Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.

Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+.

Robust Radicals Featuring B- and N-Embedded Dioxygen-Bridged Units: Synthesis, Structures, and Optical Properties.

Tris(2,4,6-trichlorophenyl)methyl (TTM) group has been widely used for constructing organic radicals, but the poor optical stabilities limit the application prospects of the TTM radicals. In this work, the rigid B- and N-embedded dioxygen-bridged (BO and NO) units were attached to the TTM skeleton as the strong electron-withdrawing and electron-donating groups, respectively. The rigidity and strong electronic effect of the BO and NO units contribute to the high chemical and optical stability of BO-TTM and NO-TTM radicals. Notably, NO-TTM exhibits near-infrared emission at 830 nm with a narrow full width at half maximum (FWHM) of 55 nm (100 meV), while BO-TTM shows blue-shifted luminescence at 635 nm and a narrower FWHM of merely 43 nm (130 meV). This study has developed a methodology to produce highly efficient and enduring luminescent radicals, which could tune emission properties such as wavelength and FWHM.

Geometric and Electronic Engineering in Co/VN Nanoparticles to Boost Bifunctional Oxygen Electrocatalysis for Aqueous/Flexible Zn-Air Batteries.

Modulating metal-metal and metal-support interactions is one of the potent tools for augmenting catalytic performance. Herein, highly active Co/VN nanoparticles are well dispersed on three-dimensional porous carbon nanofoam (Co/VN@NC) with the assistance of dicyandiamide. Studies certify that the consequential disordered carbon substrate reinforces the confinement of electrons, while the coupling of diverse components optimizes charge redistribution among species. Besides, theoretical analyses confirm that the regulated electron configuration can significantly tune the binding strength between the active sites and intermediates, thus optimizing reaction energy barriers. Therefore, Co/VN@NC exhibits a competitive potential difference (ΔE, 0.65 V) between the half-wave potential of ORR and OER potential at 10 mA cm-2, outperforming Pt/C+RuO2 (0.67 V). Further, catalyst-based aqueous/flexible ZABs present superior performances with peak power densities of 156 and 85 mW cm-2, superior to Pt/C-based counterparts (128 and 73 mW cm-2). This research provides a pivotal foundation for the evolution of bifunctional catalysts in the energy sector.

Three-Charge (0, -1, -2) Ligand-Based Binuclear and Mononuclear Deep-Red Phosphorescent Iridium Complexes Bearing Benzo[d]oxazole-2-Thiol Ligand.

A new class of three-charge (0, -1, -2) ligand-based binuclear and mononuclear iridium complexes bearing benzo[d]oxazole-2-thiol ligand have been synthesized. Notably, the binuclear complexes (IrIr1 and IrIr2) can be generated at low temperatures by reacting the iridium complex precursors (2a and 2b) with equal amounts of the benzo[d]oxazole-2-thiol ligands, while the corresponding mononuclear complexes (Ir1 and Ir2) are formed at high temperatures. X-ray diffraction analysis shows that the benzo[d]oxazole-2-thiol ligand plays an unusual and interesting bridging role in binuclear complexes and induces rich intermolecular and intramolecular interactions, while in mononuclear complexes, it forms an interesting four-membered ring coordination. More importantly, all complexes experienced efficient deep-red emission in the 628-674 nm range, and the mononuclear complexes have higher luminescent efficiency and longer excited state lifetime than the binuclear complexes. As a result, organic light-emitting diode devices incorporating two mononuclear complexes (Ir1 and Ir2) as guest material of the light-emitting layer can obtain good maximum external quantum efficiency (3.5% and 5.5%) in the deep-red region (629 and 632 nm) with CIE coordinates (0.61, 0.33) and (0.62, 0.34), along with a low turn-on voltage (2.8 V).

B-embedded disulfide-bridged π-conjugated compounds: structures and optical tuning.

Two novel B-embedded disulfide-bridged π-conjugated compounds (BS-CZ and BS-N) bearing different electron donor groups (phenyl carbazole and triphenylamine) have been prepared and show different optical mechanisms. The compound BS-CZ exhibits significant multiple resonance thermal activation delayed fluorescence (MR-TADF) properties with a small singlet-triplet energy gap (ΔEST = 0.16 eV) and a narrow half-peak full width (FWHM = 33 nm), while the compound BS-N shows traditional fluorescence luminescence (FL) characteristics with a larger ΔEST (0.28 eV) and FWHM (57 nm). Time-dependent density functional theory (TD-DFT) calculations show that the lowest excited singlet state (S1) of the compound BS-CZ exhibits local excited (LE) state characteristics, while the charge transfer (CT) state characteristics can be found in S1 of the compound BS-N. Considering good optical performance, the compound BS-CZ is used as an emitting layer of the organic light-emitting diode device and achieved saturated blue emission (473 nm) with a narrow FWHM (39 nm), and CIE color coordinates of (0.12, 0.21). This work provides an important strategy for the optical mechanism regulation and photoelectric applications of B-embedded disulfide-bridged π-conjugated molecules.

Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis.

Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.

Association between cancer health literacy and cancer-related behavior of residents in Shandong, China.

Health literacy is closely related to the incidence of major chronic diseases and its related behaviors such as cancer-related behaviors. This study explored how the cancer health literacy level affects cancer-related behaviors. About one to two villages from six cities of Shandong province were selected as sample areas. Professionals conducted face-to-face interviews with the participants. Finally, 1200 residents completed 1085 effective questionnaires. Data were analysed from a cross-sectional survey in 2019, which included 1085 residents in six cities/counties of Shandong province, China. The result showed that residents with high cancer health literacy were more likely to eat fruits and vegetables frequently, avoid eating moldy food and take exercise. Besides, they were more likely to engage in health education and have a higher willingness to pay for cancer screenings. Most residents in Shandong province have a basic level of cancer health literacy. Improving the cancer health literacy of the population can be an effective strategy to promote a healthier lifestyle, thereby reducing the incidence rates related to cancers.

A Dual-Targeting Liposome Enhances Triple-Negative Breast Cancer Chemoimmunotherapy through Inducing Immunogenic Cell Death and Inhibiting STAT3 Activation.

Immunotherapy gains increasing focus in treating triple-negative breast cancer (TNBC), while its efficacy is greatly restricted owing to low tumor immunogenicity and immunosuppressive tumor microenvironment (ITM). Herein, a LyP-1 and chondroitin sulfate (CS) dual-modified liposome co-loaded with paclitaxel (PTX) and cryptotanshinone (CTS), namely CS/LyP-1-PC Lip, is engineered for TNBC chemoimmunotherapy via induction of immunogenic cell death (ICD) and inhibition of signal transducer and activator of transcript-3 (STAT3) activation. CS/LyP-1-PC Lip enhances cellular uptake through p32 and CD44 dual receptor-mediated endocytosis. Within the tumor, the CS layer is continuously detached by hyaluronidase to release drugs. Subsequently, CTS sensitizes the cytotoxicity of PTX to 4T1 tumor cells. PTX induces ICD of tumor cells and facilitates infiltration of cytotoxic T lymphocyte to provoke immune response. Meanwhile, the concomitant delivery of CTS inhibits STAT3 activation to decrease infiltration of regulatory T cell, M2-type tumor-associated macrophage, and myeloid-derived suppressor cell, thus reversing ITM. Markedly, the dual-targeting liposome shows superior anti-tumor efficacy in subcutaneous TNBC mice and significant lung metastasis suppression in tumor metastasis model. Overall, this work offers a feasible combination regimen and a promising nanoplatform for the development of TNBC chemoimmunotherapy.

Polysaccharide-Based Stimulus-Responsive Nanomedicines for Combination Cancer Immunotherapy.

Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiability. Here, the antitumor activity of polysaccharides and several combined immunotherapy strategies (e.g., immunotherapy combined with chemotherapy, photodynamic therapy, or photothermal therapy) are summarized. More importantly, the recent progress of polysaccharide-based stimulus-responsive nanomedicines for combination cancer immunotherapy is discussed, with the focus on construction of nanomedicine, targeted delivery, drug release, and enhanced antitumor effects. Finally, the limitations and application prospects of this new field are discussed.

Construction and validation of a nomogram to predict the overall survival of small cell lung cancer: a multicenter retrospective study in Shandong province, China.

BACKGROUND: Patients diagnosed with small cell lung cancer (SCLC) typically experience a poor prognosis, and it is essential to predict overall survival (OS) and stratify patients based on distinct prognostic risks. METHODS: Totally 2309 SCLC patients from the hospitals in 15 cities of Shandong from 2010 - 2014 were included in this multicenter, population-based retrospective study. The data of SCLC patients during 2010-2013 and in 2014 SCLC were used for model development and validation, respectively. OS served as the primary outcome. Univariate and multivariate Cox regression were applied to identify the independent prognostic factors of SCLC, and a prognostic model was developed based on these factors. The discrimination and calibration of this model were assessed by the time-dependent C-index, time-dependent receiver operator characteristic curves (ROC), and calibration curves. Additionally, Decision Curve Analysis (DCA) curves, Net Reclassification Improvement (NRI), and Integrated Discriminant Improvement (IDI) were used to assess the enhanced clinical utility and predictive accuracy of the model compared to TNM staging systems. RESULTS: Multivariate analysis showed that region (Southern/Eastern, hazard ratio [HR] = 1.305 [1.046 - 1.629]; Western/Eastern, HR = 0.727 [0.617 - 0.856]; Northern/Eastern, HR = 0.927 [0.800 - 1.074]), sex (female/male, HR = 0.838 [0.737 - 0.952]), age (46-60/≤45, HR = 1.401 [1.104 - 1.778]; 61-75/≤45, HR = 1.500 [1.182 - 1.902]; >75/≤45, HR = 1.869 [1.382 - 2.523]), TNM stage (II/I, HR = 1.119[0.800 - 1.565]; III/I, HR = 1.478 [1.100 - 1.985]; IV/I, HR = 1.986 [1.477 - 2.670], surgery (yes/no, HR = 0.677 [0.521 - 0.881]), chemotherapy (yes/no, HR = 0.708 [0.616 - 0.813]), and radiotherapy (yes/no, HR = 0.802 [0.702 - 0.917]) were independent prognostic factors of SCLC patients and were included in the nomogram. The time-dependent AUCs of this model in the training set were 0.699, 0.683, and 0.683 for predicting 1-, 3-, and 5-year OS, and 0.698, 0.698, and 0.639 in the validation set, respectively. The predicted calibration curves aligned with the ideal curves, and the DCA curves, the IDI, and the NRI collectively demonstrated that the prognostic model had a superior net benefit than the TNM staging system. CONCLUSION: The nomogram using SCLC patients in Shandong surpassed the TNM staging system in survival prediction accuracy and enabled the stratification of patients with distinct prognostic risks based on nomogram scores.

Effect of perylene assembly shapes on photoelectrochemical properties and ultrasensitive biosensing behaviors toward dopamine.

In this study, a photoelectrochemical (PEC) sensor based on perylene diimide derivatives (PDIs) was developed for the ultrasensitive quantification of dopamine (DA). PDIs were able to form self-assembled semiconductor nanostructures by strong π-π stacking, suitable for photoactive substances. Moreover, the shape of the PDI significantly affected the PEC properties of these nanostructures. The results showed that amino PDI with two-dimensional (2D) wrinkled layered nanostructures exhibited superior PEC properties relative to one-dimensional (1D) nanorods and fiber-based nanostructures (methyl and carboxyl PDIs). Based on these results, a mechanism for PEC sensor action was then proposed. The presence of 2D amino-PDI resulted in accelerated charge separation and transport. Furthermore, dopamine acted as effective electron donor to cause an increase in photocurrent. The as-obtained sensor was then used to detect small molecules like DA. A blue light optimized sensor at an applied potential of 0.7 V showed a detection limit of 1.67 nM with a wide linear range of 5 nM to 10 µM. On the other hand, the sensor presented acceptable reliability in determining DA in real samples. A recovery rate between 97.99 and 101.0% was obtained. Overall, controlling the morphology of semiconductors can influence PEC performance, which is a useful finding for the future development of PEC sensors.

Lignans as multi-targeted natural products in neurodegenerative diseases and depression: Recent perspectives.

As the global population ages, the treatment of neurodegenerative diseases is becoming more and more important. There is an urgent need to discover novel drugs that are effective in treating neurological diseases. In recent years, natural products and their biological activities have gained widespread attention. Lignans are a class of metabolites extensively present in Chinese herbal medicine and possess good pharmacological effects. Latest studies have demonstrated their neuroprotective pharmacological activity in preventing acute/chronic neurodegenerative diseases and depression. In this review, the pharmacological effects of these disorders, the pharmacokinetics, safety, and clinical trials of lignans were summarized according to the scientific literature. These results proved that lignans mainly exert antioxidant and anti-inflammatory activities. Anti-apoptosis, regulation of nervous system functions, and modulation of synaptic signals are also potential effects. Despite the substantial evidence of the neuroprotective potential of lignans, it is not sufficient to support their use in the clinical management. Our study suggests that lignans can be used as prospective agents for the treatment of neurodegenerative diseases and depression, with a view to informing their further development and utilization.

Iridium(III) Complex Radical and Corresponding Ligand Radical Functionalized by a Tris(2,4,6-trichlorophenyl)methyl Unit: Synthesis, Structure, and Photophysical Properties.

Organic radical luminescent materials with doublet excited state character based on tris(2,4,6-trichlorophenyl)methyl (TTM) have attracted extensive attention in recent years. However, how they affect the phosphorescent iridium(III) complex characterized by the triplet excited state has not been studied yet. Herein, a new iridium(III) complex radical (Ir-TTM) and corresponding ligand radical (ppy-TTM) with a TTM unit have been designed and synthesized, and their radical properties were confirmed by the single crystal structure and EPR spectra. Notably, the ligand radical ppy-TTM shows an efficient red light emission, whereas the iridium complex radical Ir-TTM emits no light, which resulted from the intramolecular quenching effect of the TTM radical unit on the iridium luminescence center. DFT calculations demonstrate that the lowest doublet (D1) excited state of ppy-TTM shows an intramolecular charge transfer character from the 2-phenylpyridine moieties to the TTM unit, whereas the D1 of Ir-TTM exhibits a significant charge transfer character from the iridium luminescence center moieties to the TTM unit, which further explains the luminescence quenching mechanism of the phosphorescent iridium complex radical.

Deep-Red/Near-Infrared to Blue-Green Phosphorescent Iridium(III) Complexes Featuring Three Differently Charged (0, -1, and -2) Ligands: Structures, Photophysics, and Organic Light-Emitting Diode Application.

We have designed and synthesized a new family of neutral phosphorescent iridium(III) complexes (Ir1-Ir6) featuring three differently charged (0, -1, and -2) ligands, in which biphenyl (bp) is used as a dianionic (-2) ligand, 4,6-difluorophenylpyridine (dfppy) or 1-phenylisoquinoline (piq) is used as a monoanionic (-1) ligand, and 2,2'-bipyridyl (bpy), 1,10-phenanthroline (phen), 1,2-bis(diphenylphosphanyl)benzene (dppb), or 1,2-bis(diphenylphosphanyl)ethane (dppe) is used as a neutral (0) ligand. The X-ray structures confirm that three coordination carbon atoms of all complexes assume a facial geometry, which can be beneficial to the stability of the structure. More importantly, the emitting color of the complexes can be tuned from deep red/near-infrared (NIR) (680-710 nm) to blue-green (466-496 nm) with different monoanionic (-1) ligands and neutral (0) ligands. Interestingly, the complex Ir5 shows a significant aggregation-induced phosphorescent emission effect, while Ir6 with a similar structure shows an opposite aggregation-caused quenching effect, mainly due to slight differences in the neutral (0) ligand structure. Notably, all deep red/NIR-emitting complexes (Ir1-Ir4) exhibit a distinct charge transfer (CT) excited state from the dianionic (-2) ligand to the neutral (0) ligand according to density functional theory calculations, whereas the excited state of blue-green-emitting complexes (Ir5-Ir6) displays the CT from the dianionic (-2) ligand to the monoanionic (-1) ligand. Considering better stability and optical performance, the deep red-emitting complexes (Ir2 and Ir4) with a simple structure are used as emitting layers of organic light-emitting diode devices and achieved good maximum external quantum efficiency (4.9 and 5.8%) peaking at 676 and 655 nm, respectively, with a very low turn-on voltage (2.5 V). This research provides a good strategy for the design of phosphorescent iridium complexes based on three differently charged (0, -1, and -2) ligands and their optoelectric applications.

B- and N-Embedded π-Conjugation Units Tuning Intermolecular Interactions and Optical Properties of Platinum(II) Complexes.

A new series of neutral and cationic platinum(II) complexes containing a B- or N-embedded π-conjugation unit has been prepared. Notably, significantly different intermolecular interactions (Pt-Pt, π-π, head to tail, and head to head) and interesting optical properties exist in these complexes, which can be attributed to the difference in spatial structures and π-electron properties between B- and N-embedded π-conjugation units. Unexpectedly, under a hypoxic atmosphere, N-embedded neutral complex PtNacac can display a distinct dual-emission with both fluorescence and phosphorescence, whereas only a single fluorescence emission was observed in the air, which is different from the B-embedded neutral complex PtBacac with only a single phosphorescence emission at any atmosphere, as well confirmed by lifetime measurement and oxygen sensing experiments. DFT calculations reveal that unusual ligand-to-metal charge transfer (LMCT) excited state character and low spin orbit coupling (SOC) elements can be found in N-embedded complexes due to the strong electron-donating ability of the N-embedded unit. Based on this, as a novel ratiometric oxygen probe with a simple structure, PtNacac can be successfully used to examine intracellular oxygen levels by monitoring both fluorescence and phosphorescence signals via ratiometric photoluminescence imaging and time-resolved luminescence imaging (TRLI) technology. This work provides a completely new idea for designing fluorescence/phosphorescence dual-emissive complexes.

Three Types of Charged Ligands Based Carboxyl-Containing Iridium(III) Complexes: Structures, Photophysics, and Solution Processed OLED Application.

A novel family of three types of charged (0, -1, -2) ligands based phosphorescent iridium(III) complexes with different carboxyl-containing dianionic (-2) ligands have been synthesized. Their single-crystal structures show that all neutral complexes (Ir1, Ir2, and Ir3) show a trans-N^N configuration between dianionic (-2) and monoanionic (-1) ligands, which is in contrast with the trans-N^C configuration in cationic complex Ir4, which has an interesting hydrogen bond in the solid state. Notably, Ir4 shows higher luminescence efficiency and an obvious blue shift emission relative to those in Ir1, Ir2, and Ir3. DFT calculations demonstrate that all neutral complexes (Ir1, Ir2, and Ir3) exhibit ligand-to-ligand charge transfer (LLCT) excited state character from the dianionic (-2) ligand to the neutral (0) ligand, which are completely different from the cationic complex Ir4 that exhibits an LLCT excited state from the monoanionic (-1) ligand to the neutral (0) ligand. Considering better solubility, Ir1 was eventually used in solution-processed OLED and achieved moderate efficiency (6.6%, 14.3 cd A-1, 2.8 lm W-1) with an orange light displaying CIEx,y coordinates of (0.53, 0.46). This work provides a new strategy to construct three types of charged (0, -1, -2) ligands based phosphorescent iridium(III) complexes and extends the range of iridium complex luminescent materials.

1H-NMR-based metabolomics study on coronary heart disease with blood-stasis syndrome and phlegm syndrome. / 基于1H-NMRçš„å† å¿ƒç— è¡€ç˜€è¯ã€ç—°æµŠè¯çš„ä»£è°¢ç»„å­¦ç ”ç©¶.

OBJECTIVES: Coronary heart disease (CHD) is a serious threat to human health because of its high morbidity. It is very urgent to study the pathogenesis of CHD and the effective drug target. The purpose of this paper is using the 1H-nuclear magnetic resonance spectroscopy (1H-NMR) metabolomics technology to establish the metabolic fingerprint and find the potential biomarker metabolites of CHD with blood-stasis syndrome and phlegm syndrome, and to reveal the metabolic mechanism of Xuefu Zhuyu Decoction for the treatment of CHD with blood stasis syndrome. METHODS: The plasma samples of 69 patients with CHD blood-stasis syndrome, 60 patients with CHD phlegm syndrome, and 40 healthy volunteers were collected in this study. Based on the 1H-NMR metabolomics technology, the metabolic fingerprint of CHD with blood-stasis syndrome and phlegm syndrome was established. Multivariate statistical analysis methods including principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to find the potential biomarker metabolites of CHD with blood-stasis syndrome and phlegm syndrome. Xuefu Zhuyu Decoction was used to randomly selected blood-stasis syndrome patient. The plasma samples of pre-treatment and post-treatment were collected. 1H-NMR and multivariate statistical analysis were used to analyze the changes of metabolites in patients with CHD blood-stasis syndrome before and after Xuefu Zhuyu Decoction treatment. RESULTS: A total of 15 potential biomarkers were identified in the plasma of patients with CHD blood-stasis syndrome, including 3-hydroxybutyrate (3-HB), lactate, alanine, glutamate, glutamine, pyruvate,phosphatidylcholine (PC), glycerylphosphorylcholine (GPC), glycine, glucose, phenylalanine, citrate,tyrosine, formate,very low density lipoprotein (VLDL). The levels of glucose, 3-HB, and VLDL increased, while the levels of other 12 metabolites decreased. A total of 16 potential biomarkers were identified in the plasma of patients with CHD phlegm syndrome, including valine, lactate, alanine, N-acetyl-ß-glucosaminidase (NAG), glutamate, glutamine, pyruvate, creatine, choline, glycine, glucose, phenylalanine, citrate, histidine, tyrosine, and formate. The levels of glucose and choline increased, while the levels of other 12 metabolites decreased. After treatment with Xuefu Zhuyu Decoction, the levels of choline, phospholipids/glycerolipids, creatine, lipids, and citrate increased, while the level of lactate decreased in patients with CHD blood-stasis syndrome. CONCLUSIONS: 1H-NMR combined with multivariate statistical method could effectively establish the diagnostic model for CHD blood-stasis syndrome and CHD phlegm syndrome, and find the metabolites related to the syndrome type. The metabolic mechanism of Xuefu Zhuyu Decoction on CHD blood-stasis syndrome may be associated with regulation of lipid metabolism and energy metabolism.

Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction.

The 66-kDa Src homology 2 domain-containing protein (p66Shc) is a master regulator of reactive oxygen species (ROS). It is expressed in many tissues where it contributes to organ dysfunction by promoting oxidative stress. In the vasculature, p66Shc-induced ROS engenders endothelial dysfunction. Here we show that p66Shc is a direct target of the Sirtuin1 lysine deacetylase (Sirt1), and Sirt1-regulated acetylation of p66Shc governs its capacity to induce ROS. Using diabetes as an oxidative stimulus, we demonstrate that p66Shc is acetylated under high glucose conditions and is deacetylated by Sirt1 on lysine 81. High glucose-stimulated lysine acetylation of p66Shc facilitates its phosphorylation on serine 36 and translocation to the mitochondria, where it promotes hydrogen peroxide production. Endothelium-specific transgenic and global knockin mice expressing p66Shc that is not acetylatable on lysine 81 are protected from diabetic oxidative stress and vascular endothelial dysfunction. These findings show that p66Shc is a target of Sirt1, uncover a unique Sirt1-regulated lysine acetylation-dependent mechanism that governs the oxidative function of p66Shc, and demonstrate the importance of p66Shc lysine acetylation in vascular oxidative stress and diabetic vascular pathophysiology.

SUMO2 regulates vascular endothelial function and oxidative stress in mice.

SUMOylation is a posttranslational modification of lysine residues. Modification of proteins by small ubiquitin-like modifiers (SUMO)1, -2, and -3 can achieve varied, and often unique, physiological and pathological effects. We looked for SUMO2-specific effects on vascular endothelial function. SUMO2 expression was upregulated in the aortic endothelium of hypercholesterolemic low-density lipoprotein receptor-deficient mice and was responsible for impairment of endothelium-dependent vasorelaxation in these mice. Moreover, overexpression of SUMO2 in aortas ex vivo, in cultured endothelial cells, and transgenically in the endothelium of mice increased vascular oxidative stress and impaired endothelium-dependent vasorelaxation. Conversely, inhibition of SUMO2 impaired physiological endothelium-dependent vasorelaxation in normocholesterolemic mice. These findings indicate that while endogenous SUMO2 is important in maintenance of normal endothelium-dependent vascular function, its upregulation impairs vascular homeostasis and contributes to hypercholesterolemia-induced endothelial dysfunction.NEW & NOTEWORTHY Sumoylation is known to impair vascular function; however, the role of specific SUMOs in the regulation of vascular function is not known. Using multiple complementary approaches, we show that hyper-SUMO2ylation impairs vascular endothelial function and increases vascular oxidative stress, whereas endogenous SUMO2 is essential for maintenance of normal physiological function of the vascular endothelium.

Effects and safety of 99Tc-MDP in patients with refractory ankylosing spondylitis: a 2-stage (30-week follow-up) clinical trial.

OBJECTIVES: To evaluate the clinical efficacy and safety in patients with refractory ankylosing spondylitis (AS) initiating 99Tc-MDP therapy and explore the mechanisms. METHODS: Refractory AS patients were enrolled in the clinical trial and received 99Tc-MDP treatments for 3 or 5 courses according to ASAS improvement. Efficacy and safety evaluations were conducted during the follow-up. 37 cytokines were quantified by Luminex at baseline and week 30. p-values<0.05 were considered statistically significant. RESULTS: 51 refractory AS patients were included, with 20 healthy people serving as the control group. The patients were in an active disease state (mean (SD) ASDAS 3.66 (0.83), BASDAI 4.53 (1.92)), 42(82.35%) patients had syndesmophytes. Their cytokines were significantly higher than that in the control group. After 3 courses of 99Tc-MDP treatment, 32 (62.75%) patients achieved ASAS20 improvement, 24 (47.06%) patients achieved a clinically significant improvement (ΔASDAS-CRP≥1.1). 27 patients entered the second stage to complete 5 courses of the treatment, all of whom achieved ASAS20 improvement, 18 (66.67%) patients achieved a clinically significant improvement. All clinical parameters including ASAS and ASDAS significantly improved as the treatment was continued. Cytokines also had significant down-regulation after the treatment, and the reductions had positive correlations with the improvements of disease activity. No serious adverse event was observed. CONCLUSIONS: This investigation confirmed the remarkable efficacy of 99Tc-MDP in a large number of refractory AS patients, and highlighted the mechanism by dramatic regulation on cytokines. 99Tc-MDP was safe in clinical application.