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Humans have dopamine D5 receptors (hD5R) with single-nucleotide polymorphisms and a diminished function. We generated hD5(F173L) cDNA that has a decreased response to D5R agonist-mediated increase in cAMP production and increased production of reactive oxygen species, relative to wild-type hD5R (hD5(WT)) cDNA expressed in Chinese hamster ovary cells. To investigate the role of hD5(F173L) in the pathogenesis of salt-sensitive hypertension, we generated transgenic mice overexpressing hD5(F173L) or hD5(WT) and fed them normal (0.8% NaCl) or high (4% NaCl) salt diet. On normal salt diet, the blood pressure, and renal NADPH oxidase activity and angiotensin type 1 receptor (AT1R) expression were higher in hD5(F173L) than hD5(WT) transgenic mice. After 2 weeks on high salt diet, the blood pressure and renal NADPH oxidase activity, but not AT1R expression, were increased in hD5(F173L) but not in hD5(WT) transgenic mice. Candesartan, an AT1R antagonist, decreased the blood pressure and NADPH oxidase activity in hD5(F173L) but not in hD5(WT) transgenic mice. We suggest that the ability of the hD5R to negatively regulate the renal NADPH oxidase activity and AT1R function may have important implications in the pathogenesis of salt-sensitive blood pressure. However, the mechanisms involved in regulating the balance of renal D5R and AT1R function in the oxidative stress-mediated salt-sensitive blood pressure remain to be determined.

Objective: We investigated the association between dietary oxidative balance score (DOBS) and mortality and whether this association can be modified by sleep duration. Design: We calculated DOBS to estimate the overall oxidative effects of the diet, with higher DOBS reflecting more antioxidant intake and less pro-oxidant intake. Cox proportional hazards models were employed to examine the associations between DOBS and all-cause, CVD and cancer mortality in the general population and people with different sleep durations. Setting: Prospective analysis was conducted using data from the US National Health and Nutrition Examination Survey (NHANES, 2005–2015). Participants: A total of 15 991 US adults with complete information on dietary intake, sleep duration and mortality were included. Results: During a median follow-up of 7·4 years, 1675 deaths were observed. Participants in the highest quartile of DOBS were significantly associated with the lower risk of all-cause mortality (hazard ratio (HR) = 0·75; 95 % CI 0·61, 0·93) compared with those in the lowest. Furthermore, we found statistically significant interactions between DOBS and sleep duration on all-cause mortality (P interaction = 0·021). The inverse association between DOBS and all-cause mortality was significant in short sleepers (HR = 0·66, 95 % CI 0·48, 0·92), but not in normal and long sleepers. Conclusions: Our study observed that higher DOBS was associated with lower all-cause mortality, and this association appeared to be stronger among short sleepers. This study provides nutritional guidelines for improving health outcomes in adults, especially for short sleepers. [ABSTRACT FROM AUTHOR]

Transition metal catalysts (TMCs) mediated bioorthogonal uncaging catalysis has sparked increasing interest in prodrug activation. However, due to their "always‐on" catalytic activity as well as the complex and catalytic‐detrimental intracellular environment, the biosafety and therapeutic efficiency of TMCs are unsatisfactory. Herein, a DNA‐gated and self‐protected bioorthogonal catalyst has been designed by modifying nanozyme‐Pd0 with highly programmable nucleic acid (DNA) molecules to achieve efficient intracellular drug synthesis for cancer therapy. Monolayer DNA molecules could endow the catalyst with targeting and perform as a gatekeeper to achieve selective prodrug activation within cancer cells. Meanwhile, the prepared graphitic nitrogen‐doped carbon nanozyme with glutathione peroxidase (GPx) and catalase (CAT)‐like activities could improve the catalytic‐detrimental intracellular environment to prevent the catalyst from being inactivated and sensitize the subsequent chemotherapy. Overall, we believe that our work will promote the development of secure and efficient bioorthogonal catalytic systems and provide new insights into novel antineoplastic platforms. [ABSTRACT FROM AUTHOR]

This study aimed to explore the protective effects of L-theanine supplementation on the diquat-challenged weaned piglets. A total of 160 weaned piglets were randomly divided into 4 groups using a 2 × 2 two-factor design, there were 4 replicates per group and 10 pigs per replicate. Piglets were fed diets (with 1000 mg/kg L-theanine addition or not), then challenged with diquat or saline on day 7. 21 days after challenge, two pigs from each replicate were selected for sample collection. Results showed that supplement with 1000 mg/kg L-theanine down-regulated the diarrhea rate, serum D-lactate level, tumor necrosis factor-α, and phosphorylation of extracellular regulated protein kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling in pigs without diquat challenge (p < 0.05). While for diquat-challenged piglets, L-theanine addition increased average daily gain, jejunum villus height, and interferon-γ level (p < 0.05). Meanwhile, L-theanine addition decreased the diarrhea rates and mortality, serum D-lactate level, and phosphorylation of ERK and JNK in diquat-challenged pigs (p < 0.05). These results demonstrate that L-theanine pretreatment could alleviate diquat-induced oxidative stress and improve intestinal barrier function in diquat-challenged weaned piglets, which can be attributed to suppression of MAPK phosphorylation signaling pathways. [ABSTRACT FROM AUTHOR]

Signal-mediated cell fusion is vital for colony development in filamentous fungi. Arthrobotrys oligospora is a representative nematode-trapping (NT) fungus that produces adhesive networks (traps) to capture nematodes. Here, we characterized Aoadv-1 , Aoso , Aoham-6 , and Aoham-5 of A. oligospora , homologs of proteins involved in cellular communication and fusion in the model fungus Neurospora crassa. The deletion of four genes resulted in the complete loss of cell fusion, and traps produced by mutants did not close to form mycelial rings but were still capable of capturing nematodes. The absence of these genes inhibits aerial mycelial extension, slows colony growth, and increases mycelial branching. In addition, the mutants showed reduced sporulation capacity and tolerance to oxidative stress, increased sensitivity to SDS, and disturbed lipid droplet accumulation and autophagy. In addition, transcriptome and metabolomic analyses suggested that Aoadv-1 and Aoso are involved in multiple cellular processes and secondary metabolism. Our results revealed that Aoadv-1 , Aoso , Aoham-6 , and Aoham-5 regulate mycelial growth and trap morphogenesis through cell fusion, which contributed to elucidating the molecular mechanisms of cellular communication regulating mycelial development and trap morphogenesis in NT fungi. • AoAdv-1, AoSo, AoHam-6, and AoHam-5 are required for cell fusion and trap formation. • AoAdv-1, AoSo, AoHam-6, and AoHam-5 regulate mycelial growth and conidiation. • AoAdv-1, AoSo, AoHam-6, and AoHam-5 are involved in LD accumulation and autophagy. • AoAdv-1, AoSo, AoHam-6, and AoHam-5 regulate stress response. • AoAdv-1 and AoSo regulate secondary metabolite production. [ABSTRACT FROM AUTHOR]

• "Metabolic symbiosis" impedes the development of therapies which aim at metabolic vulnerabilities. • A yeast@MOF bioreactor has been designed as a tumor metabolic symbiosis disruptor. • The bioreactor integrates the biocompatible probiotic yeast with functional enzyme-encapsulated metal-organic-framework. • The bioreactor could disrupt metabolic symbiosis between glycolytic and oxidative tumor cells. • The bioreactor can elevate oxidative stress for further amplifying the tumor inhibition effect. [Display omitted] Metabolically heterogeneous tumors could rely on "metabolic symbiosis" to mutually regulate the access to extracellular nutrients between glycolytic and oxygenated tumor cells for impeding the development of therapies which aim at metabolic vulnerabilities. Herein, a yeast@MOF bioreactor has been designed as a tumor metabolic symbiosis disruptor to deprive the energy supply of both glycolytic and oxygenated tumor cells for the potent inhibition of metabolically heterogeneous tumors. The yeast@MOF bioreactor integrated the biocompatible probiotic yeast with functional enzyme-encapsulated metal-organic-framework. The bioreactors could competitively consume glucose to reduce their diffusion to glycolytic tumor cells and cut down the tumorous lactate pool. Meanwhile, they could decompose lactate to prevent their exploitation by oxygenated tumor cells. Moreover, the bioreactor could elevate oxidative stress for further amplifying the tumor inhibition effect. We anticipate that this study will not only promote the design of living biomaterials-based therapy, but also facilitate the development of metabolic interventions-based cancer therapy. [ABSTRACT FROM AUTHOR]

As a fast-growing tree, poplar is widely planted and typically used for wood processing in China. During poplar wood processing, a large amount of poplar sawdust (PS) and poplar leaves (PL) are produced and abandoned. To make full use of poplar resources and clarify the use of poplar as a feed additive, the active ingredients in PS and PL were extracted and isolated, and the anti-inflammatory effects of the extracts on mice with dextran sulfate sodium (DSS)-induced colitis were investigated. In vitro anti-inflammatory experiments showed that the ethyl acetate extract of PS and PL (PSE and PLE, respectively) could significantly inhibit the proliferation of concanavalin A (Con A)-activated lymphocytes. Salicortin, tremulacin and salireposide were identified in both PSE and PLE. Oral administration of PSE and PLE rescued DSS-induced colonic shortening, repaired tissue damage, and decreased the disease activity index (DAI). The antioxidant capacity, including the increased activities of glutathione peroxidase (GSH-Px), total superoxide dismutase (T-SOD and catalase (CAT) and decreased activity of myeloperoxidase (MPO), in the colons of mice with colitis was enhanced through the activation of ERK after treatment with PSE and PLE. The ratio of Th1 to Th17 cells, which can lead to inflammation in the spleen, was significantly decreased by the administration of PSE and PLE, while the phosphorylation of related transcription factors (p65, STAT1, and STAT3) was inhibited. Furthermore, PSE and PLE could induce apoptosis in Con A-activated lymphocytes, which may be associated with the increase in p-TBK1, as the molecular docking results also indicated that salireposide in PSE and PLE could interact with the TBK1 protein. Overall, our study provides a promising feed additive for improving intestinal inflammation in animals and a method for the full utilization of poplar resources. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMP) activity is upregulated in pathologies such as atherosclerosis during which endogenous nitric oxide (NO) biosynthesis is reduced. Diminished levels of NO, an antioxidant species, may result in higher oxidative stress. Oxidants are capable of activating MMPs from their zymogen forms. We examined whether basal biosynthesis of NO in the coronary circulation regulates MMP-2 activity.In isolated rat hearts perfused with Krebs-Henseleit buffer at a constant flow of 10?ml?min-1, we measured the release of MMP-2 into the coronary effluent by gelatin zymography. The main gelatinolytic activity of 72-kDa corresponds to MMP-2. Infusion of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) concentration dependently increased coronary perfusion pressure (CPP) (by 48±11?mmHg with 100?µM) and enhanced the release of the 72-kDa MMP-2 in the effluent. Coinfusion of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1?µM) with L-NAME abolished both the increase in CPP and the enhanced MMP-2 release.The thromboxane A2 mimetic U46619 increased CPP to the same extent as L-NAME without increasing 72-kDa activity in the effluent, suggesting that MMP-2 release is not caused simply by enhanced perfusion pressure.Infusion of either L-NAME or U46619 did not significantly enhance LDH release.L-NAME infusion concentration dependently increased the level of lipid hydroperoxides in homogenates prepared from the perfused hearts. Coinfusion of SNAP prevented this increase.These data reveal another cytoprotective mechanism of endogenous NO biosynthesis in the heart, the inhibition of MMP-2 release.British Journal of Pharmacology (2005) 145, 43-49. doi:10.1038/sj.bjp.0706144 [ABSTRACT FROM AUTHOR]

• Blast wave of 300 ± 50 kPa can induce injury in dogs. • PFC treatment downregulated IL-6, TNF-α, and MDA, and upregulated SOD activity. • Vaporized perfluorocarbon inhalation can attenuate the blast injury as indicated by histopathological scores and ratio of lung wet to dry weight. • The MAPK/NF-κB and Nrf2 pathway is related the effect of PFC. Blast lung injury is associated with high morbidity and mortality. Vaporized perfluorocarbon (PFC) inhalation has been reported to attenuate acute respiratory distress syndrome in humans and animal models. However, the effect of vaporized PFC on blast lung injury is still unknown. In this study, we investigated the protective effects and potential underlying mechanisms of action of vaporized PFC on blast lung injury in a canine model. This was a prospective, controlled, animal study in adult male hybrid dogs randomized to sham, blast (B), blast plus mechanical ventilation (B + M), and blast plus PFC (B + P) groups. All groups except for the sham were exposed to blast wave. The B + P group was treated with vaporized PFC for 1.5 h followed by 5.5 h mechanical ventilation. B + M group received 7.5 h mechanical ventilation and B group was observed for 7.5 h. Blast lung injury was induced using a shock tube. Blood gas, inflammatory cytokines, and oxidative stress were measured. Expression of nuclear factor (NF)-κB activation, mitogen-activated protein kinase (MAPK) and nuclear factor, erythroid 2 like 2 (Nrf2) were measured using western blot. Lung injury observed after blast exposure was marked by increased histopathological scores, ratio of lung wet to dry weight. PFC treatment attenuated blast lung injury as indicated by histopathological scores and ratio of lung wet to dry weight. PFC treatment downregulated interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malondialdehyde (MDA), and upregulated superoxide dismutase (SOD) activity. PFC also suppressed expression of MAPK/NF- κ B and Nrf2 protein levels. Our results suggest that PFC attenuated blast-induced acute lung injury by inhibiting MAPK/NF-κB activation and inducing Nrf2 expression in dogs. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension. [Display omitted] • Mitochondria fission is an integrated part in AngII-triggered VSMCs phenotypic switch. • AngII promotes Drp1 phosphorylation at Ser616, and Drp1 mitochondrial translocation. • Mdivi-1 supplementation inhibited AngII-induced VSMCs phenotypic switch, then attenuation hypertension. [ABSTRACT FROM AUTHOR]