Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such ...amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
Aerobic exercise increases M2AChR, which thus improves cardiac function in cardiovascular disease (CVD) rats. This study aimed to determine whether aerobic exercise could ameliorate pressure ...overload‐induced heart hypertrophy through M2AChR, and to elucidate the underlying mechanisms of action. Mice were used to establish the myocardial hypertrophy model by transverse aortic constriction (TAC), and subjected to 2, 4, and 8 weeks of moderate‐intensity aerobic exercise and choline intervention (14 mg/kg/day). Our results showed that 4 and 8 weeks of exercise and choline intervention reduced excessive mitochondrial fission and autophagy of myocardial mitochondria, thereby improving the ultrastructure and function of mitochondria after TAC. Moreover, 8‐week exercise and choline intervention have enhanced parasympathetic function and promoted the expression of M2AChR. In addition, 8‐week exercise and choline intervention also inhibited the protein expression of myocardial MFN2, PERK/eIF2α/ATF4, and NLRP3/caspase‐1/IL‐1β signaling pathways, thereby effectively reducing mitochondrial fusion, endoplasmic reticulum stress, and inflammation. Taken together, these data suggest that pressure overload led to cardiac hypertrophy, cardiac dysfunction, and decreased parasympathetic function in cardiac tissues. Aerobic exercise attenuated cardiac dysfunction by modulating the expression of proteins involved in mitochondrial quality control, and induced endoplasmic reticulum stress and inflammation, thereby reducing cardiac hypertrophy and improving cardiac function in impaired heart tissues following TAC, which was likely mediated by M2AChR activation.
Osteoarthritis (OA) is a major cause of disability in the elderly population and represents a significant public health problem and socioeconomic burden worldwide. However, no disease-modifying ...therapeutics are currently available for OA due to an insufficient understanding of the pathogenesis of this disability. As a unique cell type in cartilage, chondrocytes are essential for cartilage homeostasis and play a critical role in OA pathogenesis. Mitochondria are important metabolic centers in chondrocytes and contribute to cell survival, and mitochondrial quality control (MQC) is an emerging mechanism for maintaining cell homeostasis. An increasing number of recent studies have demonstrated that dysregulation of the key processes of chondrocyte MQC, which involve mitochondrial redox, biogenesis, dynamics, and mitophagy, is associated with OA pathogenesis and can be regulated by the chondroprotective molecules 5′ adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 3 (SIRT3). Moreover, AMPK and SIRT3 regulate each other, and their expression and activity are always consistent in chondrocytes, which suggests the existence of an AMPK-SIRT3 positive feedback loop (PFL). Although the precise mechanisms are not fully elucidated and need further validation, the current literature indicates that this AMPK-SIRT3 PFL regulates OA development and progression, at least partially by mediating chondrocyte MQC. Therefore, understanding the mechanisms of AMPK-SIRT3 PFL-mediated chondrocyte MQC in OA pathogenesis might yield new ideas and potential targets for subsequent research on the OA pathomechanism and therapeutics.
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The application of non-target analysis (NTA), a comprehensive approach to characterize unknown chemicals, including chemicals of emerging concern has seen a steady increase recently. Given the ...relative novelty of this type of analysis, robust quality assurance and quality control (QA/QC) measures are imperative to ensure quality and consistency of results obtained using different workflows. Due to fundamental differences to established targeted workflows, new or expanded approaches are necessary; for example to minimize the risk of losing potential substances of interest (i.e. false negatives, Type II error). We present an overview of QA/QC techniques for NTA workflows published to date, specifically focusing on the analysis of environmental samples using liquid chromatography coupled to HRMS. From a QA/QC perspective, we discuss methods used for each step of analysis: sample preparation, chromatography, mass spectrometry, and data processing. We then finish with a series of recommendations to improve the quality assurance of NTA workflows.
•Non-target analysis needs specialised quality assurance approaches.•Current procedures focus mostly on specific parts of the workflow.•Loss of information (i.e. false negatives) occurs during all workflow steps.•Improvement of current quality assurance procedures is required.•Harmonization of the reporting practice of used approaches is essential.
Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively ...removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity
. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by
administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.
Microplastics (MP) as emerging persistent pollutants were found in raw and drinking water worldwide. Since different methods were used, there is an urgent need for harmonized protocols for sampling, ...sample preparation, and analysis. In this study, a holistic and validated analytical workflow for MP analysis in aqueous matrices down to 5 μm is presented. For sampling of several cubic meters of water, an easily portable filter cascade unit with different pore sizes (100–20–5 μm) was developed and successfully applied for the sampling of three processed drinking waters, two tap waters and one groundwater. The size distribution and polymer types of MP were determined using a two-step semi-automated Raman microspectroscopy analysis. For quality control, comprehensive process blanks were considered at all times and a recovery test yielded an overall recovery of 81%. The average concentration of identified MP was 66 ± 76 MP/m
3
ranging from 1 MP/m
3
to 197 MP/m
3
. All found concentrations were below the limit of quantitation (LOQ) of 1880 MP/m
3
. The majority consisted of PE (86% ± 111%) while comparatively low numbers of PET (10% ± 25%), PP (3% ± 6%), and PA (1% ± 4%) were found. 79% of all particles were smaller than 20 μm. In summary, this study presents the application of a workflow for sampling and analysis of MP down to 5 μm with first results of no significant contamination in drinking water and groundwater.
Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion (I/R) injury. Mitochondrial quality control (MQC) mechanisms, a series of adaptive responses that preserve mitochondrial ...structure and function, ensure cardiomyocyte survival and cardiac function after I/R injury. MQC includes mitochondrial fission, mitochondrial fusion, mitophagy and mitochondria-dependent cell death. The interplay among these responses is linked to pathological changes such as redox imbalance, calcium overload, energy metabolism disorder, signal transduction arrest, the mitochondrial unfolded protein response and endoplasmic reticulum stress. Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death. Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression. Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria, thus maintaining mitochondrial network fitness. Nevertheless, abnormal mitophagy is maladaptive and has been linked to cell death. Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate, they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium. Therefore, defects in MQC may determine the fate of cardiomyocytes. In this review, we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury, highlighting potential targets for the clinical management of reperfusion.
Mitochondrial quality control contributes to acute cardiac I/R injury. The mitochondrial network is constantly reshaped by the antagonistic activities between mitochondrial fission and fusion. Mitophagy allows autophagosomes to selectively degrade damaged mitochondria. When these adaptive responses fail, programmed cell death by apoptosis or necroptosis is activated. Display omitted
Edge computing is a commonly used paradigm for providing low-latency computation services by locally deploying computation and storage resources close to the user equipments (UEs). Since the ...computation resource demand of the offloaded tasks of a UE is naturally a random variable, it is possible that the real-time computation capacity demand of a resource-limited hosting virtual machine (VM) or edge computing server (ECS) is larger than its computation capacity, causing unexpected delay or delay-jitter to the services, which should be avoided if possible, for delay-sensitive applications. We consider an edge computing scenario wherein the transmission links are unmanageable and computation resource demands of VM servers are stochastic. We propose a novel Logistic function-based service reliability probability (SRP) estimation model without specifying the distributions of the resource demands. We study the average SRP maximization problem (ASRPMP) in a VM-based edge computing server (ECS) by jointly optimizing the service quality ratios (SQRs) and the computation resource allocations, and we propose an alternative optimization algorithm (AOA) by decomposing the problem into a resource allocation problem (RAP) and a service quality control problem (SQCP). Based on the derived analytical solutions of the two subproblems, we propose an effective and low-complexity heuristic AOA (HAOA) to solve the ASRPMP. The simulation results obtained from both synthetic Gaussian workload data and PlanetLab trace data demonstrate that, given the same target SQR or computation resource, the proposed method can achieve similar performance compared with the convex AOA (CAOA) method with much higher complexity, and can improve the reliability of the services compared with the baseline weighted allocation method (WAM) in both high and low SRP regimes.
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