Mechanisms of Flavonoids and Their Derivatives in Endothelial Dysfunction Induced by Oxidative Stress in Diabetes.

Diabetic complications pose a significant threat to life and have a negative impact on quality of life in individuals with diabetes. Among the various factors contributing to the development of these complications, endothelial dysfunction plays a key role. The main mechanism underlying endothelial dysfunction in diabetes is oxidative stress, which adversely affects the production and availability of nitric oxide (NO). Flavonoids, a group of phenolic compounds found in vegetables, fruits, and fungi, exhibit strong antioxidant and anti-inflammatory properties. Several studies have provided evidence to suggest that flavonoids have a protective effect on diabetic complications. This review focuses on the imbalance between reactive oxygen species and the antioxidant system, as well as the changes in endothelial factors in diabetes. Furthermore, we summarize the protective mechanisms of flavonoids and their derivatives on endothelial dysfunction in diabetes by alleviating oxidative stress and modulating other signaling pathways. Although several studies underline the positive influence of flavonoids and their derivatives on endothelial dysfunction induced by oxidative stress in diabetes, numerous aspects still require clarification, such as optimal consumption levels, bioavailability, and side effects. Consequently, further investigations are necessary to enhance our understanding of the therapeutic potential of flavonoids and their derivatives in the treatment of diabetic complications.

All-inorganic ultrathin high-sensitivity transparent temperature sensor based on a Mn-Co-Ni-O nanofilm.

The demand for optically transparent temperature sensors in intelligent devices is increasing. However, the performance of these sensors, particularly in terms of their sensitivity and resolution, must be further enhanced. This study introduces a novel transparent and highly sensitive temperature sensor characterized by its ultrathin, freestanding design based on a Mn-Co-Ni-O nanofilm. The Mn-Co-Ni-O-based sensor exhibits remarkable sensitivity, with a temperature coefficient of resistance of -4% °C-1, and can detect minuscule temperature fluctuations as small as 0.03 °C. Additionally, the freestanding sensor can be transferred onto any substrate for versatile application while maintaining robust structural stability and excellent resistance to interference, indicating its suitability for operation in challenging environments. Its practical utility in monitoring the surface temperature of optical devices is demonstrated through vertical integration of the sensor and a micro light-emitting diode on a polyimide substrate. Moreover, an experiment in which the sensor is implanted in rats confirms its favorable biocompatibility, highlighting the promising applications of the sensor in the biomedical domain.

Uncovering the photosystem I assembly pathway in land plants.

Photosystem I (PSI) is one of two large pigment-protein complexes responsible for converting solar energy into chemical energy in all oxygenic photosynthetic organisms. The PSI supercomplex consists of the PSI core complex and peripheral light-harvesting complex I (LHCI) in eukaryotic photosynthetic organisms. However, how the PSI complex assembles in land plants is unknown. Here we describe PHOTOSYSTEM I BIOGENESIS FACTOR 8 (PBF8), a thylakoid-anchored protein in Arabidopsis thaliana that is required for PSI assembly. PBF8 regulates two key consecutive steps in this process, the building of two assembly intermediates comprising eight or nine subunits, by interacting with PSI core subunits. We identified putative PBF8 orthologues in charophytic algae and land plants but not in Cyanobacteria or Chlorophyta. Our data reveal the major PSI assembly pathway in land plants. Our findings suggest that novel assembly mechanisms evolved during plant terrestrialization to regulate PSI assembly, perhaps as a means to cope with terrestrial environments.

Sparse Dynamic Volume TransUNet with multi-level edge fusion for brain tumor segmentation.

3D MRI Brain Tumor Segmentation is of great significance in clinical diagnosis and treatment. Accurate segmentation results are critical for localization and spatial distribution of brain tumors using 3D MRI. However, most existing methods mainly focus on extracting global semantic features from the spatial and depth dimensions of a 3D volume, while ignoring voxel information, inter-layer connections, and detailed features. A 3D brain tumor segmentation network SDV-TUNet (Sparse Dynamic Volume TransUNet) based on an encoder-decoder architecture is proposed to achieve accurate segmentation by effectively combining voxel information, inter-layer feature connections, and intra-axis information. Volumetric data is fed into a 3D network consisting of extended depth modeling for dense prediction by using two modules: sparse dynamic (SD) encoder-decoder module and multi-level edge feature fusion (MEFF) module. The SD encoder-decoder module is utilized to extract global spatial semantic features for brain tumor segmentation, which employs multi-head self-attention and sparse dynamic adaptive fusion in a 3D extended shifted window strategy. In the encoding stage, dynamic perception of regional connections and multi-axis information interactions are realized through local tight correlations and long-range sparse correlations. The MEFF module achieves the fusion of multi-level local edge information in a layer-by-layer incremental manner and connects the fusion to the decoder module through skip connections to enhance the propagation ability of spatial edge information. The proposed method is applied to the BraTS2020 and BraTS2021 benchmarks, and the experimental results show its superior performance compared with state-of-the-art brain tumor segmentation methods. The source codes of the proposed method are available at https://github.com/SunMengw/SDV-TUNet.

Water-Responsive 3D Electronics for Smart Biological Interfaces.

Three-dimensional (3D) electronic systems with their potential for enhanced functionalities often require complex fabrication processes. This paper presents a water-based, stimuli-responsive approach for creating self-assembled 3D electronic systems, particularly suited for biorelated applications. We utilize laser scribing to programmatically shape a water-responsive bilayer, resulting in smart 3D electronic substrates. Control over the deformation direction, actuation time, and surface curvature of rolling structures is achieved by adjusting laser-scribing parameters, as validated through experiments and numerical simulations. Additionally, self-locking structures maintain the integrity of the 3D systems. This methodology enables the implementation of spiral twining electrodes for electrophysiological signal monitoring in plants. Furthermore, the integration of self-rolling electrodes onto peripheral nerves in a rodent model allows for stimulation and recording of in vivo neural activities with excellent biocompatibility. These innovations provide viable paths to next-generation 3D biointegrated electronic systems for life science studies and medical applications.

Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling.

BACKGROUND: Cardiac fibroblasts (CFs) and cardiomyocytes are the major cell populations in the heart. CFs not only support cardiomyocytes by producing extracellular matrix (ECM) but also assimilate myocardial nutrient metabolism. Recent studies suggest that the classical intercellular lactate shuttle may function in the heart, with lactate transported from CFs to cardiomyocytes. However, the underlying mechanisms regarding the generation and delivery of lactate from CFs to cardiomyocytes have yet to be explored. RESULTS: In this study, we found that angiotensin II (Ang II) induced CFs differentiation into myofibroblasts that, driven by cell metabolism, then underwent a shift from oxidative phosphorylation to aerobic glycolysis. During this metabolic conversion, the expression of amino acid synthesis 5-like 1 (GCN5L1) was upregulated and bound to and acetylated mitochondrial pyruvate carrier 2 (MPC2) at lysine residue 19. Hyperacetylation of MPC2k19 disrupted mitochondrial pyruvate uptake and mitochondrial respiration. GCN5L1 ablation downregulated MPC2K19 acetylation, stimulated mitochondrial pyruvate metabolism, and inhibited glycolysis and lactate accumulation. In addition, myofibroblast-specific GCN5L1-knockout mice (GCN5L1fl/fl: Periostin-Cre) showed reduced myocardial hypertrophy and collagen content in the myocardium. Moreover, cardiomyocyte-specific monocarboxylate transporter 1 (MCT1)-knockout mice (MCT1fl/fl: Myh6-Cre) exhibited blocked shuttling of lactate from CFs to cardiomyocytes and attenuated Ang II-induced cardiac hypertrophy. CONCLUSIONS: Our findings suggest that GCN5L1-MPC2 signalling pathway alters metabolic patterns, and blocking MCT1 interrupts the fibroblast-to-cardiomyocyte lactate shuttle, which may attenuate cardiac remodelling in hypertension.

SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.

BACKGROUND: Efferocytosis is an activity of macrophages that is pivotal for the resolution of inflammation in hypertension. The precise mechanism by which macrophages coordinate efferocytosis and internalize apoptotic cardiomyocytes remains unknown. The aim of this study was to determine whether SIRT3 (sirtuin-3) is required for both apoptotic cardiomyocyte engulfment and anti-inflammatory responses during efferocytosis. METHODS: We generated myeloid SIRT3 knockout mice and FXN (frataxin) knock-in mice carrying an acetylation-defective lysine to arginine K189R mutation (FXNK189R). The mice were given Ang II (angiotensin II) infusion for 7 days. We analyzed cardiac macrophages' mitochondrial iron levels, efferocytosis activity, and phenotype both in vivo and in vitro. RESULTS: We showed that SIRT3 deficiency exacerbated Ang II-induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXNK189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis. CONCLUSIONS: The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.

Ultrasensitive hydrogel grating detector for real-time continuous-flow detection of trace threat Pb2.

Ultrasensitive real-time detection of trace Pb2+ in continuous flow is vital to effectively and timely eliminate the potential hazards to ecosystem health and sustainability. This work reports on a micro-structured smart hydrogel grating with ultra-sensitivity, high selectivity, good transparency and mechanical property for real-time detection of Pb2+ in continuous flow. The hydrogel grating possesses uniform surface relief microstructures with periodic nano-height ridges made of poly(acrylamide-co-benzo-18-crown-6-acrylamide) networks that crosslinked by tetra-arm star poly(ethylene glycol)acrylamide. The hydrogel grating with good optical transparency and mechanical property can change its height via selective host-guest complexation with Pb2+ to output a changed diffraction efficiency. Meanwhile, the periodic nano-ridges with large specific area benefit the contact with Pb2+ for fast Pb2+-induced height change. Thus, with such rationally designed molecular structures and surface relief microstructures, the hydrogel grating integrated in a glass-based mini-chip allows real-time detection of Pb2+ in continuous flow with ultra-sensitivity and high selectivity. The hydrogel grating detector can achieve ultralow detection limit (10-9 M Pb2+), fast response (2 min), and selective detection of Pb2+ from dozens of interfering ions even with high concentrations. This high-performance hydrogel grating detector is general and can be extended to detect many analytes due to the wide choice of responsive hydrogels, thus opening new areas for creating advanced smart detectors in analytical science.

Serum and diet long-chain omega-3 fatty acid nutritional status in Chinese elite athletes.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are essential for improving the health and performance of athletes. The present study aimed to evaluate the nutritional status of omega-3 PUFAs in Chinese elite athletes by both dietary intake analysis and serum biomarker detection. A cross-sectional analysis of data from 54 elite athletes (24 men and 30 women) from Shanghai professional sports teams was conducted. A food frequency questionnaire (FFQ) was employed to analyze dietary intake, and gas chromatography-mass spectrometry (GC-MS/MS) was conducted to measure serum biomarkers of PUFAs. Correlation analysis was performed to investigate the relationships of PUFA biomarkers with diet, inflammation and oxidative stress. The results showed that the median intake of EPA + DHA among athletes was 132 mg/d, which is lower than the minimum value recommended by dietary guidelines (250 mg/d). The average serum EPA + DHA was 4.0 ± 1.1%, and the ratio of omega-6/omega-3 was 7.7 ± 1.7. Most (96.3%) of the athletes were below the targeted value of serum EPA + DHA, which is associated with a reduction in cardiovascular risk. Correlation analysis showed that the serum EPA + DHA was positively correlated with the long-term dietary intake of EPA + DHA and negatively correlated with inflammatory markers. In conclusion, the serum circulating EPA + DHA and omega-6/omega-3 ratio are effective biomarkers reflecting the nutritional status of PUFAs in athletes. Omega-3 PUFAs have a potential effect on inhibiting inflammatory markers. Hence, it is necessary for Chinese athletes to improve their suboptimal nutritional status of PUFAs through dietary intervention.

Laminated holmium-166-containing electrospun bandages for use against skin cancer.

The number of non-melanoma skin cancer (NMSC) cases in the US will increase significantly over the next decade due to a rise in UV exposure. One of the treatment methods used to remove NMSC lesions is radiation therapy. The two types of radiation therapy used in the clinic are external beam therapy and brachytherapy. However, both require specialized on-site instrumentation and for patients to remain immobile. In this work, we studied an alternative radiation therapy - one that does not require expensive on-site equipment and would allow for enhanced patient mobility and, thus, comfort. We prepared sealed source, nylon-laminated holmium-166-containing radiotherapeutic bandages and used them in C3H/HeN mice with murine SCCVII tumor grafts. Overall, tumor sizes were smallest when treated with therapeutically relevant radiation doses via radiotherapeutic bandages (compared to controls), and no histological evidence of toxicity to tissues was observed. Thus, our optimized radiotherapeutic bandage offers a flexible approach to treating NMSC.

In-situ formation of MnO2 nanoparticles on Ru@SiO2 nanospheres as a fluorescent probe for sensitive and rapid detection of glutathione.

Glutathione (GSH)-switched fluorescent assays have appealed much attention due to rapid signal changes of fluorescent probes. However, exposure to exterior environment of fluorescent probe causes photobleaching and premature leakage, leading to low sensitivity and poor photostability. Herein, luminescent SiO2 nanoparticles encapsulated with Ru(bpy)32+ (Ru@SiO2) were designed and synthesized as fluorescent probe to construct a GSH-switched fluorescent assay. The encapsulation of Ru(bpy)32+ in the SiO2 nanoparticles could effectively prevent the leakage of Ru(bpy)32+ molecules, improving the photostability of probe. The fluorescence of Ru@SiO2 nanoparticles was quenched by coating MnO2 nanoparticles on Ru@SiO2 surface (Ru@SiO2@MnO2 nanocomposites) through an in situ growth approach, which reduced background of the assay. The MnO2 nanoparticles not only further inhibited the leakage of Ru(bpy)32+ molecules, but also could serve as a recognition unit of GSH. In the presence of GSH, the MnO2 nanoparticles on the surface of Ru@SiO2 nanoparticles were reduced to Mn2+, resulting the fluorescence recovery of Ru@SiO2 nanoparticles. Thus, a signal-on fluorescent strategy was constructed for GSH detection. The assay displayed good analytical performance for GSH detection with a low detection limit of 16.2 nM due to excellent fluorescence quenching ability of MnO2 nanoparticles and special role of Ru@SiO2 nanoparticles to block probe leakage. The proposed assay was also applied to measure GSH levels in human serum samples. This work paves a new way to detect GSH with high sensitivity.

Preparation and Optimization of an Ultraflexible Liposomal Gel for Lidocaine Transdermal Delivery.

The pain caused by lidocaine injections into the face prior to facial plastic surgeries intended to remove growths or tumorous lesions has been reported by many patients to be the worst part of these procedures. However, the lidocaine gels and creams currently on the market do not deliver an equal or better local anesthetic effect to replace these injections. To develop an alternative to the painful local anesthetic injection, we prepared ultraflexible liposomes using soy phosphatidylcholine, lidocaine, and different amounts of sodium cholate, a surfactant. The prepared ultraflexible liposomes (UFLs) were examined for particle size, zeta potential, cytotoxicity, and in vitro release. By using a carbomer as a gelling agent, the prepared UFL lidocaine gels were evaluated for their penetration ability in a Franz diffusion cell, using Strat-M membranes. The formulation achieving the highest amount of penetrated lidocaine was chosen for further pH, viscosity, and stability tests. The local anesthetic efficacy of the formulation was investigated by an in vivo tail-flick test in rats. Our findings suggested that this topical gel formulated with ultraflexible liposomal lidocaine has enhanced skin permeation ability, as well as an improved local analgesic effect from the lidocaine.

Optimization of DOTAP/chol Cationic Lipid Nanoparticles for mRNA, pDNA, and Oligonucleotide Delivery.

Lipid nanoparticles (LNPs) can be used as delivery vehicles for nucleic acid biotherapeutics. In fact, LNPs are currently being used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. Cationic LNPs composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (chol) LNPs have been classified as one of the most efficient gene delivery systems and are being tested in numerous clinical trials. The objective of this study was to examine the effect of the molar ratio of DOTAP/chol, PEGylation, and lipid to mRNA ratio on mRNA transfection, and explore the applications of DOTAP/chol LNPs in pDNA and oligonucleotide transfection. Here we showed that PEGylation significantly decreased mRNA transfection efficiency of DOTAP/chol LNPs. Among non-PEGylated LNP formulations, 1:3 molar ratio of DOTAP/chol in DOTAP/chol LNPs showed the highest mRNA transfection efficiency. Furthermore, the optimal ratio of DOTAP/chol LNPs to mRNA was tested to be 62.5 µM lipid to 1 µg mRNA. More importantly, these mRNA-loaded nanoparticles were stable for 60 days at 4 °C storage without showing reduction in transfection efficacy. We further found that DOTAP/chol LNPs were able to transfect pDNA and oligonucleotides, demonstrating the ability of these LNPs to transport the cargo into the cell nucleus. The influence of various factors in the formulation of DOTAP/chol cationic LNPs is thus described and will help improve drug delivery of nucleic acid-based vaccines and therapies.

CircularRNA_0119872 regulates the microRNA-582-3p/E2F transcription factor 3 pathway to promote the progression of malignant melanoma.

OBJECTIVES: Malignant melanoma (MM) is an invasive tumor that poses a threat to patient health. Circular RNAs (circRNAs) are important regulators of MM carcinogenesis. In this study, we investigated the expression characteristics and biological functions of, and mechanism underlying, circ_0119872 expression in MM. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to examine the circ_0119872, microRNA (miR)-582-3p, and E2F transcription factor 3 (E2F3) mRNA expression levels in MM tissues and cell lines. Western blotting was performed to quantify E2F3 protein expression. MM cells with circ_0119872 knockdown were established, and cell counting kit 8 (CCK-8) and transwell assays were utilized to examine the function of circ_0119872 and its effects on the malignant characteristics of MM cells. The MiRDB and TargetScan databases were used to predict the target genes of miR-582-3p. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to explore the biological functions of the target genes of miR-582-3p. Additionally, a dual-luciferase reporter gene experiment was performed to verify the targeting relationship between circ_0119872 and miR-582-3p as well as that between miR-582-3p and E2F3. RESULTS: Circ_0119872 was remarkably upregulated in MM tissues and cell lines. Circ_0119872 knockdown suppressed the cell proliferation and metastasis In addition, miR-582-3p was identified as a downstream target of circ_0119872. The target genes of miR-193a-3p are involved in melanogenesis and cancer-related signaling pathways. Mechanistically, circ_0119872 facilitated MM progression by adsorbing miR-582-3p and upregulating E2F3 expression. CONCLUSION: Circ_0119872 is an oncogenic circRNA that participates in the promotion of MM progression by regulating the miR-582-3p/E2F3 axis.

A Method for Liposome Co-encapsulation of Phenethyl Isothiocyanate and Cisplatin and Determining Its Toxicity Against Lung and Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths in the United States. It is extremely difficult to treat, and its survival rate is low. Today, the most effective treatments are still those that implement the platinum anticancer drug cisplatin (CDDP) in combination with other drugs. We previously demonstrated that the naturally occurring compound phenethyl isothiocyanate (PEITC) could be used to sensitize NSCLC cells to CDDP. Furthermore, co-encapsulation of PEITC and CDDP in liposomes enhances their toxicity toward NSCLC cells. We have optimized a liposomal-PEITC-CDDP formulation and investigated its cytotoxicity. We determined that liposomal-PEITC-CDDP is much more toxic toward human NSCLC cell lines than it is toward human normal lung cell lines. In this chapter, we describe detailed methods for preparing liposomal-PEITC-CDDP and determining its cytotoxicity.

Physicochemical Factors That Influence the Biocompatibility of Cationic Liposomes and Their Ability to Deliver DNA to the Nuclei of Ovarian Cancer SK-OV-3 Cells.

Cationic liposomes composed of 3-[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-chol) and dioleoylphosphatidylethanolamine (DOPE) have previously been shown to have applications in gene delivery. Our study aims to explore the effects of inclusion of polyethylene glycol (PEG) and using different molar ratios of DC-chol/DOPE on size, zeta potential, cytotoxicity and DNA delivery of DC-chol/DOPE liposomes. Our results show that PEGylation reduces the cytotoxicity of DC-chol/DOPE liposomes, and, furthermore, PEGylated liposome-DNA lipoplexes are smaller in size and more uniform in size distribution than those that are not PEGylated. Additionally, toxicity against ovarian cancer SKOV-3 cells decreases with the amount of cationic DC-chol present in the formulation; however, decreased delivery of DNA to cellular nuclei is also observed. Transfection with the PEGylated liposomes was successfully demonstrated using plasmid DNA with a known functional outcome. These results offer further insight into physicochemical properties important for cationic liposomes as vehicles for DNA delivery and demonstrate the potential of PEGylated DC-chol/DOPE liposomes as systemic delivery carriers for DNA-mediated ovarian cancer therapy.

CircularRNA_0119872 regulates the microRNA-582-3p/E2F transcription factor 3 pathway to promote the progression of malignant melanoma

OBJECTIVES: Malignant melanoma (MM) is an invasive tumor that poses a threat to patient health. Circular RNAs (circRNAs) are important regulators of MM carcinogenesis. In this study, we investigated the expression characteristics and biological functions of, and mechanism underlying, circ_0119872 expression in MM. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to examine the circ_0119872, microRNA (miR)-582-3p, and E2F transcription factor 3 (E2F3) mRNA expression levels in MM tissues and cell lines. Western blotting was performed to quantify E2F3 protein expression. MM cells with circ_0119872 knockdown were established, and cell counting kit 8 (CCK-8) and transwell assays were utilized to examine the function of circ_0119872 and its effects on the malignant characteristics of MM cells. The MiRDB and TargetScan databases were used to predict the target genes of miR-582-3p. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to explore the biological functions of the target genes of miR-582-3p. Additionally, a dual-luciferase reporter gene experiment was performed to verify the targeting relationship between circ_0119872 and miR-582-3p as well as that between miR-582-3p and E2F3. RESULTS: Circ_0119872 was remarkably upregulated in MM tissues and cell lines. Circ_0119872 knockdown suppressed the cell proliferation and metastasis In addition, miR-582-3p was identified as a downstream target of circ_0119872. The target genes of miR-193a-3p are involved in melanogenesis and cancer-related signaling pathways. Mechanistically, circ_0119872 facilitated MM progression by adsorbing miR-582-3p and upregulating E2F3 expression. CONCLUSION: Circ_0119872 is an oncogenic circRNA that participates in the promotion of MM progression by regulating the miR-582-3p/E2F3 axis.

Sirtuin 3 governs autophagy-dependent glycolysis during Angiotensin II-induced endothelial-to-mesenchymal transition.

The impairment of autophagy can cause cellular metabolic perturbations involved in endothelial-to-mesenchymal transition (EndoMT). However, the interplay between the cellular autophagy machinery and endothelial metabolism remains elusive. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is a major cellular sensor of energy metabolism. The aim of this work was to determine the role of SIRT3-mediated autophagy in cellular metabolism and the process of EndoMT. We demonstrated that Angiotensin II (Ang II) led to defective autophagic flux and high levels of glycolysis in endothelial cells (ECs) accompanied by a loss of mitochondrial SIRT3 during EndoMT. The loss of SIRT3 further induced the hyperacetylation of endogenous autophagy-regulated gene 5 (ATG5), which in turn inhibited autophagosome maturation and increased pyruvate kinase M2 (PKM2) dimer expression. The M2 dimer is the less active form of PKM2, which drives glucose through aerobic glycolysis. Additionally, TEPP-46, a selective PKM2 tetramer activator, produced lower concentrations of lactate and led to the reduction of EndoMT both in vitro and in vivo. In parallel, the blockade of lactate influx from ECs into vascular smooth muscle cells (VSMCs) downregulated synthetic VSMC markers. EC-specific SIRT3 transgenic mice exhibited reduced endothelial cell transition but partial rescue of vascular fibrosis and collagen accumulation. Taken together, these findings reveal that SIRT3 regulates EndoMT by improving the autophagic degradation of PKM2. Pharmacological targeting of glycolysis metabolism may, therefore, represent an effective therapeutic strategy for hypertensive vascular remodeling.

Overexpression of wheat α-mannosidase gene TaMP impairs salt tolerance in transgenic Brachypodium distachyon.

KEY MESSAGE: The TaMP gene from wheat encodes an α-mannosidase induced by salt stress that functions as negative regulator of salt tolerance in plants. Salt stress significantly affects growth and yield of crop plants. The α-mannosidases function in protein folding, trafficking, and endoplasmic reticulum-associated degradation in eukaryotic cells, and they are involved in abiotic stress tolerance in plants. Previously, we identified the α-mannosidase gene TaMP in wheat (Triticum aestivum). In this study, we investigated the function of TaMP in salt stress tolerance. TaMP expression was induced in wheat leaves by salt, drought, abscisic acid, and H2O2 treatments. Overexpressing TaMP in Brachypodium distachyon was associated with a salt-sensitive phenotype. Under salt stress, the overexpressing plants had reduced height, delayed growth status, low photosynthetic rate, decreased survival rate, and diminished yield. Moreover, the overexpression of TaMP aggravated the tendency for ions to become toxic under salt stress by significantly affecting the Na+ and K+ contents in cells. In addition, TaMP could negatively regulate salt tolerance by affecting the antioxidant enzyme system capacity and increasing the reactive oxygen species accumulation. Our study was helpful to understand the underlying physiological and molecular mechanisms of salt stress tolerance in plants.

Sirtuin 3 deficiency accelerates Angiotensin II-induced skeletal muscle atrophy.

Background: It has been reported that Angiotensin II (Ang II) induced skeletal muscle atrophy. However, the precise mechanisms remain elusive. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, plays a central role in maintaining cellular metabolic homeostasis. This work aims to determine the role of SIRT3-mediated cellular metabolism in skeletal muscle wasting. Methods and Results: Eight-week-old male wild-type (WT) and SIRT3 knockout (SIRT3 KO) mice were infused with Ang II or saline for 4 weeks. Ang II induces skeletal muscle atrophy by inducing expression of the muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) and atrogin-1, accompanied by a reduction in SIRT3 in skeletal muscle. SIRT3 deficiency accelerated Ang II-induced loss of lean mass and protein hyper-acetylation, while the activities of mitochondrial oxidative enzymes, such as complex I and complex V, were significantly decreased. Furthermore, SIRT3 deficiency accelerated the Ang II-induced shift from slow-twitch towards fast-twitch fibres. Similarly, the three major rate-limiting enzymes in the glycolytic pathway, hexokinase 2 (HK2), phosphofructokinase-1(PFK) and pyruvate kinase (PK), were upregulated in Ang II-treated SIRT3 KO mice. Conclusion: These studies indicate that SIRT3 deficiency augmented Ang II-induced fibre-type shifting and metabolic reprogramming.