Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice.

Lipid overload contributes to cardiac complications of diabetes and obesity. However, the underlying mechanisms remain obscure. This study investigates the role of gamma-aminobutyrate transaminase (ABAT), the key enzyme involved in the catabolism of γ-aminobutyric acid (GABA), in lipid overload-induced cardiac injury. Microarray revealed a down-regulation of ABAT mRNA expression in high fat diet (HFD)-fed mouse hearts, which correlated with a reduction in ABAT protein level and its GABA catabolic activity. Transgenic mice with cardiomyocyte-specific ABAT over-expression (Tg-ABAT/tTA) were generated to determine the role of ABAT in lipid overload-induced cardiac injury. Feeding with a HFD to control mice for 4 months reduced ATP production and the mitochondrial DNA copy number, and induced myocardial oxidative stress, hypertrophy, fibrosis and dysfunction. Such pathological effects of HFD were mitigated by ABAT over-expression in Tg-ABAT/tTA mice. In cultured cardiomyocytes, palmitate increased mitochondrial ROS production, depleted ATP production and promoted apoptosis, all of which were attenuated by ABAT over-expression. With the inhibition of ABAT's GABA catabolic activity, the protective effects of ABAT remained unchanged in palmitate-induced cardiomyocytes. Thus, ABAT protects the mitochondrial function in defending the heart against lipid overload-induced injury through mechanisms independent of its GABA catabolic activity, and may represent a new therapeutic target for lipid overload-induced cardiac injury.

Panax Notoginseng Saponins Protect H9c2 Cells From Hypoxia-reoxygenation Injury Through the Forkhead Box O3a Hypoxia-inducible Factor-1 Alpha Cell Signaling Pathway.

ABSTRACT: Panax notoginseng saponins (PNS) are commonly used in the treatment of cardiovascular diseases. Whether PNS can protect myocardial ischemia-reperfusion injury by regulating the forkhead box O3a hypoxia-inducible factor-1 alpha (FOXO3a/HIF-1α) cell signaling pathway remains unclear. The purpose of this study was to investigate the protective effect of PNS on H9c2 cardiomyocytes through the FOXO3a/HIF-1α cell signaling pathway. Hypoxia and reoxygenation of H9C2 cells were used to mimic MIRI in vitro, and the cells were treated with PNS, 2-methoxyestradiol (2ME2), and LY294002." Cell proliferation, lactate dehydrogenase, and malonaldehyde were used to evaluate the degree of cell injury. The level of reactive oxygen species was detected with a fluorescence microscope. The apoptosis rate was detected by flow cytometry. The expression of autophagy-related proteins and apoptosis-related proteins was detected by western blot assay. PNS could reduce H9c2 hypoxia-reoxygenation injury by promoting autophagy and inhibiting apoptosis through the HIF-1α/FOXO3a cell signaling pathway. Furthermore, the protective effects of PNS were abolished by HIF-1α inhibitor 2ME2 and PI3K/Akt inhibitor LY294002. PNS could reduce H9c2 hypoxia-reoxygenation injury by promoting autophagy and inhibiting apoptosis through the HIF-1α/FOXO3a cell signaling pathway.

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer.

Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc finger-homeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-ß, ß-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis.

AIMS/HYPOTHESIS: The role of non-cardiomyocytes in diabetic cardiomyopathy has not been fully addressed. This study investigated whether endothelial cell calpain plays a role in myocardial endothelial injury and microvascular rarefaction in diabetes, thereby contributing to diabetic cardiomyopathy. METHODS: Endothelial cell-specific Capns1-knockout (KO) mice were generated. Conditions mimicking prediabetes and type 1 and type 2 diabetes were induced in these KO mice and their wild-type littermates. Myocardial function and coronary flow reserve were assessed by echocardiography. Histological analyses were performed to determine capillary density, cardiomyocyte size and fibrosis in the heart. Isolated aortas were assayed for neovascularisation. Cultured cardiac microvascular endothelial cells were stimulated with high palmitate. Angiogenesis and apoptosis were analysed. RESULTS: Endothelial cell-specific deletion of Capns1 disrupted calpain 1 and calpain 2 in endothelial cells, reduced cardiac fibrosis and hypertrophy, and alleviated myocardial dysfunction in mouse models of diabetes without significantly affecting systemic metabolic variables. These protective effects of calpain disruption in endothelial cells were associated with an increase in myocardial capillary density (wild-type vs Capns1-KO 3646.14 ± 423.51 vs 4708.7 ± 417.93 capillary number/high-power field in prediabetes, 2999.36 ± 854.77 vs 4579.22 ± 672.56 capillary number/high-power field in type 2 diabetes and 2364.87 ± 249.57 vs 3014.63 ± 215.46 capillary number/high-power field in type 1 diabetes) and coronary flow reserve. Ex vivo analysis of neovascularisation revealed more endothelial cell sprouts from aortic rings of prediabetic and diabetic Capns1-KO mice compared with their wild-type littermates. In cultured cardiac microvascular endothelial cells, inhibition of calpain improved angiogenesis and prevented apoptosis under metabolic stress. Mechanistically, deletion of Capns1 elevated the protein levels of ß-catenin in endothelial cells of Capns1-KO mice and constitutive activity of calpain 2 suppressed ß-catenin protein expression in cultured endothelial cells. Upregulation of ß-catenin promoted angiogenesis and inhibited apoptosis whereas knockdown of ß-catenin offset the protective effects of calpain inhibition in endothelial cells under metabolic stress. CONCLUSIONS/INTERPRETATION: These results delineate a primary role of calpain in inducing cardiac endothelial cell injury and impairing neovascularisation via suppression of ß-catenin, thereby promoting diabetic cardiomyopathy, and indicate that calpain is a promising therapeutic target to prevent diabetic cardiac complications.

Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.

Panax Notoginseng Saponins Attenuate Myocardial Ischemia-Reperfusion Injury Through the HIF-1α/BNIP3 Pathway of Autophagy.

BACKGROUND AND OBJECTIVE: Panax Notoginseng Saponins (PNS) is a formula of Chinese medicine commonly used for treating ischemia myocardial in China. However, its mechanism of action is yet unclear. This study investigated the effect and the mechanism of PNS on myocardial ischemia-reperfusion injury (MIRI) through the hypoxia-inducible factor 1α (HIF-1α)/bcl-2/adenovirus E1B19kDa-interacting protein3 (BNIP3) pathway of autophagy. METHODS: We constructed a rat model of myocardial injury and compared among 4 groups (n = 10, each): the sham-operated group (Sham), the ischemia-reperfusion group (IR), the PNS low-dose group, and the PNS high-dose group were pretreated with PNS (30 and 60 mg/kg, respectively). Serum creatine kinase, malonaldehyde (MDA), lactate dehydrogenase, myocardial tissue superoxide dismutase, and reactive oxygen species were detected in rats with myocardial ischemia-reperfusion after the intervention of PNS. The rat myocardial tissue was examined using hematoxylin and eosin (H&E) staining, and the mitochondria of myocardial cells were observed using transmission electron microscopy. The expressions of microtubule-associated protein light chain 3 (LC3), HIF-1α, BNIP3, Beclin-1, and autophagy-related gene-5 (Atg5) in rat myocardial tissue were detected using Western blotting. RESULTS: The results showed that PNS was significantly protected against MIRI, as evidenced by the decreasing in the concentration of serum CK, MDA, lactate dehydrogenase, and myocardial tissue superoxide dismutase, reactive oxygen species, the attenuation of myocardial tissue histopathological changes and the mitochondrial damages of myocardial cells, and the increase of mitochondria autophagosome in myocardial cells. In addition, PNS significantly increased the expression of LC3 and the ratio of LC3II/LC3I in rat myocardial tissue. Moreover, PNS significantly increased the expression of HIF-1α, BNIP3, Atg5, and Beclin-1 in rat myocardial tissue. CONCLUSIONS: The protective effect of PNS on MIRI was mainly due to its ability to enhance the mitochondrial autophagy of myocardial tissue through the HIF-1α/BNIP3 pathway.

NOTCH3 inhibits transcription factor ZEB1 expression and metastasis of breast cancer cells via transcriptionally upregulating miR-223.

Background: NOTCH receptor 3 (NOTCH3) and zinc finger E-box binding protein 1 (ZEB1) play important roles in breast cancer respectively. NOTCH3 maintains the luminal phenotype and inhibits epithelial-mesenchymal transition (EMT) in breast cancer, while ZEB1 and NOTCH3 have the opposite effects. Methods: Public databases were used to predict the expression of NOTCH3 and ZEB1 in breast cancer cell lines. The regulatory effect of NOTCH3 on ZEB1 expression was verified by western blot and RT-PCR. MiRNAs regulating ZEB1 expression were identified by using multiple databases and confirmed by reporter gene experiments. Cellular function experiments were conducted to evaluate the role of NOTCH3/miR-223/ZEB1 in the proliferation and invasion of triple-negative breast cancer (TNBC). Results: NOTCH3 and ZEB1 have opposite expression pattern in MCF-7 cells that over-express LncATB or were incubated in TGF-ß to induce EMT. Western blotting and RT-PCR showed that NOTCH3 could regulate expression of ZEB1. MiR-223 inhibited the proliferation and invasion of breast cancer cells via down-regulating the expression of ZEB1. NOTCH3 inhibited the proliferation and invasion of breast cancer cells via up-regulating the expression of miR-223. Clinically, high expression of NOTCH3, miR-223 or low expression of ZEB1 were related to good prognosis of breast cancer patients. Conclusion: The current study reports a novel NOTCH3/miR-223/ZEB1 axis, which can inhibit the proliferation and invasion of breast cancer cells, and may serve as a potential biomarker for the prognosis of breast cancer.

Current and Emerging Therapies for Atopic Dermatitis in the Elderly.

Atopic dermatitis (AD) in the elderly has recently emerged as a distinct subgroup of AD, garnering widespread concern due to its increasing global incidence rate. Epidermal barrier dysfunction, inflammatory response, and chronic pruritus interact with each other, contributing to the pathogenesis and pathophysiology of AD in the elderly. Although fundamental medications are essential for managing AD in the elderly, older adults often struggle with regular usage of moisturizing emollients, topical medications, and avoidance of environmental triggers, leading to recurrent or even exacerbated disease progression. Therefore, a systematic medication approach is necessary to control pruritus and skin lesions. Traditional systemic treatments may not adequately meet the treatment needs of moderate and severe AD in the elderly and may even pose certain safety risks. Biologics and Janus kinase (JAK) inhibitors, exhibiting excellent clinical efficacy, have made significant breakthroughs in AD treatment. Existing evidence suggests that dupilumab, a human monoclonal IgG4 antibody, has been confirmed as an effective and safe first-line systematic treatment for moderate to severe AD in the elderly, with no notable differences between adults and the elderly. However, the limited inclusion of elderly patients in related clinical studies hinders the generalizability of these findings. As older patients face a higher risk of adverse events with JAK inhibitors, JAK inhibitors are recommended when no other suitable treatment options are available. Obtaining population-specific data is crucial for making evidence-based treatment choices when managing AD in older adults with JAK inhibitors.

Evaluation of partial salt-replacement with konjac glucomannan on chicken batters: Edible quality and physicochemical properties of heat-set gel.

The edible quality and gel properties of chicken batter influenced by partial salt-replacement with konjac glucomannan (KGM) (CSK group) were studied. CSK group had higher water/fat retention capacity, but similar gel strength and color distribution compared with normal salt addition. The gels with low salt level manifested decreased hardness and loose structure due to the weak interaction of salt-soluble proteins. CSK promoted the formation of uniform composite gel network by modifying moisture loss channels with the KGM-moisture phase. The relaxation properties illustrated salt provided KGM possibility for the conversion of free water to immobilized water. Additionally, the results of chemical interactions and sulfydryl content reflected KGM alleviated protein denaturation and the interaction of KGM-water was more dominant. Compared with the batters only added with KGM, the relatively low heat-denatured temperature and storage modulus indicated appropriate salt supplement reduced the excessively high viscosity of KGM and accelerated the gel formation.

Drug-related problems in hospitalised Parkinson's disease patients in China.

BACKGROUND: There has been a lack of studies on the types and severity of drug-related problems (DRPs) in hospitalised patients with Parkinson's disease (PD) in China until now. OBJECTIVE: To investigate the types and causes of DRPs, and to assess the severity of these DRPs in PD patients in neurology wards. METHODS: A retrospective study involving 209 PD inpatients was conducted at a tertiary hospital in China from January 2017 to December 2018. The identification and assessment of DRPs were based on the Pharmaceutical Care Network Europe (PCNE) tool version 8.03. The severity ratings of these DRPs was assessed based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) classification. RESULTS: A total of 274 DRPs with an average of 1.31±1.00 problems per patient were identified, in which 83.3% of the population had at least one DRP. Using the PCNE classification system, the most common domain of DRPs was "Other, P3" (62.8%), followed by "Treatment effectiveness, P1" (19.3%) and "Treatment safety, P2" (17.9%). A total of 88.7% of the DRPs were rated at severity categories B to D (causing no or potential harm), whereas 11.3% were rated as categories E to H (causing actual harm). CONCLUSIONS: These data indicate that the prevalence of DRPs is high among PD patients. The identification of different subtypes of DRPs may facilitate risk reduction for PD patients.

Predictive Value of Serum Cholic Acid and Lithocholic Acid for the Diagnosis in an Intrahepatic Cholestasis of Pregnancy Population with High Levels of Total Bile Acids and the Correlation with Placental Hypoxia-Inducible Factor-1α.

Objective: This study aimed to investigate the ability of serum cholic acid (CA) and lithocholic acid (LCA) in the diagnosis and perinatal prognosis assessment of intrahepatic cholestasis of pregnancy (ICP), and the relationship between both indicators and hypoxia-inducible factor-1α (HIF-1α). Methods: Between March 2020 and March 2021, pregnant women with high levels of total bile acid (TBA) in the late pregnancy with TBA ≥10 µmol/L and TBA <10 µmol/L (control group) were included for the retrospective study. Those with TBA ≥10 µmol/L were divided into the ICP group and the asymptomatic hypercholanaemia of pregnancy (AHP) group based on ICP symptoms. The comparison of the bile acid profiles, the receiver operating characteristic (ROC) curve analysis, and Pearson correlation analysis were conducted successively. Results: Nine types of bile acids were significantly higher in ICP and AHP than in the control group, while CA and LCA serum levels in the AHP group were significantly lower than those in the ICP group (P < 0.05). The ROC curve analysis showed that LCA, CA, and LCA+CA were all diagnostic indicators for ICP, and LCA+CA displayed the greatest diagnostic value (area under the curve (AUC), 0.923). Subgroup analysis using the LCA+CA cut-off point (3.28 µmol/L) as the subgroup indicator proved that the incidence of adverse perinatal outcomes and the placental HIF-1α positivity were significantly higher in the high LCA+CA group than in the low LCA+CA group (P < 0.05). Pearson correlation analysis revealed significant positive correlations of HIF-1α expression levels to LCA, CA and LCA+CA (r = 0.473, 0.537, 0.619, respectively. P < 0.05 in all). Conclusion: This study confirmed that CA and LCA have a predictive diagnostic value for ICP in pregnant women, and the combined evaluation is associated with adverse perinatal outcomes, and LCA+CA positively correlates to placental HIF-1α expression levels.

The Roles of Consonant, Rime, and Tone in Mandarin Spoken Word Recognition: An Eye-Tracking Study.

This study investigated the relative role of sub-syllabic components (initial consonant, rime, and tone) in spoken word recognition of Mandarin Chinese using an eye-tracking experiment with a visual world paradigm. Native Mandarin speakers (all born and grew up in Beijing) were presented with four pictures and an auditory stimulus. They were required to click the picture according to the sound stimulus they heard, and their eye movements were tracked during this process. For a target word (e.g., tang2 "candy"), nine conditions of competitors were constructed in terms of the amount of their phonological overlap with the target: consonant competitor (e.g., ti1 "ladder"), rime competitor (e.g., lang4 "wave"), tone competitor (e.g., niu2 "cow"), consonant plus rime competitor (e.g., tang1"soup"), consonant plus tone competitor (e.g., tou2 "head"), rime plus tone competitor (e.g., yang2 "sheep"), cohort competitor (e.g., ta3 "tower"), cohort plus tone competitor (e.g., tao2 "peach"), and baseline competitor (e.g., xue3 "snow"). A growth curve analysis was conducted with the fixation to competitors, targets, and distractors, and the results showed that (1) competitors with consonant or rime overlap can be adequately activated, while tone overlap plays a weaker role since additional tonal information can strengthen the competitive effect only when it was added to a candidate that already bears much phonological similarity with the target. (2) Mandarin words are processed in an incremental way in the time course of word recognition since different partially overlapping competitors could be activated immediately; (3) like the pattern found in English, both cohort and rime competitors were activated to compete for lexical activation, but these two competitors were not temporally distinctive and mainly differed in the size of their competitive effects. Generally, the gradation of activation based on the phonological similarity between target and candidates found in this study was in line with the continuous mapping models and may reflect a strategy of native speakers shaped by the informative characteristics of the interaction among different sub-syllabic components.

Impact mechanisms of supercritical CO2-ethanol-water on extraction behavior and chemical structure of eucalyptus lignin.

A compounded medium of supercritical CO2, ethanol, and water (SEW) was used to extract lignin from eucalyptus fiber and the mechanism of the extraction was studied. Compared with the extraction method based on high-temperature ethanol (HTE), the lignin yield of the SEW method was 49.7% higher with higher average molecular weight. Physical and chemical synergies occurred during the extraction process. SEW compound medium penetrated eucalyptus fiber cell walls because of strong permeability, while the fast discharge of the compounded medium facilitated efficient lignin dissociation and removal. Carbonic acid formed from CO2 and water under high temperature and pressure can provide an acidic environment to effectively degrade hemicellulose. Formaldehyde formed from CO2 and ethanol in the process also prevented condensation of the extracted lignin fragments. The obtained lignin had high content of ß-O-4 linkages and syringyl units.

Synthesis of a bioadsorbent from jute cellulose, and application for aqueous Cd (II) removal.

A low-cost, high-adsorption-capacity, eco-friendly bioadsorbent for removing Cd2+ from aqueous solution is reported. J-g-P(AM-co-AANa) was prepared by hydrolysis of the grafted copolymer, which was synthesized by free radical polymerization of acrylamide (AM) with jute fibers (JSE) pretreated by continuous screw-extrusion steam explosion. Fourier transform infrared and solid-state 13C nuclear magnetic resonance spectroscopies, confirmed that amino and carboxylate groups were introduced into J-g-P(AM-co-AANa). X-ray diffraction showed that the crystallinity of J-g-P(AM-co-AANa) was significantly lower than that of JSE. The surface morphology of bioadsorbent was investigated by scanning electron microscopy (SEM). The adsorption capacity of Cd2+ on J-g-P(AM-co-AANa) was evaluated for different solution pH values, contact times, and initial Cd2+ concentrations. The adsorption kinetics followed the pseudo-second-order kinetic model, and the rate controlling step was chemisorption. The adsorption isotherm was well fitted by the Freundlich model, and the adsorption process was multilayer adsorption. The maximum adsorption capacity was 344.8 mg/g, which indicated that the bioadsorbent was effective for removing Cd2+ from aqueous solution.