Loss of BCAA catabolism enhances Rab1A-mTORC1 signaling activity and promotes tumor proliferation in NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Branched-chain amino acid (BCAA) homeostasis is important for normal physiological metabolism. Branched-chain keto acid dehydrogenase kinase (BCKDK) is a rate-limiting enzyme involved in BCAA degradation. BCAA metabolism has been highlighted in human cancers. The aberrant activation of mTORC1 has been implicated in tumor progression. Rab1A is a small GTPase, an activator of mTORC1, and an oncogene. This study aimed to reveal the specific role of BCKDK-BCAA-Rab1A-mTORC1 signaling in NSCLC. METHODS: We analyzed a cohort of 79 patients with NSCLC and 79 healthy controls. Plasma BCAA assays, immunohistochemistry, and network and pathway analyses were performed. The stable cell lines BCKDK-KD, BCKDK-OV A549, and H1299 were constructed. BCKDK, Rab1A, p-S6 and S6 were detected using western blotting to explore their molecular mechanisms of action in NSCLC. The effects of BCAA and BCKDK on the apoptosis and proliferation of H1299 cells were detected by cell function assays. RESULTS: We demonstrated that NSCLC was primarily involved in BCAA degradation. Therefore, combining BCAA, CEA, and Cyfra21-1 is clinically useful for treating NSCLC. We observed a significant increase in BCAA levels, downregulation of BCKDHA expression, and upregulation of BCKDK expression in NSCLC cells. BCKDK promotes proliferation and inhibits apoptosis in NSCLC cells, and we observed that BCKDK affected Rab1A and p-S6 in A549 and H1299 cells via BCAA modulation. Leucine affected Rab1A and p-S6 in A549 and H1299 cells and affected the apoptosis rate of H1299 cells. In conclusion, BCKDK enhances Rab1A-mTORC1 signaling and promotes tumor proliferation by suppressing BCAA catabolism in NSCLC, suggesting a new biomarker for the early diagnosis and identification of metabolism-based targeted approaches for patients with NSCLC.

Achieving Enhanced Capacitive Deionization by Interfacial Coupling in PEDOT Reinforced Cobalt Hexacyanoferrate Nanoflake Arrays.

Capacitive deionization (CDI) as a novel energy and cost-efficient water treatment technology has attracted increasing attention. The recent development of various faradaic electrode materials has greatly enhanced the performance of CDI as compared with traditional carbon electrodes. Prussian blue (PB) has emerged as a promising CDI electrode material due to its open framework for the rapid intercalation/de-intercalation of sodium ions. However, the desalination efficiency, and durability of previously reported PB-based materials are still unsatisfactory. Herein, a self-template strategy is employed to prepare a Poly(3,4-ethylenedioxythiophene) (PEDOT) reinforced cobalt hexacyanoferrate nanoflakes anchored on carbon cloth (denoted as CoHCF@PEDOT). With the high conductivity and structural stability achieved by coupling with a thin PEDOT layer, the as-prepared CoHCF@PEDOT electrode exhibits a high capacity of 126.7 mAh g-1 at 125 mA g-1. The fabricated hybrid CDI cell delivers a high desalination capacity of 146.2 mg g-1 at 100 mA g-1, and good cycling stability. This strategy provides an efficient method for the design of high-performance faradaic electrode materials in CDI applications.

Bismuth Nanoparticle-Embedded Porous Carbon Frameworks as a High-Rate Chloride Storage Electrode for Water Desalination.

Capacitive deionization (CDI) is a promising cost-effective and low energy consumption technology for water desalination. However, most of the previous works focus on only one side of the CDI system, i.e., Na+ ion capture, while the other side that stores chloride ions, which is equally important, receives very little attention. This is attributed to the limited Cl- storage materials as well as their sluggish kinetics and poor stability. In this article, we demonstrate that a N-doped porous carbon framework is capable of suppressing the phase-transformation-induced performance decay of bismuth, affording an excellent Cl- storage and showing potential for water desalination. The obtained Bi-carbon composite (Bi/N-PC) shows a capacity of up to 410.4 mAh g-1 at 250 mA g-1 and a high rate performance. As a demonstration for water desalination, a superior desalination capacity of 113.4 mg g-1 is achieved at 100 mA g-1 with excellent durability. Impressively, the CDI system exhibits fast ion capturing with a desalination rate as high as 0.392 mg g-1 s-1, outperforming most of the recently reported Cl- capturing electrodes. This strategy is applicable to other Cl- storage materials for next-generation capacitive deionization.

Corin plays a protective role via upregulating MAPK and downregulating eNOS in diabetic nephropathy endothelial dysfunction.

Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients, but its pathogenesis is unclear. We aimed to study the role of the pro-ANP convertase Corin in the pathogenesis of DN. Corin and ANP expression in DN rat kidneys and high-glucose-treated HK-2 cells was analyzed by real-time PCR, western blotting, and immunohistochemical staining. The effect of Corin-siRNA or ANP-siRNA HK-2 cells on EA.hy926 cell migration was determined by scratch-wound healing assay. The expression of mitogen-activated protein kinase (MAPK) and endothelial NO synthase (eNOS) in EA.hy926 cells treated with conditioned medium from Corin-siRNA- or ANP-siRNA-transfected HK-2 cells was determined by western blotting. We found a significant reduction in Corin and ANP expression in DN rat kidneys. These results were recapitulated in HK-2 cells treated with high glucose. EA.hy926 cells treated with conditioned medium from Corin-deficient HK-2 cells had inhibited migration, increased MAPK activity, and decreased eNOS activity. Similar effects were observed with ANP-siRNA transfection. Finally, adding ANP to the Corin-deficient HK-2 conditioned medium rescued the above defects, indicating that Corin mediates its effects through ANP. In conclusion, Corin plays a renoprotective role through pro-ANP processing, and defects in Corin cause endothelial dysfunction through MAPK and eNOS signaling in DN.

Spleen tyrosine kinase­induced JNK­dependent NLRP3 activation is involved in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a leading contributor to the increased morbidity and mortality rates associated with diabetes. Persistent inflammation has previously been reported to be involved in the pathogenesis of DCM. However, the exact underlying molecular mechanisms remain to be fully elucidated. In the present study, the role of spleen tyrosine kinase (Syk) and c­Jun N­terminal kinase (JNK) in NLR family pyrin domain­containing 3 (NLRP3 inflammasome) activation in DCM were investigated in vivo and in vitro. Streptozotocin (65 mg/kg) was injected intraperitoneally into Sprague­Dawley rats to induce a rat model of diabetes. Neonatal rat cardiomyocytes and H9c2 cells were cultured to detect the expression of JNK, NLRP3 and its associated downstream molecules, following treatment with Syk/JNK inhibitor or Syk/JNK­small interfering (si)RNA in high glucose (HG) conditions. It was revealed that the protein and mRNA expression levels of phospho (p)­Syk, p­JNK, NLRP3 and its associated downstream molecules, including interleukin (IL)­1ß, were upregulated in vivo and in vitro. The JNK inhibitor significantly decreased the expression of NLRP3 and its downstream molecules in neonatal rat cardiomyocytes and H9c2 cells treated with HG. Furthermore, Syk­siRNA and the Syk inhibitor markedly inhibited the HG­induced activation of JNK, followed by the downregulation of NLRP3 and its downstream molecules at the mRNA and protein levels in cells. Therefore, it was demonstrated that the HG­induced activation of NLRP3 was mediated by the activation of Syk/JNK, which subsequently increased the protein expression levels of mature IL­1ß, suggesting that the Syk/JNK/NLRP3 signaling pathway serves a critical role in the pathogenesis of DCM.

Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasome­mediated IL­1ß secretion via c­Jun N­terminal kinase activation and cell apoptosis during diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes and can cause an increased mortality risk. It was previously reported that NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the pathogenesis of diabetes. However, the underlying mechanism is not clearly understood. In the present study, the effects of spleen tyrosine kinase (Syk) and c­Jun N­terminal kinase (JNK) on the NLRP3 inflammasome were examined in vivo and in vitro. Sprague­Dawley rats were injected intraperitoneally with streptozotocin (65 mg/kg) to induce diabetes. HK2 cells and rat glomerular mesangial cells (RGMCs) were examined to detect the expression of JNK and NLRP3 inflammasome­associated proteins following treatment with a Syk inhibitor or Syk­small interfering (si)RNA in a high glucose condition. In the present study, it was revealed that the protein and mRNA expression levels of NLRP3 inflammasome­associated molecules and the downstream mature interleukin (IL)­1ß were upregulated in vivo and in vitro. The Syk inhibitor and Syk­siRNA suppressed high glucose­induced JNK activation, and subsequently downregulated the activation of the NLRP3 inflammasome and mature IL­1ß in HK2 cells and RGMCs. Furthermore, high glucose­induced apoptosis of HK2 cells was reduced by the Syk inhibitor BAY61­3606. Therefore, the present results determined that high glucose­induced activation of the NLRP3 inflammasome is mediated by Syk/JNK activation, which subsequently increased the protein expression level of IL­1ß and mature IL­1ß. The present study identified that the Syk/JNK/NLRP3 signaling pathway may serve a vital role in the pathogenesis of DN.