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• Preoperative CSDS could promote prolongation of incisional pain in male mice. • CSDS-induced prolonged postoperative pain is not correlated with stress-caused social avoidance. • Perioperative CNSDS or VSDS similarly prolonged postoperative pain in both sexes. • Spinal microglial activation promotes stress-induced pain transition in a sex-dependent manner. Prolonged postsurgical pain, which is associated with multiple risk factors in the perioperative stage, is a common medical and social problem worldwide. Suitable animal models should be established to elucidate the mechanisms underlying the perioperative prolonged postsurgical pain. In this study, standard and modified social defeat stress mice models, including chronic social defeat stress (CSDS), chronic nondiscriminatory social defeat stress (CNSDS) and vicarious social defeat stress (VSDS), were applied to explore the effect of perioperative social defeat stress on postsurgical pain in male and female mice. Our results showed that exposure to preoperative CSDS could induce prolonged postsurgical pain in defeated mice regardless of susceptibility or resilience differentiated by the social interaction test. Similar prolongation of incision-induced mechanical hypersensitivity was also observed in both sexes upon exposing to CNSDS or VSDS in the preoperative period. Moreover, we found that using the modified CNSDS or VSDS models at different recovery stages after surgery could still promote abnormal pain without sex differences. Further studies revealed the key role of spinal microglial activation in the stress-induced transition from acute to prolonged postoperative pain in male but not female mice. Together, these data indicate that perioperative social defeat stress is a vital risk factor for developing prolonged postoperative pain in both sexes, but the promotion of stress-induced prolonged postoperative pain by spinal microglial activation is sexually dimorphic in mice. [ABSTRACT FROM AUTHOR]

Echinacoside, a natural phenylethanoid glycoside, was discovered and isolated from the garden plant Echinacea angustifolia DC., belonging to the Compositae family, approximately sixty years ago. Extensive investigations have revealed that it possesses a wide array of pharmacologically beneficial activities for human health, particularly notable for its neuroprotective and anticancer activity. Several crucial concerns surfaced, encompassing the recognition of active metabolites that exhibited inadequate bioavailability in their prototype form, the establishment of precise molecular signal pathways or targets associated with the aforementioned effects of echinacoside, and the scarcity of dependable clinical trials. Hence, the question remains unanswered as to whether scientific research can effectively utilize this natural compound. To support future studies on this natural product, it is imperative to provide a systematic overview and insights into potential future prospects. The current review provides a comprehensive analysis of the existing knowledge on echinacoside, encompassing its wide distribution, structural diversity and metabolism, diverse therapeutic applications, and improvement of echinacoside bioavailability for its potential utilization. [Display omitted] ● ECH, a natural phenylethanoid glycoside, has been isolated from numerous medicinal or horticultural plants. ● The latest research progress in distribution, pharmacological action and bioavailability improvement of ECH was reviewed. ● ECH is effective in oxidative stress, neurodegenerative disease, and cancer etc. ● ECH should be explored for pharmaceutical and biomedical applications. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Severe deactivation occurred in LaMnO 3 for catalytic CB oxidation. • Oxidation byproducts involved certain polychlorinated chain organics. • CeO 2 loading reduced coke deposition and retained redox ability. • HF etching promoted surf-O latt and bulk-O latt mobility. • Chlorine desorption played an important role in retaining catalyst durability. Abstract Chlorobenzene (CB) was selected as a representative chloroaromatic to evaluate its oxidation process over a perovskite LaMnO 3 catalyst. It was noted that in catalytic CB oxidation, severe deactivation occurred in the LaMnO 3 catalyst. This was mainly ascribed to surface coke deposition (involving long-chain organics) and the loss of redox ability. The byproducts in the oxidation process involved certain polychlorinated chain organics of C 2 OCl 4 , C 2 HCl 3 , and C 2 Cl 4 , which were believed to be generated through nucleophilic substitution at the Lewis acid sites of exposed MnCl x or MnO y Cl z. Modification of LaMnO 3 by introduction of CeO 2 and HF etching was found to distinctly retard catalyst deactivation. The loaded CeO 2 with enriched oxygen vacancies reduced coke deposition and retained the redox ability of LaMnO 3. The HF etching forced the fluoride ions (F−) to replace the surface lattice oxygen, which significantly promoted the mobility of surf-O latt and bulk-O latt and facilitated Cl desorption (via a Deacon reaction mechanism) from the catalyst surface, ensuring superior oxidation efficiency and stability for catalytic chloroaromatics oxidation. As calculated, the TOF of investigated catalysts followed the sequence LaMnO 3 -CeO 2 -HF (11.58 × 10−5 s−1) > LaMnO 3 -CeO 2 (10.14 × 10−5 s−1) > LaMnO 3 (5.44 × 10−5 s−1) at 120 °C in catalytic CB oxidation. [ABSTRACT FROM AUTHOR]

Mitochondrion is an organelle critically responsible for energy production and intracellular signaling in eukaryotic cells and its dysfunction often accompanies and contributes to human disease. Superoxide is the primary reactive oxygen species (ROS) produced in mitochondria. In vivo detection of superoxide has been a challenge in biomedical research. Here we describe the methods used to characterize a circularly permuted yellow fluorescent protein (cpYFP) as a biosensor for mitochondrial superoxide and pH dynamics. In vitro characterization reveals the high selectivity of cpYFP to superoxide over other ROS species and its dual sensitivity to pH. Confocal and two-photon imaging in conjunction with transgenic expression of the biosensor cpYFP targeted to the mitochondrial matrix detects mitochondrial flash events in living cells, perfused intact hearts, and live animals. The mitochondrial flashes are discrete and stochastic single mitochondrial events triggered by transient mitochondrial permeability transition (tMPT) and composed of a bursting superoxide signal and a transient alkalization signal. The real-time monitoring of single mitochondrial flashes provides a unique tool to study the integrated dynamism of mitochondrial respiration, ROS production, pH regulation and tMPT kinetics under diverse physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of death and disability. However, the molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI; however, the underlying mechanisms and consequences are not clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally, and function as important mediators of neuronal development, synaptic plasticity, and neurodegeneration. Several miRNAs show altered expression following TBI; however, the relevance of mitochondria in these pathways is unknown. Here, we present evidence supporting the association of miRNA with hippocampal mitochondria, as well as changes in mitochondria-associated miRNA expression following a controlled cortical impact (CCI) injury in rats. Specifically, we found that the miRNA processing proteins Argonaute (AGO) and Dicer are present in mitochondria fractions from uninjured rat hippocampus, and immunoprecipitation of AGO associated miRNA from mitochondria suggests the presence of functional RNA-induced silencing complexes. Interestingly, RT-qPCR miRNA array studies revealed that a subset of miRNA is enriched in mitochondria relative to cytoplasm. At 12 h following CCI, several miRNAs are significantly altered in hippocampal mitochondria and cytoplasm. In addition, levels of miR-155 and miR-223, both of which play a role in inflammatory processes, are significantly elevated in both cytoplasm and mitochondria. We propose that mitochondria-associated miRNAs may play an important role in regulating the response to TBI. [ABSTRACT FROM AUTHOR]

Abstract: Defective intracellular calcium (Ca2+) handling is implicated in the pathogenesis of heart failure. Novel approaches targeting both cardiac Ca2+ release and reuptake processes, such as S100A1, have the potential to rescue the function of failing cardiac myocytes. Here, we show that two members of the S100 Ca2+ binding protein family, S100A2 and S100A6 that share high sequence homology, differentially influence cardiac Ca2+ handling and contractility. Cardiac gene expression of S100A2 significantly enhanced both contractile and relaxation performance of rodent and canine cardiac myocytes, mimicking the functional effects of its cardiac homologue, S100A1. To interrogate mechanism, Ca2+ spark frequency, a measure of the gating of the ryanodine receptor Ca2+ release channel, was found to be significantly increased by S100A2. Therapeutic testing showed that S100A2 rescued the contractile defects of failing cardiac myocytes. In contrast, cardiac expression of S100A6 had no significant effects on contractility or Ca2+ handling. These data reveal novel differential effects of S100 proteins on cardiac myocyte performance that may be useful in application to diseased cardiac muscle. [Copyright &y& Elsevier]

Abstract: The miR-15/107 group of microRNA (miRNA) gene is increasingly appreciated to serve key functions in humans. These miRNAs regulate gene expression involved in cell division, metabolism, stress response, and angiogenesis in vertebrate species. The miR-15/107 group has also been implicated in human cancers, cardiovascular disease and neurodegenerative disease, including Alzheimer''s disease. Here we provide an overview of the following: (1) the evolution of miR-15/107 group member genes; (2) the expression levels of miRNAs in mammalian tissues; (3) evidence for overlapping gene-regulatory functions by different miRNAs; (4) the normal biochemical pathways regulated by miR-15/107 group miRNAs; and (5) the roles played by these miRNAs in human diseases. Membership in this group is defined based on sequence similarity near the mature miRNAs'' 5′ end: all include the sequence AGCAGC. Phylogeny of this group of miRNAs is incomplete; thus, a definitive taxonomic classification (e.g., designation as a “superfamily”) is currently not possible. While all vertebrates studied to date express miR-15a, miR-15b, miR-16, miR-103, and miR-107, mammals alone are known to express miR-195, miR-424, miR-497, miR-503, and miR-646. Multiple different miRNAs in the miR-15/107 group are expressed at moderate to high levels in human tissues. We present data on the expression of all known miR-15/107 group members in human cerebral cortical gray matter and white matter using new miRNA profiling microarrays. There is extensive overlap in the mRNAs targeted by miR-15/107 group members. We show new data from cultured H4 cancer cells that demonstrate similarities in mRNAs targeted by miR-16 and miR-103 and also support the importance of the mature miRNAs'' 5′ seed region in mRNA target recognition. In conclusion, the miR-15/107 group of miRNA genes is a fascinating topic of study for evolutionary biologists, miRNA biochemists, and clinically oriented translational researchers alike. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) are powerful regulators of gene expression. Although first discovered in worm larvae, miRNAs play fundamental biological roles—including in humans—well beyond development. MiRNAs participate in the regulation of metabolism (including lipid metabolism) for all animal species studied. A review of the fascinating and fast-growing literature on miRNA regulation of metabolism can be parsed into three main categories: (1) adipocyte biochemistry and cell fate determination; (2) regulation of metabolic biochemistry in invertebrates; and (3) regulation of metabolic biochemistry in mammals. Most research into the ‘function’ of a given miRNA in metabolic pathways has concentrated on a given miRNA acting upon a particular ‘target’ mRNA. Whereas in some biological contexts the effects of a given miRNA:mRNA pair may predominate, this might not be the case generally. In order to provide an example of how a single miRNA could regulate multiple ‘target’ mRNAs or even entire human metabolic pathways, we include a discussion of metabolic pathways that are predicted to be regulated by the miRNA paralogs, miR-103 and miR-107. These miRNAs, which exist in vertebrate genomes within introns of the pantothenate kinase (PANK) genes, are predicted by bioinformatics to affect multiple mRNA targets in pathways that involve cellular Acetyl-CoA and lipid levels. Significantly, PANK enzymes also affect these pathways, so the miRNA and ‘host’ gene may act synergistically. These predictions require experimental verification. In conclusion, a review of the literature on miRNA regulation of metabolism leads us believe that the future will provide researchers with many additional energizing revelations. [Copyright &y& Elsevier]

Abstract TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p =.051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p =.025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy. Highlights • Clinical, pathological, genetic, and biochemical parameters were analyzed from 136 subjects. • ABCC9 and SLCO1A2 genes are near human brain thyroid hormone receptor gene. • Cases with ABCC9 and SLCO1A2 trended toward lower brain T3/T4 (thyroid hormone) ratio. • Cases with lowest brain T3/T4 ratios had elevated risk for hippocampal sclerosis pathology. • Thyroid hormone dysregulation is implicated in HS/TDP-43 pathology but more work is required. [ABSTRACT FROM AUTHOR]

[Display omitted] • Compounds with unique cage-like units in nature are summarized for the first time. • The broad biological activities of cage compounds are summarized. • Some possible biosynthetic pathways of cage-like compounds are introduced. • Special compounds in natural products are summarized to develop new drugs. Natural products with diverse structures and significant biological activities are essential sources of drug lead compounds, and play an important role in the research and development of innovative drugs. Cage-like compounds have various structures and are widely distributed in nature, especially caged xanthones isolated from Garcinia genus, paeoniflorin and its derivatives isolated from Paeonia lactiflora Pall, tetrodotoxin (TTX) and its derivatives, and so on. In recent years, the development and utilization of cage-like compounds have been a research hotspot in chemistry, biology and other fields due to their special structures and remarkable biological activities. In this review, we mainly summarized the cage-like compounds with various structures found and isolated from natural drugs since 1956, summarized its broad biological activities, and introduced the progress in the biosynthesis of some compounds, so as to provide a reference for the discovery of more novel compounds, and the development and application of innovative drugs. [ABSTRACT FROM AUTHOR]

The heart is an excitable organ that undergoes spontaneous force generation and relaxation cycles driven by excitation–contraction (EC) coupling. A fraction of the oscillating cytosolic Ca 2 + during each heartbeat is taken up by mitochondria to stimulate mitochondrial metabolism, the major source of energy in the heart. Whether the mitochondrial metabolism is regulated individually during EC coupling and whether this heterogeneous regulation bears any physiological or pathological relevance have not been studied. Here, we developed a novel approach to determine the regulation of individual mitochondrial metabolism during cardiac EC coupling. Through monitoring superoxide flashes, which are stochastic and bursting superoxide production events arising from increased metabolism in individual mitochondria, we found that EC coupling stimulated the metabolism in individual mitochondria as indicated by significantly increased superoxide flash activity during electrical stimulation of the cultured intact myocytes or perfused heart. Mechanistically, cytosolic calcium transients promoted individual mitochondria to take up calcium via mitochondrial calcium uniporter, which subsequently triggered transient opening of the permeability transition pore and stimulated metabolism and bursting superoxide flash in that mitochondrion. The bursting superoxide, in turn, promoted local calcium release. In the early stage of heart failure, EC coupling regulation of superoxide flashes was compromised. This study highlights the heterogeneity in the regulation of cardiac mitochondrial metabolism, which may contribute to local redox signaling. [ABSTRACT FROM AUTHOR]

Abstract: Classical ischemia–reperfusion (IR) preconditioning relies on phosphatidylinositol 3-kinase (PI3K) for protective signaling. Surprisingly, inhibition of PI3Kα activity using a dominant negative (DN) strategy protected the murine heart from IR injury. It has been proposed that increased signaling through PI3Kγ may contribute to the improved recovery of PI3KαDN hearts following IR. To investigate the mechanism by which PI3KαDN hearts are protected from IR injury, we created a double mutant (PI3KDM) model by crossing p110γ−/– (PI3KγKO) with cardiac-specific PI3KαDN mice. The PI3KDM model has morphological and hemodynamic features that are characteristic of both PI3Kγ–/– and PI3KαDN mice. Interestingly, when subjected to IR using ex vivo Langendorff perfusion, PI3KDM hearts showed significantly enhanced functional recovery when compared to wildtype (WT) hearts. However, signaling downstream of PI3K through Akt and GSK3β, which has been associated with IR protection, was reduced in PI3KDM hearts. Using ex vivo working heart perfusion, we found no difference in functional recovery after IR between PI3KDM and PI3KαDN; also, glucose oxidation rates were significantly increased in PI3KαDN hearts when compared to WT, and this metabolic shift has been associated with enhanced IR recovery. However, we found that PI3KαDN hearts still had enhanced recovery when perfused exclusively with fatty acids (FA). We then investigated parallel signaling pathways, and found that mitogen-activated protein kinase signaling was increased in PI3KαDN hearts, possibly through the inhibition of negative feedback loops downstream of PI3Kα. [Copyright &y& Elsevier]

Potent neutralizing antibodies (Abs) have been proven with therapeutic efficacy for the intervention against SARS-CoV-2. Majority of these Abs function by directly interfering with the virus entry to host cells. Here, we identified a receptor binding domain (RBD) specific monoclonal Ab (mAb) 82A6 with efficient neutralizing potency against authentic SARS-CoV-2 virus. As most Abs targeting the non-receptor binding motif (RBM) region, 82A6 was incapable to block the RBD-ACE2 interaction. In particular, it actively promoted the S1 subunit shedding from the S protein, which may lead to effective reduction of intact SARS-CoV-2 viruses. Importantly, it could block potential syncytia formation associated with post-infectious cell surface expression of S proteins. Our study evidenced a RBD specific Ab with unique beneficial efficacy against SARS-CoV-2 infection, which might bring informative significance to understand the collective effects of neutralizing Abs elicited in COVID-19 patients. • 82A6 could efficiently neutralize authentic SARS-CoV-2 virus with high binding affinity. • S334-353 might represent an essential site within the non-RBM region for the recognition of 82A6. • 82A6 triggered S1 shedding with high efficiency. • 82A6 could significantly block syncytia formation. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) has fully engaged and played an essential role in the prevention and treatment of Coronavirus Disease 2019 (COVID-19). This study compares relevant standards on high-frequent Chinese Materia Medicia (CMM) used in this pandemic aiming at reaching a global consensus and ensuring the use of Chinese medicines safely. 141 representative Chinese formulas and Chinese Patent Medicines from the National Protocol and the most of Provincial Protocols for controlling COVID-19 in China have been collected to statistical analyze the composition and characteristics of CMM. Among them, the domestic and international standards of 47 varieties with the frequency usage over 10 times were selected to compare their quality requirements in the mainstream pharmacopoeias and international standards. The quality requirements of used CMM for fighting COVID-19 on the terms of overall quality control, marker compounds, and safety indicators showed different patterns in these mainstream pharmacopoeias and international standards. The uniformed and scientific quality standards of CMM were urgently needed to promote global acceptation and trade. These findings will provide evidence for building unified quality and safety standards that can adapt to the characteristics of CMM and promote international trade, and also will be stated that it is of the highest priority for ISO/TC 249 to formulate high-quality standards that consolidate international consensus to ensure quality and safety of the urgently needed CMM. [ABSTRACT FROM AUTHOR]

[Display omitted] • 46 New C- seco -rutaecarpines were designed and synthesized using PNP design strategy. • Significant anti-inflammatory effects with inhibitory preference on ILs and TNF-α. • Identification of MAPK/NF-κB pathways as the key downstream pathways. • Alleviate the hyperinflammatory state of LPS-induced mice models. • Potent hepatoprotective effect in vivo at low dosage. Pseudo-natural products (PNPs) design strategy provides a great valuable entrance to effectively identify of novel bioactive scaffolds. In this report, novel pseudo-rutaecarpines were designed via the combination of several privileged structure units and 46 target compounds were synthesized. Most of them display moderate to potent inhibitory effect on LPS-induced NO production and low cytotoxicity in RAW264.7 macrophage. The results of the anti-inflammatory efficacy and action mechanism of compounds 7l and 8c indicated that they significantly reduced the release of IL-6, IL-1β and TNF-α. Further studies revealed that they can strongly inhibit the activation of NF-κB and MAPK signal pathways. The LPS-induced acute liver injury mice model studies not only confirmed their anti-inflammatory efficacy in vivo but also could effectively relieve the liver injury in mice. The results suggest that compounds 7l and 8c might serve as lead compounds to develop therapeutic drugs for treatment of inflammation. [ABSTRACT FROM AUTHOR]

Abstract Rationale Ischemic heart disease (IHD) is a leading cause of mortality. The most effective intervention for IHD is reperfusion, which ironically causes ischemia reperfusion (I/R) injury mainly due to oxidative stress-induced cardiomyocyte death. The exact mechanism and site of reactive oxygen species (ROS) generation during I/R injury remain elusive. Objective We aim to test the hypothesis that Complex I-mediated forward and reverse electron flows are the major source of ROS in I/R injury of the heart. Methods and results We used a genetic model of mitochondrial Complex I deficiency, in which a Complex I assembling subunit, Ndufs4 was knocked out in the heart (Ndufs4H−/−). The Langendorff perfused Ndufs4H−/− hearts exhibited significantly reduced infarct size (45.3 ± 5.5% in wild type vs 20.9 ± 8.1% in Ndufs4H−/−), recovered contractile function, and maintained mitochondrial membrane potential after no flow ischemia and subsequent reperfusion. In cultured adult cardiomyocytes from Ndufs4H−/− mice, I/R mimetic treatments caused minimal cell death. Reintroducing Ndufs4 in Ndufs4H−/− cardiomyocytes abolished the protection. Mitochondrial NADH declined much slower in Ndufs4H−/− cardiomyocytes during reperfusion suggesting decreased forward electron flow. Mitochondrial flashes, a marker for mitochondrial respiration, were inhibited in Ndufs4H−/− cardiomyocytes at baseline and during I/R, which was accompanied by preserved aconitase activity suggesting lack of oxidative damage. Finally, pharmacological blockade of forward and reverse electron flow at Complex I inhibited I/R-induced cell death. Conclusions These results provide the first genetic evidence supporting the central role of mitochondrial Complex I in I/R injury of mouse heart. The study also suggests that both forward and reverse electron flows underlie oxidative cardiomyocyte death during reperfusion. Highlights • Genetic inhibition of mitochondrial Complex I protected I/R injury in mouse heart • Complex I deficiency inhibited respiration, ROS generation and cardiomyocyte death • Complex I mediated forward and reverse electron flow contributes to I/R injury [ABSTRACT FROM AUTHOR]

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse- FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling. [ABSTRACT FROM AUTHOR]

Rationale Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart. Objective To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart. Methods and results We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20 mg/kg/day for 5 days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer + mice (iKO). After 4 weeks of AngII (1.1 mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E′ and E′/A′ ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a ~ 50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities. Conclusion These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Excitotoxicity plays a critical role in neurodegenerative disease. Cytosolic calcium overload and mitochondrial dysfunction are among the major mediators of high level glutamate-induced neuron death. Here, we show that the transient opening of mitochondrial permeability transition pore (tMPT) bridges cytosolic calcium signaling and mitochondrial dysfunction and mediates glutamate-induced neuron death. Incubation of the differentiated motor neuron-like NSC34 D cells with glutamate (1 mM) acutely induces cytosolic calcium transient (30% increase). Glutamate also stimulates tMPT opening, as reflected by a 2-fold increase in the frequency of superoxide flash, a bursting superoxide production event in individual mitochondria coupled to tMPT opening. The glutamate-induced tMPT opening is attenuated by suppressing cytosolic calcium influx and abolished by inhibiting mitochondrial calcium uniporter (MCU) with Ru360 (100 μM) or MCU shRNA. Further, increased cytosolic calcium is sufficient to induce tMPT in a mitochondrial calcium dependent manner. Finally, chronic glutamate incubation (24 h) persistently elevates the probability of tMPT opening, promotes oxidative stress and induces neuron death. Attenuating tMPT activity or inhibiting MCU protects NSC34 D cells from glutamate-induced cell death. These results indicate that high level glutamate-induced neuron toxicity is mediated by tMPT, which connects increased cytosolic calcium signal to mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Phosphatidylinositide 3-kinase (PI3K) signaling plays a critical role in maintaining normal cardiac structure and function. PI3Kα and PI3Kγ are the dominant cardiac isoforms and have both adaptive and maladaptive roles in heart disease. Broad spectrum PI3K inhibitors are emerging as potential new chemotherapeutic agents which may have deleterious long-term effects on the heart. We created a double mutant (PI3KDM) model by crossing p110γ −/− (PI3KγKO) with cardiac-specific PI3KαDN mice and studied cardiac structure and function at 1-year of age. Pressure–volume loop analysis and echocardiographic assessment showed PI3KDM mice developed marked impairment in systolic function while the wildtype, PI3KαDN, and PI3KγKO mice maintained normal systolic and diastolic function at 1-year of age. The PI3KDM hearts displayed increased expression of disease markers, increased myocardial fibrosis and matrix metalloproteinase (MMP) activity, depolymerization of intracellular F-actin, loss of phospho(threonine-308)-Akt, and normalization of phospho-Erk1/2 signaling. Dual loss of PI3Kα and PI3Kγ isoforms results in an age-dependent cardiomyopathy implying that long-term exposure to pan-PI3K inhibitors may lead to severe cardiotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: The pleiotropic cytokine, interleukin-6 (IL-6), has emerged in recent years as a key regulator of the transition from innate to adaptive immunity through its ability to modulate leukocyte recruitment at inflammatory sites. This review highlights a newly identified role for IL-6 trans-signaling, initiated by an agonistic complex of IL-6 and a soluble form of IL-6 receptor α, in heightening immune surveillance of peripheral lymphoid organs during febrile inflammatory responses. Inflammatory cues provided by the thermal component of fever trigger IL-6 trans-signaling to act at discrete levels in the multistep adhesion cascade that governs the entry of blood-borne lymphocytes across ‘gatekeeper’ high endothelial venules (HEVs) in lymph nodes and Peyer patches. IL-6 trans-signaling-dependent mechanisms have been elucidated during thermal stimulation of primary tethering and rolling of lymphocytes along the lumenal surface of HEVs as well as during secondary firm arrest of lymphocytes in HEVs prior to their migration into the underlying parenchyma. These mechanisms profoundly increase the probability that lymphocytes that continuously patrol the body will engage in productive encounters with target antigens sequestered within lymphoid organs. Findings that the lymphocyte–HEV–IL-6 trans-signaling biological axis functions as a thermally-sensitive alert system that promotes immune surveillance provide insight into one of the unresolved mysteries in immunology regarding the benefits of mounting a febrile reaction during inflammation. [Copyright &y& Elsevier]

Compound 10E is a new Nur77 exporter and autophagic death inducer which showed potent antiproliferative activity at micromolar concentrations against three different liver cancer cells. [Display omitted] • New Quinoline-Indole-Schiff base derivatives with naphthalene are potent anti-HCC agents. • 10E greatly inhibits cell migration and promotes cell apoptosis in liver cancer cells. • Molecular docking and MD simulation studies suggest 10E as a valuable small ligand of Nur77. • 10E has a good affinity to Nur77 with K D values of 2.25–4.10 μM. • 10E induces the sub-cellular localization of Nur77 and results in autophagic death. We previously reported 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1 H -indole- 2-carbohydrazide derivatives as new Nur77 modulators. In this study, we explored whether the 8-methoxy-2-methylquinoline moiety and bicyclic aromatic rings at the N '-methylene position were critical for their antitumor activity against hepatocellular carcinoma (HCC). For this purpose, a small library of 5-substituted 1 H -indole-2-carbohydrazide derivatives was designed and synthesized. We found that the 8-methoxy-2-methylquinoline moiety was a fundamental structure for its biological function, while the introduction of the bicyclic aromatic ring into the N '-methylene greatly improved its anti-tumor effect. We found that the representative compound 10E had a high affinity to Nur77. The K D values were in the low micromolar (2.25–4.10 μM), which were coincident with its IC 50 values against the tumor cell lines (IC 50 < 3.78 μM). Compound 10E could induce autophagic cell death of liver cancer cells by targeting Nur77 to mitochondria while knocking down Nur77 greatly impaired anti-tumor effect. These findings provide an insight into the structure–activity relation of Quinoline-Indole-Schiff base derivatives and further demonstrate that antitumor agents targeting Nur77 may be considered as a promising strategy for HCC therapy. [ABSTRACT FROM AUTHOR]