Resveratrol is a bioactive compound in many foods. Since its anticancer activity was reported in 1997, its health benefits have been intensively investigated. Resveratrol has antioxidant, anti-inflammatory, immunomodulatory, glucose and lipid regulatory, neuroprotective, and cardiovascular protective effects, therefore, can protect against diverse chronic diseases, such as cardiovascular diseases (CVDs), cancer, liver diseases, obesity, diabetes, Alzheimer’s disease, and Parkinson’s disease. This review summarizes the main findings of resveratrol-related health benefits in recent epidemiological surveys, experimental studies, and clinical trials, highlighting its related molecular mechanisms. Resveratrol, therefore, has been regarded as a potent candidate for the development of nutraceuticals and pharmaceuticals to prevent and treat certain chronic diseases.

/pdf/health-benefits-and-molecular-mechanisms-of-resveratrol-a-2fh5sqi3wa.pdf

Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review.

Combined Single-Cell Profiling of lncRNAs and Functional Screening Reveals that H19 Is Pivotal for Embryonic Hematopoietic Stem Cell Development.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder mediated by antiplatelet autoantibodies and antigen-specific T cells that either destroy platelets peripherally in the spleen or impair platelet production in the bone marrow. There have been a plethora of publications relating to the pathophysiology of ITP and since January of 2019, at least 50 papers have been published on ITP pathophysiology. PURPOSE OF REVIEW: To summarize the literature relating to the pathophysiology of ITP including the working mechanisms of therapies, T-cell and B-cell physiology, protein/RNA/DNA biochemistry, and animal models in an attempt to unify the perceived abnormal immune processes. RECENT FINDINGS: The most recent pathophysiologic irregularities associated with ITP relate to abnormal T-cell responses, particularly, defective T regulatory cell activity and how therapeutics can restore these responses. The robust literature on T cells in ITP points to the notion that ITP is a disease initiated by faulty self-tolerance mechanisms very much like that of other organ-specific autoimmune diseases. There is also a large literature on new and existing animal models of ITP and these will be discussed. It appears that understanding how to specifically modulate T cells in patients with ITP will undoubtedly lead to effective antigen-specific therapeutics. CONCLUSIONS: ITP is predominately a T cell disorder which leads to a breakdown in self tolerance mechanisms and allows for the generation of anti-platelet autoantibodies and T cells. Novel therapeutics that target T cells may be the most effective way to perhaps cure this disorder.

An update on the pathophysiology of immune thrombocytopenia.

The pathogenesis of multiple myeloma (MM) is not completely known. Uncovering the potential mechanism of MM initiation and progression is essential for identifying novel diagnostic and therapeutic targets. Herein, we explored the function and the working mechanism of circular RNA circ_0007841 in MM progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of circ_0007841, microRNA-338-3p (miR-338-3p) and bromodomain containing 4 (BRD4). Cell proliferation ability was analyzed through cell counting kit-8 (CCK8) assay, colony formation assay and flow cytometry. Transwell assays were conducted to measure the migration and invasion abilities of MM cells. Cell apoptosis was also assessed by flow cytometry. The interaction between miR-338-3p and circ_0007841 or BRD4 was confirmed by dual-luciferase reporter assay and RNA-pull down assay. Circ_0007841 was highly expressed in bone marrow (BM)-derived plasma cells of MM patients and MM cell lines than that in healthy volunteers and normal plasma cell line nPCs. Circ_0007841 promoted the proliferation, cell cycle and metastasis and impeded the apoptosis of MM cells. miR-338-3p was a direct target of circ_0007841 in MM cells and circ_0007841 accelerated the progression of MM through targeting miR-338-3p. BRD4 could directly bind to miR-338-3p in MM cells and miR-338-3p exerted an anti-tumor role through targeting BRD4. Circ_0007841 promoted the activation of PI3K/AKT signaling via miR-338-3p/BRD4 axis. Exosomes generated from mesenchymal stromal cells (MSCs) elevated the malignant behaviors of MM cells via circ_0007841. Circ_0007841 acted as an oncogene to promote the proliferation, cell cycle and motility and restrain the apoptosis of MM cells through sequestering miR-338-3p to up-regulate the expression of BRD4.

/pdf/circ-0007841-promotes-the-progression-of-multiple-myeloma-5guj38g74r.pdf

Circ_0007841 promotes the progression of multiple myeloma through targeting miR-338-3p/BRD4 signaling cascade

Super-enhancers (SEs) consist of a cluster of many enhancers bound to a great number of transcription factors. They are critical cis-regulatory elements that determine the identity of various human cell types. During tumorigenesis, DNA mutations and indels, chromosomal rearrangements, three-dimensional chromatin structural changes, and viral infections mediate oncogenic SE activation, and activated SEs have been found to regulate the expression of oncogenic genes. Inhibition specifically targeted to oncogenic SE assembly and activation provides a novel powerful therapeutic strategy for various cancers. In this paper, we first introduce the current understanding of oncogenic SE assembly and activation and then summarize the pathogenic factors and mechanism of oncogenic SE activation. Next, we elaborate on the oncogenic functions of SEs in cancers and the application of SEs as therapeutic targets. Finally, we turn our focus to the use of SEs in basic research and clinical trials. Drugs that block the assembly and activation of large DNA segments involved in enhancing gene expression could help in the treatment of cancer. Faqing Tang of Hunan Cancer Hospital in Changsha, China, and colleagues review the ways in which cancer cells hijack clusters of gene-regulating sequences known as super-enhancers, regulatory gene regions that normally help determine a cell’s unique identity, to drive the aberrant gene activity that fuels tumor growth. The researchers describe how numerous factors, ranging from internal DNA alterations, both large and small, to viral infections and other external assaults, can spur the formation of cancer-causing super-enhancers, leading to out-of-control gene expression. Therapies that selectively target these super-enhancers are now in early clinical testing. However, more studies of super-enhancers and their role in cancer development are needed to inform future drug development.

/pdf/oncogenic-super-enhancer-formation-in-tumorigenesis-and-its-1wfpubi1ti.pdf

Oncogenic super-enhancer formation in tumorigenesis and its molecular mechanisms

Multiple myeloma (MM) accounts for over twenty percent of hematological cancer-related death worldwide. Long noncoding RNA (lncRNA) H19 is associated with multiple tumorigenesis and is increased in MM, but the underlying mechanism of H19 in MM is unclear. In this study, the expression of H19, microRNA 152-3p (miR-152-3p), and BRD4 in MM patients was evaluated by quantitative real-time PCR (qRT-PCR) and Western blotting. Colony formation and flow cytometry analysis were used to determine the effects of H19 and miR-152-3p on MM cell proliferation, apoptosis, and cell cycle. A luciferase reporter assay was conducted to confirm the interaction among H19, miR-152-3p, and BRD4. A nude mouse xenograft model was established, and the cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) staining and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay. We found that levels of H19 and BRD4 were upregulated and the expression of miR-152-3p was downregulated in MM patients. Dual luciferase reporter assay showed H19 targeted miR-152-3p to promote BRD4 expression. Knockdown of H19 repressed proliferation and enhanced apoptosis and cell cycle G1 arrest by upregulating miR-152-3p in MM cells. Furthermore, H19 knockdown suppressed the growth of xenograft tumor, reduced Ki-67 and BRD4 levels, and increased cell apoptosis in xenograft tumor tissues. Taking these results together, H19 knockdown suppresses MM tumorigenesis via inhibiting BRD4-mediated cell proliferation through targeting miR-152-3p, implying that H19 is a promising biomarker and drug target for MM.

Long Noncoding RNA H19 Promotes Tumorigenesis of Multiple Myeloma by Activating BRD4 Signaling by Targeting MicroRNA 152-3p.

The potential therapeutic benefit of resveratrol on Th17/Treg imbalance in immune thrombocytopenic purpura.

Background: Multiple myeloma (MM) is an incurable hematologic cancer, accompanied by excessive osteoclast formation and inflammatory cytokine secretion. The mechanisms by which bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 regulates osteoclast differentiation and inflammatory cytokine secretion in MM are largely unknown. Methods: The isolated peripheral blood mononuclear cells from normal or patients with MM were treated with receptor activator of NF-κB ligand (RANKL) and M-CSF to induce osteoclast differentiation. RAW 264.7 cells were treated with RANKL. I-BET151 was applied to investigate the effects of BRD4 inhibition on osteoclast formation and inflammatory cytokine secretion. Osteoclast formation was determined by tartrate-resistant acid phosphatase (TRACP) staining. The expression of osteoclast-specific genes TRACP, matrix metalloproteinase-9 (MMP-9), cathepsin K (Ctsk), and c-Src was tested using quantitative real-time PCR. And the level of inflammatory cytokines TNF-α, IL-1β, and IL-6 was assessed by ELISA. Tumor necrosis factor receptor-associated factor 6 (TRAF6), BRD4, nuclear and cytoplasm p65, IκB-α, nuclear factor of activated T cells cytoplasmic (NFATc1), and osteoprotegerin (OPG) expression were measured by Western blotting. RNAi technology was applied to knock down BET family member BRD4. Results: I-BET151 dose-dependently suppressed osteoclast formation, inhibited the levels of osteoclast-specific genes TRACP, MMP-9, Ctsk, and c-Src and inflammatory cytokines TNF-α, IL-1β, and IL-6 secretion in peripheral blood mononuclear cells and RAW 264.7. I-BET151 inhibited the protein levels of BRD4 and NFATc1, increased OPG expression, and suppressed IκB-α degradation and p65 nuclear translocation. Further, the effects of I-BET151 on osteoclast formation, osteoclast-specific genes expression, inflammatory cytokine secretion, and NF-κB inhibition were promoted by BRD4 knockdown. Conclusion: I-BET151 inhibits osteoclast formation and inflammatory cytokine secretion by targetting BRD4-mediated RANKL-NF-κB signal pathway and BRD4 inhibition might be beneficial for MM treatment.

/pdf/i-bet151-suppresses-osteoclast-formation-and-inflammatory-4rniqysw6n.pdf

I-BET151 suppresses osteoclast formation and inflammatory cytokines secretion by targetting BRD4 in multiple myeloma.

A transgene-encoded truncated human epidermal growth factor receptor for depletion of anti- B-cell maturation antigen CAR-T cells.

Excessive bone resorption mediated by osteoclasts may lead to the risk of various lytic bone diseases. In the present study, the effects of I‑BET151, a bromodomain and extra terminal domain protein inhibitor, on osteoclastogenesis in RAW264.7 cells and the underlying mechanism of this process was investigated. Cells were divided into 6 groups, including the control group, receptor activator of nuclear factor‑κB ligand (RANKL) group and 4 other groups containing RANKL and I‑BET151 at different concentrations. Tartrate‑resistant acid phosphatase (TRACP) staining was used to observe the effect of I‑BET151 on osteoclastogenesis and the number of TRACP positive multinucleated cells was calculated. Western blotting was used to evaluate the expression of tumor necrosis factor receptor associated factor (TRAF6), nuclear factor of activated T‑cells cytoplasmic 1 (NFATcl), transcription factor p65 (p65), nuclear factor of κ light polypeptide gene enhancer in B‑cells inhibitor‑α (IκB‑α), extracellular signal‑regulated kinase, Jun N‑terminal kinase (JNK) and p38. mRNA expression levels of osteoclast specific genes TRACP, matrix metalloproteinase‑9 (MMP9), cathepsin K (CtsK) and proto‑oncogene tyrosine‑protein kinase Src (c‑Src) were measured using the reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). TRACP staining results demonstrated that I‑BET151 inhibited osteoclastogenesis induced by RANKL and the inhibition was dose dependent. TRACP multinucleated positive cells were significantly decreased when treated with I‑BET151 compared with the RANKL group. The inhibitory effect on TRAF6 was significant when concentrations of 100 and 200 nM I‑BET151 were used, and NFATcl was significantly inhibited when a concentration of 200 nM was used compared with the RANKL group, in a dose-dependent manner. Nuclear translocation of p65 was significantly inhibited by I‑BET151 at all concentrations. The degradation of IκB‑α, and phosphorylation of JNK and p38 were also significantly inhibited by I‑BET151, with the exception of the expression of IκB‑α following treatment with 50 nM I‑BET151. The RT‑qPCR results revealed that osteoclast‑specific genes TRACP, MMP9, CtsK and c‑Src were all dose‑dependently inhibited by I‑BET151, except for CtsK. In conclusion, I‑BET151 may significantly suppress the osteoclastogenesis of RAW264.7 cells via the RANKL signaling pathway.

/pdf/i-bet151-inhibits-osteoclastogenesis-via-the-rankl-signaling-514p6zq5mh.pdf

Fu-Ming Zi

Papers

Long Noncoding RNA H19 Promotes Tumorigenesis of Multiple Myeloma by Activating BRD4 Signaling by Targeting MicroRNA 152-3p.

The potential therapeutic benefit of resveratrol on Th17/Treg imbalance in immune thrombocytopenic purpura.

I-BET151 suppresses osteoclast formation and inflammatory cytokines secretion by targetting BRD4 in multiple myeloma.

A transgene-encoded truncated human epidermal growth factor receptor for depletion of anti- B-cell maturation antigen CAR-T cells.

I‑BET151 inhibits osteoclastogenesis via the RANKL signaling pathway in RAW264.7 macrophages