Vaccarin alleviates septic cardiomyopathy by potentiating NLRP3 palmitoylation and inactivation.

BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.

Tobramycin-resistant small colony variant mutant of Salmonella enterica serovar Typhimurium shows collateral sensitivity to nitrofurantoin.

The increasing antibiotic resistance poses a significant global health challenge, threatening our ability to combat infectious diseases. The phenomenon of collateral sensitivity, whereby resistance to one antibiotic is accompanied by increased sensitivity to another, offers potential avenues for novel therapeutic interventions against infections unresponsive to classical treatments. In this study, we elucidate the emergence of tobramycin (TOB)-resistant small colony variants (SCVs) due to mutations in the hemL gene, which render S. Typhimurium more susceptible to nitrofurantoin (NIT). Mechanistic studies demonstrate that the collateral sensitivity in TOB-resistant S. Typhimurium SCVs primarily stems from disruptions in haem biosynthesis. This leads to dysfunction in the electron transport chain (ETC) and redox imbalance, ultimately inducing lethal accumulation of reactive oxygen species (ROS). Additionally, the upregulation of nfsA/B expressions facilitates the conversion of NIT prodrug into its active form, promoting ROS-mediated bacterial killing and contributing to this collateral sensitivity pattern. Importantly, alternative NIT therapy demonstrates a significant reduction of bacterial load by more than 2.24-log10 cfu/g in the murine thigh infection and colitis models. Our findings corroborate the collateral sensitivity of S. Typhimurium to nitrofurans as a consequence of evolving resistance to aminoglycosides. This provides a promising approach for treating infections due to aminoglycoside-resistant strains.

Spontaneous rotational symmetry breaking in KTaO3 heterointerface superconductors.

Broken symmetries play a fundamental role in superconductivity and influence many of its properties in a profound way. Understanding these symmetry breaking states is essential to elucidate the various exotic quantum behaviors in non-trivial superconductors. Here, we report an experimental observation of spontaneous rotational symmetry breaking of superconductivity at the heterointerface of amorphous (a)-YAlO3/KTaO3(111) with a superconducting transition temperature of 1.86 K. Both the magnetoresistance and superconducting critical field in an in-plane field manifest striking twofold symmetric oscillations deep inside the superconducting state, whereas the anisotropy vanishes in the normal state, demonstrating that it is an intrinsic property of the superconducting phase. We attribute this behavior to the mixed-parity superconducting state, which is an admixture of s-wave and p-wave pairing components induced by strong spin-orbit coupling inherent to inversion symmetry breaking at the heterointerface of a-YAlO3/KTaO3. Our work suggests an unconventional nature of the underlying pairing interaction in the KTaO3 heterointerface superconductors, and brings a new broad of perspective on understanding non-trivial superconducting properties at the artificial heterointerfaces.

[Experimental research on characteristics of temperature field distribution of mild moxibustion and sparrow-pecking moxibustion].

OBJECTIVE: To explore the temperature field distribution and variation rules during treatment with mild moxibustion and sparrow-pecking moxibustion of TCM. METHODS: Six healthy subjects were selected. Mild moxibustion and sparrow-pecking moxibustion were exerted at Zusanli (ST 36) respectively, for 25 min. Using infrared thermal imaging instrument, the temperature field distribution was measured during moxibustion at Zusanli (ST 36). The simulated thermometer was adopted to measure the temperature field distribution during moxibustion at the imitated cortex. At 20 min of mild moxibustion and sparrow-pecking moxibustion, the temperature field distribution generated by moxibustion was observed at the imitated cortex and Zusanli (ST 36) separately. The temperature values were collected at the sites 0.7, 2.1 and 3.5 cm far from the center of the moxibustion-exerted places successively, and then the characteristics of temperature field distribution and variation rules were compared between different moxibustion methods at the imitated cortex and Zusanli (ST 36). RESULTS: At 20 min of mild moxibustion and sparrow-pecking moxibustion at Zusanli (ST 36), the temperature field distribution focused on the center of moxibustion-exerted site and the temperature was reduced to all directions and illustrated as a curved surface graph, whereas, the temperature field distribution at the imitated cortex was consistent with that at Zusanli (ST 36). With mild moxibustion, the temperature field was distributed uniformly along the longitudinal temperature gradient; whereas, with sparrow-pecking moxibustion, the longitudinal temperature of the temperature field was greatly different, in which, the maximum temperature and the average temperature were higher than those with mild moxibustion respectively and the first time up to the peak value of sparrow-pecking moxibustion was shorter than that with mild moxibustion. The thermal transfer was presented at the non-moxibustion exerted areas during the moxibustion experiment at Zusanli (ST 36). CONCLUSION: A distance feature is presented in the temperature field measured by simulated thermometer and generated under suspension moxibustion at Zusanli (ST 36). The warm stimulation effect of sparrow-pecking moxibustion is much more obvious at the moxibustion-exerted center as compared with mild moxibustion and the area of warm stimulation generated by sparrow-pecking moxibustion is more concentrated as compared with mild moxibustion. The radiation energy produced by suspension moxibustion is scattered and attenuated in skin tissue, resulting in a certain temperature gradient in the temperature field. The warm stimulation generated at skin surface by moxibustion has a warming-dredging effect.

Effects of ozone water irrigation and spraying on physiological characteristics and gene expression of tomato seedlings.

Tomato seedlings were used as experimental materials and treated with 1.0, 2.0, 3.0, and 4.0 mg/L ozone water irrigation and 0.2, 0.4, 0.6, and 0.8 mg/L ozone water spray treatments. Indexes including the malondialdehyde (MDA) content, superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), activities, soil and plant analysis development (SPAD) value, and nitrogen content of leaves were measured. Furthermore, the expression of antioxidant enzyme, chlorophyll synthesis and nitrogen absorption genes was analyzed after optimal ozone water treatment. The results showed that the activities of antioxidant enzymes in tomato leaves were significantly increased, and the MDA content in tomato leaves was significantly reduced by ozone water irrigation and spray treatment, which indicated that ozone water treatment can significantly improve the stress tolerance of tomato seedlings. Ozone water irrigation and spraying could also significantly increase the leaf SPAD value and nitrogen content of tomato seedlings, and the optimal concentrations of ozone water irrigation and spraying were 3.0 mg/L and 0.6 mg/L, respectively. The effect of ozone water irrigation on improving the physiological characteristics of tomato seedlings was better than that of spraying. After treatment with the optimal concentration of ozone water, the relative expression of antioxidant enzyme, chlorophyll synthesis, and nitrogen absorption genes was significantly increased, and the maximum expression level was reached at 12 h. In addition, ozone water irrigation could promote the expression of genes more than ozone water spraying, which was consistent with the improvements in the physiological characteristics of the tomato seedlings.

Experimental detection of a Majorana mode in the core of a magnetic vortex inside a topological insulator-superconductor Bi(2)Te(3)/NbSe(2) heterostructure.

Majorana fermions have been intensively studied in recent years for their importance to both fundamental science and potential applications in topological quantum computing. They are predicted to exist in a vortex core of superconducting topological insulators. However, it is extremely difficult to distinguish them experimentally from other quasiparticle states for the tiny energy difference between Majorana fermions and these states, which is beyond the energy resolution of most available techniques. Here, we circumvent the problem by systematically investigating the spatial profile of the Majorana mode and the bound quasiparticle states within a vortex in Bi(2)Te(3) films grown on a superconductor NbSe(2). While the zero bias peak in local conductance splits right off the vortex center in conventional superconductors, it splits off at a finite distance ∼20 nm away from the vortex center in Bi(2)Te(3). This unusual splitting behavior has never been observed before and could be possibly due to the Majorana fermion zero mode. While the Majorana mode is destroyed by the interaction between vortices, the zero bias peak splits as a conventional superconductor again. This work provides self-consistent evidences of Majorana fermions and also suggests a possible route to manipulating them.

Protective effect of metformin on myocardial injury in metabolic syndrome patients following percutaneous coronary intervention.

OBJECTIVES: The present study tested the hypothesis that pretreatment with metformin decreases postprocedural myocardial injury and improves clinical outcomes in metabolic syndrome patients following percutaneous coronary intervention (PCI). METHODS: We enrolled 152 metabolic syndrome patients with no prior history of metformin treatment. Patients scheduled for elective coronary intervention were randomized to the metformin or control group 7 days before the procedure. Creatine kinase-MB (CK-MB) and troponin I levels were measured at baseline and 8 and 24 h after the procedure, and clinical outcomes were monitored for 1 year. RESULTS: Post-PCI myocardial injury as indicated by CK-MB elevation (14.5 vs. 32.9%, p = 0.008) and troponin I elevation (14.5 vs. 34.2%, p = 0.005) was significantly lower in the metformin group than in the control group. Postprocedural peak values of CK-MB (2.70 ± 4.30 vs. 6.29 ± 8.03 ng/ml, p < 0.001) and troponin I (0.02 ± 0.05 vs. 0.07 ± 0.10 ng/ml, p = 0.001) were also significantly lower in the metformin group than in the control group. At 1 year, the composite endpoint of death from any cause, post-PCI myocardial infarction (MI), MI after PCI hospitalization or ischemia-driven target lesion revascularization occurred in 7.9% of metformin-treated patients and 28.9% of controls (hazard ratio 0.25, 95% CI 0.10-0.62, log rank p = 0.001). CONCLUSIONS: A 7-day metformin pretreatment regimen (250 mg 3 times a day) significantly reduces postprocedural myocardial injury and improves 1-year clinical outcomes in metabolic syndrome patients undergoing PCI.

Spatial and energy distribution of topological edge states in single Bi(111) bilayer.

By combining scanning tunneling microscopy and spectroscopy, angle-resolved photoemission spectroscopy, and density functional theory band calculations, we directly observe and resolve the one-dimensional edge states of single bilayer (BL) Bi(111) islands on clean Bi(2)Te(3) and Bi(111)-covered Bi(2)Te(3) substrates. The edge states are localized in the vicinity of step edges having an ∼2 nm wide spatial distribution in real space and reside in the energy gap of the Bi(111) BL. Our results demonstrate the existence of nontrivial topological edge states of single Bi(111) bilayer as a two-dimensional topological insulator.

The coexistence of superconductivity and topological order in the Bi2Se3 thin films.

Three-dimensional topological insulators (TIs) are characterized by their nontrivial surface states, in which electrons have their spin locked at a right angle to their momentum under the protection of time-reversal symmetry. The topologically ordered phase in TIs does not break any symmetry. The interplay between topological order and symmetry breaking, such as that observed in superconductivity, can lead to new quantum phenomena and devices. We fabricated a superconducting TI/superconductor heterostructure by growing dibismuth triselenide (Bi(2)Se(3)) thin films on superconductor niobium diselenide substrate. Using scanning tunneling microscopy and angle-resolved photoemission spectroscopy, we observed the superconducting gap at the Bi(2)Se(3) surface in the regime of Bi(2)Se(3) film thickness where topological surface states form. This observation lays the groundwork for experimentally realizing Majorana fermions in condensed matter physics.

[Coupling analysis of agro-ecolomic system in gully area of Loess Plateau in 1949-2008: a case study in Changwu County of Shaanxi Province].

Based on the analysis of the coercing and dynamic evolution relationships between agro-economic system and agro-ecological system, and by using modified entropy method, the weight of each evaluation index for the agro-ecolomic system in Changwu County of Shaanxi Province was determined, and, by employing coupling degree model, the coupling processes of agro-ecolomic system in the gullyarea of Loess Plateau were investigated. From 1949 to 2008, the agro-ecolomic system in the County experienced three stages of "traditional extensive agriculture", "agricultural mechanization", and "agricultural pre-modernization". In corresponding to the implement of national macro policies, the coupling degree of the agro-ecolomic system reached two peaks standing for utmost increasing phase and three valleys standing for coordinate development phase. Periods 1955-1961 and 1984-1992 were the utmost increasing phases of the coupling degree; periods 1962-1965 and 1981-1983 were the rapid transition periods responding to the national-wide policies controlling; while periods 1949-1954 and 1966-1980 were the low-level coordinated development phases. Since 1993, the system had been in the harmonious phase by a spiral development. At present, the system had a potential risk of changing from the harmonious phase to the utmost development phase. Appropriate agricultural policies and better external environment could promote the stable development of the agro-ecolomic system on a harmonious level; otherwise, a retrogressive system might be expected.

[In vivo noninvasive detection of vulnerable atherosclerotic plaque by (99)Tc(m)-Annexin V imaging in an atherosclerotic rabbit model.].

OBJECTIVE: Apoptosis contributes to the instability of the atherosclerotic (AS) lesions. The vulnerable plaque was identified in vivo by detecting the apoptosis with radiolabeled annexin V in an atherosclerotic rabbit model. METHODS: Eight male New Zealand white rabbits on 2% cholesterol diet for 2 weeks had abdominal aortic balloon injury and fed a 2% cholesterol diet for another 15 weeks (AS group), 3 rabbits fed a normal rabbit chow for 17 weeks without balloon injury served as controls. Annexin V labeled with (99)Tc(m) was then intravenously administered and planar whole-body images were captured using a gamma camera in the left lateral position. The entire length of the abdominal aorta was explanted for ex vivo imaging with gamma camera. The aorta then was divided into several segments according to the severity of AS. The segments were separated weighted and counted in an gamma counter for the absorptive dose of annexin per gram of tissue. Histology examinations were made on specimens. RESULTS: At 2 hours post annexin V injection, clear delineation of radiolabel within the abdominal aorta could be evidenced in vivo gamma imaging. After explanation of the aorta, ex vivo imaging showed a robust uptake of radiotracer in the infradiaphragmatic aorta corresponding to the in vivo images and conforming to the macroscopic distribution of atherosclerotic lesions. The uptake of radiolabel was absent in areas without grossly visible atherosclerotic lesions. The in vivo and ex vivo images identified plaque areas were identical and corresponded histological results on the explanted specimen. The aortic specimen was divided into 18 segments on lesions. The magority of the lesions (14/18) manifested as type IV or type V lesions of AHA classification (vulnerable lesions), except segments 1 - 4, which manifested as type I or type II lesions. The thickness of fibrous cap (TFC) and the ratio of cap and lipid nuclear (RCN) were significantly reversely correlated to the unit radioactivity counts, and the correlation between RCN and the unit radioactivity counts was more significant than that between TFC and the unit radioactivity counts (r = -0.904, P < 0.01, and r = -0.8, P < 0.01). Apoptosis detection (TUNEL): annexin V intake in plaques was positively correlated to apoptotic index(r = 0.651, P = 0.012). CONCLUSION: Noninvasive Annexin V imaging could be used to detect vulnerable atherosclerotic plaques in vivo.

[Rosiglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice].

OBJECTIVE: To study the effect of rosiglitazone on atherosclerosis and potential mechanism in ApoE-knockout mice. METHODS: Thirty-two 6-week-old ApoE-knockout mice were used as atherosclerosis model in two groups: rosiglitazone group (n = 18) and control group (n = 14). Each group contained equal numbers of male and female mice. All mice were fed with normal chow diet. In addition to normal diet, rosiglitazone group received rosiglitazone 17 mg/kg of body weight/day. Venous bloods were collected for plasma glucose and lipid analysis, and aorta were prepared for morphologic and immunohistochemical analysis after 14 weeks. Aortic root (1 cm) was cut and prepared for paraffin slice. The histomorphometric analysis of atherosclerotic lesion was performed by means of HE; positive percentage of macrophage cell and tumor necrosis factor-alpha were measured by means of immunohistochemistry in cross section. The ratio of lesion/aortic wall surface in the rest aorta was measured by means of Sudan IV staining in longitudinal section. RESULTS: The amount of fatty streak in rosiglitazone group was significantly greater than that of control group; the gross number of lesions and the number of fibrous plaque and atheromatous plaque were similar in two groups. There were no differences in percentage of lesions in cross section in two groups. Rosiglitazone could significantly reduce the extend of atherosclerosis of longitudinal section, decrease the amount of macrophage cell and the level of tumor necrosis factor-alpha in lesions. The plasma glucose was normal and similar in two groups, and total cholesterol, LDL-cholesterol and triglyceride were significantly higher in rosiglitazone group. CONCLUSION: Rosiglitazone suppresses the expression of tumor necrosis factor-alpha, reduces the number of macrophage cell in lesion, and inhibits the development of atherosclerosis.