Surface engineering of pure magnesium in medical implant applications.

This review comprehensively surveys the latest advancements in surface modification of pure magnesium (Mg) in recent years, with a focus on various cost-effective procedures, comparative analyses, and assessments of outcomes, addressing the merits and drawbacks of pure Mg and its alloys. Diverse economically feasible methods for surface modification, such as hydrothermal processes and ultrasonic micro-arc oxidation (UMAO), are discussed, emphasizing their exceptional performance in enhancing surface properties. The attention is directed towards the biocompatibility and corrosion resistance of pure Mg, underscoring the remarkable efficacy of techniques such as Ca-deficientca-deficient hydroxyapatite (CDHA)/MgF2 bi-layer coating and UMAO coating in electrochemical processes. These methods open up novel avenues for the application of pure Mg in medical implants. Emphasis is placed on the significance of adhering to the principles of reinforcing the foundation and addressing the source. The advocacy is for a judicious approach to corrosion protection on high-purity Mg surfaces, aiming to optimize the overall mechanical performance. Lastly, a call is made for future in-depth investigations into areas such as composite coatings and the biodegradation mechanisms of pure Mg surfaces, aiming to propel the field towards more sustainable and innovative developments.

IDH1 mutation produces R-2-hydroxyglutarate (R-2HG) and induces mir-182-5p expression to regulate cell cycle and tumor formation in glioma.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood. RESULTS: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models. CONCLUSIONS: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.

One-step regeneration and upgrading of spent LiFePO4 cathodes with phytic acid.

The regeneration and upgrading of spent LiFePO4 cathodes (S-LFP) were achieved via a one-step hydrothermal treatment. The reducing effect of phytic acid could restore the degraded structure associated with an aqueous Li source. Meanwhile, Li ions are easily chelated by phytic acid groups, and a Li3PO4 coating layer could be formed to reconstruct the surface of the LFP. The regenerated LFP exhibits faster reaction kinetics, larger high-rate charge/discharge capacity, and better cycling performance than commercial LFPs, suggesting that our proposed strategy is a promising technology for the recovery of spent cathode materials.

Coupling the recovery of spent lithium-ion batteries and the treatment of phenol wastewater: A "treating waste with waste" strategy.

The recovery of spent lithium-ion batteries and the treatment of phenol wastewater are both environmental and social issues. In this study, the enhanced recovery of spent lithium-ion batteries and the efficient treatment of phenol wastewater are smartly coupled via a "treating waste with waste" strategy. Under optimal conditions, the leaching process involving phenol achieves 98% and 96% efficiency for Co and Li, respectively. After precipitation, Co and Li could be recovered as Co(OH)2 and Li2CO3, and the precipitated Co(OH)2 was further calcined to generate Co3O4. Furthermore, the organic contaminants that remained in the waste-leaching solution could be removed by a spent graphite-activating peroxymonosulfate (PMS) process. It is noteworthy that the total organic carbon (TOC) in the waste-leaching solution could be removed using fewer PMS compared with the original phenol wastewater owing to the pre-oxidation of phenol during the leaching process, further confirming the advantage of this "treating waste with waste" strategy.

The Cdk5 inhibitor ß-butyrolactone impairs reconsolidation of heroin-associated memory in the rat basolateral amygdala.

The persistence of maladaptive heroin-associated memory, which is triggered by drug-related stimuli that remind the individual of the drug's pleasurable and rewarding effects, can impede abstinence efforts. Cyclin-dependent kinase 5 (Cdk5), a neuronal serine/threonine protein kinase that plays a role in multiple neuronal functions, has been demonstrated to be involved in drug addiction and learning and memory. Here, we aimed to investigate the role of cdk5 activity in the basolateral amygdala (BLA) in relapse to heroin seeking, using a self-administration rat model. Male rats underwent 10 days of heroin self-administration training, during which an active nose poke resulted in an intravenous infusion of heroin that was accompanied by a cue. The rats then underwent nose poke extinction for 10 days, followed by subsequent tests of heroin-seeking behaviour. We found that intra-BLA infusion of ß-butyrolactone (100 ng/side), a Cdk5 inhibitor, administered 5 min after reactivation, led to a subsequent decrease in heroin-seeking behaviour. Further experiments demonstrated that the effects of ß-butyrolactone are dependent on reactivated memories, temporal-specific and long-lasting on relapse of heroin-associated memory. Results provide suggestive evidence that the activity of Cdk5 in BLA is critical for heroin-associated memory and that the specific inhibitor, ß-butyrolactone, may hold potential as a substance for the treatment of heroin abuse.

Recycling Valuable Metals from Spent Lithium-Ion Batteries Using Carbothermal Shock Method.

Pyrometallurgy technique is usually applied as a pretreatment to enhance the leaching efficiencies in the hydrometallurgy process for recovering valuable metals from spent lithium-ion batteries. However, traditional pyrometallurgy processes are energy and time consuming. Here, we report a carbothermal shock (CTS) method for reducing LiNi0.3 Co0.2 Mn0.5 O2 (NCM325) cathode materials with uniform temperature distribution, high heating and cooling rates, high temperatures, and ultrafast reaction times. Li can be selectively leached through water leaching after CTS process with an efficiency of >90 %. Ni, Co, and Mn are recovered by dilute acid leaching with efficiencies >98 %. The CTS reduction strategy is feasible for various spent cathode materials, including NCM111, NCM523, NCM622, NCM811, LiCoO2 , and LiMn2 O4 . The CTS process, with its low energy consumption and potential scale application, provides an efficient and environmentally friendly way for recovering spent lithium-ion batteries.

The miR-27a-3p/FTO axis modifies hypoxia-induced malignant behaviors of glioma cells.

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system (CNS) tumors. N6-methyladenine (m6A) RNA modification is a main type of RNA modification in eukaryotic cells. In this study, we find that the m6A RNA methylation eraser FTO is dramatically downregulated in glioma samples and cell lines, particularly in intermediate and core regions and hypoxia-challenged glioma cells. In vitro, FTO overexpression inhibits the hypoxia-induced capacities of glioma cells to proliferate, migrate and invade, and decreases the percentage of cells with m6A RNA methylation. In vivo, FTO overexpression inhibits tumor growth in the xenograft model and decreases the protein levels of migration markers, including Vimentin and Twist. miR-27a-3p is upregulated within glioma intermediate and core regions and hypoxia-challenged glioma cells. miR-27a-3p inhibits the expression of FTO via direct binding to FTO. miR-27a-3p overexpression promotes hypoxia-challenged glioma cell aggressiveness, whereas FTO overexpression partially diminishes the oncogenic effects of miR-27a-3p overexpression. FTO overexpression promotes the nuclear translocation of FOXO3a and upregulates the expression levels of the FOXO3a downstream targets BIM, BNIP3, BCL-6, and PUMA, possibly by interacting with FOXO3a. Conclusively, FTO serves as a tumor suppressor in glioma by suppressing hypoxia-induced malignant behaviors of glioma cells, possibly by promoting the nuclear translocation of FOXO3a and upregulating FOXO3a downstream targets. miR-27a-3p is a major contributor to FTO downregulation in glioma under hypoxia.

Mechanisms for hypoxia-induced long non-coding small nucleolar RNA host gene 14 in promoting temozolomide resistance of glioma. / ä½Žæ°§è¯±å¯¼é•¿é“¾éžç¼–ç æ ¸å† å°RNAå®¿ä¸»åŸºå› 14促进胶质瘤替莫唑胺耐药的机制.

OBJECTIVES: This study aims to investigate the role of hypoxia-induced long non-coding small nucleolar RNA host gene 14 (lncRNA SNHG14) in glioma temozolomide (TMZ) resistance and underlying mechanisms. METHODS: According to different treatments, the experiment was divided into a normoxia group and a hypoxia group, a control group and a TMZ group. The lncRNA SNHG14 and O6-methylguanine DNA methyltransferase (MGMT) levels in glioma SNB19 and U251 cell line were detected by real-time PCR and Western blotting, respectively, and the association of lncRNA SNHG14 level with hypoxia and TMZ treatment was analyzed. siRNA was used to knockdown the lncRNA SNHG14 expression in glioma cells, and the transfected glioma cells were divided into a negative control group (si-NC group) and a si-SNHG14 group. The interference efficiency was examined by real-time PCR, the key factor MGMT of lncRNA SNHG14 sensitivity regulation was detected by Western blotting, and the cell apoptosis was detected by cytometry. In addition, MTT method was used to detect the cell viability of gliomas in the different groups under the different TMZ concentrations, and the effect of lncRNA SNHG14 on TMZ sensitivity of gliomas was analyzed. Online tools were used to predict miRNAs that could specifically bind to lncRNAs SNHG14 and MGMT. A si-NC group, a si-SNHG14 group, a normoxia group and a hypoxia group were set up, and the changes of miR-143 abundance in different environments were observed by real-time PCR. miR-143 mimics and inhibitor were used to change the level of miR-143 in glioma cells. A NC inhibitor group, a miR-143 inhibitor group, a NC mimics group and a miR-143 mimics group were set up, the interference efficiency was detected by real-time PCR, the expression level of MGMT was detected by Western blotting, and the effect of miR-143 on the level of MGMT were analyzed. The NC inhibitor group, the miR-143 inhibitor group, the NC mimics group and the miR-143 mimics group were treated with different interventions, and the dual luciferase reporter assay was used to observe the changes of lncRNA SNHG14 and MGMT luciferase activities, and to verify the relationship among lncRNA SNHG14, miR-143 and MGMT. Finally, a NC group and a lncRNA SNHG14 overexpression group were set up, and the changes in the abundance of miR-143 and MGMT in each group were detected by RNA-binding protein immunoprecipitation experiments, and the competitive binding relationship among lncRNA SNHG14, miR-143 and MGMT was analyzed. RESULTS: Compared with the normoxia group, the hypoxia group could promote the expression of lncRNA SNHG14 in glioma cells. Compared with the control group, the expression of lncRNA SNHG14 could be significantly inhibited in the TMZ group (P<0.05). Compared with the si-NC group, the expression of lncRNA SNHG14 in the si-SNHG14 group could be effectively inhibited, and the expression level of MGMT was significantly decreased, and the apoptosis rate was significantly increased (all P<0.05). With the increase of TMZ concentrations, the glioma cell viability in the si-SNHG14 group was significantly lower than that in the si-NC group, and the cell viability in the hypoxia group was significantly higher than that in the normoxia group (both P<0.05). Online tool prediction found that miR-143 had binding sites with lncRNA SNHG14 and MGMT. The abundance of miR-143 in the hypoxia group was significantly lower than that in the normoxic group, and the abundance of miR-143 in the si-SNHG14 group was significantly higher than that in the si-NC group (both P<0.05). The miR-143 mimics group or the miR-143 inhibitor group could significantly over-express or under-express miR-143 (both P<0.05). But there was no significant difference between the NC mimics group (or the NC inhibitor group) and the control group (both P>0.05). The level of MGMT protein could significantly up-regulate in the miR-143 inhibitor group, and on the contrary which could significantly down-regulate in the miR-143 mimics group (both P<0.01). The dual luciferase reporter assay showed that there was no significant difference between the NC mimics group (or the NC inhibitor group) and the control group (both P>0.05). The wild-type SNHG14 and MGMT luciferase activities were significantly down-regulated in the miR-143 mimics group, which were significantly up-regulated in the miR-143 inhibitor group (P<0.01 and P<0.05, respectively), but there was no significant change in the luciferase activities of mutant SNHG14 and MGMT (both P>0.05). The results of the RNA-binding protein immunoprecipitation experiment showed that: compared with the NC group, more lncRNA SNHG14 was bound to the precipitated argonaute 2 protein in the cells in the lncRNA SNHG14 overexpression group, but the abundance of MGMT mRNA was decreased significantly, and there were significant differences (both P<0.01). There was a targeting regulatory relationship among lncRNA SNHG14, miR-143 and MGMT. CONCLUSIONS: The up-regulated lncRNA SNHG14 can target miR-143, relieve the inhibition of miR-143 on MGMT, and promote the TMZ resistance in the hypoxia-induced glioma cells.

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling.

RATIONALE: Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated. OBJECTIVE: To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. METHODS AND RESULTS: Mouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1-GRP75-VDAC1 (inositol 1,4,5-trisphosphate receptor 1-glucose-regulated protein 75-voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. CONCLUSIONS: The IP3R1-GRP75-VDAC1 complex mediates ER stress-mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR-133a.

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

Dynamic Changes of Serum Heart Type-Fatty Acid Binding Protein in Cancer Patients Treated With Immune Checkpoint Inhibitors.

Objective: Immune checkpoint inhibitors (ICIs) are effective anti-cancer drugs that can improve survival in cancer patients, but their use may be associated with adverse cardiovascular side effects. Therefore, there is a clinical unmet need to identify non-invasive biomarker to detect subclinical cardiac toxicity after ICI treatment. The aim of this study is to examine the plasma levels of biomarkers in cancer survivors who were treated with ICIs. Patients and Methods: In a cohort of 19 cancer patients, biomarkers were evaluated at baseline, 1 month, 3 and 6 months after ICI administration. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included cardiac troponin I (cTnI), high-sensitivity C-reactive protein (Hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), CK (creatine kinase), CK-MB (creatine kinase-MB), Pentraxin-related protein 3 (PTX3), growth differentiation factor 15 (GDF-15), heart type-fatty acid binding protein (H-FABP) and galectin 3 (Gal-3). Results: H-FABP, but not other biomarkers, were increased at 3 months, which persisted at 6 months (529.28 ± 312.83 vs. 752.33 ± 283.65 vs. 808.00 ± 289.69 pg/ml, p = 0.031 and p = 0.013). Left ventricular ejection fraction (63.00 ± 4.15% vs. 63.74 ± 4.07%, p > 0.05) was not significantly reduced at this time point. Conclusions: H-FABP, but not other biomarkers, were increased in patients who were treated using ICIs. H-FABP might be a more sensitive biomarker to detect ICI-related subclinical myocardial damage than traditional cardiac biomarkers.

Soluble suppression of tumorigenicity 2 (sST2) for predicting disease severity or mortality outcomes in cardiovascular diseases: A systematic review and meta-analysis.

OBJECTIVES: Soluble suppression of tumorigenicity 2 (sST2) is a member of the interleukin-1 receptor family. It is raised in various cardiovascular diseases, but its value in predicting disease severity or mortality outcomes has been controversial. Therefore, we conducted a systematic review and meta-analysis to determine whether sST2 levels differed between survivors and non-survivors of patients with cardiovascular diseases, and whether elevated sST2 levels correlated with adverse outcomes. METHODS: PubMed and Embase were searched until 23rd June 2021 for studies that evaluated the relationship between sST2 levels and cardiovascular disease severity or mortality. RESULTS: A total of 707 entries were retrieved from both databases, of which 14 studies were included in the final meta-analysis. In acute heart failure, sST2 levels did not differ between survivors and non-survivors (mean difference [MD]: 24.2 ± 13.0 ng/ml; P = 0.06; I 2: 95%). Elevated sST2 levels tend to be associated with increased mortality risk (hazard ratio [HR]: 1.12, 95 %CI: 0.99-1.27, P = 0.07; I 2: 88%). In chronic heart failure, sST2 levels were higher in non-survivors than in survivors (MD: 0.19 ± 0.04 ng/ml; P = 0.001; I 2: 0%) and elevated levels were associated with increased mortality risk (HR: 1.64, 95% CI: 1.27-2.12, P < 0.001; I 2: 82%). sST2 levels were significantly higher in severe disease compared to less severe disease (MD: 1.56 ± 0.46 ng/ml; P = 0.001; I 2: 98%). Finally, in stable coronary artery disease, sST2 levels were higher in non-survivors than survivors (MD: 3.0 ± 1.1 ng/ml; P = 0.005; I 2: 80%) and elevated levels were significantly associated with increased mortality risk (HR: 1.32, 95% CI: 1.04-1.68, P < 0.05; I 2: 57%). CONCLUSIONS: sST2 significantly predicts disease severity and mortality in cardiovascular disease and is a good predictor of mortality in patients with stable coronary artery disease and chronic heart failure.

Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis.

Background: Atrial fibrillation (AF) is associated with calcium (Ca2+) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism remains unclear, resulting in suboptimal primary and secondary preventative strategies. Methods: We searched the PubMed database for studies that investigated the relationship between SCaEs and AF and/or its risk factors. Meta-analysis was used to examine the Ca2+ mechanisms involved in the primary and secondary AF preventative groups. Results: We included a total of 74 studies, out of the identified 446 publications from inception (1982) until March 31, 2020. Forty-five were primary and 29 were secondary prevention studies for AF. The main Ca2+ release events, calcium transient (standardized mean difference (SMD) = 0.49; I 2 = 35%; confidence interval (CI) = 0.33-0.66; p < 0.0001), and spark amplitude (SMD = 0.48; I 2 = 0%; CI = -0.98-1.93; p = 0.054) were enhanced in the primary diseased group, while calcium transient frequency was increased in the secondary group. Calcium spark frequency was elevated in both the primary diseased and secondary AF groups. One of the key cardiac currents, the L-type calcium current (ICaL) was significantly downregulated in primary diseased (SMD = -1.07; I 2 = 88%; CI = -1.94 to -0.20; p < 0.0001) and secondary AF groups (SMD = -1.28; I 2 = 91%; CI = -2.04 to -0.52; p < 0.0001). Furthermore, the sodium-calcium exchanger (INCX) and NCX1 protein expression were significantly enhanced in the primary diseased group, while only NCX1 protein expression was shown to increase in the secondary AF studies. The phosphorylation of the ryanodine receptor at S2808 (pRyR-S2808) was significantly elevated in both the primary and secondary groups. It was increased in the primary diseased and proarrhythmic subgroups (SMD = 0.95; I 2 = 64%; CI = 0.12-1.79; p = 0.074) and secondary AF group (SMD = 0.66; I 2 = 63%; CI = 0.01-1.31; p < 0.0001). Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) expression was elevated in the primary diseased and proarrhythmic drug subgroups but substantially reduced in the secondary paroxysmal AF subgroup. Conclusions: Our study identified that ICaL is reduced in both the primary and secondary diseased groups. Furthermore, pRyR-S2808 and NCX1 protein expression are enhanced. The remodeling leads to elevated Ca2+ functional activities, such as increased frequencies or amplitude of Ca2+ spark and Ca2+ transient. The main difference identified between the primary and secondary diseased groups is SERCA expression, which is elevated in the primary diseased group and substantially reduced in the secondary paroxysmal AF subgroup. We believe our study will add new evidence to AF mechanisms and treatment targets.

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway.

Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes. Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-ß1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress. Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-ß1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-ß1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells. Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.

Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression.

The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenic factor in cardiovascular diseases. The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. A total of 30 rats were randomly divided into control, ER stress inducer (tunicamycin[TN]) and ER stress inhibitor (tunicamycin+4-phenylbutyric acid [4-PBA]) groups. ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), left ventricular peaksystolic pressure(LVSP) and LV end-diastolic pressure(LVEDP). Epicardial mapping performed in vivo revealed reduced conduction velocity and increased conduction heterogeneity associated with the development of spontaneous ventricular tachycardia. Masson's trichrome staining revealed marked fibrosis in the myocardial interstitial and sub-pericardial regions, and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor transforming growth factor-ß1 (TGF-ß1), decreased mitochondrial biogenesis protein peroxlsome proliferator-activated receptor-γ coactlvator-1α （PGC-1a）, and decreased mitochondrial fusion protein mitofusin-2 (MFN2). These changes were associated with mitochondria dysfunction and connexin 43(CX43)translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodelling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA.

The use of minimal fluoroscopy for cardiac electrophysiology procedures: A meta-analysis and review of the literature.

BACKGROUND: Conventional catheter ablation involves prolonged exposure to ionizing radiation, potentially leading to detrimental health effects. Minimal fluoroscopy (MF) represents a safer alternative, which should be explored. Data on the safety and efficacy of this technique are limited. HYPOTHESIS: Our hypothesis is that MF is of equal efficacy and safety to conventional catheter ablation with the use of fluoroscopy by performing a meta-analysis of both randomized controlled trials (RCTs) and real-world registry studies. METHODS: Pubmed and Embase were searched from their inception to July 2020 for RCTs, cohort and observational studies that assessed the outcomes of catheter ablation using a MF technique versus the conventional approach. RESULTS: Fifteen studies involving 3795 patients were included in this meta-analysis. There was a significant reduction in fluoroscopy and procedural time with no difference in acute success (odds ratio [OR]:0.74, 95% CI: 0.50-1.10, p = .14), long-term success (OR:0.92, 95% CI: 0.65-1.31, p = .38), arrhythmia recurrence (OR:1.24, 95% CI: 0.75-2.06, p = .97) or rate of complications. (OR:0.83, 95% CI: 0.46-1.48, p = .65). Additionally sub-group analysis for those undergoing catheter ablation for atrial fibrillation (AF) did not demonstrate a difference in success or complication rates (OR:0.86, 95% CI: 0.30-2.42, p = .77). Multivariate meta-regression did not identify the presence of moderator variables. CONCLUSION: This updated meta-analysis demonstrated an overall reduction in procedural and fluoroscopy time for those undergoing a minimal fluoroscopic approach. There was no significant difference in either acute or chronic success rates or complications between a MF approach and conventional approach for the management of all arrhythmias including those undergoing catheter ablation for AF.

Research on the nonlinear dynamic relationship between FDI and CO2 emissions in the "One Belt, One Road" countries.

This study examines the relationship between FDI and CO2 emissions in a nonlinear framework using data from countries along the "One Belt, One Road" from 1979 to 2017 as the sample. First, the linear analysis method was used to examine the stability of FDI and CO2 emissions in countries along the "One Belt, One Road." In addition, the BDS (Brock-Dechert-Scheinkman test) method and nonlinear Granger causality test are used to investigate the nonlinear relationship between variables. Finally, a threshold vector autoregressive model (TVAR) is used to analyze the dynamic change mechanism between China's FDI and CO2 emissions, and a threshold vector error correction model (TVECM) is used to test how the variables respond to deviations from equilibrium. Then, the Markov switching model is used to test the robustness of the results. The research results show that China, India, South Africa, and other countries all have a nonlinear causal relationship between FDI and CO2 emissions. At the same time, the comovement of FDI and CO2 emissions in China has obvious structural break features, which are relevant for the underlying regime. Furthermore, the results also show that the adjustment process of the FDI toward equilibrium is highly persistent in the first regime, and CO2 emissions will adjust to an equilibrium state at a faster speed in the second regime. Therefore, this paper puts forward different policy suggestions for different countries. For China, we should pay attention to the long-term benefits of FDI and introduce high-tech green FDI.

Diagnostic and prognostic value of serum C-reactive protein in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Heart failure (HF) is a major epidemic with rising morbidity and mortality rates that encumber global healthcare systems. While some studies have demonstrated the value of CRP in predicting (i) the development of HFpEF and (ii) long-term clinical outcomes in HFpEF patients, others have shown no such correlation. As a result, we conducted the following systematic review and meta-analysis to assess both the diagnostic and prognostic role of CRP in HFpEF. PubMed and Embase were searched for studies that assess the relationship between CRP and HFpEF using the following search terms: (((C-reactive protein) AND ((preserved ejection fraction) OR (diastolic heart failure))). The search period was from the start of database to August 6, 2019, with no language restrictions. A total of 312 and 233 studies were obtained from PubMed and Embase respectively, from which 19 studies were included. Our meta-analysis demonstrated the value of a high CRP in predicting the development of not only new onset HFpEF (HR: 1.08; 95% CI: 1.00-1.16; P = 0.04; I2 = 22%), but also an increased risk of cardiovascular mortality when used as a categorical (HR: 2.52; 95% CI: 1.61-3.96; P < 0.0001; I2 = 19%) or a continuous variable (HR: 1.24; 95% CI: 1.04-1.47; P = 0.01; I2 = 28%), as well as all-cause mortality when used as a categorical (HR: 1.78; 95% CI: 1.53-2.06; P < 0.00001; I2 = 0%) or a continuous variable: (HR: 1.06; 95% CI: 1.02-1.06; P = 0.003; I2 = 61%) in HFpEF patients. CRP can be used as a biomarker to predict the development of HFpEF and long-term clinical outcomes in HFpEF patients, in turn justifying its use as a simple, accessible parameter to guide clinical management in this patient population. However, more prospective studies are still required to not only explore the utility and dynamicity of CRP in HFpEF but also to determine whether risk stratification algorithms incorporating CRP actually provide a material benefit in improving patient prognosis.

Takotsubo cardiomyopathy with low ventricular ejection fraction and apical ballooning predicts mortality: a systematic review and meta-analysis.

Takotsubo cardiomyopathy (TCM) is characterized by temporary wall motion abnormality of the left ventricle. There is much debate upon the prognostic parameters. We conducted a systematic review and meta-analysis to investigate whether LVEF and the presence of apical ballooning predict long-term mortality in TCM. PubMed and Embase were searched through to October 30, 2017 without language restrictions, followed by an additional search through to February 2, 2020. Our search identified 18 studies that met the inclusion criteria, with a total of 5168 patients. Reduced LVEF as a categorical variable was associated with more than threefold increase in mortality risk in TCM patients (HR 3.10; 95% CI 1.78-5.42; P < 0.0001; I2 = 57%). Further subset analyses with the exclusion of studies consisting of patients with coronary artery disease revealed another significant relationship between LVEF and mortality (HR 3.13; 95% CI 1.392-7.031; P < 0.006; I2 = 58%). LVEF as a continuous variable was also found to be associated with increased mortality risk. However, this relationship only retained significance when computing odds ratios instead of hazard ratios (OR 0.95; 95% CI 0.93-0.98; P < 0.001; I2 = 0%). Finally, the existence of apical ballooning failed to demonstrate any link with an increased risk of mortality (HR 1.26; 95% CI 0.97-1.64; P = 0.09; I2 = 34%). LVEF and apical ballooning are both potential prognostic markers for mortality.

The Value of IGF-1 and IGFBP-1 in Patients With Heart Failure With Reduced, Mid-range, and Preserved Ejection Fraction.

BACKGROUND: Previous studies have reported inconsistent results regarding the implications of deranged insulin-like growth factor 1 (IGF-1)/insulin-like growth factor-binding protein 1 (IGFBP-1) axis in patients with heart failure (HF). This study evaluates the roles of IGF1/IGFBP-1 axis in patients with HF with reduced ejection fraction (HFrEF), mid-range ejection fraction (HFmrEF), or preserved ejection fraction (HFpEF). METHODS: Consecutive patients with HFrEF, HFmrEF, and HFpEF who underwent comprehensive cardiac assessment were included. The primary endpoint was the composite endpoint of all-cause death and HF rehospitalization at one year. RESULTS: A total of 151 patients with HF (HFrEF: n = 51; HFmrEF: n = 30; HFpEF: n = 70) and 50 control subjects were included. The concentrations of IGFBP-1 (p < 0.001) and IGFBP-1/IGF-1 ratio (p < 0.001) were significantly lower in patients with HF compared to controls and can readily distinguish patients with and without HF (IGFBP-1: areas under the curve (AUC): 0.725, p < 0.001; IGFBP-1/IGF-1 ratio: AUC:0.755, p < 0.001; respectively). The concentrations of IGF-1, IGFBP-1, and IGFBP-1/IGF-1 ratio were similar among HFpEF, HFmrEF, and HFrEF patients. IGFBP-1 and IGFBP-1/IGF-1 ratio positively correlated with N-terminal probrain natriuretic peptide (NT-proBNP) levels (r = 0.255, p = 0.002; r = 0.224, p = 0.007, respectively). IGF-1, IGFBP-1, and IGFBP-1/IGF-1 ratio did not predict the primary endpoint at 1 year for the whole patients with HF and HF subtypes on both univariable and multivariable Cox regression. CONCLUSION: The concentrations of plasma IGFBP-1 and IGFBP-1/IGF-1 ratio can distinguish patients with and without HF. In HF, IGFBP-1 and IGFBP-1/IGF-1 ratio positively correlated with NT-proBNP levels.