Previous studies have suggested the involvement of CD4 + T lymphocytes in cardiac remodelling. T-bet can direct Th1 lineage commitment. This study aimed to investigate the functional significance of ...T-bet in cardiac remodelling induced by pressure overload using T-bet global knockout rats. Increased T-bet levels were observed in rodent and human hypertrophied hearts. T-bet deficiency resulted in a less severe hypertrophic phenotype in rats. CD4 + T-lymphocyte reconstitution in T-bet−/− rats resulted in aggravated cardiac remodelling. T-cell homing molecule expression and cytokine secretion were altered in T-bet-deficient rat hearts. Administration of exogenous interferon-γ (IFN-γ) offset T-bet deficiency-mediated cardioprotection. Cardiomyocytes cultured in T-bet−/− CD4 + T-cell-conditioned media showed a reduced hypertrophic response after hypertrophic stimuli, which was abolished by an IFN-γ-neutralizing antibody. Taken together, our findings show that T-bet deficiency attenuates pressure overload-induced cardiac remodelling in rats. Specifically, targeting T-bet in T cells may be of great importance for the treatment of pathological cardiac remodelling and heart failure.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
T-cell infiltration and the subsequent increased intracardial chronic inflammation play crucial roles in the development of cardiac hypertrophy and heart failure (HF). A77 1726, the active metabolite ...of leflunomide, has been reported to have powerful anti-inflammatory and T cell-inhibiting properties. However, the effect of A77 1726 on cardiac hypertrophy remains completely unknown. Herein, we found that A77 1726 treatment attenuated pressure overload or angiotensin II (Ang II)-induced cardiac hypertrophy
, as well as agonist-induced hypertrophic response of cardiomyocytes
In addition, we showed that A77 1726 administration prevented induction of cardiac fibrosis by inhibiting cardiac fibroblast (CF) transformation into myofibroblast. Surprisingly, we found that the protective effect of A77 1726 was not dependent on its T lymphocyte-inhibiting property. A77 1726 suppressed the activation of protein kinase B (AKT) signaling pathway, and overexpression of constitutively active AKT completely abolished A77 1726-mediated cardioprotective effects
and
Pretreatment with siRNA targetting
(si
) blunted the protective effect elicited by A77 1726
More importantly, A77 1726 was capable of blocking pre-established cardiac hypertrophy in mice. In conclusion, A77 1726 attenuated cardiac hypertrophy and cardiac fibrosis via inhibiting FYN/AKT signaling pathway.
Mitogen-activated protein kinases (MAPKs) and AMPactivated protein kinase α (AMPKα) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine ...activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO) injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β) or angiotensin II (Ang II) in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT) and, downstream, glycogen synthase kinase 3β (GSK3β). The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ), reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β.
•Piperine attenuated cardiac fibrosis induced by pressure overload or isoprenaline in mice.•Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts via the attenuation of the AKT/GSK3β pathway.•Piperine acted as an agonist of PPAR-γ in cardiac fibroblasts.
Cardiac fibrosis plays key roles in the processes of cardiac remodeling and heart failure. The lack of therapy against cardiac fibrosis contributes to the high morbidity and mortality caused by HF. We found that piperine attenuates cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β. Our study provides evidence for the application of piperine in the treatment of cardiac fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This brief presents a new algorithm optimized for radix-2 real-valued fast Fourier transform (RFFT) through rigorous formula derivation. Based on that, a novel two-parallel pipelined radix-2 RFFT ...architecture is proposed with only real datapaths instead of hybrid datapaths. The architecture takes advantage of saving the arithmetic resource in the time-division multiplexing approach to achieve 100% hardware resource utilization. Thereby, it reduces the required number of complex multipliers from log 2 N-2 to (1/2)(log 2 N -3), in contrast with existing two-parallel pipelined architectures. The experimental result shows that the proposed two-parallel architecture can reduce the slice and power consumption by a factor of 30% compared with a recently published work for a 64-point CFFT. Furthermore, a systematic method is also explicated to generalize the architecture to higher level of parallelism and higher radix.
This brief presents a novel conflict-free access scheme for memory-based fast Fourier transform (FFT) processors. It is proved to satisfy the constraints of the mixed-radix, continuous-flow, ...parallel-processing, and variable-size FFT computations. An address generation unit is also designed and outperforms existing architectures with reduced gate delay and lower hardware complexity.
This brief presents a novel architecture for memory-based fast Fourier transform (FFT) computation for real-valued signals based on radix-2 decimation-in-frequency algorithm. A superior strategy of ...stage partition for the real FFT (RFFT) is proposed to minimize the computation clock cycles and maximize the utilization of the processing element (PE). The PE employed in our RFFT architecture can process four inputs in parallel by using two radix-2 butterflies and only two multiplexers. The proposed memory-addressing scheme and control of the multiplexers can be expressed in terms of a counter according to the RFFT computation stage. Furthermore, the proposed RFFT architecture can support more PEs in two dimensions as well. Compared with prior works, the proposed RFFT processors have the advantages of fewer computation cycles and lower hardware usage. The experiment shows that the proposed processor reduces the computation cycles by a factor of 17.5% for a 32-point RFFT computation compared with a recently presented work while maintaining lower hardware usage and complexity in the PE design.
Rationale: Clinical application of doxorubicin (DOX) is limited by its toxic cardiovascular side effects. Our previous study found that toll-like receptor (TLR) 5 deficiency attenuated cardiac ...fibrosis in mice. However, the role of TLR5 in DOX-induced cardiotoxicity remains unclear. Methods: To further investigate this, TLR5-deficient mice were subjected to a single intraperitoneal injection of DOX to mimic an acute model. Results: Here, we reported that TLR5 expression was markedly increased in response to DOX injection. Moreover, TLR5 deficiency exerted potent protective effects against DOX-related cardiac injury, whereas activation of TLR5 by flagellin exacerbated DOX injection-induced cardiotoxicity. Mechanistically, the effects of TLR5 were largely attributed to direct interaction with spleen tyrosine kinase to activate NADPH oxidase (NOX) 2, increasing the production of superoxide and subsequent activation of p38. The toxic effects of TLR5 activation in DOX-related acute cardiac injury were abolished by NOX2 deficiency in mice. Our further study showed that neutralizing antibody-mediated TLR5 depletion also attenuated DOX-induced acute cardiotoxicity. Conclusion: These findings suggest that TLR5 deficiency attenuates DOX-induced cardiotoxicity in mice, and targeting TLR5 may provide feasible therapies for DOX-induced acute cardiotoxicity.
Equi-join operations are fundamental in database management. Hash join algorithms are often used to reduce the computational complexity of join operations; however, their performance is influenced by ...imperfect data distributions caused by hash collisions. To resolve these collisions, this brief designs a hardware-accelerated hash join architecture. This architecture aims to break the trade-off between complex hash functions, which is computationally expensive, and hash join performance. First, two hash functions are employed to distribute data as evenly as possible, and then multiple entries of the collision list are provided; finally, a small number of the static random-access memory (SRAM) of the field-programmable gate arrays (FPGAs) are used to conduct the join operation in parallel. The proposed method yields high-throughput and is resource-efficient, as it does not require reprocessing of data; further, it improves hash table utilization. The results of implementing this architecture on a Xilinx Zynq FPGA platform indicate an accelerated throughput that is a minimum of 4.2× that of previous hardware-accelerated hash join methods.
Geniposide (GE) is a major component in the fruit of
Ellis. Oxidative stress, endoplasmic reticulum (ER) stress, and canonical Smad3 pathway are implicated in the pathogenesis of cardiac fibrosis. We ...aim to investigate the protective roles of GE in isoproterenol (ISO)-induced cardiac fibrosis.
ISO was used to induce cardiac fibrosis in male C57BL/6 mice. GE and the EX-527 were given for 2 weeks to detect the effects of GE on cardiac fibrosis. Levels of oxidative stress, ER stress, and Smad3 were evaluated by real time-PCR, Western blots, immunohistochemistry staining, immunofluorescence staining, and assay kits.
GE treatment alleviated cardiac dysfunction, fibrosis, and hypertrophy in mice response to ISO. Additionally, GE also suppressed the transformation of cardiac fibroblasts to myofibroblasts stimulated by transforming growth factor-β (TGF-β)
. Mechanistically, GE inhibited the oxidative stress, ER stress, as well as Smad3 pathway activated by ISO or TGF-β. A selective antagonist of sirtuin 1 deacetylase (SIRT1), EX-527, partially counteracted the anti-fibrotic effect and weakened the inhibitory effect on the transformation of cardiac fibroblasts to myofibroblasts after the treatment of GE. Acetylated Smad3 (ac-Smad3), oxidative stress, as well as ER stress pathway were significantly enhanced after SIRT1 was blocked while phosphorylated Smad3 (P-Smad3) was not affected.
GE could combat cardiac fibrosis
and
by inhibiting oxidative stress, ER stress, and ac-Smad3 in a SIRT1-dependent manner and suppressing P-Samd3 pathway independent of SIRT1 activation. GE is expected to be a promising agent against cardiac fibrosis.
Our previous study found that geniposide, an agonist of glucagon-like peptide-1 receptor (GLP-1R), protected against cardiac hypertrophy via the activation of AMP-activated protein kinase α (AMPKα). ...However, the effects of geniposide on obesity-related cardiac injury remain unknown. Here, we examine whether geniposide attenuates obesity-related cardiac dysfunction. Adult mice were fed a high-fat diet (HFD) for 24 weeks to induce obesity, with the last 3 weeks including a 21-day treatment with geniposide. Morphological changes, cardiac function, and remodeling were assessed. HFD-induced metabolic syndrome, featured as obesity, hyperglycemia, and cardiac hypertrophy, was prevented by geniposide treatment. Geniposide preserved cardiac function in the obese mice. Furthermore, geniposide attenuated myocardial inflammation and myocyte apoptosis induced by HFD. Geniposide activated AMPKα and sirtuin (Sirt1) in vivo and in vitro. Ampkα deficiency reversed the inhibitory effects of geniposide on cell loss. Sirt1 deficiency abolished the inhibitory effects of geniposide on inflammation in the cardiomyocytes. Geniposide completely lost its protective effects on Ampkα knockout mice after Sirt1 deficiency achieved by a nanoparticle transfection reagent. The activation of Sirt1 by geniposide was abolished by Glp-1r deficiency in vitro. Geniposide reverses molecular pathology and cardiac dysfunction via both AMPKα- and Sirt1-dependent mechanisms. Geniposide is a potential therapeutic drug for cardiovascular complications induced by obesity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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