Alpha-lipoic Acid Protects Against Chronic Alcohol Consumption-induced Cardiac Damage by the Aldehyde Dehydrogenase 2-associated PINK/Parkin Pathway.

ABSTRACT: Chronic alcohol intake contributes to high mortality rates due to ethanol-induced cardiac hypertrophy and contractile dysfunction, which are accompanied by increased oxidative stress and disrupted mitophagy. Alpha-lipoic acid (α-LA), a well-known antioxidant, has been shown to protect against cardiac hypertrophy and inflammation. However, little is known about its role and mechanism in the treatment of alcoholic cardiomyopathy. Here, we evaluated the role of α-LA in alcohol-induced cardiac damage by feeding mice a 4.8% (v/v) alcohol diet with or without α-LA for 6 w. Our results suggested that chronic alcohol consumption increased mortality, blood alcohol concentrations, and serum aldehyde levels, but a-LA attenuated the elevations in mortality and aldehydes. Chronic alcohol intake also induced cardiac dysfunction, including enlarged left ventricles, reduced left ventricular ejection fraction, enhanced cardiomyocyte size, and increased serum levels of brain natriuretic peptide, lactate dehydrogenase, and creatine kinase myocardial isoenzyme. Moreover, alcohol intake led to the accumulation of collagen fiber and mitochondrial dysfunction, the effects of which were alleviated by α-LA. In addition, α-LA intake also prevented the increase in reactive oxygen species production and the decrease in mitochondrial number that were observed after alcohol consumption. Chronic alcohol exposure activated PINK1/Parkin-mediated mitophagy. These effects were diminished by α-LA intake by the activation of aldehyde dehydrogenase 2. Our data indicated that α-LA helps protect cardiac cells against the effects of chronic alcohol intake, likely by inhibiting PINK1/Parkin-related mitophagy through the activation of aldehyde dehydrogenase 2.

Unraveling the molecular crosstalk and immune landscape between COVID-19 infections and ischemic heart failure comorbidity: New insights into diagnostic biomarkers and therapeutic approaches.

BACKGROUND: Coronavirus disease 2019 (COVID-19), resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), remains a persistent global health concern. Evidence has highlighted a significant association between COVID-19 and ischemic heart failure (IHF), contributing to disease progression and increased mortality. This study identified diagnostic biomarkers for these comorbidities and elucidated disease progression's molecular mechanisms. METHODS: We retrieved differentially expressed gene (DEG) data for COVID-19 and IHF from publicly available microarray and RNA-Seq datasets to investigate the underlying mechanisms and potential pathways associated with the co-occurrence of COVID-19 and IHF. By intersecting the results from the two diseases, we obtained diagnostic biomarkers using SVM-RFE and LASSO algorithms. Animal experiments and immunological analyses were conducted to help understand the association between SARS-CoV-2 and IHF in patients, enabling early diagnosis of disease progression. Finally, we analyzed the regulatory network of critical genes and identified potential drug compounds that could target the genetic links identified in our study. RESULTS: 1974 common DEGs were identified between COVID-19 and IHF, contributing to disease progression and potential cancer risk by participating in immune and cancer-related pathways. In addition, we identified six hub genes (VDAC3, EIF2AK2, CHMP5, FTL, VPS4A, and CHMP4B) associated with the co-morbidity, and their diagnostic potential was confirmed through validation using relevant datasets and a mouse model. Functional enrichment analysis and examination of immune cell infiltration revealed immune dysregulation after disease progression. The comorbid hub genes exhibited outstanding immunomodulatory capacities. We also constructed regulatory networks tightly linked to both disorders, including transcription factors (TFs), miRNAs, and genes at both transcriptional and post-transcriptional levels. Finally, we identified 92 potential drug candidates to enhance the precision of anti-comorbidity treatment strategies. CONCLUSION: Our study reveals a shared pathogenesis between COVID-19 and IHF, demonstrating that their coexistence exacerbates disease severity. By identifying and consolidating hub genes as pivotal diagnostic biomarkers for COVID-19 and IHF comorbidity, we have made significant advancements in understanding the underlying mechanisms of these conditions. Moreover, our study highlights dysregulated immunity and increased cancer risk in the advanced stages of disease progression. These findings offer novel perspectives for diagnosing and treating IHF progression during SARS-CoV-2 infection.

Drug-coated balloons for treating de novo lesions in large coronary vessels: A case report.

BACKGROUND: Percutaneous transluminal coronary angioplasty, while an effective intervention, can frequently lead to acute occlusion with severe consequences. Although clinical trials have demonstrated the efficacy of drug-coated balloons (DCB) in treating acute coronary artery occlusion and in preventing restenosis, there has been limited exploration on the use of DCB in treating de novo lesions in large vessels. Currently, DCB are only recommended for patients with small vessel lesions and in-stent restenosis lesions, those at high risk of bleeding, and other special groups of patients. CASE SUMMARY: This report presents a case of successful drug-coated balloon treatment of de novo lesions in large coronary vessels. Postoperatively, the patient demonstrated favorable recovery, with subsequent examination results revealing no significant differences from the previous examination. CONCLUSION: The successful treatment of the patient in our case highlights the potential of DCB in the treatment of de novo lesions in large coronary vessels.

Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction.

BACKGROUND: Doxorubicin (DOX) is an effective broad-spectrum antitumor drug, but its clinical application is limited due to the side effects of cardiac damage. Astragaloside IV (AS-IV) is a significant active component of Astragalus membranaceus that exerts cardioprotective effects through various pathways. However, whether AS-IV exerts protective effects against DOX-induced myocardial injury by regulating the pyroptosis is still unknown and is investigated in this study. METHODS: The myocardial injury model was constructed by intraperitoneal injection of DOX, and AS-IV was administered via oral gavage to explore its specific protective mechanism. Cardiac function and cardiac injury indicators, including lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and brain natriuretic peptide (BNP), and histopathology of the cardiomyocytes were assessed 4 weeks post DOX challenge. Serum levels of IL-1ß, IL-18, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) and the expression of pyroptosis and signaling proteins were also determined. RESULTS: Cardiac dysfunction was observed after the DOX challenge, as evidenced by reduced ejection fraction, increased myocardial fibrosis, and increased BNP, LDH, cTnI, and CK-MB levels (p < 0.05, N = 3-10). AS-IV attenuated DOX-induced myocardial injury. The mitochondrial morphology and structure were also significantly damaged after DOX treatment, and these changes were restored after AS-IV treatment. DOX induced an increase in the serum levels of IL-1ß, IL-18, SOD, MDA and GSH as well as an increase in the expression of pyroptosis-related proteins (p < 0.05, N = 3-6). Besides, AS-IV depressed myocardial inflammatory-related pyroptosis via activation of the expressions of nuclear factor E2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) (p < 0.05, N = 3). CONCLUSIONS: Our results showed that AS-IV had a significant protective effect against DOX-induced myocardial injury, which may be associated with the activation of Nrf-2/HO-1 to inhibit pyroptosis.

Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSC-EXO) regulate autophagy through AMPK-ULK1 signaling pathway to ameliorate diabetic cardiomyopathy.

One of the main causes of severe diabetic heart failure and mortality is diabetic cardiomyopathy (DCM), a cardiovascular condition attributable to diabetes with a high incidence, a complicated and unexplained pathophysiology, and poor treatment results. Current findings have demonstrated that the onset of diabetic cardiomyopathy involves autophagy, inflammation, and mitochondrial damage. Myocardial autophagy behaves differently in different states,and one of the targets for the detection and treatment of cardiovascular illnesses like diabetic cardiomyopathy may be the control of autophagy. The role of human umbilical cord Mesenchymal stem cells-derived exosomes (HUCMSC-EXO) as a non-cellular system in the repair of cardiomyocytes, the evolution of diabetic cardiomyopathy and their cardioprotective effects are gradually being recognized. This study's objectives were to assess the therapeutic benefits of HUCMSC-EXO for diabetic cardiomyopathy and to look into their potential mechanisms of action. High-speed centrifugation was used to extract HUCMSC-EXO, and the shape of the exosomes was examined using transmission electron microscopy. Immunoblotting was used to determine the expression of CD9, CD63, and TSG101 molecules on the surface of the exosomes. A high-fat, high-sugar diet mixed with streptozotocin was used to build a rat model of type 2 diabetic cardiomyopathy. Cardiac function, ventricular wall thickness and cardiac histological changes were examined by cardiac ultrasound, serum BNP and histology. In cardiac myocytes, HUCMSC-EXO reduced the levels of autophagy-related protein expression. Additionally, immunoblotting supported our suspicion that this mechanism is strongly tied to the activation of the AMPK-ULK1 signaling pathway. So, we propose that it would be a good strategy to follow for treating diabetic cardiomyopathy. These findings offer both fresh concepts for building a model of diabetic cardiomyopathy and a creative theoretical framework for using HUCMSC-EXO to treat diabetic cardiomyopathy in a clinical setting.

Quality markers for processed products of Morinda officinalis how based on the "oligosaccharides-spectrum-effect".

Morinda officinalis How (MO) possesses prominent tonifying kidney yang and strengthening bone and muscle effects in traditional Chinese medicine (TCM). Due to the complexity of MO components, the chemical mechanism leading to efficacy changes of MO caused by processing remain unclear. This study aimed to investigate and discover quality markers (Q-markers) related to the clinical efficacy of processed MO. The different processed products of MO have different clinical applications, although they originate from the same medicinal herb. The active chemical components from raw and processed MO that protect against reproductive oxidative stress damage were evaluated. The processed products of MO were prepared by different processing methods. The changes in oligosaccharides during processing were characterized by high-performance liquid chromatography with an evaporative light scattering detector (HPLC-ELSD), and the differential components in raw and processed MO were analyzed using SA, HCA, PCA, and OPLS-DA methods. The protective effects of raw and processed MO oligosaccharides (MOOs) against reproductive oxidative stress damage were evaluated based on the spermatic number, spermatic survival rate, abnormal sperm ratio and serum biochemical indicators in cyclophosphamide-induced (CTX-induced) male mice. The results revealed that processed MOOs had better pharmacological effects than raw MOOs. Therefore, gray correlation analysis (GRA) and the technique for order preference by similarity to ideal solution (TOPSIS) methods were used to investigate the spectrum-effect relationships of MOOs. Spectrum-effect relationship analysis revealed that all of the characteristic peaks contributed to the treatment of reproductive oxidative stress damage, and the relative correlation degrees were greater than 0.6. Among them, the peaks 1 F-fructofuranosylnystose, nystose, and 1-kestose and the peaks X2-X5, which were most closely correlated to the treatment of reproductive oxidative stress damage, were identified as inulin-oligosaccharides and inulo-oligosaccharides, respectively. It was proposed that these constituents could be considered Q-markers for processed products of MO. Thus, this study aimed to explore chemical markers that correlate with the clinical efficacy of processed MO.

The correlation between atmospheric visibility and influenza in Wuxi city, China.

Influenza is an acute respiratory infectious disease that poses a threat to public health. We assessed the association between atmospheric visibility and influenza and influenza-like illness (ILI) in Wuxi city, China.Daily meteorological data, ILI activity, and influenza virus infection rates were collected between 31 December 2012 and 31 December 2017. A distributed lag non-linear model (DLNM) was used to analyze the exposure-lag-response of ILI and influenza activity and daily average visibility.A total of 12,800 cases were detected; 1046 cases (8.17%) were of Flu-A and 527 (4.12%) were of Flu-B infection. Our analysis suggested a non-linear relationship between atmospheric visibility and influenza: U-shaped for ILI, and L-shaped for Flu-A and Flu-B. Comparing low visibility (2.5 km) to ILI cases, the risk appeared between day 1 and day 2. For Flu-A, the risk appeared between days 5 and 9, whereas for Flu-B, the risk effect was much stronger and had a longer reaction delay, staying above zero until day 9. The protective effects of high visibility (14 km) on ILI and Flu-B occurred the same day or one day later. However, we found no association between high visibility and Flu-A.In conclusion, our study contributes novel evidence for the effects of atmospheric visibility on influenza. These findings are important for the development of influenza surveillance and early warning systems in Wuxi city.

Identification of gene products that control lipid droplet size in yeast using a high-throughput quantitative image analysis.

Lipid droplets (LDs) are important organelles involved in energy storage and expenditure. LD dynamics has been investigated using genome-wide image screening methods in yeast and other model organisms. For most studies, genes were identified using two-dimensional images with LD enlargement as readout. Due to imaging limitation, reduction of LD size is seldom explored. Here, we aim to set up a screen that specifically utilizes reduced LD size as the readout. To achieve this, a novel yeast screen is set up to quantitatively and systematically identify genes that regulate LD size through a three-dimensional imaging-based approach. Cidea which promotes LD fusion and growth in mammalian cells was overexpressed in a yeast knockout library to induce large LD formation. Next, an automated, high-throughput image analysis method that monitors LD size was utilized. With this screen, we identified twelve genes that reduced LD size when deleted. The effects of eight of these genes on LD size were further validated in fld1 null strain background. In addition, six genes were previously identified as LD-regulating genes. To conclude, this methodology represents a promising strategy to screen for players in LD size control in both yeast and mammalian cells to aid in the investigation of LD-associated metabolic diseases.

Construction of Comprehensive Dosage-Matching Core Histone Mutant Libraries for Saccharomyces cerevisiae.

Saccharomyces cerevisiae contains two genes for each core histone, which are presented as pairs under the control of a divergent promoter, i.e., HHT1-HHF1, HHT2-HHF2, HTA1-HTB1 and HTA2-HTB2HHT1-HHF1, and HHT2-HHF2 encode histone H3 and H4 with identical amino acid sequences but under the control of differently regulated promoters. Previous mutagenesis studies were carried out by deleting one pair and mutating the other one. Here, we present the design and construction of three additional libraries covering HTA1-HTB1, HTA2-HTB2, and HHT1-HHF1 respectively. Together with the previously described library of HHT2-HHF2 mutants, a systematic and complete collection of mutants for each of the eight core S. cerevisiae histone genes becomes available. Each designed mutant was incorporated into the genome, generating three more corresponding libraries of yeast strains. We demonstrated that, although, under normal growth conditions, strains with single-copy integrated histone genes lacked phenotypes, in some growth conditions, growth deficiencies were observed. Specifically, we showed that addition of a second copy of the mutant histone gene could rescue the lethality in some previously known mutants that cannot survive with a single copy. This resource enables systematic studies of function of each nucleosome residue in plasmid, single-copy, and double-copy integrated formats.

Engineering the ribosomal DNA in a megabase synthetic chromosome.

We designed and synthesized a 976,067-base pair linear chromosome, synXII, based on native chromosome XII in Saccharomyces cerevisiae SynXII was assembled using a two-step method, specified by successive megachunk integration and meiotic recombination-mediated assembly, producing a functional chromosome in S. cerevisiae. Minor growth defect "bugs" detected in synXII, caused by deletion of tRNA genes, were rescued by introducing an ectopic copy of a single tRNA gene. The ribosomal gene cluster (rDNA) on synXII was left intact during the assembly process and subsequently replaced by a modified rDNA unit used to regenerate rDNA at three distinct chromosomal locations. The signature sequences within rDNA, which can be used to determine species identity, were swapped to generate a Saccharomyces synXII strain that would be identified as Saccharomyces bayanus by standard DNA barcoding procedures.

EcoExpress-Highly Efficient Construction and Expression of Multicomponent Protein Complexes in Escherichia coli.

The bacterium Escherichia coli remains the leading host for protein expression in large quantity for the purpose of crystallization or other biochemical studies. However, expression of multicomponent protein complexes remains a challenge, and is often laborious and time-consuming. Here we developed a method named EcoExpress, which allows efficient construction of plasmids to express individual protein with user-defined epitope-tag, followed by one-pot assembly of a single vector to express the entire protein complex for copurification. A versatile set of vectors was designed to provide various choices to control the expression of a protein with different promoters, and to accept different number of components for coexpression. Using EcoExpress, we demonstrated that each subunit within a protein complex could be expressed individually or simultaneously, and the entire complex could be copurified. In addition, to overcome the decreased assembly efficiency with the increasing number of components, a novel oligonucleotides blocking method was designed and tested. EcoExpress provides the scientific community with a toolbox to rapidly investigate the function of protein complexes.