Curcumin is a natural compound derived from the spice, turmeric, that has been extensively reported for its efficacy in controlling or treatment of several inflammatory diseases. There is a growing body of literature that recognizes the anti-inflammatory effects of curcumin in the immune system. On the other hand, the role of inflammatory signaling pathways has been highlighted in the pathogenesis of several inflammatory diseases, and signaling molecules involved in these pathways are considered as valuable targets for new treatment approaches. We aimed to provide a comprehensive overview of the modulatory effects of curcumin on inflammatory signaling pathways which leads to inhibition of inflammation in different types of immune cells and animal models. In this comprehensive review, we elaborate on how curcumin can effectively inhibit multiple signaling molecules involved in inflammation including NF-κB, JAKs/STATs, MAPKs, β-catenin, and Notch-1.

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Curcumin: a modulator of inflammatory signaling pathways in the immune system

T-cell clonality testing is integral to the diagnostic work-up of T-cell malignancies; however, current methods lack specificity and sensitivity, which can make the diagnostic process difficult. The recent discovery of a monoclonal antibody (mAb) specific for human TRBC1 will greatly improve the outlook for T-cell malignancy diagnostics. The anti-TRBC1 mAb can be used in flow cytometry immunophenotyping assays to provide a low-cost, robust, and highly specific test that detects clonality of immunophenotypically distinct T-cell populations. Recent studies demonstrate the clinical utility of this approach in several contexts; use of this antibody in appropriately designed flow cytometry panels improves detection of circulating disease in patients with cutaneous T-cell lymphoma, eliminates the need for molecular clonality testing in the context of large granular lymphocyte leukemia, and provides more conclusive results in the context of many other T-cell disorders. It is worth noting that the increased ability to detect discrete clonal T-cell populations means that identification of T-cell clones of uncertain clinical significance (T-CUS) will become more common. This review discusses this new antibody and describes how it defines clonal T-cells. We present and discuss assay design and summarize findings to date about the use of flow cytometry TRBC1 analysis in the field of diagnostics, including lymph node and fluid sample investigations. We also make suggestions about how to apply the assay results in clinical work-ups, including how to interpret and report findings of T-CUS. Finally, we highlight areas that we think will benefit from further research.

Emerging Role of T-cell Receptor Constant β Chain-1 (TRBC1) Expression in the Flow Cytometric Diagnosis of T-cell Malignancies

Background The immune microenvironment plays a vital role in the development of hepatocellular carcinoma (HCC). This study explored novel immune-related biomarkers to predict the prognosis of patients with HCC. Methods RNA-Seq data were downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to identify prognosis-related genes; the Lasso method was used to construct the prognosis risk model. Validation was performed on the International Cancer Genome Consortium (ICGC) cohort, and the C-index was calculated to evaluate its overall predictive performance. Western blots were conducted to evaluate the expression of genes. Results There were 320 immune-related genes, 40 of which were significantly related to prognosis. Eight immune gene signatures (CKLF, IL12A, CCL20, PRELID1, GLMN, ACVR2A, CD7, and FYN) were established by Lasso Cox regression analysis. This immune signature performed well in different cohorts and can be an independent risk factor for prognosis. In addition, the overall predictive performance of this model was higher than the other models reported previously. Conclusion The predictive immune model will enable patients with HCC to be more accurately managed in immunotherapy.

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Development and Validation of a Novel 8 Immune Gene Prognostic Signature Based on the Immune Expression Profile for Hepatocellular Carcinoma.

Introduction: Chronic inflammation and immune system dysfunction have been evaluated as major factors in the pathogenesis of chronic kidney disease (CKD), contributing to the high mortality rates observed in these populations. Uremic toxins seem to be the potential "missing link." Indoxyl sulfate (IS) is one of the protein-bound renal toxins. It participates in multiple pathologies of CKD complications, yet its effect on immune cell has not been studied. This study aimed to explore the genome-wide expression profile in human peripheral blood T cells under stimulation by IS. Methods: In this study, we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) responding to IS stimulation in human peripheral T cells in vitro. Flow cytometry and western blot were used to verify the discovery in RNA-sequencing analysis. Results: Our results yielded a total of 5129 DEGs that were at least twofold up-regulated or down-regulated significantly by IS stimulation and half of them were concentration-specific. Analysis of T cell functional markers revealed a quite different transcription profile under various IS concentration. Transcription factors analysis showed the similar pattern. Aryl hydrocarbon receptor (AhR) target genes CYP1A1, CYP1B1, NQO1, and AhRR were up-regulated by IS stimulation. Pro-inflammatory genes TNF-α and IFN-γ were up-regulated as verified by flow cytometry analysis. DNA damage was induced by IS stimulation as confirmed by elevated protein level of p-ATM, p-ATR, p-BRCA1, and p-p53 in T cells. Conclusion: The toxicity of IS to T cells could be an important source of chronic inflammation in CKD patients. As an endogenous ligand of AhR, IS may influence multiple biological functions of T cells including inflammatory response and cell cycle regulation. Further researches are required to promulgate the underling mechanism and explore effective method of reserving T cell function in CKD.

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Transcriptome Profiling Reveals Indoxyl Sulfate Should Be Culpable of Impaired T Cell Function in Chronic Kidney Disease.

Background Clinical and histological diagnosis of Sezary syndrome (SS) and mycosis fungoides (MF) is challenging in clinical routine. Objectives We investigated five blood markers previously described for SS (T-plastin, Twist, KIR3DL2, NKp46 and Tox) in a prospective validation cohort of patients. Methods We included 447 patients in this study and 107 patients were followed up for prognosis. The markers were analysed by reverse transcriptase quantitative real-time polymerase chain reaction (RT-qPCR) on peripheral blood leucocytes and CD4+ T cells in a cohort of consecutive patients with early MF, erythrodermic MF and SS and compared with patients presenting with benign inflammatory dermatoses (BID) and erythrodermic BID. The markers were assessed in parallel to gold standard values such as CD4/CD8 ratio, loss of CD7 and CD26 membrane expression and CD4 absolute values. Sensitivity and specificity were analysed by receiver operator characteristic curves. The prognostic value of selected markers was analysed on a subset of patients. This study was conducted in one centre. Results We defined cut-off values for each marker. T-plastin, Twist and KIR3DL2 had the best validity. SS may be overrepresented. The combination of T-plastin and Twist was able to differentiate between erythrodermic MF or BID and SS. The additional analysis of KIR3DL2 may be useful to predict the prognosis. Conclusions We propose T-plastin, Twist and KIR3DL2 measured by RT-qPCR as new diagnostic markers for Sezary syndrome.

The value of five blood markers in differentiating mycosis fungoides and Sézary syndrome: a validation cohort.

The CD7 antigen is a member of the immunoglobulin superfamily that expresses on the surface of all thymocytes, a majority of mature T cells, and also natural killer cells. Interestingly, under physiological and different pathological conditions, the loss of CD7 antigen occurred in the subset of CD4+ memory T cells. Various functions have been proposed for CD7, including its role in the activation and intercellular adhesiveness of T cells. Several studies indicate that the number of CD4+ CD7- T cells increases in diseases such as chronic inflammation and T-cell malignancies, these being skin inflammatory lesions. Therefore, this can be useful for the diagnosis of cancer cells, especially with reference to blood origin, treatment monitoring, and establishment of new therapies. Therefore, a comprehensive review could be useful to increase our knowledge about the clinical importance of these cells in human disease.

The clinical importance of CD4+ CD7- in human diseases.

Adult T-cell leukemia/lymphoma (ATLL) is a serious blood malignancy with distinct geographical distribution. ATLL patients have a short survival time because of intrinsic chemoresistance and severe immunosuppression. To introduce a novel treatment, we investigated whether umbelliprenin (UMB), a natural coumarin derivative, could improve the toxicity of arsenic trioxide (ATO) on ATLL cells. To determine the viability of MT-2 cells upon treatment with different concentrations of UMB and ATO, alamarBlue assay was applied. Cell cycle analysis was carried out by propidium iodide staining and the expression of candidate genes was assessed by quantitative reverse transcription-polymerase chain reaction. Our findings revealed that combination of UMB and ATO induced considerable cytotoxic effects on ATLL cells. Flow cytometry analysis indicated accumulation of MT-2 cells in the sub G1 phase of the cell cycle after combinatorial treatment. In addition, significant downregulation in BMI-1, CD44, c-MYC, and nuclear factor-κB (REL-A) expression was observed after UMB + ATO administration. Agents with low side effects are potential candidates for novel cancer treatments. We demonstrated, for the first time, that combination of UMB and ATO might be regarded as an effective regimen for ATLL treatment.

https://journals.sagepub.com/doi/pdf/10.1177/1934578X211072334

Mohaddese Kazemi

Papers

The clinical importance of CD4+ CD7- in human diseases.

Combination of Umbelliprenin and Arsenic Trioxide Acts as an Effective Modality Against T-Cell Leukemia/Lymphoma Cells