BH3-only members of the Bcl-2 intracellular protein family, which include Bim, Bmf, Bik, Bad, Bid, Puma, Noxa and Hrk, mediate many developmentally programmed and induced cytotoxic signals. They have ...key roles in development, tissue homeostasis, immunity and tumor suppression, and compounds mimicking them are promising anti-cancer agents. Their activity is normally constrained by transcriptional and/or diverse post-transcriptional controls. When activated, these death ligands engage pro-survival Bcl-2-like proteins via the BH3 domain, inactivating their function. Bim and Puma bind all the pro-survival proteins, whereas others, such as Noxa and Bad, engage distinct subsets and exhibit complementary killing. Hence, multiple pro-survival proteins must be inactivated to unleash Bax and Bak, which drive apoptosis. Whether certain BH3-only proteins also directly activate Bax/Bak remains controversial.
When B cells encounter an antigen, they alter their physiological state and anatomical localization and initiate a differentiation process that ultimately produces antibody-secreting cells (ASCs). We ...have defined the transcriptomes of many mature B cell populations and stages of plasma cell differentiation in mice. We provide a molecular signature of ASCs that highlights the stark transcriptional divide between B cells and plasma cells and enables the demarcation of ASCs on the basis of location and maturity. Changes in gene expression correlated with cell-division history and the acquisition of permissive histone modifications, and they included many regulators that had not been previously implicated in B cell differentiation. These findings both highlight and expand the core program that guides B cell terminal differentiation and the production of antibodies.
•Multiple intrinsic and extrinsic inputs control B cell terminal differentiation.•Differentiation is associated with loss of CpG methylation at promoters/enhancers.•Ezh2 functions a several points to ...coordinate the B cell to plasma cell transition.•B cell terminal differentiation is associated with changes in genome architecture.•The B1 cell subset utilizes distinct regulatory factors.
The differentiation of B cells into antibody-secreting plasma cells is associated with profound changes in morphology, lifespan, and cellular metabolism that are needed to support high rates of antibody production. These processes are driven by dramatic alterations to the transcriptional program and to the organization of the nucleus itself that in turn are regulated by the activity of a select group of transcription factors and epigenetic regulators. Although the core differentiation program is conserved in all mature B cells, subset-specific regulators, such as those found in B1 or memory B cells, provide additional complexity. Here, we review the key components of the gene regulatory network controlling B-cell terminal differentiation, with an emphasis on the new players and processes that have emerged in recent years.
Humoral immunity requires B cells to respond to multiple stimuli, including antigen, membrane and soluble ligands, and microbial products. Ets family transcription factors regulate many aspects of ...haematopoiesis, although their functions in humoral immunity are difficult to decipher as a result of redundancy between the family members. Here we show that mice lacking both PU.1 and SpiB in mature B cells do not generate germinal centers and high-affinity antibody after protein immunization. PU.1 and SpiB double-deficient B cells have a survival defect after engagement of CD40 or Toll-like receptors (TLR), despite paradoxically enhanced plasma cell differentiation. PU.1 and SpiB regulate the expression of many components of the B cell receptor signaling pathway and the receptors for CD40L, BAFF and TLR ligands. Thus, PU.1 and SpiB enable B cells to appropriately respond to environmental cues.
Randomised controlled trials (RCTs) have observed contrasting results on the effects of vitamin C on circulating biomarkers of glycaemic and insulin regulation. We conducted a systematic review and ...meta-analysis of RCTs testing the effect of vitamin C administration on glucose, HbA1c and insulin concentrations. Four databases (PubMed, Embase, Scopus and Cochrane Library) were used to retrieve RCTs published from inception until April 2016 and testing the effects of vitamin C in adult participants. The screening of 2008 articles yielded 22 eligible studies (937 participants). Overall, vitamin C did not modify glucose, HbA1c and insulin concentrations. However, subgroup analyses showed that vitamin C significantly reduced glucose concentrations (-0.44 mmol/l, 95% CI: -0.81, -0.07, P=0.01) in patients with type 2 diabetes and in interventions with a duration greater than 30 days (-0.53%, 95% CI: -0.79, -0.10, P=0.02). Vitamin C administration had greater effects on fasting (-13.63 pmol/l, 95% CI: -22.73, -4.54, P<0.01) compared to postprandial insulin concentration. Meta-regression analyses showed that age was a modifier of the effect of vitamin C on insulin concentration. Furthermore, the effect size was associated with baseline BMI and plasma glucose levels, and with the duration of the intervention. In conclusion, greater reduction in glucose concentrations observed in patients with diabetes, older individuals and with more prolonged supplementation. Personalised interventions with vitamin C may represent a feasible future strategy to enhance benefits and efficacy of interventions. Nevertheless, results need to be interpreted cautiously due to limitations in the primary studies analysed.
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple ...myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis,” as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.
•Inactivation of Ikaros and Aiolos recapitulates the cell-intrinsic action of the IMiDs in MM, as well as transcriptional changes.•Loss of Ikaros or Aiolos results in upregulation of ISGs, including CD38, priming MM cells for anti-CD38 targeting.
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Heavy metal pollution in surface waters has become a major worldwide issue as people tend to settle where there is readily available source of water like a river. This research evaluates the causes, ...concentration and associated health risks of heavy metals in River Sosiani as it passes through the town of Eldoret. Seven water samples were collected and analysed for zinc (Zn), copper (Cu) and lead (Pb. The results disclosed that Pb concentrations were estimated to be in the range of 0.06 mg/l to 0.23 mg/l, higher than the permitted limit by WHO of 0.01 mg/l. Cu and Zn concentration levels were below the permissible limits. The chronic daily intake (CDI) indicated that total hazard quotient of non-cancer risk of Pb was above one and the total HI values for children were greatly elevated compared to those of adults in the studied area. This showed a high risk in exposure to Pb. Health human risk was assessed and the incremental life cancer risk (ILCR) values of Pb for children and adults in all sites were found to be negligible with values below 10
−6
. However, there is higher cancer and non-cancer risk for children than adults as far as lead metal is concerned. Therefore, measures should be taken in accordance with the standards to prevent potential risk of the river pollution.
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Human activities make a significant contribution to heavy metal pollution to surface waters which is a threat to humans.
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Water from Sosiani River is not safe for use domestically as far as lead metal levels are concerned.
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The results of this study can be used by decision makers to develop measures which can improve the quality of water in the river catchment.
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Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are ...maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell-promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1-IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration-dependent competition between these factors controls B cell terminal differentiation.
Since apoptosis is impaired in malignant cells overexpressing prosurvival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven ...putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-x
L, and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects ABT-737's inability to target another prosurvival relative, Mcl-1. Downregulation of Mcl-1 by several strategies conferred sensitivity to ABT-737. Furthermore, enforced Mcl-1 expression in a mouse lymphoma model conferred resistance. In contrast, cells overexpressing Bcl-2 remained highly sensitive to ABT-737. Hence, ABT-737 should prove efficacious in tumors with low Mcl-1 levels, or when combined with agents that inactivate Mcl-1, even to treat those tumors that overexpress Bcl-2.
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