Hydrogen Sulfide Ameliorates Heart Aging by Downregulating Matrix Metalloproteinase-9.

PURPOSE: Aging contributes significantly to cardiovascular diseases and cardiac dysfunction, leading to the upregulation of matrix metalloproteinase-9 (MMP-9) in the heart and a significant decrease in hydrogen sulfide (H2S) content, coupled with impaired cardiac diastolic function. This study explores whether supplementing exogenous hydrogen sulfide during aging ameliorates the decline in H2S concentration in the heart, suppresses MMP-9 expression, and improves the age-associated impairment in cardiac morphology and function. METHODS: We collected plasma from healthy individuals of different ages to determine the relationship between aging and H2S and MMP-9 levels through Elisa detection and liquid chromatography-tandem mass spectrometry (LC/MC) detection of plasma H2S content. Three-month-old mice were selected as the young group, while 18-month-old mice were selected as the old group, and sodium hydrosulfide (NaHS) was injected intraperitoneally from 15 months old until 18 months old as the old + NaHS group. Plasma MMP-9 content was detected using Elisa, plasma H2S content, cardiac H2S content, and cystathionine gamma-lyase (CSE) activity were detected using LC/MC, and cardiac function was detected using echocardiography. Heart structure was assessed using hematoxylin and eosin staining, Masone staining was used to detect the degree of cardiac fibrosis, while western blot was used to detect the expression of MMP-9, CSE, and aging marker proteins. Knockdown of MMP-9 and CSE in H9c2 cells using small interfering RNA was carried out to determine the upstream-downstream relationship between MMP-9 and CSE. RESULTS: H2S content in the plasma of healthy individuals decreases with escalating age, whereas MMP-9 level rises with age progression. Aging leads to a decrease in H2S levels in the heart and plasma of mice, severe impairment of cardiac diastolic function, interstitial relaxation, and fibrosis of the heart. Supplementing with exogenous H2S can improve these phenomena. CONCLUSION: H2S maintains the structure and function of the heart by inhibiting the expression of MMP-9 during the aging process.

Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability.

Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, boasts significant potential for therapeutic intervention in cardiovascular dysfunctions. However, its impact on regulating fibrosis remains unexplored. This study aims to elucidate the role and mechanism of FGF13 on cardiac fibrosis. Here, we show that following transverse aortic constriction (TAC) surgery, interstitial fibrosis and collagen content increase in mice, along with reduced ejection fraction and fractional shortening, augmented heart mass. However, following Fgf13 deletion, interstitial fibrosis is decreased, ejection fraction and fractional shortening are increased, and heart mass is decreased, compared with those in the TAC group. Mechanistically, incubation of cardiac fibroblasts with transforming growth factor ß (TGFß) increases the expressions of types I and III collagen proteins, as well as α-smooth muscle actin (α-SMA) proteins, and enhances fibroblast proliferation and migration. In the absence of Fgf13, the expressions of these proteins are decreased, and fibroblast proliferation and migration are suppressed, compared with those in the TGFß-stimulated group. Overexpression of FGF13, but not FGF13 mutants defective in microtubule binding and stabilization, rescues the decrease in collagen and α-SMA protein and weakens the proliferation and migration function of the Fgf13 knockdown group. Furthermore, Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. Collectively, cardiac Fgf13 knockdown protects the heart from fibrosis in response to haemodynamic stress by modulating microtubule stabilization and ROCK signaling pathway.

Pectin-based double network hydrogels as local depots of celastrol for enhanced antitumor therapy.

In this study, A double-network (DN) hydrogel composed of a physical glycyrrhizic acid (GA) network and a chemically crosslinked pectin-based network was fabricated as a local depot of celastrol (CEL) for cancer treatment. The obtained DN hydrogel possessed excellent mechanical performance, flexibility, biocompatibility, biodegradability and self-healing property. Furthermore, the release profile of CEL loaded DN hydrogel maintained a controlled and sustained release of CEL for a prolonged period. Finally, in vivo animal experiments demonstrated that the DN hydrogel could significantly enhance the therapeutic efficiency of CEL in CT-26 tumor-bearing mice upon intratumoral injection while effectively alleviate the toxicity of the CEL. In summary, this injectable pectin-based double network hydrogels are ideal delivery vehicle for tumor therapy.

Erratum: CD151 promotes Colorectal Cancer progression by a crosstalk involving CEACAM6, LGR5 and Wnt signaling via TGFß1: Erratum.

[This corrects the article DOI: 10.7150/ijbs.53657.].

Modulation of Kv7 Channel Currents by Echinocystic Acid.

Modulation of KCNQ-encoded voltage-gated potassium Kv7/M channel function represents an attractive strategy to treat neuronal excitability disorders such as epilepsy, pain, and depression. The Kv7 channel group includes five subfamily members (Kv7.1-Kv7.5). Pentacyclic triterpenes display extensive pharmacological activities including antitumor, anti-inflammatory, and antidepression effects. In this study, we investigated the effects of pentacyclic triterpenes on Kv7 channels. Our results show that echinocystic acid, ursonic acid, oleanonic acid, demethylzeylasteral, corosolic acid, betulinaldehyde, acetylursolic acid, and α-boswellic acid gradually exert decreasing degrees of Kv7.2/Kv7.3 channel current inhibition. Echinocystic acid was the most potent inhibitor, with a half-maximal inhibitory concentration (IC50) of 2.5 µM. It significantly shifted the voltage-dependent activation curve in a positive direction and slowed the time constant of activation for Kv7.2/Kv7.3 channel currents. Furthermore, echinocystic acid nonselectively inhibited Kv7.1-Kv7.5 channels. Taken together, our findings indicate that echinocystic acid is a novel and potent inhibitor that could be used as a tool to further understand the pharmacological functions of neuronal Kv7 channels. SIGNIFICANCE STATEMENT: Pentacyclic triterpenes reportedly have multiple potential therapeutic uses such as anticancer, anti-inflammatory, antioxidant, and antidepression effects. In the present study, we show that echinocystic acid, ursonic acid, oleanonic acid, and demethylzeylasteral inhibit Kv7.2/Kv7.3 channels to varying degrees. Of these, echinocystic acid was the most potent Kv7.2/Kv7.3 current inhibitor and inhibited Kv7.1-Kv7.5 currents in a nonselective manner.

Liquiritigenin Attenuated Collagen-Induced Arthritis and Cardiac Complication via Inflammation and Fibrosis Inhibition in Mice.

Rheumatoid arthritis (RA) is a common autoimmune disease with increased cardiovascular disease risk. Liquiritigenin (LG) is a triterpene with anti-inflammatory properties. Our study aimed to explore the effect of LG on RA and the cardiac complication. Collagen-induced arthritis (CIA) mice with LG treatment exhibited obvious alleviation in histopathological changes, accompanied by the decreased expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-17A in synovium and serum. LG attenuated cartilage destruction by reducing matrix metalloproteinase (MMP)-3 and MMP-13 expression in the synovium of CIA mice. The echocardiography results proved the alleviation of cardiac dysfunction in CIA mice. The electrocardiogram, biochemical, and histochemical analysis proved the cardioprotection effect of LG against RA. The decreased expression of inflammatory factors (TNF-α, IL-1ß, and IL-6) and fibrotic markers (fibronectin, Collagen I, and Collagen III) in cardiac tissues of CIA mice further corroborated the attenuation of myocardial inflammation and fibrosis by LG. Mechanistic studies showed that LG could inhibit transforming growth factor ß-1 (TGF-ß1) and phos-Smad2/3 expression in cardiac tissues of CIA mice. Our study suggested that LG could relieve RA and its cardiac complication probably by inhibiting the TGF-ß1/Smad2/3 pathway. All these suggested that LG might be a potential candidate for RA and its cardiac complication therapy.

Perfluorooctane sulfonate promotes atherosclerosis by modulating M1 polarization of macrophages through the NF-κB pathway.

Perfluorooctane sulfonate (PFOS) is a widely used and distributed perfluorinated compounds and is reported to be harmful to cardiovascular health; however, the direct association between PFOS exposure and atherosclerosis and the underlying mechanisms remain unknown. Therefore, this study aimed to investigate the effects of PFOS exposure on the atherosclerosis progression and the underlying mechanisms. PFOS was administered through oral gavage to apolipoprotein E-deficient (ApoE-/-) mice for 12 weeks. PFOS exposure significantly increased pulse wave velocity (PWV) and intima-media thickness (IMT), increased aortic plaque burden and vulnerability, and elevated serum lipid and inflammatory cytokine levels. PFOS promoted aortic and RAW264.7 M1 macrophage polarization, which increased the secretion of nitric oxide synthase (iNOS) and pro-inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1ß [IL-1ß]), and suppressed M2 macrophage polarization, which decreased the expression of CD206, arginine I (Arg-1), and interleukin-10 (IL-10). Moreover, PFOS activated nuclear factor-kappa B (NF-κB) in the aorta and macrophages. BAY11-7082 was used to inhibit NF-κB-alleviated M1 macrophage polarization and the inflammatory response induced by PFOS in RAW264.7 macrophages. Our results are the first to reveal the acceleratory effect of PFOS on the atherosclerosis progression in ApoE-/- mice, which is associated with the NF-κB activation of macrophages to M1 polarization to induce inflammation.

Risks of postoperative respiratory failure in elderly patients after hip surgery: a retrospective study.

BACKGROUND: The purpose of this retrospective study was to investigate the determinants of postoperative respiratory failure in elderly patients with hip fracture. METHODS: The subjects of this study were 663 elderly patients who had hip fracture and had been treated with total hip arthroplasty at our hospital from January 2014 to May 2020. According to the occurrence of postoperative respiratory failure, 626 patients with no respiratory failure were retrospectively included in the control group, and 37 cases combined with respiratory failure were enrolled in the PRF group. The clinical and surgical data of the two groups were collected and analyzed to evaluate the determinants of respiratory failure by logistic regression analysis. RESULTS: There were no significant differences in the demographics and baseline variables including age, gender, fracture type and location between the groups (P > 0.05). All patients received hip surgery including total hip arthroplasty (THA), hemiarthroplasty (HA) and internal fixation with PFNA (proximal femoral nail anti-rotation). There were no significant differences in operative time and intraoperative blood loss between the groups (P > 0.05). However, close associations were found between pulmonary hypertension (univariate analysis: OR = 3.792, 95% CI = 1.421-10.203; multivariate analysis: OR = 1.132, 95% CI = 1.003-1.251), obstructive pulmonary disease (OR = 1.119, 95% CI = 1.009-1.238; multivariate analysis: OR = 13.298, 95% CI = 4.021-43.298), bronchiectasis and emphysema (OR = 4.949, 95% CI = 1.919-9.873; multivariate analysis: OR = 11.231, 95% CI = 187.87), and history of respiratory failure (OR = 6.098, 95% CI = 2.012-12.198; multivariate analysis: OR = 8.389, 95% CI = 2.391-21.982) with postoperative respiratory failure (P < 0.05). CONCLUSION: Pulmonary hypertension, abnormal lung texture, obstructive pulmonary disease, bronchiectasis, emphysema, history of respiratory failure, and hypoproteinemia may be risk factors for postoperative respiratory failure in elderly patients with hip fracture.

Hydrogen Sulfide Restored the Diurnal Variation in Cardiac Function of Aging Mice.

The present study was performed to investigate whether H2S could restore the diurnal variation in cardiac function of aging mice and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS) in 3-month-old mice exhibited diurnal variations over a 24-hour period. However, the diurnal variations were disrupted in 18-month-old mice, and there was a decline in EF and FS. In addition, the plasma malondialdehyde (MDA) levels were increased, and H2S concentrations and superoxide dismutase (SOD) activities were decreased in 18-month-old mice. Then, CSE KO mice were used to determine if there was a relationship between endogenous H2S and diurnal variations in EF and FS. There was no difference in 12-hour averaged EF and FS between dark and light periods in CSE KO mice accompanying increased MDA levels and decreased SOD activities in plasma, indicating that deficiency of endogenous H2S blunted diurnal variations of cardiac function. To determine whether oxidative stress disrupted the diurnal variations in cardiac function, D-galactose-induced subacute aging mice were employed. After 3-month D-gal treatment, both 12-hour averaged EF and FS in dark or light periods were decreased; meanwhile, there was no difference in 12-hour averaged EF and FS between dark and light periods. After 3-month NaHS treatment in the D-gal group, the plasma MDA levels were decreased and SOD activities were increased. The EF and FS were lower during the 12-hour light period than those during the 12-hour dark period which was fit to sine curves in the D-gal+NaHS group. Identical findings were also observed in 18-month-old mice. In conclusion, our studies revealed that the disrupted diurnal variation in cardiac function was associated with increased oxidative stress and decreased H2S levels in aging mice. H2S could restore the diurnal variation in cardiac function of aging mice by reducing oxidative stress.

CD151 promotes Colorectal Cancer progression by a crosstalk involving CEACAM6, LGR5 and Wnt signaling via TGFß1.

CD151 impacts various signaling pathways in different cancers, and promotes colorectal cancer (CRC) cell malignancy by yet undefined mechanisms. This study aimed to comprehensively assess CD151's function in CRC. CD151 levels were significantly higher in CRC tissues and cells compared with controls in the tissue microarray. Cell viability, migration and invasion were suppressed by CD151 downregulation in CRC cells. Consistently, mouse xenografts were inhibited by CD151 silencing. RNA-seq revealed that multiple genes were significantly altered by CD151 knockdown in cultured CRC cells and xenografts. Particularly, transforming growth factor ß1 (TGFß1), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) alongside CD151 were downregulated both in vitro and in vivo. Co-immunoprecipitation and mass spectrometry results were validated by qRT-PCR and immunoblot. Moreover, pull-down assay and immunofluorescence confirmed the associations of TGFß1, CEACAM6 and LGR5 with CD151. This study demonstrated CEACAM6, LGR5 and Wnt pathway suppression by CD151 silencing might occur through TGFß1 regulation, offering a comprehensive view of CD151's roles in colorectal carcinogenesis. Our findings provide an insight into the CD151-involved signaling network in CRC oncogenesis, which could be utilized to design novel targeted therapies against CD151-based signaling in treatment for CRC.

A surgical reduction technique for posterior cruciate ligament avulsion fracture in total knee arthroplasty: a comparison study.

BACKGROUND: Posterior cruciate ligament (PCL) avulsion fracture of the tibia is an uncommon but serious complication during primary cruciate-retaining total knee arthroplasty (TKA). The first objective of this report was to conduct a retrospective cohort study to investigate the incidence and potential risk factors of PCL avulsion fracture in primary cruciate-retaining TKA. The second objective was to assess the functional outcomes of the knee after reduction of PCL avulsion fracture. METHODS: From January 2014 to January 2016, 56 patients who experienced PCL avulsion fracture of the tibia in primary cruciate-retaining TKA were included in the study group. Patients in this group underwent reduction of avulsion fracture. In this period, we selected 224 patients (control group) for comparison. Patients in this group also underwent the same TKA, but no PCL avulsion fracture occurred. The range of motion of the knee and Knee Society Scores were assessed. The Forgotten Joint Score was used to analyze the ability to forget the joint. Differences were considered statistically significant at p < 0.05. RESULTS: In our series, the incidence of PCL avulsion fracture was 4.6%. There were no significant differences (p > 0.05) with regard to the preoperative or postoperative range of motion of the knee, final 4-year mean clinical score in the study and control groups 92.4 ± 2.7 and 93.6 ± 1.9, respectively, and mean functional scores of 85.1 ± 1.8 and 87.1 ± 1.2, respectively. CONCLUSIONS: The incidence of PCL avulsion fracture of the tibia is relatively high. Older age and female gender were the two risk factors of fracture in primary cruciate-retaining TKA. Reduction of PCL avulsion fracture with a high-strength line can achieve good stability and function of the knee.

Risk Factors of Pulmonary Complications After Minimally Invasive Surgery for Elderly Patients with Vertebral Compression Fractures.

PURPOSE: To determine the risk factors for pulmonary complications after minimally invasive surgery in elderly patients with vertebral compression fractures (VCFs). METHODS: A total of 233 elderly patients (age ≥ 65 years) with VCFs, who underwent percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) surgery at Hebei General Hospital from January 2011 to December 2016, were retrospectively analyzed. Risk factors and the effects of the model were determined by univariate logistic regression analyses and the receiver operating characteristic (ROC) curve, respectively. A risk assessment scale was established based on the risk factors, as well as physiological and surgical scores for mortality and morbidity. The risk assessment scale prospectively evaluated risk factors of pulmonary complications after minimally invasive surgery for elderly patients with VCFs from January to June 2017. RESULTS: 27 patients were diagnosed with pulmonary complications (27/233, 11.59%). There were statistically significant differences between patients with and without pulmonary complications in terms of age, body mass index (BMI), smoking, cardiovascular diseases and old fractures between patients with and without pulmonary complications (P < 0.05). Logistic regression analysis showed that smoking, cardiovascular diseases and old fractures were risk factors (P < 0.05) and area under the curve was 0.738 (95% confidence intervals (CI): 0.648-0.828). 53 elderly patients with VCFs were assessed, 5 of them occurred pulmonary complications. Areas under the curve of preoperative and total risk assessment values were all 0.925. CONCLUSION: Significant risk factors of pulmonary complications were BMI, cardiovascular diseases and old fractures for patients aged 65 years or elderly with VCFs after minimally invasive surgery. The risk assessment scale gained high accuracy.

Application of a combination of echocardiographic techniques in an experimental model of epirubicin-induced cardiotoxicity.

This study compared the potential ability of multinomial echocardiographic parameters in early detection, prediction and combined diagnosis of antineoplastic-related cardiotoxicity. Male Balb/c mice were repeatedly administered with low doses of epirubicin (6 × 3 mg/kg; n = 20) to induce cardiac injury or with placebo as control (n = 10). Conventional and strain parameters as well as myocardial performance index (MPI) were analyzed at baseline, 1 day after the second, fourth and sixth cycle, and 12 days after completion of chemotherapy (as follow-up) by a high-resolution rodent ultrasound machine. After the experiment, serum cTnI levels were measured, and myocardial injury was evaluated by histological analyses. Thirteen mice developed cardiotoxicity after epirubicin exposure. Global longitudinal (GLS), radial strain (GRS) and longitudinal strain rate (LSR) were markedly decreased (all P ≤ 0.01) and MPI was increased (P ≤ 0.05) at the completion of treatment compared with baseline values. GLS expressed the best correlations with myocardial pathological injury, especially with collagen content (ρ = - 0.68, P < 0.01). Additionally, GLS and MPI were associated with serum cTnI levels. A > 9.5% decrease in GLS from baseline to the fourth cycle of chemotherapy could predict future cardiotoxicity (odds ratio = 0.331, P < 0.05). GLS (cutoff value, - 15.16%) combined with MPI (cutoff value, 0.64) could improve the accuracy of diagnosing cardiotoxicity (sensitivity, 92%; specificity, 87%). GLS was the only predictor of cardiotoxicity. GLS combined with MPI may provide a noninvasive and accurate method for the early detection of cardiotoxicity.

Pd-Catalyzed Direct C-H Functionalization/Annulation of BODIPYs with Alkynes to Access Unsymmetrical Benzo[ b]-Fused BODIPYs: Discovery of Lysosome-Targeted Turn-On Fluorescent Probes.

A highly efficient palladium-catalyzed direct C-H functionalization/annulation of BODIPYs with alkynes has been developed for the first time to construct a series of unsymmetrical benzo[ b]-fused BODIPYs from readily available starting materials. These unsymmetrical benzo[ b]-fused BODIPYs exhibit remarkably red-shifted emissions and larger Stokes shifts than classical BODIPY dyes. Cell imaging experiments and cytotoxicity assays demonstrate that BODIPYs 4c and 4d have specific lysosome-labeling capacities, turn-on fluorescence emissions in cells, and low cytotoxicity.

Silver-mediated direct C-H amination of BODIPYs for screening endoplasmic reticulum-targeting reagents.

A highly efficient direct C-H amination of BODIPYs has been accomplished through the Ag(i)-mediated nucleophilic addition of an amino radical to BODIPY at the C3- and/or C5-position and deprotonation processes under mild conditions. This protocol greatly streamlines the access to a variety of 3-aminated and 3,5-diaminated BODIPYs. The resulting BODIPYs with morpholine groups (3q and 4b) exhibit specific endoplasmic reticulum (ER)-localization capacities and negligible cytotoxicities, which would be potential ER-targeting reagents.

Prepubertal octylphenol exposure up-regulate BRCA1 expression, down-regulate ERalpha expression and reduce rat mammary tumorigenesis.

BACKGROUND: Endogenous estrogens play an important role in the development of breast cancer. Octylphenol (OP) and genistein (GEN) are estrogen-like chemicals. Prepubertal estradiol and genistein exposure can up-regulate BRCA1 mRNA in mammary gland and reduce futuer breast cancer risk. In the present study, the effects of prepubertal exposure to high-dose OP and GEN on mammary carcinogenesis and the association with the expression of BRCA1 and ERalpha were investigated. METHODS: Prepubertal female Sprague-Dawley rats were exposed to 20, 40, 80mg/kg OP daily from postnatal day (PND) 22-28, subsequently, the rats were given a single dose of 100mg/kg 7,12-dimethylbenz [a] anthracene (DMBA) on PND42 to induce mammary tumor. RESULTS: The incidence of DMBA-induced mammary tumors significantly decreased when rats were treated with 40mg/kg OP. BRCA1 mRNA and protein expression were found up-regulated and ERalpha expression was down-regulated in the mammary tumor when rats were exposed to 40mg/kg octylphenol. CONCLUSION: Exposure 40mg/kg octylphenol can reduce later breast cancer risk in prepubertal Sprague-Dawley rats, the protective effect of OP is associated with persistent up-regulation of BRCA1 and down-regulation of ERalpha in the mammary tumor.

Three-dimensional QSAR of HPPD inhibitors, PSA inhibitors, and anxiolytic agents: effect of tautomerism on the CoMFA models.

The present study was design to examine the effect of tautomerism upon the CoMFA results. Three selected data sets involving protropic tautomerism, which are 21 p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, 35 inhibitors of puromycin-sensitive aminopeptidase (PSA), and 67 anxiolytic agents, were used for this purpose. Atom-by-atom alignment technique was adopted to superimpose the molecules in the data sets onto a template. The structural alignments using different tautomeric forms had no significant difference except the atoms involved in tautomerism, which ensures, to a great extent, that the differences of the CoMFA results result primarily from the tautomerism. All-orientation and all-placement search (AOS-APS) based CoMFA models, in addition to the conventional ones, were derived for each system and proved to be capable of yielding much improved statistical results. In the cases of the data sets of HPPD inhibitors and PSA inhibitors, excellent AOS-APS CoMFA models (q2>0.8 with four components for the former and q2>0.7 with seven components for the latter) were obtained, and almost no significant difference in statistical quality was observed when using different tautomeric forms to derive the models. However, it was not the case when treating the data set of anxiolytic agents. The keto tautomer, which was the active form of the PBI type inhibitors, produced measurably better results (q2=0.54 with eight components) than that the enol one (q2=0.37 with five components), indicating the importance of selecting proper tautomer in the CoMFA studies. Furthermore, there existed some substantial differences of the electrostatic field contours between the two different tautomeric forms for all of the three systems considered, whereas the differences in the steric field contour maps were limited. This implies that the resulting new potent ligands may be quite different if one utilizes the CoMFA models of different tautomeric forms for guiding further structural refinements.