmicutes bacteria at both 3 and 6 months post-operation, compared to pre-surgery levels. In contrast, non-diabetic subjects experienced a notable decrease in Firmicutes during the same timeframe. Regarding Bacteroidetes bacteria, the trend was reversed; diabetic patients showed a significant reduction, while non-diabetics exhibited an increase after the surgery. These findings highlight the dynamic changes in gut microbiota composition associated with bariatric surgery and its potential link to metabolic changes post-operation. CONCLUSION: These findings suggest that obesity alters the gut's microbial composition. The observed bacterial fluctuations, particularly in the dominant Firmicutes and Bacteroidetes groups, are likely contributors to the weight loss experienced post-surgery. This alteration in gut bacteria underscores the complex interplay between microbiota and metabolic health, highlighting potential avenues for therapeutic intervention.

Glycyrrhiza Glabra Extract Modulates Type 1 T Helper (TH1) and Regulatory T Cell-Related Immune Responses in an Animal Model of Breast Cancer.

Background: It is well-known that TH1 and Treg cells exert anti- and pro-tumorigenic activity, respectively. Thus, TH1 cell suppression together with Treg cell hyperactivation contribute to tumor development. Glycyrrhiza glabra (G. glabra) has various immunomodulatory and anti-tumorigenic properties. Objective: To explore the impacts of G. glabra extract on different parameters related to TH1 and Treg cells using a breast cancer (BC) model. Methods: Four groups of Balb/C mice bearing 4T1 cell-induced BC were treated intraperitoneally with either saline or G. glabra extract at dosages of 50, 100 and 150 mg/kg (G. glabra-50, G. glabra-100, and G. glabra-150, respectively). After sacrificing animals on day 26, the frequency of splenic TH1 and Treg cells, the levels of serum IFN-γ, TGF-ß, and IL-12, and intra-tumoral expressions of granzyme-B, T-bet, and FOXP3 were assessed. Results: Compared to untreated tumor control (UTC) group, treatment with G. glabra-50, G. glabra-100, or G. glabra-150 increased the survival rate, percentage of TH1 cells, and T-bet expression. Conversely, they reduced the percentage of Treg cells, and serum TGF-ß levels. In comparison to the UTC group, treatment with G. glabra-50 and G. glabra-150 increased the serum IL-12 levels. Treatment with G. glabra-100 and G. glabra-150 boosted granzyme-B expression. Treatment with G. glabra-150 elevated IFN-γ levels, while treatment with G. glabra-50 decreased the FOXP3 expression. IL-12 levels were higher in mice treated with G. glabra-150 compared to those treated with G. glabra-100. Conclusion: Treatment of mice with BC using G. glabra extract improved survival rate, reduced tumor growth, and modulated T cell-mediated immune responses.

Neutrophil generation from hematopoietic progenitor cells and induced pluripotent stem cells (iPSCs): potential applications.

Neutrophils are the most frequent immune cell type in peripheral blood, performing an essential role against pathogens. People with neutrophil deficiencies are susceptible to deadly infections, highlighting the importance of generating these cells in host immunity. Neutrophils can be generated from hematopoietic progenitor cells (HPCs) and embryonic stem cells (ESCs) using a cocktail of cytokines. In addition, induced pluripotent stem cells (iPSCs) can be differentiated into various functional cell types, including neutrophils. iPSCs can be derived from differentiated cells, such as skin and blood cells, by reprogramming them to a pluripotent state. Neutrophil generation from iPSCs involves a multistep process that can be performed through feeder cell-dependent and feeder cell-independent manners. Various cytokines and growth factors, in particular, stem cell facto, IL-3, thrombopoietin and granulocyte colony-stimulating factor (G-CSF), are used in both methods, especially, G-CSF which induces the final differentiation of neutrophils in the granulocyte lineage. iPSC-derived neutrophils have been used as a valuable tool for studying rare genetic disorders affecting neutrophils. The iPSC-derived neutrophils can also be used for disease modeling, infection research and drug discovery. However, several challenges must be overcome before iPSC-derived neutrophils can be used therapeutically in transplantation medicine. This review provides an overview of the commonly employed protocols for generating neutrophils from HPCs, ESCs and iPSCs and discusses the potential applications of the generated cells in research and medicine.

Leptin/lipopolysaccharide-treated dendritic cell vaccine improved cellular immune responses in an animal model of breast cancer.

PURPOSE: In dendritic cells (DCs), leptin as an immune-regulating hormone, increases the IL-12 generation whereas it reduces the IL-10 production, thus contributing to TH1 cell differentiation. Using a murine model of breast cancer (BC), we evaluated the impacts of the Leptin and/or lipopolysaccharide (LPS)-treated DC vaccine on various T-cell-related immunological markers. MATERIALS AND METHODS: Tumors were established in mice by subcutaneously injecting 7 × 105 4T1 cells into the right flank. Mice received the DC vaccines pretreated with Leptin, LPS, and both Leptin/LPS, on days 12 and 19 following tumor induction. The animals were sacrificed on day 26 and after that the frequency of the splenic cytotoxic T lymphocytes (CTLs) and TH1 cells; interferon gamma (IFN-γ), interleukin 12 (IL-12) and tumor growth factor beta (TGF-ß) generation by tumor lysate-stimulated spleen cells, and the mRNA expression of T-bet, FOXP3 and Granzyme B in the tumors were measured with flow cytometry, ELISA and real-time PCR methods, respectively. RESULTS: Leptin/LPS-treated mDC group was more efficient in blunting tumor growth (p = .0002), increasing survival rate (p = .001), and preventing metastasis in comparison with the untreated tumor-bearing mice (UT-control). In comparison to the UT-control group, treatment with Leptin/LPS-treated mDC also significantly increased the splenic frequencies of CTLs (p < .001) and TH1 cells (p < .01); promoted the production of IFN-γ (p < .0001) and IL-12 (p < .001) by splenocytes; enhanced the T-bet (p < .05) and Granzyme B (p < .001) expression, whereas decreased the TGF-ß and FOXP3 expression (p < .05). CONCLUSION: Compared to the Leptin-treated mDC and LPS-treated mDC vaccines, the Leptin/LPS-treated mDC vaccine was more effective in inhibiting BC development and boosting immune responses against tumor.

Role of Interleukin-17 family cytokines in disease severity of patients with knee osteoarthritis

Abstract Background Interleukin-17 (IL-17) family plays a role in the pathogenesis of knee osteoarthritis (KOA) by contributing to the inflammatory and destructive processes in the affected joint. This study aimed to measure levels of IL-17 A and IL-25 (IL-17E) in serum of KOA patients and determine their roles in the disease severity of patients. Methods In this, 34 patients with KOA and 30 age and sex-matched healthy subjects (HS) were enrolled. Patients were categorized based on their Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analog Scale (VAS), and Body Mass Index (BMI) scores. The enzyme-linked immunosorbent assay (ELISA) technique was employed to measure serum levels of IL-17 A and IL-25. Results Level of IL-25 was significantly higher (P < 0.0001) in the KOA subjects than HS. IL-17 A level was significantly higher in KOA cases with WOMAC < 40 (P < 0.0001) in comparison to HS. IL-25 level was significantly higher in the KOA cases with WOMAC < 40 (P < 0.0001) and with WOMAC ≥ 40 (P < 0.0001) compared to HS. IL-17 A concentration was significantly higher in the KOA cases with VAS < 5 (P < 0.0001) compared to HS. IL-25 level was significantly higher in the KOA cases with VAS < 5 (P < 0.0001) and with VAS ≥ 5 (P < 0.0001) in comparison to HS. KOA patients with BMI ≥ 30 had significantly higher IL-17 A and IL-25 concentration in comparison to HS. Conclusions The serum level of IL-25 in KOA patients is increased probably due to negative controlling feedback on inflammatory responses, which can be associated with obesity and disease activity.

Modulation of semaphorin 3C & 4D expression in cancerous tissues from individuals with laryngeal squamous cell carcinoma.

BACKGROUND OBJECTIVES: Semaphorins were initially characterized as axon guidance factors but were subsequently implicated in the regulation of immune responses, angiogenesis, organ formation and a variety of other physiological and developmental functions. Various semaphorins enhance or inhibit tumour progression through different mechanisms. The objective of this study was to assess the expression of various semaphorins and vascular endothelial growth factor (VEGF) gene transcripts as well as the serum level of Sema3A in individuals with laryngeal squamous cell carcinoma (LSCC). METHODS: Tissue expression of Sema3A, Sema3C, Sema4D, Sema6D and VEGF was determined in both tumour tissues and tissues around the tumour from 30 individuals with pathologically confirmed LSCC using quantitative real-time PCR. Furthermore, the serum level of Sema3A in these individuals was assessed using enzyme-linked immunosorbent assay. RESULTS: Sema3C gene transcript showed a significant increase (P=0.001), while Sema4D was observed with a significant decrease in tumour samples compared to non-tumoural tissues (P≤0.01). The expression of the Sema3C gene was found to be associated with the stage of LSCC tumour as it was statistically significant for tumours with stage IV (P<0.01). The serum level of Sema3A was not found to be significant between cases and controls. INTERPRETATION CONCLUSIONS: Increased expression of Sema3C but decreased expression of Sema4D in tumour tissue of LSCC may introduce these two growth factors as crucial mediators orchestrating tumour growth in individuals with LSCC. This result could open a new vision for the treatment of this malignancy.

Radiotherapy Improves the Disability in Patients with Secondary Progressive Multiple Sclerosis.

Background: Multiple sclerosis (MS) as a complex neurological abnormality is marked with loss of myelin and axons due to chronic inflammatory and autoimmune responses. The modulatory properties of the low dose radiation (LDR) on inflammatory and immune responses have well known. Objective: The current research aimed to assess the impacts of LDR on the disability in patients suffering from MS. Material and Methods: This experimental pilot study was done on 10 patients with secondary progressive multiple sclerosis (SPMS). After magnetic resonance imaging, the SPMS patients were treated by LDR at a daily dose of 2 Gray for 5 consecutive days (totally 10 Gray dose) using a linear accelerator. The extent of the disability was evaluated one week after the completion of radiotherapy using expanded disability status scale (EDSS). Results: After receiving radiotherapy, the patients had a feeling of wellbeing of some sort. The mean of EDSS was significantly reduced after radiotherapy compared with before irradiation (7.4±0.45 vs 6.35±1.18; P<0.017). EDSS more decreased in younger SPMS patients (P=0.0001), and in the women after LDR (P=0.027). Conclusion: Radiotherapy can reduce fatigue and EDSS in patients with SPMS. The age and gender of patients may influence the LDR efficacy.

Inflammatory responses during trichomoniasis: The role of Toll-like receptors and inflammasomes.

Toll-like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis-derived components such as glycosyl-phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis-induced inflammasomes can lead to pyroptosis as well as the release of IL-1ß and IL-18 promoting innate and adaptive immune responses. The PRR-mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co-infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR-mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection.

Apelin receptor antagonist boosts dendritic cell vaccine efficacy in controlling angiogenic, metastatic and apoptotic-related factors in 4T1 breast tumor-bearing mice.

Apelin/APJ axis plays a critical role in cancer progression, thus its targeting inhibits tumor growth. However, blocking of Apelin/APJ axis in combination with immunotherapeutic approaches may be more effective. This study aimed to investigate the effects of APJ antagonist ML221 in combination with a DC vaccine on angiogenic, metastatic and apoptotic-related factors in a breast cancer (BC) model. Four groups of female BALB/c mice with 4T1-induced BC were treated with PBS, APJ antagonist ML221, DC vaccine, and "ML221 + DC vaccine". After completion of the treatment, the mice were sacrificed and the serum levels of IL-9 and IL-35 as well as the mRNA expression of angiogenesis (including VEGF, FGF-2, and TGF-ß), metastasis (including MMP-2, MMP-9, CXCR4) and apoptosis-related markers (Bcl-2, Bax, Caspase-3) in tumor tissues were determined using ELISA and real-time PCR, respectively. Angiogenesis was also evaluated by co-immunostaining of tumor tissues with CD31 and DAPI. Primary tumor metastasis to the liver was analyzed using hematoxylin-eosin staining. The efficiency of combination therapy with "ML221 + DC vaccine" was remarkably higher than single therapies in preventing liver metastasis compared to the control group. In comparison with the control group, combination therapy could significantly reduce the expression of MMP-2, MMP-9, CXCR4, VEGF, FGF-2, and TGF-ß in tumor tissues (P < 0.05). It also decreased the serum level of IL-9 and IL-35 compared with the control group (P < 0.0001). Moreover, vascular density and vessel diameter were significantly reduced in the combination therapy group compared with the control group (P < 0.0001). Overall, our findings demonstrate that combination therapy using a blocker of the apelin/APJ axis and DC vaccine can be considered a promising therapeutic program in cancers.

Vaccination with celecoxib-treated dendritic cells improved cellular immune responses in an animal breast cancer model.

PURPOSE: Prostaglandin E2 (PGE2), a product of cyclooxygenase (COX) pathway of arachidonic acid, exerts inhibitory impacts on dendritic cell (DC) activity to repress anti-tumor immune responses. Therefore, targeting COX during DC vaccine generation may enhance DC-mediated antitumor responses. We aimed to investigate the impacts of DC vaccine treated with celecoxib (CXB), a selective COX2 inhibitor, on some T cell-related parameters. MATERIALS AND METHODS: Breast cancer (BC) was induced in BALB/c mice, and then they received DC vaccine treated with lipopolysaccharide (LPS-mDCs), LPS with a 5 â€‹µM dose of CXB (LPS/CXB5-mDCs) and LPS with a 10 â€‹µM dose of CXB (LPS/CXB10-mDCs). The frequency of splenic Th1 and Treg cells and amounts of IFN-γ, IL-12 and TGF-ß production by splenocytes, as well as, the expression of Granzyme-B, T-bet and FOXP3 in tumors were determined using flow cytometry, ELISA, and real-time PCR, respectively. RESULTS: Compared with untreated tumor group (T-control), treatment with LPS/CXB5-mDCs and LPS/CXB10-mDCs decreased tumor growth (P â€‹= â€‹0.009 and P â€‹< â€‹0.0001), escalated survival rate (P â€‹= â€‹0.002), increased the frequency of splenic Th1 cells (P â€‹= â€‹0.0872, and P â€‹= â€‹0.0155), increased the IFN-γ (P â€‹= â€‹0.0003 and P â€‹= â€‹0.0061) and IL-12 (P â€‹= â€‹0.001 and P â€‹= â€‹0.0009) production by splenocytes, upregulated T-bet (P â€‹= â€‹0.062 and P â€‹< â€‹0.0001) and Granzyme-B (P â€‹= â€‹0.0448 and P â€‹= â€‹0.4485), whereas decreased the number of Treg cells (P â€‹= â€‹0.0014, and P â€‹= â€‹0.0219), reduced the amounts of TGF-ß production by splenocytes (P â€‹= â€‹0.0535 and P â€‹= â€‹0.0169), and reduced the expression of FOXP3 (P â€‹= â€‹0.0006 and P â€‹= â€‹0.0057) in comparison with T-control group. CONCLUSIONS: Our findings show that LPS/CXB-treated DC vaccine potently modulated antitumor immune responses in a mouse BC model.

Interferon-γ-Treated Mesenchymal Stem Cells Modulate the T Cell-Related Chemokines and Chemokine Receptors in an Animal Model of Experimental Autoimmune Encephalomyelitis.

BACKGROUND: Mesenchymal stem cells (MSCs) modulate immune responses, and their immunomodulatory potential can be enhanced using inflammatory cytokines. Here, the modulatory effects of IFN-γ-licensed MSCs on expression of T cell-related chemokines and chemokine receptors were evaluated using an experimental autoimmune encephalomyelitis (EAE) model. MATERIAL AND METHODS: EAE was induced in 3 groups of C57bl/6 mice and then treated with PBS, MSCs and IFN-γ-treated MSCs. The EAE manifestations were registered daily and finally, the brain and spinal cords were isolated for histopathological and gene expression studies. RESULTS: The clinical scores were lowered in MSCs and IFN-γ-licensed MSCs groups, however, mice treated with IFN-γ-licensed MSCs exhibited lower clinical scores than MSCs-treated mice. Leukocyte infiltration into the brain was reduced after treatment with MSCs or IFN-γ-licensed MSCs compared to untreated group (P<0.05 and P<0.01, respectively). In comparison with untreated EAE mice, treatment with MSCs reduced CCL20 expression (P<0.001) and decreased CXCR3 and CCR6 expression (P<0.02 and P<0.04, respectively). In comparison with untreated EAE mice, treatment with IFN-γ-licensed MSCs reduced CXCL10, CCL17 and CCL20 expression (P<0.05, P<0.05, and P<0.001, respectively) as well as decreased CXCR3 and CCR6 expression (P<0.002 and P<0.02, respectively), whilst promoting expression of CCL22 and its receptor CCR4 (P<0.0001 and P<0.02, respectively). In comparison with MSC-treated group, mice treated with IFN-γ-licensed MSCs exhibited lower CXCL10 and CCR6 expression (P<0.002 and P<0.01, respectively), whereas greater expression of CCL22 and CCR4 (P<0.0001 and P<0.01, respectively). CONCLUSION: Priming the MSC with IFN-γ can be an efficient approach to enhance the immunomodulatory potential of MSCs.

Contribution of survivin to the immune system, allergies and autoimmune diseases.

In addition to malignancies, survivin (a member of the apoptosis inhibitor family) has been implicated in the pathogenesis of inflammatory disorders, including autoimmune and allergic diseases. Survivin is constantly expressed in the proliferating hematopoietic progenitor cells, and it is re-expressed in the mature cells of the innate and adaptive immunity, upon activation. Survivin enhances the expression of co-stimulatory molecules and MHC class II molecules in dendritic cells, and promotes the lifespan of macrophages, neutrophils, and eosinophils, while suppressing natural killer (NK) cell activity. Survivin has been implicated in T cell maturation, T cell expansion, effector CD4+ T cell differentiation, maintenance of memory CD4+ T and CD8+ T cells, as well as antibody production. Upregulated expression of survivin was indicated in the T cells as well as various samples collected from allergic patients. Survivin can contribute to the pathogenesis of allergic diseases via the promotion of the Th2 polarization, promoting IL-4 expression, compromising activation-induced cell death (AICD) in Th2 cells, and preventing apoptosis of eosinophils, as well as, amplification of eosinophilia. Moreover, survivin can interfere with clonal deletion of autoreactive T and B cells, as well as suppress Treg cell development and activity supporting the development of autoimmune diseases. This review discusses the role of survivin in immunity, allergy and autoimmunity as well as provides evidence that survivin may be considered as a novel therapeutic target for the treatment of allergic and autoimmune diseases.

MicroRNA-383: A tumor suppressor miRNA in human cancer.

Downregulated expression of anti-tumor miR-383 has been found in many kinds of cancer. MiR-383 family members can directly target the 3'-untranslated region (3'-UTR) of the mRNA of some pro-tumor genes to attenuate several cancer-related processes, including cell proliferation, invasion, migration, angiogenesis, immunosuppression, epithelial-mesenchymal transition, glycolysis, chemoresistance, and the development of cancer stem cells, whilst promoting apoptosis. Functionally, miR-383 operates as a tumor inhibitor miRNA in many types of cancer, including breast cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, colorectal cancer, esophageal cancer, lung cancer, head and neck cancer, glioma, medulloblastoma, melanoma, prostate cancer, cervical cancer, oral squamous cell carcinoma, thyroid cancer, and B-cell lymphoma. Both pro-tumor and anti-tumor effects have been attributed to miR-383 in ovarian cancer. However, only the pro-tumor effects of miR-383 were reported in cholangiocarcinoma. The restoration of miR-383 expression could be considered a possible treatment for cancer. This review discusses the anti-tumor effects of miR-383 in human cancers, emphasizing their downstream target genes and potential treatment approaches.

Effect of turmeric extract on bone healing in an experimental model of femoral bone fracture.

Objective: Following bone trauma, several factors participate in making a balance between the activity of osteoblasts and osteoclasts. The receptor activator of nuclear factor kappa B ligand (RANKL), receptor activator of nuclear factor kappa B (RANK), and osteoprotegerin (OPG) molecules play critical roles in the healing process via regulation of osteoclasts function. Turmeric is suggested to have an anti-osteogenic potential; however, its effect on accelerating bone healing has not been adequately studied. Here, we used a rat model of femur fracture to explore the effect of treatment with turmeric extract on the bone repair and the expression of RANK, RANKL, and OPG molecules. Materials and Methods: Eight rats were subjected to surgery, randomly divided into two groups, and treated orally with turmeric (200 mg/kg), or olive oil. Four oil-treated rats without bone fracture were used as control group. After six weeks of treatment, the femurs of animals were examined for radiological, histological, and gene expression analysis. Results: X-ray radiography showed thicker callus and a more obscure fracture line in the turmeric group. Furthermore, higher osteoblast percentages but no osteoclasts were observed in turmeric-treated animals, representing better repair of bone in the fracture site. Also, real-time analyses showed that treatment with turmeric reduced RANK and RANKL expression (p<0.0001) and lowered RANKL/OPG ratio (p=0.01) in femoral bone tissue. Conclusion: Our findings indicated the turmeric ability to facilitate bone hemostasis and optimize the expression of key markers involved in the bone metabolism.

SARS-CoV-2 Infection: A Possible Risk Factor for Incidence and Recurrence of Cancers.

COVID-19 and malignancy can affect the susceptibility of one another. Clinically recovered COVID-19 individuals display immune abnormalities that persist several months after discharge. The lymphopenia-related immunosuppression, functional exhaustion of cytotoxic lymphocytes (such as CD8+ cytotoxic T-cells and natural killer cells), hyperinflammatory responses, oxidative stress, downregulation of interferon response, development of the myeloid-derived suppressor cells, downregulation of tumor suppressor proteins and perhaps reactivation of the latent oncogenic viruses may directly and/or indirectly play a role in the cancer development and recurrence in severe COVID-19 patients. SARS-CoV-2-infected malignant patients may be at higher risk of death of their cancer than SARS-CoV-2-uninfected patients with the same cancers. On the other side, the patients with some types of cancers may be more vulnerable to SARS-CoV-2 infection compared with the non-cancerous individuals, due to their immunocompromised state resulted from malignancy, chemotherapy, and other concomitant abnormalities as well as perhaps greater expression of angiotensin-converting enzyme 2. SARS-CoV-2-infected cancerous patients are unable to produce an effective anti-virus immune response and may exhibit more severe forms of COVID-19. This review described the possible impacts of SARS-CoV-2 infection on cancer development and recurrence, and the potential cancer impacts on COVID-19 development, while the possible interventions are highlighted.

Development of anti-rituximab antibodies in rituximab-treated patients: Related parameters & consequences.

The utilization of the monoclonal antibodies (mAbs) as therapeutic agents is one of the most favourable fields in immunotherapy. The immunogenicity of mAbs is one of the major parameters that may restrict their therapeutic and diagnostic applications. Rituximab, a chimeric mAb against CD20, is attached to the B-cell membrane-linked CD20 and is used to treat some B-cell-related malignancies, a number of autoantibody-mediated autoimmune disorders and improvement of graft survival. The risk of anti-rituximab antibody (ARA) development and ARA-related adverse events are low in rituximab-treated patients with lymphoma. No important association was reported between the ARA positivity and drug levels, and drug efficacy in rituximab-treated patients with lymphoma. The patients with autoimmune disorders exhibit greater risk of ARA development and ARA-related adverse events. In autoimmune diseases, ARA positivity may have no significant impact on either the drug level or its efficacy, (i.e.), it may reduce drug levels without influencing drug efficacy and, vice versa, or may reduce both drug level as well as its efficacy. The characterization of the parameters affecting the production of ARA can be used to design strategies to reduce the immunogenicity of mAb and promote its efficacy in humans. In this review, the host and therapeutic programme-related parameters affecting the development of the ARA have been discussed to suggest novel insights to reduce ARA-associated adverse events and enhance the drug efficacy.

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis.

As effector innate immune cells and as a host to the protozoan parasite Leishmania, macrophages play a dual role in antileishmanial immunoregulation. The 2 key players in this immunoregulation are the macrophage-expressed microRNAs (miRNAs) and the macrophage-secreted cytokines. miRNAs, as small noncoding RNAs, play vital roles in macrophage functions including cytokines and chemokines production. In the reverse direction, Leishmania-regulated cytokines alter miRNAs expression to regulate the antileishmanial functions of macrophages. The miRNA patterns vary with the time and stage of infection. The cytokine-regulated macrophage miRNAs not only help parasite elimination or persistence but also regulate cytokine production from macrophages. Based on these observations, we propose a novel immunoregulatory framework as a scientific rationale for antileishmanial therapy.

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

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