Platycodi radix aqueous extract salvages doxorubicin-induced senescence by mitochondrial reactive oxygen species reduction in umbilical cord matrix stem cells.

Platycodi radix is a widely used herbal medicine that contains numerous phytochemicals beneficial to health. The health and biological benefits of P. radix have been found across various diseases. The utilization of umbilical cord stromal stem cells, derived from Wharton's jelly of the human umbilical cord, has emerged as a promising approach for treating degenerative diseases. Nevertheless, growing evidence indicates that the function of stem cells declines with age, thereby limiting their regenerative capacity. The primary objective in this study is to investigate the beneficial effects of P. radix in senescent stem cells. We conducted experiments to showcase that diminished levels of Lamin B1 and Sox-2, along with an elevation in p21, which serve as indicative markers for the senescent stem cells. Our findings revealed the loss of Lamin B1 and Sox-2, coupled with an increase in p21, in umbilical cord stromal stem cells subjected to a low-dose (0.1 µM) doxorubicin (Dox) stimulation. However, P. radix restored the Dox-damage in the umbilical cord stromal stem cells. P. radix reversed the senescent conditions when the umbilical cord stromal stem cells exposed to Dox-induced reactive oxygen species (ROS) and mitochondrial membrane potential are significantly changed. In Dox-challenged aged umbilical cord stromal stem cells, P. radix reduced senescence, increased longevity, prevented mitochondrial dysfunction and ROS and protected against senescence-associated apoptosis. This study suggests that P. radix might be as a therapeutic and rescue agent for the aging effect in stem cells. Inhibition of cell death, mitochondrial dysfunction and aging-associated ROS with P. radix provides additional insights into the underlying molecular mechanisms.

Prescribing cascades of antigout medications from thiazide diuretics in gout-naïve hypertensive adults receiving first-line pharmacological management.

Prescribing cascade is a significant clinical problem but is often overlooked. We explore the incidence of the prescribing cascades of antigout medications related to thiazide treatment in gout-naïve hypertensive adults newly exposed to the pharmacological treatment. This population-based, retrospective cohort study used the Taiwan National Health Insurance Registry Database. Gout-naïve hypertensive adults who were newly dispensed first-line antihypertensive drugs between January 1, 2000, and December 31, 2016, were enrolled. Patients were divided into the thiazide group (n = 4192) and the non-thiazide group (n = 81,083). The non-thiazide group included patients who received an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-blocker. The study utilized propensity score matching and multivariable Cox regression models to investigate the prescribing cascade of antigout agents following antihypertensive treatment, adjusting for factors like age, sex, comorbidities, and concurrent medications. After propensity score matching, each group consisted of 4045 patients, with the thiazide group exhibiting a higher risk of being prescribed antigout medications across different time intervals post-treatment initiation. Specifically, adjusted hazard ratios (aHRs) for the thiazide group were 2.23, 2.07, and 2.41 for < 30 days, 31-180 days, and > 180 days, respectively, indicating a sustained and significant risk over time. Comparative analyses revealed thiazide diuretics were associated with a higher risk of antigout medication prescriptions compared to other antihypertensive classes, particularly evident after 180 days. Subgroup analyses across various demographics and comorbidities consistently showed an increased risk in the thiazide cohort. Gout-naïve hypertensive adults newly dispensed thiazide had a higher risk of subsequently adding antigout agents than those taking other first-line antihypertensive medications. The awareness and interruption of these prescribing cascades are critical to improving patient safety.

Diallyl trisulfide (DATS) protects cardiac cells against advanced glycation end-product-induced apoptosis by enhancing FoxO3A-dependent upregulation of miRNA-210.

Diabetic cardiomyopathy is a common complication of diabetes, resulting in cardiac hypertrophy and heart failure associated with excessive reactive oxygen species and mitochondria-mediated apoptosis generation. Mitogen-activated protein kinase-c-Jun N-terminal kinase (MAPK-JNK), regulated by microRNA (miR)-210, affects mitochondrial function and is activated by advanced glycation end-products (AGE) in cardiac cells. Diallyl trisulfide (DATS), an antioxidant in garlic oil, inhibits stress-induced cardiac apoptosis. This study examined whether DATS enhances miR-210 expression to attenuate cardiac apoptosis. We investigated the DATS-mediated attenuation mechanism of AGE-enhanced cardiac apoptosis by modulating miR-210 and its upstream transcriptional regulator, FoxO3a. We found FoxO3a binding sites in the miR-210 promoter region. Our results indicated that DATS treatment inhibited AGE-induced JNK activation, phosphoprotein c-Jun nuclear transactivation, and cardiac apoptosis and reversed the AGE-induced reduction in cardiac miR-210 levels. The luciferase activity after DATS treatment was significantly lower than that of the control and was reversed following AGE treatment. We also showed that FoxO3a, upregulated by DATS treatment, may bind to the miR-210 promoter to enhance its expression and downregulates JNK expression to attenuate AGE-induced cardiac apoptosis. Oral administration of DATS enhanced FoxO3a expression in the heart and reduced diabetes-induced heart apoptosis. Our findings indicate that DATS mediates AGE-induced cardiac cell apoptosis attenuation by promoting FoxO3a nuclear transactivation to enhance miR-210 expression and regulate JNK activation. Our results suggest that DATS can be used as a cardioprotective agent, and miR-210 is a critical regulator in inhibiting diabetic cardiomyopathy.

Protective Effects of Statins on Limb and Cardiovascular Outcomes in Patients with Peripheral Artery Disease and End-Stage Renal Disease.

Background: Previous studies have reported that statins have inconsistent and marginal cardiovascular (CV) benefits in patients with end-stage renal disease (ESRD). However, whether statins play a secondary preventive role in patients with peripheral artery disease (PAD) and ESRD remains unclear. Objectives: This study aimed to compare the long-term clinical outcomes between statin users and nonusers with PAD and ESRD. Methods: This retrospective cohort study assessed the long-term protective effects of statins using data from the National Health Insurance Research Database in Taiwan. Propensity score matching was performed according to sex, age, index year, related comorbidities, and medications. The main outcomes were limb events and major adverse CV events (MACEs). Results: The statin user group (n = 4,460) was compared with the propensity score-matched statin nonuser group (n = 4,460). The mean age of the matched patients was 64 years, and 40% of the patients were men. The baseline characteristics of the groups were well-balanced. The overall limb event and MACE rates were not different between the two groups. However, the statin user group had lower rates of limb amputation [adjusted hazard ratio (aHR): 0.85, 95% confidence interval (CI): 0.73-0.99], stroke (aHR: 0.71, 95% CI: 0.62-0.83), CV death (aHR: 0.46, 95% CI: 0.32-0.66), and all-cause death (aHR: 0.45, 95% CI: 0.42-0.48) despite having a higher rate of percutaneous transluminal angioplasty for PAD. Conclusions: This population-based retrospective cohort study demonstrated that statin therapy was associated with a lower risk of limb amputation, nonfatal stroke, CV death, and all-cause death in patients with PAD and ESRD.

Ohwia caudata aqueous extract attenuates doxorubicin-induced mitochondrial dysfunction in Wharton's jelly-derived mesenchymal stem cells.

Mitochondrial dysfunction has been linked to many diseases, including organ degeneration and cancer. Wharton's jelly-derived mesenchymal stem cells provide a valuable source for stem cell-based therapy and represent an emerging therapeutic approach for tissue regeneration. This study focused on screening the senomorphic properties of Ohwia caudata aqueous extract as an emerging strategy for preventing or treating mitochondrial dysfunction in stem cells. Wharton's jelly-derived mesenchymal stem cells were incubated with 0.1 µM doxorubicin, for 24 h to induce mitochondrial dysfunction. Next, the cells were treated with a series concentration of Ohwia caudata aqueous extract (25, 50, 100, and 200 µg/mL) for another 24 h. In addition, an untreated control group and a doxorubicin-induced mitochondrial dysfunction positive control group were maintained under the same conditions. Our data showed that Ohwia caudata aqueous extract markedly suppressed doxorubicin-induced mitochondrial dysfunction by increasing Tid1 and Tom20 expression, decreased reactive oxygen species production, and maintained mitochondrial membrane potential to promote mitochondrial stability. Ohwia caudata aqueous extract retained the stemness of Wharton's jelly-derived mesenchymal stem cells and reduced the apoptotic rate. These results indicate that Ohwia caudata aqueous extract protects Wharton's jelly-derived mesenchymal stem cells against doxorubicin-induced mitochondrial dysfunction and can potentially prevent mitochondrial dysfunction in other cells. This study provides new directions for the medical application of Ohwia caudata.

Cardiac-specific overexpression of insulin-like growth factor II receptor-α interferes with the regulation of calcium homeostasis in the heart under hyperglycemic conditions.

BACKGROUND: Diabetic cardiomyopathy is a progressive disease caused by inexplicit mechanisms, and a novel factor, insulin-like growth factor II receptor-α (IGF-IIRα), may contribute to aggravating its pathogenesis. We hypothesized that IGF-IIRα could intensify diabetic heart injury. METHODS AND RESULTS: To demonstrate the potential role of IGF-IIRα in the diabetic heart, we used (SD-TG [IGF-IIRα]) transgenic rat model with cardiac-specific overexpression of IGF-IIRα, along with H9c2 cells, to study the effects of IGF-IIRα in the heart under hyperglycemic conditions. IGF-IIRα was found to remodel calcium homeostasis and intracellular Ca2+ overload-induced autophagy disturbance in the heart during diabetes. IGF-IIRα overexpression induced intracellular Ca2+ alteration by downregulating phosphorylated phospholamban/sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (PLB/SERCA2a), resulting in the suppression of Ca2+ uptake into the endoplasmic reticulum. Additionally, IGF-IIRα itself contributed to Ca2+ withdrawal from the endoplasmic reticulum by increasing the expression of CaMKIIδ in the active form. Furthermore, alterations in Ca2+ homeostasis significantly dysregulated autophagy in the heart during diabetes. CONCLUSIONS: Our study reveals the novel role of IGF-IIRα in regulating cardiac intracellular Ca2+ homeostasis and its related autophagy interference, which contribute to the development of diabetic cardiomyopathy. In future, the present study findings have implications in the development of appropriate therapy to reduce diabetic cardiomyopathy.

Insulin-like growth factor II receptor alpha overexpression in heart aggravates hyperglycemia-induced cardiac inflammation and myocardial necrosis.

Diabetes-induced cardiovascular complications are mainly associated with high morbidity and mortality in patients with diabetes. Insulin-like growth factor II receptor α (IGF-IIRα) is a cardiac risk factor. In this study, we hypothesized IGF-IIRα could also deteriorate diabetic heart injury. The results presented that both in vivo transgenic Sprague-Dawley rat model with specific IGF-IIRα overexpression in the heart and in vitro myocardium H9c2 cells were used to investigate the negative function of IGF-IIRα in diabetic hearts. The results showed that IGF-IIRα overexpression aided hyperglycemia in creating more myocardial injury. Pro-inflammatory factors, such as Tumor necrosis factor-alpha, Interleukin-6, Cyclooxygenase-2, Inducible nitric oxide synthase, and Nuclear factor-kappaB inflammatory cascade, are enhanced in the diabetic myocardium with cardiac-specific IGF-IIRα overexpression. Correspondingly, IGF-IIRα overexpression in the diabetic myocardium also reduced the PI3K-AKT survival axis and activated mitochondrial-dependent apoptosis. Finally, both ejection fraction and fractional shortening were be significantly decrease in diabetic rats with cardiac-specific IGF-IIRα overexpression. Overall, all results provid clear evidence that IGF-IIRα can enhance cardiac damage and is a harmful factor to the heart under high-blood glucose conditions. However, the pathophysiology of IGF-IIRα under different stresses and its downstream regulation in the heart still require further research.

Angiotensin II prompts heart cell apoptosis via AT1 receptor-augmented phosphatase and tensin homolog and miR-320-3p functions to enhance suppression of the IGF1R-PI3K-AKT survival pathway.

BACKGROUND: Hypertension is a severe public health risk factor worldwide. Elevated angiotensin II (Ang II) produced by the renin-angiotensin-aldosterone system can lead to hypertension and its complications. METHOD: In this study, we addressed the cardiac-injury effects of Ang II and investigated the signaling mechanism induced by Ang II. Both H9c2 cardiomyoblast cells and neonatal rat cardiomyocytes were exposed to Ang II to observe hypertension-related cardiac apoptosis. RESULTS: The results of western blotting revealed that Ang II significantly attenuated the IGF1R-PI3K-AKT pathway via the Ang II-AT1 receptor axis and phosphatase and tensin homolog expression. Furthermore, real-time PCR showed that Ang II also activated miR-320-3p transcription to repress the PI3K-Akt pathway. In the heart tissue of spontaneously hypertensive rats, activation of the IGF1R survival pathway was also reduced compared with that in Wistar-Kyoto rats, especially in aged spontaneously hypertensive rats. CONCLUSION: Hence, we speculate that the Ang II-AT1 receptor axis induces both phosphatase and tensin homolog and miR-320-3p expression to downregulate the IGF1R-PI3K-AKT survival pathway and cause cell apoptosis in the heart.

First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction.

Background: Acute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization. Objectives: This phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention. Methods: Consenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period. Results: Eight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline. Conclusion: This pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.

ZAKß Alleviates Oxidized Low-density Lipoprotein (ox-LDL)-Induced Apoptosis and B-type Natriuretic Peptide (BNP) Upregulation in Cardiomyoblast.

Oxidized low-density lipoprotein (ox-LDL) is a type of modified cholesterol that promotes apoptosis and inflammation and advances the progression of heart failure. Leucine-zipper and sterile-α motif kinase (ZAK) is a kinase of the MAP3K family which is highly expressed in the heart and encodes two variants, ZAKα and ZAKß. Our previous study serendipitously found opposite effects of ZAKα and ZAKß in which ZAKß antagonizes ZAKα-induced apoptosis and hypertrophy of the heart. This study aims to test the hypothesis of whether ZAKα and ZAKß are involved in the damaging effects of ox-LDL in the cardiomyoblast. Cardiomyoblast cells H9c2 were treated with different concentrations of ox-LDL. Cell viability and apoptosis were measured by MTT and TUNEL assay, respectively. Western blot was used to detect apoptosis, hypertrophy, and pro-survival signaling proteins. Plasmid transfection, pharmacological inhibition with D2825, and siRNA transfection were utilized to upregulate or downregulate ZAKß, respectively. Ox-LDL concentration-dependently reduces the viability and expression of several pro-survival proteins, such as phospho-PI3K, phospho-Akt, and Bcl-xL. Furthermore, ox-LDL increases cleaved caspase-3, cleaved caspase-9 as indicators of apoptosis and increases B-type natriuretic peptide (BNP) as an indicator of hypertrophy. Overexpression of ZAKß by plasmid transfection attenuates apoptosis and prevents upregulation of BNP. Importantly, these effects were abolished by inhibiting ZAKß either by D2825 or siZAKß application. Our results suggest that ZAKß upregulation in response to ox-LDL treatment confers protective effects on cardiomyoblast.

Cardioprotective potential of amygdalin against angiotensin II induced cardiac hypertrophy, oxidative stress and inflammatory responses through modulation of Nrf2 and NF-κB activation.

Heart failure (HF) and cardiac hypertrophy is an unfavorable outcome of pathological cardiac remodeling and represents the most important contributing factor for HF and cardiac hypertrophy. Amygdalin (AMG) is a cyanogenic glycoside derived from bitter almonds. Accumulating evidences have highlighted their pharmacological potentials against various diseases. However, there is no report delineating the potential of AMG against angiotensin (Ang II) induced cardiac injuries. Thus, the present study was performed to explore whether AMG could ameliorate Ang II induced cardiomyopathies and thereby ascertain the underlying mechanisms thereof. To this end, H9c2 cells were treated with Ang II and thereafter treated with various concentration of AMG and finally the cardio-protective effects of AMG were analyzed through Western blotting, immunofluorescence, and insilico analysis. Our results showed that the cardiomyocyte cell size, inflammatory markers and cytokines(pNF-κB, TNF-α, iNOS and COX-2) were markedly increased following Ang II treatment; nevertheless, treatment with AMG led to considerable decrement in the Ang II induced enlargement of the cardiomyocytes, and attenuate the expression of hypertrophic markers(ANP, BNP and MHC-7), inflammatory markers and cytokines. Additionally, oxidative stress related proteins (Nrf2, catalase, SOD-2, and GPX-4) were markedly increased following AMG treatment. Molecular docking reveals the interaction of AMG with Nrf2 possessing good binding affinity. Cumulatively, our study highlights the cardio-protective role of AMG against Ang II induced cardiomyopathies, including oxidative stress and inflammation effects. The intriguing in vitro results warrants the need of further animal studies to truly ascertain their potentialities.

The predictors of successful percutaneous coronary intervention in ostial left anterior descending artery chronic total occlusion.

BACKGROUND: Percutaneous coronary intervention (PCI) to chronic total occlusion (CTO) has become one of the treatment strategies in recent era. The ostium of the left anterior descending artery (LAD) is one of the most difficult positions for CTO revascularization. Until now, limited data has been made available for the prediction of successful ostial LAD CTO PCI. OBJECTIVE: The aim of the study was to compare the differences between ostial LAD and all other CTOs and to identify the predictors of successful ostial LAD CTO PCI. METHODS: This retrospective analysis included consecutive patients referred for CTO PCI between January 2001 and September 2013. Ostial LAD CTO was defined as CTO at the position whose distance between lesion and left main bifurcation was less than 1 mm. Baseline demographics, lesion characteristics, interventional procedure details, and devices were compared between the ostial LAD group and the all other CTOs group. The predictors of successful ostial LAD CTO PCI were also evaluated. RESULTS: 621 patients who underwent CTO PCI were enrolled retrospectively to this study. A total of 70 patients of ostial LAD CTO were compared with 551 patients of all other CTOs group in this study. Ostial LAD CTO was found to have more bridging and better collaterals than all other CTOs. Procedure time, fluoroscopic time, contrast volumes, the use of contralateral injection, and the use of the retrograde approach were significantly greater in the ostial LAD CTO group. The ostial LAD CTO group also had significantly higher J-CTO scores (2.7 ± 0.8 vs. 2.2 ± 1.1, P = 0.011) and higher Syntax Scores (28.3 ± 6.5 vs. 20.9 ± 9.7, P < 0.001). A slightly lower final success rate, but statistically non-significant, was observed in the ostial LAD CTO group (80.0% vs. 81.9%, P = 0.706). Univariate and multivariate logistic regression revealed that without antegrade failure and with retrograde success were predictors of the success of ostial LAD CTO PCI. Syntax Score was also capable of predicting the ostial LAD CTO PCI outcome. J-CTO score was not found to be associated with final success for ostial LAD CTO patients. CONCLUSIONS: Ostial LAD CTO resulted in higher lesion complexity in J-CTO scores and Syntax Scores. Ostial LAD CTO PCI had a slightly lower final success rate than that of all other CTOs PCI with longer procedure duration, fluoroscopic time and larger contrast volume. Without antegrade failure, with retrograde success, and lower Syntax Score were found to predict the success of ostial LAD CTO PCI.