Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism

Proteolytic cleavage is an important post-translational mechanism to increase protein variability and functionality. In cancer, this process can be deregulated to shut off tumor-suppressive functions. Here, we report that in glioblastoma (GBM), the tumor suppressor ZBTB18 is targeted for protein cleavage by the intracellular protease calpain. The N-terminal (Nte) ZBTB18 cleaved fragment localizes to the cytoplasm and thus, is unable to exert the gene expression repressive function of the uncleaved protein. Mass spectrometry (MS) analysis indicates that the Nte ZBTB18 short form (SF) interacts with C-terminal (Cte) binding proteins 1 and 2 (CTBP1/2), which appear to be involved in HIF1A signaling activation. In fact, we show that the new ZBTB18 product activates HIF1A-regulated genes, which in turn lead to increased lipid uptake, lipid droplets (LD) accumulation, and enhanced metabolic activity. We propose that calpain-mediated ZBTB18 cleavage represents a new mechanism to counteract ZBTB18 tumor suppression and increase tumor-promoting functions in GBM cells

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions

Improving vasomotor symptoms; psychological symptoms; and health-related quality of life in peri- or post-menopausal women through yoga: An umbrella systematic review and meta-analysis

ObjectivesVasomotor symptoms (VMS), commonly reported during menopausal transition, negatively affect psychological health and health-related quality of life (HRQoL). While hormone therapy is an effective treatment, its use is limited by concerns about possible harms. Thus, many women with VMS seek nonhormonal, nonpharmacologic treatment options. However, evidence to guide clinical recommendations is inconclusive. This study reviewed the effectiveness of yoga, tai chi and qigong on vasomotor, psychological symptoms, and HRQoL in peri- or post-menopausal women.DesignMEDLINE, Cochrane Database of Systematic Reviews, EMBASE, CINAHL and the Allied and Complementary Medicine Database were searched. Researchers identified systematic reviews (SR) or RCTs that evaluated yoga, tai chi, or qigong for vasomotor, psychological symptoms, and health-related quality of life (HRQoL) in peri- or post-menopausal women. Data were abstracted on study design, participants, interventions and outcomes. Risk of bias (ROB) was assessed and updated meta-analyses were performed.ResultsWe identified one high-quality SR (5 RCTs, 582 participants) and 3 new RCTs (345 participants) published after the SR evaluating yoga for vasomotor, psychological symptoms, and HRQoL; no studies evaluated tai chi or qigong. Updated meta-analyses indicate that, compared to controls, yoga reduced VMS (5 trials, standardized mean difference (SMD) -0.27, 95% CI -0.49 to -0.05) and psychological symptoms (6 trials, SDM -0.32; 95% CI -0.47 to -0.17). Effects on quality of life were reported infrequently. Key limitations are that adverse effects were rarely reported and outcome measures lacked standardization.ConclusionsResults from this meta-analysis suggest that yoga may be a useful therapy to manage bothersome vasomotor and psychological symptoms