Separation of Chloride and Sulfate Ions from Desulfurization Wastewater Using Monovalent Anions Selective Electrodialysis.

The high concentration of chloride ions in desulphurization wastewater is the primary limiting factor for its reusability. Monovalent anion selective electrodialysis (S-ED) enables the selective removal of chloride ions, thereby facilitating the reuse of desulfurization wastewater. In this study, different concentrations of NaCl and Na2SO4 were used to simulate different softened desulfurization wastewater. The effects of current density and NaCl and Na2SO4 concentration on ion flux, permselectivity (PSO42-Cl-) and specific energy consumption were studied. The results show that Selemion ASA membrane exhibits excellent permselectivity for Cl- and SO42-, with a significantly lower flux observed for SO42- compared to Cl-. Current density exerts a significant influence on ion flux; as the current density increases, the flux of SO42- also increases but at a lower rate than that of Cl-, resulting in an increase in permselectivity. When the current density reaches 25 mA/cm2, the permselectivity reaches a maximum of 50.4. The increase in NaCl concentration leads to a decrease in the SO42- flux; however, the permselectivity is reduced due to the elevated Cl-/SO42- ratio. The SO42- flux increases with the increase in Na2SO4 concentration, while the permselectivity increases with the decrease in Cl-/SO42- ratio.

The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis.

The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.

Short-term effects of cupping and scraping therapy for chronic nonspecific low-back pain: A prospective, multicenter randomized trial.

BACKGROUND: As one of the most common musculoskeletal ailments, chronic nonspecific low-back pain (CNLBP) causes persistent disability and substantial medical expenses. Epidemiological evidence shows that the incidence rate of CNLBP in young and middle-aged people who are demanded rapidly recovery and social contribution is rising. Recent guidelines indicate a reduced role for medicines in the management of CNLBP. OBJECTIVE: The present study investigates the short-term effects of cupping and scraping therapy using a medicated balm, compared to nonsteroidal anti-inflammatory drug (NSAID) with a capsaicin plaster, in the treatment of CNLBP. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: We designed a prospective multicenter randomized clinical trial enrolling patients from January 1, 2022 to December 31, 2022. A total of 156 patients with CNLBP were randomized into two parallel groups. Diclofenac sodium-sustained release tablets were administered orally to participants in the control group for one week while a capsaicin plaster was applied externally. Patients in the test group were treated with cupping and scraping using a medical device and medicated balm. MAIN OUTCOME MEASURES: Primary outcome was pain recorded using the visual analogue scale (VAS). Two secondary outcomes were recorded using the Japanese Orthopedic Association low-back pain scale (JOA) and the traditional Chinese medicine (TCM) syndrome integral scale (TCMS) as assessment tools. RESULTS: Between baseline and postintervention, all changes in outcome metric scales were statistically significant (P < 0.001). Compared to the control group, patients in the test group had a significantly greater treatment effect in all outcome variables, as indicated by lower VAS and TCMS scores and higher JOA scores, after the one-week intervention period (P < 0.001). Further, according to the findings of multivariate linear regression analysis, the participants' pain (VAS score) was related to their marital status, age, smoking habits and body mass index. No adverse reactions were reported for any participants in this trial. CONCLUSION: The effectiveness of TCM combined with the new physiotherapy tool is superior to that of NSAID combined with topical plasters, regarding to pain intensity, TCM symptoms and quality of life. The TCM plus physiotherapy also showed more stable and long-lasting therapeutic effects. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry (ChiCTR2200055655). Please cite this article as: He JY, Tu XY, Yin ZF, Mu H, Luo MJ, Chen XY, Cai WB, Zhao X, Peng C, Fang FF, Lü C, Li B. Short-term effects of cupping and scraping therapy for chronic nonspecific low-back pain: A prospective, multicenter randomized trial. J Integr Med. 2024; 22(1): 39-45.

Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47.

Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa-/- mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8hi and gMDSC_H2-Q10hi subsets showing strong antitumor activity. Sirpa-/- macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa-/- macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer immunotherapy efficacy.

Progress in Programmable DNA-Aided Self-Assembly of the Master Frame of a Drug Delivery System.

Every year cancer causes approximately 10 million deaths globally. Researchers have developed numerous targeted drug delivery systems (DDSs) with nanoparticles, polymers, and liposomes, but these synthetic materials have poor degradability and low biocompatibility. Because DNA nanostructures have good degradability and high biocompatibility, extensive studies have been performed to construct DDSs with DNA nanostructures as the molecular-layer master frame (MF) assembled via programmable DNA-aided self-assembly for targeted drug release. To learn the progressing trend of self-assembly techniques and keep pace with their recent rapid advancements, it is crucial to provide an overview of their past and recent progress. In this review article, we first present the techniques to assemble the MF of a DDS with solely DNA strands; to assemble MFs with one or more additional type of construction materials, e.g., polymers (including RNA and protein), inorganic nanoparticle, or metal ions, in addition to DNA strands; and to assemble the more complex DNA nanocomplexes. It is observed that both the techniques used and the MFs constructed have become increasingly complex and that the DDS constructed has an increasing number of advanced functions. From our focused review, we anticipate that DDSs with the MF of multiple building materials and DNA nanocomplexes will attract an increasing number of researchers' interests. On the basis of knowledge about materials and functional components (e.g., targeting aptamers/peptides/antibodies and stimuli for drug release) obtained from previously performed studies, researchers can combine more materials with DNA strands to assemble more powerful MFs and incorporate more components to endow DDSs with improved or additional properties/functions, thereby subsequently contributing to cancer prevention.

Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice.

Diabetic cardiomyopathy is a primary myocardial injury induced by diabetes with complex pathogenesis. In this study, we identify disordered cardiac retinol metabolism in type 2 diabetic male mice and patients characterized by retinol overload, all-trans retinoic acid deficiency. By supplementing type 2 diabetic male mice with retinol or all-trans retinoic acid, we demonstrate that both cardiac retinol overload and all-trans retinoic acid deficiency promote diabetic cardiomyopathy. Mechanistically, by constructing cardiomyocyte-specific conditional retinol dehydrogenase 10-knockout male mice and overexpressing retinol dehydrogenase 10 in male type 2 diabetic mice via adeno-associated virus, we verify that the reduction in cardiac retinol dehydrogenase 10 is the initiating factor for cardiac retinol metabolism disorder and results in diabetic cardiomyopathy through lipotoxicity and ferroptosis. Therefore, we suggest that the reduction of cardiac retinol dehydrogenase 10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying diabetic cardiomyopathy.

Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.

Statins play an important role in the treatment of diabetic nephropathy. Increasing attention has been given to the relationship between statins and insulin resistance, but many randomized controlled trials confirm that the therapeutic effects of statins on diabetic nephropathy are more beneficial than harmful. However, further confirmation of whether the beneficial effects of chronic statin administration on diabetic nephropathy outweigh the detrimental effects is urgently needed. Here, we find that long-term statin administration may increase insulin resistance, interfere with lipid metabolism, leads to inflammation and fibrosis, and ultimately fuel diabetic nephropathy progression in diabetic mice. Mechanistically, activation of insulin-regulated phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway leads to increased fatty acid synthesis. Furthermore, statins administration increases lipid uptake and inhibits fatty acid oxidation, leading to lipid deposition. Here we show that long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways.

INTRODUCTION: High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood. OBJECTIVES: This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation. METHODS: The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression. RESULTS: ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo. CONCLUSIONS: Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.

Regulation of the Keap1-Nrf2 Signaling Axis by Glycyrrhetinic Acid Promoted Oxidative Stress-Induced H9C2 Cell Apoptosis.

Excessive reactive oxygen species (ROS) could interfere with the physiological capacities of H9C2 cells and cause cardiomyocyte apoptosis. Glycyrrhetinic acid (GA), one of the main medicinal component of Glycyrrhetinic Radix et Rhizoma, shows toxic and adverse side effects in the clinic setting. In particular, some studies have reported that GA exerts toxic effects on H9C2 cells. The purpose of this study is to assess the effect of GA-induced oxidative stress on cultured H9C2 cells and reveal the relevant signaling pathways. LDH assay was used to assess cell damage. Apoptosis was detected using Hoechst 33242 and a propidium iodide (PI) assay. An Annexin V-fluorescein isothiocyanate/PI double-staining assay was utilized to investigate GA-induced apoptosis in H9C2 cells. The expression level of specific genes/proteins was evaluated by RT-qPCR and Western blotting. Flow cytometry and DCFH-DA fluorescent testing were used to determine the ROS levels of H9C2 cells. The potential mechanism of GA-induced cardiomyocyte injury was also investigated. GA treatment increased ROS generation and mitochondrial membrane depolarization and triggered caspase-3/9 activation and apoptosis. GA treatment also caused the nuclear translocation of NF-E2-related factor 2 after its dissociation from Keap1. This change was accompanied by a dose-dependent decline in the expression of the downstream target gene heme oxygenase-1. The findings demonstrated that GA could regulate the Keap1-Nrf2 signaling axis and induce oxidative stress to promote the apoptosis of H9C2 cells.

Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch.

As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. Myocardial energy metabolism was recently reported to be related to the loss of proliferative capacity in cardiomyocytes (CMs). However, the intrinsic relationship between beating rate and proliferation in CMs and whether energy metabolism can regulate this relationship remains unclear. In this study, we find that moderate heart rate reduction (HRR) induces CM proliferation under physiological conditions and promotes cardiac regenerative repair after myocardial injury. Mechanistically, moderate HRR induces G1/S transition and increases the expression of glycolytic enzymes in CMs. Furthermore, moderate HRR induces a metabolic pattern switch, activating glucose metabolism and increasing the relative proportion of ATP production by the glycolytic pathway for biosynthesis of substrates needed for proliferative CMs. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restoration.

Targeting ACSL1 promotes cardiomyocyte proliferation and cardiac regeneration.

BACKGROUND: Neonatal hearts have considerable regenerative potential within 7 days post birth (P7), but the rate of regeneration is extremely low after P7. Interestingly, lipid metabolism increases dramatically after P7. The similarities in these age profiles suggests a possible link between cardiac regeneration and lipid metabolism. Acyl CoA synthase long chain family member 1 (ACSL1) is the key enzyme that regulates lipid metabolism. The aim of this study was to identify the role of ACSL1 in the regeneration of cardiomyocytes. METHODS AND RESULTS: The uptake of fatty acids in hearts increased after P7; however, myocardial regeneration was decreased. We profiled an RNA-sequence array of hearts from mice of different ages, including E10.5 (embryonic stage)-, 3-, 7-, 21-, 30-, and 60-day-old mice, and found that the expression of ACSL1 was significantly increased after P7. By establishing ACSL1 knockdown mice with adeno-associated virus (AAV9). Then, we verified that knockdown of ACSL1 enhanced the capacity for myocardial regeneration both in mice and in primary cardiomyocytes. Indeed, ACSL1 knockdown in primary cardiomyocytes promoted the cell cycle progression from G0 to G2 phase by regulating specific factors, which may correlate with the activation of AKT by ACSL1 and withdrawal of FOXO1 from the nucleus. In vivo, knockdown of ACSL1 effectively restored cardiac function and myocardial regeneration in adult mice with myocardial infarction (MI). CONCLUSIONS: ACSL1 possibly induces the loss of the myocardial regenerative potential beginning at P7 in mice, and inhibition of ACSL1 effectively promoted myocardial repair after MI in mice.

Exploration of Ion Transport in Blends of an Ionic Liquid and a Polymerized Ionic Liquid Graft Copolymer.

In this study, we prepared a composite membrane consisting of a poly(1-butyl-3-vinylimidazolium-tetrafluoroborate) (poly([BVIM]-[BF4])) polymerized ionic liquid graft copolymer (PILGC) and a blend of PILGC and 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]-[BF4]) ionic liquid (IL) to explore techniques for improving the conductivity of PILGCs, which is normally three orders of magnitude lower than that of ILs. PILGCs, which are environmentally friendly, have attracted much interest. To gain a better understanding of ion transport in composites, the mechanisms of ion transport in composite components should be explored. We investigated anion transport in ILs and PILGCs and were able to obtain the correct ion transport mechanisms in IL-PILGC blends based on a previous work. We performed molecular dynamics (MD) simulations, which are commonly used to investigate molecular mechanisms. According to the MD simulation results, in most IL-PILGC blends of various compositions, the contributions of cations are greater than those of anions. This is one reason that blends have higher conductivities than their component PILGCs. To the best of our knowledge, we are the first to identify ion transport mechanisms in PILGCs and their blends with ILs by exploring subdiffusive ion motion regimes. The ratio of the number of cages with more than three cationic branch chains in the blend with 50 wt % PILGC, the blend with 80 wt % PILGC, and the PILGC was 0.26:0.39:0.65. Therefore, the ratio of firm cages gets a promotion as the PILGC content increases. Because the ratio of fast ions decreases as the ratio of firm cages increases, the blend with 80 wt % PILGC has lower anion diffusivities than the blend with 50 wt % PILGC. It was inappropriate to probe ion transport in PILGCs (or IL-PILGC blends) solely via analyzing ion association interactions. Analysis of only ion association interactions led to the incorrect conclusion that the time scales of ion transport in PILGCs are given by the continuous ion association time, which is the time when the ion association remains paired rather than the time when an ion is caught inside a cage. Proper methods should be used to obtain more accurate theories.

Molecular Dynamics Simulation of Ion Adsorption and Ligand Exchange on an Orthoclase Surface.

Orthoclase (K-feldspar) is one of the natural inorganic materials, which shows remarkable potential toward removing heavy metal ions from aqueous solutions. Understanding the interactions of the orthoclase and metal ions is important in the treatment of saline wastewater. In this paper, molecular dynamics simulations were used to prove the adsorption of different ions onto orthoclase. The adsorption isotherms show that orthoclase has remarkable efficiency in the removal of cations at low ion concentrations. Aluminol groups are the preferential adsorption sites of cations due to higher negative charges. The adsorption types and adsorption sites are influenced by the valence, radius, and hydration stability of ions. Monovalent cations can be adsorbed in the cavities, whereas divalent cations cannot. The hydrated cation may form an outer-sphere complex or an inner-sphere complex in association with the loss of hydration water. Na+, K+, and Ca2+ ions mainly undergo inner-sphere adsorption and Mg2+ ions prefer outer-sphere adsorption. On the basis of simulation results, the mechanism of ion removal in the presence of orthoclase is demonstrated at a molecular level.

Study on the anti-infection ability of vancomycin cationic liposome combined with polylactide fracture internal fixator.

A polylactide composite fracture fixator loaded with vancomycin cationic liposome (PLA@VL) was prepared by reverse evaporation method. The method of cationic liposome encapsulating vancomycin could effectively improve antibacterial property and achieve drug sustained release effect, so as to reduce toxicity of antibiotics in vivo. Scanning electron microscope (SEM) was used to observe morphology and Fourier transform infrared spectroscopy (FTIR) was used to detect the composition of the internal fixator. In vitro drug release model, in vitro degradation model and body fluid osteogenesis model were designed in this study. On the other hand, the experiments of inhibition zone and MC3T3-E1 osteoblasts in mice were conducted to explore antibacterial property, cell activity and adhesion of the PLA@VL composite internal fixator. Alkaline phosphatase (ALP) staining method and alizarin red assay were used to detect the osteogenic induction ability of the composite internal fixator. Finally, mice fracture models were established to verify osteogenic and anti-infection abilities of the composite internal fixator in vivo. The results showed that MC3T3-E1 cells had better adhesion and proliferation abilities on the PLA@VL composite internal fixator than on the PLA fixator, which indicated that the PLA@VL composite internal fixator possessed excellent osteogenic and anti-infection abilities both in vivo and in vitro. Therefore, the above experiments showed that the fracture internal fixator combined with vancomycin cationic liposome had better biocompatibility, antibacterial ability and osteogenic ability, which provides a promising anti-infection material for the clinical field of fracture.

Wnt2bb Induces Cardiomyocyte Proliferation in Zebrafish Hearts via the jnk1/c-jun/creb1 Pathway.

Previous studies have demonstrated that inhibition of canonical Wnt signaling promotes zebrafish heart regeneration and that treatment of injured heart tissue with the Wnt activator 6-bromo-indirubin-3-oxime (BIO) can impede cardiomyocyte proliferation. However, the mechanism by which Wnt signaling regulates downstream gene expression following heart injury remains unknown. In this study, we have demonstrated that inhibition of injury-induced myocardial wnt2bb and jnk1/creb1/c-jun signaling impedes heart repair following apex resection. The expression of jnk1, creb1, and c-jun were inhibited in wnt2bb dominant negative (dn) mutant hearts and elevated in wnt2bb-overexpresssing hearts following ventricular amputation. The overexpression of creb1 sufficiently rescued the dn-wnt2bb-induced phenotype of reduced nkx2.5 expression and attenuated heart regeneration. In addition, wnt2bb/jnk1/c-jun/creb1 signaling was increased in Tg(hsp70l:dkk1) transgenic fish, whereas it was inhibited in Tg(hsp70l:wnt8) transgenic fish, indicating that canonical Wnt and non-canonical Wnt antagonize each other to regulate heart regeneration. Overall, the results of our study demonstrate that the wnt2bb-mediated jnk1/c-jun/creb1 non-canonical Wnt pathway regulates cardiomyocyte proliferation.

Poly(vinyl alcohol)-Modified Membranes by Ti3C2T x for Ethanol Dehydration via Pervaporation.

In this paper, PVA/Ti3C2T x mixed matrix membranes (MMMs) were prepared by mixing the synthesized Ti3C2T x with the PVA matrix, and the pervaporation (PV) performance of the ethanol-water binary system was tested. The morphology, structural properties, and surface characteristics of the membranes were investigated by scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, degree of swelling, and water contact angle. The PVA/Ti3C2T x MMMs exhibit excellent compatibility and swelling resistance. Moreover the effects of the Ti3C2T x filling level, feed concentration, and operating temperature on the ethanol dehydration performance were systematically studied. The results demonstrated that the separation factor of PVA/Ti3C2T x MMMs was significantly increased because of Ti3C2T x promoting the cross-linking density of the membrane. Specifically, the membrane showed the best PV performance when Ti3C2T x loading was 3.0 wt %, achieving a separation factor of 2585 and a suitable total flux of 0.074 kg/m2 h for separating 93 wt % ethanol solution at 37 °C.

Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus.

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans. Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests. Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3ß), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3ß and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples. Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.

Schaftoside alleviates HFD-induced hepatic lipid accumulation in mice via upregulating farnesoid X receptor.

ETHNOPHARMACOLOGY RELEVANCE: The farnesoid X receptor (FXR) is a therapeutic target of for the treatment of non-alcoholic fatty liver disease (NAFLD) owing to its regulatory role in lipid homeostasis. Schaftoside (SS) is a bioactive compound of Herba Desmodii Styracifolii, which has traditionally been used to treat hepatitis and cholelithiasis. However, the potential hepatoprotective effect of SS against NAFLD and the underlying mechanisms remain unknown. AIM OF THE STUDY: We investigated whether SS could improve NAFLD-induced liver injury by decreasing lipid accumulation via the activation of FXR signalling. MATERIALS AND METHODS: In vivo, the effects of SS on high-fat diet (HFD)-induced lipid accumulation in the liver of mice were evaluated by serum biochemical parameters and histopathological analysis. In vitro, the intracellular triglyceride (TG) level and Oil Red O staining were used to evaluate the lipid removal ability of SS in Huh-7 cells or FXR knockout mouse primary hepatocytes (MPHs) induced by oleic acid (OA). Moreover, FXR/sterol regulatory element-binding protein 1 (SREBP1) mRNA and protein expression levels were detected. RESULTS: SS reduced HFD-induced lipid accumulation in the liver, as indicated by decreased aspartate aminotransferase (AST), cholesterol (Ch), and TG levels in serum and TG levels in liver tissue, and subsequently resulting in attenuation of liver histopathological injury. Gene expression profiles demonstrated that SS dose-dependently prevented HFD-induced decrease of FXR expression and inversely inhibited SREBP1 expression in the nucleus. Furthermore, SS significantly suppressed excessive TG accumulation and decreased intracellular TG level in Huh-7 cells or MPHs via the upregulation of FXR and inhibition of SREBP1 expression in the nucleus. CONCLUSION: Our results suggest that SS ameliorates HFD-induced NAFLD by the decrease of lipid accumulation via the control of FXR-SREBP1 signalling.

Discovery of a novel niacin-lipoic acid dimer N2L attenuating atherosclerosis and dyslipidemia with non-flushing effects.

Niacin has been widely used as an antihyperlipidemic drug, but the flushing effect restricted its clinical application. Here, we developed novel niacin-lipoic acid dimers which lead to better lipid modulation, higher synergistic effects and less side effects. We utilized molecular docking simulation to design a novel series of niacin-lipoic acid dimers. The compound N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)nicotinamide (N2L) was selected for the in vitro and in vivo evaluation, including the agonist activity in CHO-hGPR109A cells, cell protective effects in HT22 and HUVECs cells, flushing effect in guinea pigs and rats, lipid modulation in C57BL/6 mice and high fat diet-rats and atherosclerotic lesions regulation in apolipoprotein E null mice. N2L worked as potent and selective agonists for the high affinity niacin receptor GPR109A. N2L retained antioxidation and cytoprotection of lipoic acid. In addition, N2L displayed a good therapeutic index regarding lipid modulation and atherosclerotic lesions regulation, and minimized niacin-induced vasodilation (flushing) effect in vivo. N2L showed effective treatment regarding to lipid regulation and atherosclerosis inhibition effects, also with excellent antioxidant effects, safety profiles and non-flushing. All these results suggest N2L promising application prospects in the drug development for the treatment of atherosclerosis.

Pigment Epithelial-Derived Factor Deficiency Accelerates Atherosclerosis Development via Promoting Endothelial Fatty Acid Uptake in Mice With Hyperlipidemia.

Background Endothelial cell injury, induced by dyslipidemia, is the initiation of atherosclerosis, resulting in an imbalance in endothelial fatty acid (FA) transport. Pigment epithelial-derived factor (PEDF) is an important regulator in lipid metabolism. We hypothesized that PEDF is involved in endothelium-mediated FA uptake under hyperlipidemic conditions. Methods and Results Circulating PEDF levels were higher in patients with atherosclerotic cardiovascular disease than in normal individuals. However, decreasing trends of serum PEDF levels were confirmed in both wild-type and apolipoprotein E-deficient mice fed a long-term high-fat diet. Apolipoprotein E-deficient/PEDF-deficient mice were generated by crossing PEDF-deficient mice with apolipoprotein E-deficient mice, and then mice were fed with 24, 36, or 48 weeks of high-fat diet. Greater increases in body fat and plasma lipids were displayed in PEDF-deficient mice. In addition, PEDF deficiency in mice accelerated atherosclerosis, as evidenced by increased atherosclerotic plaques, pronounced vascular dysfunction, and increased lipid accumulation in peripheral tissues, whereas injection of adeno-associated virus encoding PEDF exerted opposite effects. Mechanistically, PEDF inhibited the vascular endothelial growth factor B paracrine signaling by reducing secretion of protein vascular endothelial growth factor B in peripheral tissue cells and decreasing expression of its downstream targets in endothelial cells, including its receptors (namely, vascular endothelial growth factor receptor-1 and neuropilin-1), and FA transport proteins 3 and 4, to suppress endothelial FA uptake, whereas PEDF deletion in mice activated the vascular endothelial growth factor B signaling pathway, thus causing markedly increased lipid accumulation. Conclusions Decreasing expression of PEDF aggravates atherosclerosis by significantly impaired vascular function and enhanced endothelial FA uptake, thus exacerbating ectopic lipid deposition in peripheral tissues.