Energy Metabolism: From Physiological Changes to Targets in Sepsis-induced Cardiomyopathy.

Sepsis is a systemic inflammatory response syndrome caused by a variety of dysregulated responses to host infection with life-threatening multi-organ dysfunction. Among the injuries or dysfunctions involved in the course of sepsis, cardiac injury and dysfunction often occur and are associated with the pathogenesis of hemodynamic disturbances, also defined as sepsis-induced cardiomyopathy (SIC). The process of myocardial metabolism is tightly regulated and adapts to various cardiac output demands. The heart is a metabolically flexible organ capable of utilizing all classes of energy substrates, including carbohydrates, lipids, amino acids, and ketone bodies to produce ATP. The demand of cardiac cells for energy metabolism changes substantially in septic cardiomyopathy with distinct etiological causes and different times. This review describes changes in cardiomyocyte energy metabolism under normal physiological conditions and some features of myocardial energy metabolism in septic cardiomyopathy, and briefly outlines the role of the mitochondria as a center of energy metabolism in the septic myocardium, revealing that changes in energy metabolism can serve as a potential future therapy for infectious cardiomyopathy.

Green synthesis for diverse bioactive benzo-fused spiroindolines through DBU-catalysed post-Ugi double cyclization.

A metal-free protocol utilizing DBU catalysis for post-Ugi amide-ester exchange and Conia-ene double cyclization has been successfully developed, allowing the synthesis of diverse highly functionalized benzo-fused spiroindolines with anti-cancer activities under mild conditions. Remarkably, this methodology demonstrates promising prospects for green chemistry, as it allows for the preparation of the spiroindolines in water. Control experiments indicate that a crucial role of the cyclic imide, specifically ring rigidification, facilitates the subsequent Conia-ene cyclization.

[4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

Cell death in atherosclerosis.

A complex and evolutionary process that involves the buildup of lipids in the arterial wall and the invasion of inflammatory cells results in atherosclerosis. Cell death is a fundamental biological process that is essential to the growth and dynamic equilibrium of all living things. Serious cell damage can cause a number of metabolic processes to stop, cell structure to be destroyed, or other irreversible changes that result in cell death. It is important to note that studies have shown that the two types of programmed cell death, apoptosis and autophagy, influence the onset and progression of atherosclerosis by controlling these cells. This could serve as a foundation for the creation of fresh atherosclerosis prevention and treatment strategies. Therefore, in this review, we summarized the molecular mechanisms of cell death, including apoptosis, pyroptosis, autophagy, necroptosis, ferroptosis and necrosis, and discussed their effects on endothelial cells, vascular smooth muscle cells and macrophages in the process of atherosclerosis, so as to provide reference for the next step to reveal the mechanism of atherosclerosis.

Insight into modulators of sphingosine-1-phosphate receptor and implications for cardiovascular therapeutics.

Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.

miR-186-5p targets TGFßR2 to inhibit RAW264.7 cell migration and proliferation during mouse skin wound healing.

BACKGROUND: Active peptides play a vital role in the development of new drugs and the identification and discovery of drug targets. As the first reported native peptide homodimer with pro-regenerative potency, OA-GP11d could potentially be used as a novel molecular probe to help elucidate the molecular mechanism of skin wound repair and provide new drug targets. METHODS: Bioinformatics analysis and luciferase assay were adopted to determine microRNAs (miRNAs) and its target. The prohealing potency of the miRNA was determined by MTS and a Transwell experiment against mouse macrophages. Enzyme-linked immunosorbent assay, realtime polymerase chain reaction, and western blotting were performed to explore the molecular mechanisms. RESULTS: In this study, OA-GP11d was shown to induce Mus musculus microRNA-186-5p (mmu-miR-186-5p) down-regulation. Results showed that miR-186-5p had a negative effect on macrophage migration and proliferation as well as a targeted and negative effect on TGF-ß type II receptor (TGFßR2) expression and an inhibitory effect on activation of the downstream SMAD family member 2 (Smad2) and protein-p38 kinase signaling pathways. Importantly, delivery of a miR-186-5p mimic delayed skin wound healing in mice. CONCLUSION: miR-186-5p regulated macrophage migration and proliferation to delay wound healing through the TGFßR2/Smad2/p38 molecular axes, thus providing a promising new pro-repair drug target.

Association between the beta-blockers, calcium channel blockers, all-cause mortality and length of hospitalization in patients with heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.

PURPOSE: To establish an association between beta-blockers (BBs), calcium channel blockers (CCBs), all-cause mortality, and hospitalization in patients with Heart failure with preserved Ejection Fraction (HFpEF). METHODS: The present meta-analysis has been performed as per the guidelines of (PRISMA). An inclusive literature search was made without any limitations on language using the electronic databases Cochrane Library, EMBASE, and PubMed up to November 2022. The outcomes evaluated in this meta-analysis involved all-cause mortality and hospitalization due to heart failure. The number of patients with HFpEF and their positive outcomes was extracted and analyzed using RevMan software. RESULTS: In total, 10 articles were included in the present meta-analysis, with a pooled sample size of 12 940 HFpEF patients. In comparison with placebo, both BB and CCB substantially reduced the risk of all-cause mortality and hospitalization. However, BB are more effective because they provide a significant reduction in all-cause mortality (risk ratio (RR) = 0.60; 95% confidence interval [CI] = 0.43-0.83; p = .002] and hospitalization (RR = 0.54; 95% CI = 0.37-0.80; p = .002) as compared with CCB with a risk ratio of all-cause mortality (RR = 0.77; 95% CI = 0.60-0.98; p = .03) and hospitalization (RR = 0.63; 95% CI = 0.44-0.90; p < .00001). A random-effects model was used because of high heterogeneity between the studies (I2 > 70%). CONCLUSIONS: The current meta-analysis suggests that BBs were more beneficial than CCB in reducing all-cause mortality and hospitalization duration in patients with HFpEF.

Consistent and low is the only way to go: A polynomial regression approach to the effect of abusive supervision inconsistency.

The literature on abusive supervision largely presumes that employees respond to abuse in a relatively straightforward way: When abuse is present, outcomes are unfavorable, and when abuse is absent, outcomes are favorable (or, at least less unfavorable). Yet despite the recognition that abusive supervision can vary over time, little consideration has been given to how past experiences of abuse may impact the ways employees react to it (or, its absence) in the present. This is a notable oversight, as it is widely acknowledged that past experiences create a context against which experiences in the present are compared. By applying a temporal lens to the experience of abusive supervision, we identify abusive supervision inconsistency as a phenomenon that may have different outcomes than would otherwise be predicted by the current consensus in this literature. We draw from theories on time and stress appraisal to develop a model that explains when, why, and for which employees, inconsistent abusive supervision may have negative outcomes (specifically, identifying anxiety as a proximal outcome of abusive supervision inconsistency that has downstream effects on turnover intentions). Moreover, the aforementioned theoretical perspectives dovetail in identifying employee workplace status as a moderator that may buffer employees from the stressful consequences of inconsistent abusive supervision. We test our model using two experience sampling studies with polynomial regression and response surface analyses. Our research makes important theoretical and practical contributions to the abusive supervision literature, as well as the literature on time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Visualizing Macrophage Phenotypes and Polarization in Diseases: From Biomarkers to Molecular Probes.

Macrophage is a kind of immune cell and performs multiple functions including pathogen phagocytosis, antigen presentation and tissue remodeling. To fulfill their functionally distinct roles, macrophages undergo polarization towards a spectrum of phenotypes, particularly the classically activated (M1) and alternatively activated (M2) subtypes. However, the binary M1/M2 phenotype fails to capture the complexity of macrophages subpopulations in vivo. Hence, it is crucial to employ spatiotemporal imaging techniques to visualize macrophage phenotypes and polarization, enabling the monitoring of disease progression and assessment of therapeutic responses to drug candidates. This review begins by discussing the origin, function and diversity of macrophage under physiological and pathological conditions. Subsequently, we summarize the identified macrophage phenotypes and their specific biomarkers. In addition, we present the imaging probes locating the lesions by visualizing macrophages with specific phenotype in vivo. Finally, we discuss the challenges and prospects associated with monitoring immune microenvironment and disease progression through imaging of macrophage phenotypes.

Amphibian-derived peptide homodimer OA-GL17d promotes skin wound regeneration through the miR-663a/TGF-ß1/Smad axis.

Background: Amphibian-derived peptides exhibit considerable potential in the discovery and development of new therapeutic interventions for clinically challenging chronic skin wounds. MicroRNAs (miRNAs) are also considered promising targets for the development of effective therapies against skin wounds. However, further research in this field is anticipated. This study aims to identify and provide a new peptide drug candidate, as well as to explore the underlying miRNA mechanisms and possible miRNA drug target for skin wound healing. Methods: A combination of Edman degradation, mass spectrometry and cDNA cloning were adopted to determine the amino acid sequence of a peptide that was fractionated from the secretion of Odorrana andersonii frog skin using gel-filtration and reversed-phase high-performance liquid chromatography. The toxicity of the peptide was evaluated by Calcein-AM/propidium iodide (PI) double staining against human keratinocytes (HaCaT cells), hemolytic activity against mice blood cells and acute toxicity against mice. The stability of the peptide in plasma was also evaluated. The prohealing potency of the peptide was determined by MTS, scratch healing and a Transwell experiment against HaCaT cells, full-thickness injury wounds and scald wounds in the dorsal skin of mice. miRNA transcriptome sequencing analysis, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting were performed to explore the molecular mechanisms. Results: A novel peptide homodimer (named OA-GL17d) that contains a disulfide bond between the 16th cysteine residue of the peptide monomer and the sequence 'GLFKWHPRCGEEQSMWT' was identified. Analysis showed that OA-GL17d exhibited no hemolytic activity or acute toxicity, but effectively promoted keratinocyte proliferation and migration and strongly stimulated the repair of full-thickness injury wounds and scald wounds in the dorsal skin of mice. Mechanistically, OA-GL17d decreased the level of miR-663a to increase the level of transforming growth factor-ß1 (TGF-ß1) and activate the subsequent TGF-ß1/Smad signaling pathway, thereby resulting in accelerated skin wound re-epithelialization and granular tissue formation. Conclusions: Our results suggest that OA-GL17d is a new peptide drug candidate for skin wound repair. This study emphasizes the importance of exogenous peptides as molecular probes for exploring competing endogenous RNA mechanisms and indicates that miR-663a may be an effective target for promoting skin repair.

OL-FS13 alleviates experimental cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion (I/R) is the main cause of neurological injury after stroke. However, existing treatments for I/R injury are relatively poor, and relevant drugs need to be further explored. Amphibians have received increasing attention as a resource bank of bioactive peptides. However, reports on neuroprotective peptides from amphibians remain extremely rare. Here, we identified a new neuroprotective peptide (OL-FS13, amino acid sequence: FSLLLTWWRRRVC) from the odorous frog species Odorrana livida using a constructed cDNA library. OL-FS13 significantly improving infarct volume, behavioral and histological abnormalities in rats, and also showed neuroprotective activities in PC12 cell (by oxygen glucose deprivation/reoxygenation, OGD/R). Mechanistically, OL-FS13 increased the level of antioxidative enzymes to resist oxidative stress and alleviated endoplasmic reticulum (ER) stress induced by I/R and OGD/R. The use of ML385 (Nrf2 inhibitor) indicated that OL-FS13 relieved nerve damage caused by oxidative and ER stress by increasing the nuclear displacement of Nrf2. Collectively, this research provides a novel drug candidate for the clinical cerebral I/R curation.

Targeted mitochondrial drugs for treatment of myocardial ischaemia-reperfusion injury.

Myocardial ischaemia-reperfusion injury (MI/RI) refers to the further damage done to ischaemic cardiomyocytes when restoring blood flow. A large body of evidence shows that MI/RI is closely associated with excessive production of mitochondrial reactive oxygen species, mitochondrial calcium overload, disordered mitochondrial energy metabolism, mitophagy, mitochondrial fission, and mitochondrial fusion. According to the way it affects mitochondria, it can be divided into mitochondrial quality abnormalities and mitochondrial quantity abnormalities. Abnormal mitochondrial quality refers to the dysfunction caused by the severe destruction of mitochondria, which then affects the balance of mitochondrial density and number, causing an abnormal mitochondrial quantity. In the past, most of the reports were limited to the study of the mechanism of myocardial ischaemia-reperfusion injury, some of which involved mitochondria, but no specific countermeasures were proposed. In this review, we outline the mechanisms for treating myocardial ischaemia-reperfusion injury from the direction of mitochondria and focus on targeted interventions and drugs to restore mitochondrial health during abnormal mitochondrial quality control and abnormal mitochondrial quantity control. This is an update in the field of myocardial ischaemia-reperfusion injury.

Intramural pregnancy after in vitro fertilization and embryo transfer: A case report.

BACKGROUND: Intramural pregnancy is a rare type of ectopic pregnancy, which is diagnosed by transvaginal ultrasound and magnetic resonance imaging. Management strategies vary depending on the site of the pregnancy, the gestational age and the desire to maintain fertility. The incidence of intramural pregnancy in assisted reproductive technology is higher than that in natural pregnancy. CASE SUMMARY: We present a case of intramural pregnancy after in vitro fertilization and elective single embryo transfer following salpingectomy. The patient was completely asymptomatic and her serum ß-human chorionic gonadotropin level increased from 290 mIU/mL to 1759 mIU/mL. Three-dimensional transvaginal ultrasound indicated a heterogeneous echogenic mass arising from the uterine fundus which was surrounded by myometrium and a slender and extremely hypoechoic area stretching to the uterine cavity which was thought to be a fistulous tract. Therefore, we considered a diagnosis of intramural pregnancy and laparoscopic surgery was conducted at 7 wk gestation. CONCLUSION: Early diagnosis and treatment of intramural pregnancy is significant for maintaining fertility.

cGAS-STING signaling in ischemic diseases.

Double stranded DNA (dsDNA) is known to act as a damage-associated molecular pattern (DAMP) that stimulates the body's innate immune response. In general, cyclicGMP-AMP(cGAMP)synthase(cGAS), a DNA sensor, detects these disease-causing DNA and activates the stimulator of interferon gene (STING), which in turn phosphorylates interferon regulatory factor 3 (IRF3), triggering the synthesis of type I interferon (IFN). During this process, the cGAS-STING pathway interacts with different modes of cell death, including autophagy, apoptosis, pyroptosis, and necroptosis. Importantly, cGAS might get stimulated by self-DNA, such as nuclear DNA (nuDNA) and mitochondrial DNA (mtDNA), which ensures a close association between the cGAS-STING signaling pathway and autoimmune responses. Following an ischemic attack, damaged or necrotic cells release large amounts of self-DNA that subsequently activate cGAS, resulting in a range of consequences related to an injury. The present study presents an overview of studies focused on cGAS-STING signaling and cell death, and summarizes the findings of this pathway with regard to ischemia or ischemia/reperfusion (I/R) in different organs of the body, including heart, brain, liver, kidney, and intestine.

One-pot synthesis of multi-substituted conjugated dienones by trapping allene carbocations with active ylides.

A Rh(II)/boron reagent co-catalyzed unprecedent transformation was established for the rapid construction of multi-substituted conjugated dienones under mild conditions by trapping allene carbocations with oxonium ylides from simple starting points in yields up to 85%. Two CC double bonds, one C-C and one C-O single bond were built in this one-pot reaction. The diversity-oriented strategy was also established to synthesize alkyne ether and dihydrofuran derivatives by a substrate-depended fashion.

Galectin-1 alleviates myocardial ischemia-reperfusion injury by reducing the inflammation and apoptosis of cardiomyocytes.

Myocardial ischemia-reperfusion injury (MIRI) is one of the leading causes of morbidity and mortality worldwide, for which there is no effective treatment. The present study aimed to assess novel methods of clinical MIRI treatment by studying the effects of galectin-1 (Gal-1) on MIRI. Male 2-month-old Sprague Dawley rats and the rat cardiomyocyte cell line H9c2 were utilized in the present study. A rat model of MIRI was constructed by ligating the left anterior descending coronary artery, which was subsequently treated with Gal-1. Differences in myocardial injury were then assessed by hematoxylin and eosin (H&E) staining. In addition, the levels of inflammation and apoptosis in rat myocardial tissue were determined by immunohistochemistry staining. Hypoxia-reoxygenation was used to construct a model of MIRI in H9c2 cells. The effect of Gal-1 on the apoptosis and viability of H9c2 cells was also verified by flow cytometry and a Cell Counting Kit-8 assay. The results of H&E staining revealed that Gal-1 alleviated MIRI. Echocardiography demonstrated that Gal-1 improved cardiac function in rats following MIRI. In addition, MIRI increased levels of inflammation and apoptosis in rat myocardial tissues, with Gal-1 treatment reversing this effect. In cellular experiments, Gal-1 served anti-inflammatory and anti-apoptotic effects in hypoxic/reoxygenated cardiomyocytes. In conclusion, Gal-1 served a significant protective effect on the myocardial tissue after ischemia-reperfusion by reducing the level of inflammation and apoptosis in cardiomyocytes.

Novel 2-phenyl-3-(Pyridin-2-yl) thiazolidin-4-one derivatives as potent inhibitors for proliferation of osteosarcoma cells in vitro and in vivo.

Due to unknown pathogenesis and unidentified drug target, no drug for the treatment of osteosarcoma (OS) has been launched to the market. Herein, thiazolidinone 1a was discovered as a hit compound by phenotypic screening with an in-house patrimonial collection of structural diversity. The following SAR (Structure-Activity Relationship) study affords the final water-soluble lead compound (R)-8i as a potential inhibitor for the proliferation of OS cells by the modulation of solubility of the compounds with remarkable cellular potency (IC50 = 21.9 nM for MNNG/HOS cells) and in vivo efficacy (52.9% inhibition OS growth in mice), as well as pharmacokinetic properties. (R)-8i also significantly suppresses OS cell migration in vitro and showed to be well-tolerated. Our preliminary investigation shows that the effects of (R)-8i are not dependent on p53 and myoferlin (MYOF). These results suggest that (R)-8i might be a potential drug candidate for OS treatment.

Secondary myelodysplastic syndromes identified via next-generation sequencing in a non-small cell lung cancer patient.

BACKGROUND: Myelodysplastic syndrome (MDS) is a group of clonal disorders characterized by ineffective and dysplastic hematopoiesis in the bone marrow with a high risk of progression to leukemia. Many studies have demonstrated that chemo-radiotherapy for cancer patients and exposure to certain chemicals may increase the risk of secondary MDS, which is characterized by specific chromosomal abnormalities and genomic alterations. Since next-generation sequencing (NGS) has been widely used for the diagnosis of cancer patients, advanced analysis of the sequencing data may provide supplementary information for secondary MDS. CASE PRESENTATION: A male patient with non-small cell lung cancer (NSCLC) and bone metastases has presented distal obstructive inflammation, the enlargement of the left hilar, mediastinal lymph node metastases, and multiple bone metastases. This patient has undergone long-term exposures to certain chemicals. Moreover, the deletion of chromosome 7 and 5q is detected in his peripheral blood sequencing, indicating secondary MDS, subsequently confirmed by bone marrow examination. CONCLUSION: In this case, an NSCLC patient was diagnosed with secondary MDS via NGS analysis, indicating that the NGS analysis may serve as supplementary for diagnosis of secondary MDS and provide useful information of therapeutic regimens for subsequent-line treatment of EGFR-mutated lung cancer. To the best of our knowledge, this is the first report of acquired MDS in a lung adenocarcinoma patient.

Subordinate poor performance as a stressor on leader well-being: The mediating role of abusive supervision and the moderating role of motives for abuse.

Drawing upon Stress-as-Offense-to-Self theory, we develop a moderated mediation model whereby subordinate poor performance and leader well-being is linked by abusive supervision and this mediated relationship is further moderated by leaders' motives for abuse. Specifically, we posit that higher performance promotion motives will attenuate, whereas higher injury motives will exacerbate the relationship between abusive supervision and leader emotional exhaustion, due to their differential implications for leaders' ability to see themselves in a positive light. In a pilot study, we first examined and found support for the theorized mediation chain in a multiwave field study of organizational leaders (N = 71). In Study 1, we conducted a multiwave and multisource field study of leader-follower dyads (N = 274), which supported our predictions that the indirect effect between subordinate poor performance and leader emotional exhaustion via abusive supervision was strengthened for leaders higher on injury motives. In Study 2, we undertook a 2-week daily diary study with leaders (N = 129) to hone in on the latter half of our model, focusing on within-person dynamics linking abusive supervision and leader well-being and the moderating role of leader motives for abuse. Although the within-person relationship between abusive supervision and emotional exhaustion was positive within a given day across leaders, the lagged within-person relationship between abusive supervision and emotional exhaustion unfolded differently for leaders higher versus lower on injury motives. Namely, abusive supervision had a lingering detrimental effect on leader emotional exhaustion among leaders higher on injury motives. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Thanks for Your Recognition, Boss! a Study of How and When Voice Endorsement Promotes Job Performance and Voice.

Existing studies mainly explore the antecedents and distal outcomes of voice behavior of employees. Less is known about what may occur after supervisors endorse ideas of employees. Based on the conservation of resources theory, we explored how and when voice endorsement affects job performance and voice behavior of employees. With the sample of 444 matched supervisor-subordinate pairs from a large organization, we found that voice endorsement of supervisors positively influences voice behavior and job performance of employees through the mediating effects of positive mood and work engagement. Additionally, we found that the voice commitment of employees strengthens the influence of voice endorsement of supervisors on positive mood of employees. Theoretical and practical implications of these findings are discussed.