Achieving Non-Interfacial Blocking Zinc Ion Transport Based on MOF Derived Manganese Oxides and Amorphous Carbon Hybrid Materials.

How to coordinate electron and ion transport behavior across scales and interfaces within ion battery electrodes? The exponential increase in surface area observed in nanoscale electrode materials results in an incomprehensibly vast spatial interval. Herein, to address the problems of volume expansion, dissolution of cathode material, and the charge accumulation problem existing in manganiferous materials for zinc ion batteries, metal organic framework is utilized to form the architecture of non-interfacial blocking ~10 nm Mn2O3 nanoparticles and amorphous carbon hybrid electrode materials, demonstrating a high specific capacity of 361 mAh g-1 (0.1 A g-1), and excellent cycle stability of 105 mAh g-1 after 2000 cycles under 1 A g-1. The uniform and non-separated disposition of Mn and C atoms constitutes an interconnected network with high electronic and ionic conductivity, minimizing issues like structural collapse and volume expansion of the electrode material during cycling. The cooperative insert mechanism of H+ and Zn2+ are analyzed via ex-situ XRD and in-situ Raman tests. The model battery is assembled to present practical possibilities. The results indicate that MOF-derived carbonization provides an effective strategy for exploring Mn-based electrode materials with high ion and electron transport capacity.

Effects of regional cerebral oxygen saturation monitoring on postoperative cognitive dysfunction in older patients: a systematic review and meta-analysis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is common after surgery and anesthesia, particularly in older patients. It has been reported that regional cerebral oxygen saturation (rSO2) monitoring potentially influences the occurrence of POCD. However, its role in the prevention of POCD remains controversial in older patients. Additionally, the quality of evidence on this topic is still relatively poor. METHODS: The electronic databases PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched using the indicated keywords from their inception to June 10, 2022. We limited our meta-analysis to randomized controlled trials (RCTs) that assessed the effects of rSO2 monitoring on POCD in older patients. Methodological quality and risk of bias were assessed. The primary outcome was the incidence of POCD during hospitalization. The secondary outcomes were postoperative complications and the length of hospital stay (LOS). Odds ratios (OR) and 95% confidence intervals (CI) were calculated to determine the incidence of POCD and postoperative complications. The standardized mean difference (SMD) instead of the raw mean difference and 95% CI were calculated for LOS. RESULTS: Six RCTs, involving 377 older patients, were included in this meta-analysis. The incidence of POCD ranges from 17 to 89%, with an overall prevalence of 47% in our pooled analysis. Our results demonstrated that rSO2-guided intervention could reduce the incidence of POCD in older patients undergoing non-cardiac surgery (OR, 0.44; 95% CI, 0.25 to 0.79; P = 0.006) rather than cardiac surgery (OR, 0.69; 95% CI, 0.32 to 1.52; P = 0.36). Intraoperative rSO2 monitoring was also associated with a significantly shorter LOS in older patients undergoing non-cardiac surgery (SMD, -0.93; 95% CI, -1.75 to -0.11; P = 0.03). Neither the incidence of postoperative cardiovascular (OR, 1.12; 95% CI, 0.40 to 3.17; P = 0.83) nor surgical (OR, 0.78; 95% CI, 0.35 to 1.75; P = 0.54) complications were affected by the use of rSO2 monitoring. CONCLUSION: The use of rSO2 monitoring is associated with a lower risk of POCD and a shorter LOS in older patients undergoing non-cardiac surgery. This may have the potential to prevent POCD in high-risk populations. Further large RCTs are still warranted to support these preliminary findings.

Use of sugammadex is associated with reduced incidence and severity of postoperative nausea and vomiting in adult patients with obesity undergoing laparoscopic bariatric surgery: a post-hoc analysis.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common but troublesome complication in patients who undergo laparoscopic bariatric surgery (LBS). Whether sugammadex use is related to the persistent decrease in the occurrence of PONV during postoperative inpatient hospitalization, which is critical for the rehabilitation of patients after LBS, remains unknown. METHODS: The study was based on a randomized controlled trial conducted in an accredited bariatric centre. A total of 205 patients who underwent LBS were included in the analysis. Univariate analysis and multivariable logistic regression model were used to identify the significant variables related to PONV. Then propensity score matching and inverse probability of treatment weighting (IPTW) were employed to compare outcomes between the sugammadex and neostigmine groups. The primary outcome was the incidence of PONV within 48 h after LBS. The secondary endpoints included the severity of PONV, time to first flatus, need for rescue antiemetic therapy, and water intake. RESULTS: The incidence of PONV was 43.4% (89/205) within the first 48 h after LBS. In multivariable analysis, sugammadex use (OR 0.03, 95% CI 0.01-0.09, P < 0.001) was an independent protective factor of PONV. After IPTW adjustment, sugammadex use was associated with lower incidence of PONV (OR 0.54, 95% CI 0.48-0.61, P < 0.001), postoperative nausea (PON) (OR 0.77, 95% CI 0.67-0.88, P < 0.001), and postoperative vomiting (POV) (OR 0.60, 95% CI 0.53-0.68, P < 0.001) within postoperative 48 h. The severity of PON as well as the incidence and severity of POV within the first 24 h were also lower in the sugammadex group (all P < 0.05). Reduced need for rescue antiemetic therapy within the first 24 h, increased water intake for both periods, and earlier first passage of flatus were observed in the sugammadex group (all P < 0.05). CONCLUSIONS: Compared with neostigmine, sugammadex can reduce the incidence and severity of PONV, increase postoperative water intake, and shorten the time to first flatus in bariatric patients during postoperative inpatient hospitalization, which may play a pivotal role in enhanced recovery. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052418, http://www.chictr.org.cn/showprojen.aspx?proj=134893 , date of registration: October 25, 2021).

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy.

OBJECTIVES: Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive. METHODS: Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system. RESULTS: A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM. CONCLUSIONS: The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode ß-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

Exercise and Type 1 Diabetes.

Diabetes mellitus (DM) is the most common endocrine and metabolic disease caused by absolute or insufficient insulin secretion. Under the context of an aging population worldwide, the number of diabetic patients is increasing year by year. Most patients with diabetes have multiple complications that severely threaten their survival and living quality. DM is mainly divided into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is caused by absolute lack of insulin secretion, so the current treatment for T1DM patients is exogenous insulin replacement therapy. At present, exercise therapy has been widely recognized in the prevention and treatment of diabetes, and regular aerobic exercise has become an important part of T1DM treatment. At the same time, exercise therapy is also used in conjunction with other treatments in the prevention and treatment of diabetic complications. However, for patients with T1DM, exercise still has the risk of hypoglycemia or hyperglycemia. T1DM Patients and specialist physician need to fully understand the effects of exercise on metabolism and implement individualized exercise programs. This chapter reviews the related content of exercise and T1DM.

Non-coding RNAs and Cardiac Aging.

Aging is an important risk factor for cardiovascular diseases. Aging increasing the morbidity and mortality in cardiovascular disease patients. With the society is aging rapidly in the world, medical burden of aging-related cardiovascular diseases increasing drastically. Hence, it is urgent to explore the underlying mechanism and treatment of cardiac aging. Noncoding RNAs (ncRNAs, including microRNAs, long noncoding RNAs and circular RNAs) have been reported to be involved in many pathological processes, including cell proliferation, cell death differentiation, hypertrophy and aging in wide variety of cells and tissues. In this chapter, we will summarize the physiology and molecular mechanisms of cardiac aging. Then, the recent research advances of ncRNAs in cardiac aging will be provided. The lessons learned from ncRNAs and cardiac aging studies would bring new insights into the regulatory mechanisms ncRNAs as well as treatment of aging-related cardiovascular diseases.

A New TBX5 Loss-of-Function Mutation Contributes to Congenital Heart Defect and Atrioventricular Block.

Congenital heart defect (CHD) represents the most common birth deformity, afflicting 1% of all births worldwide, and accounts for substantial morbidity and mortality. Increasing evidence highlights the pivotal roles of genetic etiologies in the pathogenesis of CHD, and pathogenic mutations in multiple genes, including TBX5 encoding a cardiac core transcription factor key to cardiovascular morphogenesis, have been involved in CHD. However, due to pronounced genetic heterogeneity of CHD, the genetic determinants underlying CHD in most cases remain obscure. In this investigation, by sequencing analysis of the coding exons and flanking introns of the TBX5 gene in 198 unrelated patients affected with CHD, a novel heterozygous mutation, NM_000192.3: c.692C>T; p. (Pro231Leu), was identified in an index patient with familial double outlet right ventricle (DORV), ventricular septal defect (VSD), and atrioventricular block (AVB). Genetic analysis of the proband's pedigree showed that the mutation co-segregated with the diseases. The missense mutation, which altered the amino acid conserved evolutionarily, was absent from 266 unrelated healthy subjects. Functional analyses with a dual-luciferase reporter assay system unveiled that the Pro231Leu-mutant TBX5 was associated with significantly reduced transcriptional activity on its target genes MYH6 and NPPA. Furthermore, the mutation disrupted the synergistic transactivation between TBX5 and NKX2-5 as well as GATA4, two other transcription factors causally linked to CHD. This study firstly links TBX5 loss-of-function mutation to familial DORV, VSD, and AVB, which provides novel insight into the mechanism underpinning CHD and AVB, suggesting potential implications for genetic evaluation and individualized treatment of patients affected by CHD and AVB.

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve.

TBX5 has been linked to Holt-Oram syndrome, with congenital heart defect (CHD) and atrial fibrillation (AF) being two major cardiac phenotypes. However, the prevalence of a TBX5 variation in patients with CHD and AF remains obscure. In this research, by sequencing analysis of TBX5 in 178 index patients with both CHD and AF, a novel heterozygous variation, NM_000192.3: c.577G>T; p.(Gly193*), was identified in one index patient with CHD and AF as well as bicuspid aortic valve (BAV), with an allele frequency of approximately 0.28%. Genetic analysis of the proband's pedigree showed that the variation co-segregated with the diseases. The pathogenic variation was not detected in 292 unrelated healthy subjects. Functional analysis by using a dual-luciferase reporter assay system showed that the Gly193*-mutant TBX5 protein failed to transcriptionally activate its target genes MYH6 and NPPA. Moreover, the mutation nullified the synergistic transactivation between TBX5 and GATA4 as well as NKX2-5. Additionally, whole-exome sequencing analysis showed no other genes contributing to the diseases. This investigation firstly links a pathogenic variant in the TBX5 gene to familial CHD and AF as well as BAV, suggesting that CHD and AF as well as BAV share a common developmental basis in a subset of patients.

Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury.

BACKGROUND: Cathelicidins are a major group of natural antimicrobial peptides which play essential roles in regulating host defense and immunity. In addition to the antimicrobial and immunomodulatory activities, recent studies have reported the involvement of cathelicidins in cardiovascular diseases by regulating inflammatory response and microvascular dysfunction. However, the role of cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown. METHODS: CRAMP (cathelicidin-related antimicrobial peptide) levels were measured in the heart and serum from I/R mice and in neonatal mouse cardiomyocytes treated with oxygen glucose deprivation/reperfusion (OGDR). Human serum cathelicidin antimicrobial peptide (LL-37) levels were measured in myocardial infarction (MI) patients. The role of CRAMP in myocardial apoptosis upon I/R injury was investigated in mice injected with the CRAMP peptide and in CRAMP knockout (KO) mice, as well as in OGDR-treated cardiomyocytes. RESULTS: We observed reduced CRAMP level in both heart and serum samples from I/R mice and in OGDR-treated cardiomyocytes, as well as reduced LL-37 level in MI patients. Knockdown of CRAMP enhanced cardiomyocyte apoptosis, and CRAMP KO mice displayed increased infarct size and myocardial apoptosis. In contrast, the CRAMP peptide reduced cardiomyocyte apoptosis and I/R injury. The CRAMP peptide inhibited cardiomyocyte apoptosis by activation of Akt and ERK1/2 and phosphorylation and nuclear export of FoxO3a. c-Jun was identified as a negative regulator of the CRAMP gene. Moreover, lower level of serum LL-37/neutrophil ratio was associated with readmission and/or death in MI patients during 1-year follow-up. CONCLUSIONS: CRAMP protects against cardiomyocyte apoptosis and cardiac I/R injury via activation of Akt and ERK and phosphorylation and nuclear export of FoxO3a. Increasing LL-37 might be a novel therapy for cardiac ischemic injury.

Validation and application of a novel LC/MS/MS method for the determination of isoginkgetin in rat plasma.

Isoginkgetin is a biflavonoid compound isolated from the leaf extracts of Ginkgo biloba. In this study, an liquid chromatography-tandem mass spectrometry (LC/MS/MS) with liquid-liquid extraction was developed and validated for the analysis of isoginkgetin in rat plasma. In the process of chromatographic separation, selected reaction monitoring transitions for isoginkgetin and IS were m/z 566.8 → 134.7 and m/z 430.8 → 269.3, respectively. The validation parameters including selectivity, linearity, LLOQ, accuracy, precision, matrix effect, stability and recovery were satisfactory. The intra- and inter-batch precision (RSD) were <12.1% in plasma, while the accuracy (RE) was within ±14.3%. This method was employed in a pharmacokinetic study on rats after the intravenous administration of isoginkgetin.

A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle.

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225C>G; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.

Preparation and Characterization of Zn1-xNixO Nanoparticles: Application as a SERS Substrate.

In this paper, the study of the Zn1-xNixO (x = 0, 0.01, 0.03, 0.05) nanoparticles as SERS active substrate has been reported. The structural, morphological and optical studies are carried out by XRD, XPS, SEM, UV-vis and Raman spectroscopy. The XRD spectra indicate that the four Zn1-xNixO nanoparticles (x = 0, 0.01, 0.03, 0.05) are all single wurtzite structure. XPS study further demonstrates that Ni atoms are successfully doped into ZnO lattice. We have observed strong SERS signals when the 4-mercaptobenzoic acid used as the probe molecules. An interesting phenomenon is that an appropriate amount of the Ni atoms doping can enhance the SERS spectrum, and the maximum SERS intensity appeared when the Zn1-xNixO (x = 0.03) as the SERS active substrate, and we ascribe the SERS mechanism to the charge-transfer mechanism. The energy levels caused by the surface defects of ZnO NPs by Ni doping have influence on the charge-transfer process and have benefit for the SERS performance.

TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of congestive heart failure, sudden cardiac death and cardiac transplantation. Aggregating evidence highlights the genetic origin of DCM. However, DCM is a genetically heterogeneous disorder, and the genetic components underlying DCM in most cases remain unknown. METHODS: The coding regions and splicing junction sites of the TBX20 gene were sequenced in 120 unrelated patients with idiopathic DCM. The available close relatives of the index patient carrying an identified mutation and 300 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX20. The functional characteristics of the mutant TBX20 were assayed in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous TBX20 mutation, p.F256I, was identified in a family with DCM transmitted in an autosomal dominant fashion, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 600 control chromosomes and the altered amino acid was completely conserved evolutionarily among various species. Functional assays revealed that the mutant TBX20 had significantly diminished transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4. CONCLUSIONS: This study links TBX20 loss-of-function mutation to idiopathic DCM in humans for the first time, providing novel insight into the molecular mechanism underpinning DCM.

miR-218 Involvement in Cardiomyocyte Hypertrophy Is Likely through Targeting REST.

MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with significant risks of heart failure. However, many microRNAs are still not recognized for their functions in pathophysiological processes. In this study, we evaluated effects of miR-218 in cardiomyocyte hypertrophy using both in vitro and in vivo models. We found that miR-218 was evidently downregulated in a transverse aortic constriction (TAC) mouse model. Overexpression of miR-218 is sufficient to reduce hypertrophy, whereas the suppression of miR-218 aggravates hypertrophy in primary cardiomyocytes induced by isoprenaline (ISO). In addition, we identified RE1-silencing transcription factor (REST) as a novel target of miR-218; it negatively regulated the expression of REST in hypertrophic cardiomyocytes and the TAC model. These results showed that miR-218 plays a crucial role in cardiomyocyte hypertrophy, likely via targeting REST, suggesting a potential candidate target for interfering hypertrophy.

TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy.

The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in TBX5 have been associated with various congenital heart diseases and arrhythmias in humans. However, whether mutated TBX5 contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons and flanking introns of the TBX5 gene were sequenced in 190 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX5. The functional characteristics of the mutant TBX5 were explored in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.S154A, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across various species. Functional assays revealed that the mutant TBX5 had significantly decreased transcriptional activity. Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM. This study firstly associates TBX5 loss-of-function mutation with enhanced susceptibility to DCM, providing novel insight into the molecular mechanisms of DCM, and suggesting the potential implications in the development of new treatment strategies for this common form of myocardial disorder.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

BACKGROUND: Cardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia. METHODS: Rats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared. RESULTS: At baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P<0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P<0.05). CONCLUSIONS: Fenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Methylglyoxal accumulation contributes to accelerated brain aging in spontaneously hypertensive rats.

While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.

A novel three-dimensional porous Ag/TiO2 hybrid aerogels with high dense hot spot as effective SERS substrate for ultrasensitive detection.

This research focuses on preparing a series of new TiO2/Ag hybrid aerogels with varying TiO2 contents, and demonstrates their application as ultrasensitive SERS substrates. The synthesized TiO2/Ag hybrid aerogels exhibited excellent SERS behavior when detecting 4-Mercaptobenzoic acid (4-MBA), and the calculated SERS enhancement factor (EF) was 6.34 × 106. 3D structured aerogels can create more hot spots and adsorption sites, and multiple interband chemical transfer (CT) pathways emerged and enhanced CT efficiency because of the large number of surface oxygen vacancies of meso-TiO2 NPs. Therefore, the synergy of electromagnetic field enhancement and chemical enhancement leads to SERS enhancement. In addition, the composite SERS substrate has high sensitivity, and the detection limit of adsorbed 4-MBA probe molecules reaches 10-11 M. Furthermore, the TiO2/Ag hybrid aerogels demonstrate good reproducibility with minimal standard deviation in terms of SERS signals. In addition, even after standing for 6 months, there is almost no attenuation in the SERS signal intensity, which highlights the excellent stability of this substrate. Therefore, these highly sensitive TiO2/Ag hybrid aerogels SERS substrates have important practical value in environmental monitoring, medical inspection and food supervision.

miR-30d Attenuates Pulmonary Arterial Hypertension via Targeting MTDH and PDE5A and Modulates the Beneficial Effect of Sildenafil.

Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular smooth muscle cell (PASMC) function and vascular remodeling. MiR-30d plays an important role in the pathogenesis of several cardiovascular disorders. However, the function of miR-30d in PAH progression remained unknown. Our study shows that circulating miR-30d level is significantly reduced in the plasma from PAH patients. In miR-30d transgenic (TG) rats, overexpressing miR-30d attenuates monocrotaline (MCT)-induced pulmonary hypertension (PH) and pulmonary vascular remodeling. Increasing miR-30d also inhibits platelet-derived growth factor-bb (PDGF-bb)-induced proliferation and migration of human PASMC. Metadherin (MTDH) and phosphodiesterase 5A (PDE5A) are identified as direct target genes of miR-30d. Meanwhile, nuclear respiratory factor 1 (NRF1) acts as a positive upstream regulator of miR-30d. Using miR-30d knockout (KO) rats treated with sildenafil, a PDE5A inhibitor that is used in clinical PAH therapies, it is further found that suppressing miR-30d partially attenuates the beneficial effect of sildenafil against MCT-induced PH and vascular remodeling. The present study shows a protective effect of miR-30d against PAH and pulmonary vascular remodeling through targeting MTDH and PDE5A and reveals that miR-30d modulates the beneficial effect of sildenafil in treating PAH. MiR-30d should be a prospective target to treat PAH and pulmonary vascular remodeling.