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Rigosertib is more potent than wortmannin and rapamycin against adult T‐cell leukemia‐lymphoma

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Rigosertib is more potent than wortmannin and rapamycin against adult T-cell leukemia-lymphoma

HTLV-1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K-Akt-mTOR phosphorylation by HTLV-1. Rigosertib was more effective than wortmannin and rapamycin in inducing cell cycle arrest, as well as a significant late apoptosis in the Inf-3T3 and MT-2 cells.


Abstract

Human T lymphotropic virus type 1 (HTLV-1) infection can cause adult T-cell lymphoblastic leukemia (ATLL), an incurable, chemotherapy-resistant malignancy. In a quest for new therapeutic targets, our study sought to determine the levels of AKT, mTOR, and PI3K in ATLL MT-2 cells, HTLV-1 infected NIH/3T3 cells (Inf-3T3), and HTLV-1 infected patients (Carrier, HAM/TSP, and ATLL). Furthermore, the effects of rigosertib, wortmannin, and rapamycin on the PI3K/Akt/mTOR pathway to inhibit the proliferation of ATLL cells were examined. The results showed that mRNA expression of Akt/PI3K/mTOR was down-regulated in carrier, HAM/TSP, and ATLL patients, as well as MT-2, and Inf-3T3 cells, compared to the healthy individuals and untreated MT-2 and Inf-3T3 as controls. However, western blotting revealed an increase in the phosphorylated and activated forms of AKT and mTOR. Treating the cells with rapamycin, wortmannin, and rigosertib decreased the phosphorylated forms of Akt and mTOR and restored their mRNA expression levels. Using these inhibitors also significantly boosted the expression of the pro-apoptotic genes, Bax/Bcl-2 ratio as well as the expression of the tumor suppressor gene p53 in the MT-2 and Inf-3T3cells. Rigosertib was more potent than wortmannin and rapamycin in inducing sub-G1 and G2-M cell cycle arrest, as well as late apoptosis in the Inf-3T3 and MT-2 cells. It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV-1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K-Akt-mTOR phosphorylation by HTLV-1. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.

Silicon alleviates drought damage by increasing antioxidant and photosynthetic performance in cowpea

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Abstract

Water deficits have been considered the most restrictive environmental constraint on agricultural production worldwide. The current study aimed to investigate the role of silicon nutrition (Si) in activating defence mechanisms against drought damage in cowpea cultivars. The experiments were carried out in a randomized block design in a 2 × 2 × 4 factorial scheme, corresponding to two cowpea cultivars (BRS Novaera and BRS Tumucumaque), two water regimes (control well-irrigated and water deficit) and four Si levels (0, 1.0, 2.0 and 4.0 mM). Plant growth and physiological and biochemical indicators were evaluated 28 days after drought imposition. Drought significantly reduced the photosynthetic pigments (Chl b and Chl total), gas exchanges (net photosynthesis, transpiration and stomatal conductance) and, consequently, all growth parameters of cowpea plants compared with well-irrigated plants. However, Si at 2.0 mM activated critical responses in the BRS Novaera cultivar under drought, almost recovering plant performance and increasing drought tolerance. The beneficial Si-induced effects were closely related to increased accumulation of Si, carbohydrates and free amino acids that likely promoted osmoregulation and were associated with an improved antioxidant system composed of proline and the activity of SOD, CAT and APX. These metabolic alterations were sufficient to enable enhanced net photosynthesis and plant growth. In conclusion, Si counteracts the deleterious effects of water deficit by efficiently inducing antioxidant defence and photosynthetic performance in Novaera plants. Si nutrition may constitute a potential strategy to cultivate cowpea plants in water-scarce areas from arid and semiarid regions.

Salinity effects on the activities of ROS scavenging enzymes in leaves of two sweet potato clones

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Abstract

Sweet potato production, particularly in coastal areas is often prone to salinity. Salt-tolerant clones will be needed to maintain production, but to date, little is known about salt tolerance traits in sweet potato. Salt stress may result in excessive uptake of unwanted ions into plant tissues leading to the formation of reactive oxygen species (ROS), which in turn may destroy membranes and reduce photosynthesis and growth. Antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POX), catalase (CAT), glutathione reductase (GR) and ascorbate peroxidase (APX) scavenge ROS and early changes in the activities of such enzymes could be used to identify salinity tolerant genotypes. Therefore, cuttings of two contrasting cultivars of sweet potato, BARI SP 8 (tolerant) and BARI SP 4 (sensitive) were greenhouse-cultivated in nutrient solution for 21 days and then exposed to 100 mmol NaCl for 7 days. Three, five and seven days after salt application the youngest leaves were sampled individually and enzyme activities, potassium (K) and sodium (Na) concentrations, and SPAD (as a proxy for chlorophyll content) were determined. In both varieties leaf growth was not affected by salinity and young leaves grown under salinity had higher SPAD values than older leaves. Na concentration increased over time, particularly in earlier and in older leaves, whereas K was reduced in younger leaves. In general, enzyme activities were strongly affected by leaf age and leaf position. SOD and APX showed varietal but no salinity effects, CAT increased under salinity in both varieties, whereas POX was strongly reduced and GR was strongly increased under salinity in BARI SP 8 with no effect in BARI SP 4. Enzyme activities were not correlated to leaf Na, neither in relation to leaf age, nor leaf number or duration of salt stress in both varieties. However, varietal differences were observed regarding leaf K. Activities of SOD were highly positive and of CAT highly negatively correlated with leaf K under salinity in BARI SP 8 but not in BARI SP 4, whereas activities of GR and POX were strongly positively correlated with leaf K in BARI SP 4 under salinity but not in BARI SP 8. We conclude that potassium may have a strong regulating role on leaf stress levels and therefore on the activities of antioxidant enzymes. Varieties may differ in their tolerance strategy and we have shown that salinity does not generally increase levels of ROS-scavenging enzymes in sweet potato leaves under salt stress. Confounding factors such as leaf age and leaf position as well as maintaining high leaf level K concentrations need to be considered when evaluating metabolic traits for salinity tolerance traits.

Angiotensin II type 2 receptor as a novel activator of brown adipose tissue in obesity

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Angiotensin II type 2 receptor as a novel activator of brown adipose tissue in obesity

Angiotensin II type 2 receptor as a noval activator of brown adipose tissue in obesity.


Abstract

The angiotensin II type 2 receptor (AT2R) exerts vasorelaxant, anti-inflammatory, and antioxidant properties. In obesity, its activation counterbalances the adverse cardiovascular effects of angiotensin II mediated by the AT1R. Preliminary results indicate that it also promotes brown adipocyte differentiation in vitro. Our hypothesis is that AT2R activation could increase BAT mass and activity in obesity. Five-week-old male C57BL/6J mice were fed a standard or a high-fat (HF) diet for 6 weeks. Half of the animals were treated with compound 21 (C21), a selective AT2R agonist, (1 mg/kg/day) in the drinking water. Electron transport chain (ETC), oxidative phosphorylation, and UCP1 proteins were measured in the interscapular BAT (iBAT) and thoracic perivascular adipose tissue (tPVAT) as well as inflammatory and oxidative parameters. Differentiation and oxygen consumption rate (OCR) in the presence of C21 was tested in brown preadipocytes. In vitro, C21-differentiated brown adipocytes showed an AT2R-dependent increase of differentiation markers (Ucp1, Cidea, Pparg) and increased basal and H+ leak-linked OCR. In vivo, HF-C21 mice showed increased iBAT mass compared to HF animals. Both their iBAT and tPVAT showed higher protein levels of the ETC protein complexes and UCP1, together with a reduction of inflammatory and oxidative markers. The activation of the AT2R increases BAT mass, mitochondrial activity, and reduces markers of tissue inflammation and oxidative stress in obesity. Therefore, insulin reduction and better vascular responses are achieved. Thus, the activation of the protective arm of the renin–angiotensin system arises as a promising tool in the treatment of obesity.

Genomic approaches to enhance adaptive plasticity to cope with soil constraints amidst climate change in wheat

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Abstract

Climate change is varying the availability of resources, soil physicochemical properties, and rainfall events, which collectively determines soil physical and chemical properties. Soil constraints—acidity (pH < 6), salinity (pH ≤ 8.5), sodicity, and dispersion (pH > 8.5)—are major causes of wheat yield loss in arid and semiarid cropping systems. To cope with changing environments, plants employ adaptive strategies such as phenotypic plasticity, a key multifaceted trait, to promote shifts in phenotypes. Adaptive strategies for constrained soils are complex, determined by key functional traits and genotype × environment × management interactions. The understanding of the molecular basis of stress tolerance is particularly challenging for plasticity traits. Advances in sequencing and high-throughput genomics technologies have identified functional alleles in gene-rich regions, haplotypes, candidate genes, mechanisms, and in silico gene expression profiles at various growth developmental stages. Our review focuses on favorable alleles for enhanced gene expression, quantitative trait loci, and epigenetic regulation of plant responses to soil constraints, including heavy metal stress and nutrient limitations. A strategy is then described for quantitative traits in wheat by investigating significant alleles and functional characterization of variants, followed by gene validation using advanced genomic tools, and marker development for molecular breeding and genome editing. Moreover, the review highlights the progress of gene editing in wheat, multiplex gene editing, and novel alleles for smart control of gene expression. Application of these advanced genomic technologies to enhance plasticity traits along with soil management practices will be an effective tool to build yield, stability, and sustainability on constrained soils in the face of climate change.

Breeding evaluation and precise mapping of Fhb8 for Fusarium head blight resistance in wheat (Triticum aestivum)

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Abstract

The percentage of Fusarium-damaged kernels (FDK) was proposed as a type of Fusarium head blight (FHB) resistance displayed in matured wheat kernels. In this study, Qfdk.nau-7D, a QTL identified in the Wangshuibai genome for its association with FDK, was introduced into FHB-susceptible common wheat line PH691 through marker-assisted selection and backcrossing. Evaluation of two resulted near-isogenic lines (NILs) showed that the contribution of Qfdk.nau-7D interval to lower FDK resulted from its effects on resistance to pathogen infection and to disease spread within the spike. Of a few major agronomic traits evaluated, head length was the only one that made difference between PH691 and the NILs. To reduce the QTL interval, a high-density marker map was constructed using a BC3F2 population of 97 plants. Through resistance evaluation of the homozygous recombinant lines in repeated field trials, Qfdk.nau-7D, designated as Fhb8, was placed in a 1.0-cM Xwgrb1500-Xwgrb1559 interval (from 93.9–96.5 Mb in CS) and showed co-segregation with Xwgrb1587. Moreover, it was found that the association of Fhb8 with head length was due to close linkage with spike length QTL HL2.