Adenosine Triphosphate Research Articles

An ATP-activated spatiotemporally controlled hydrogel prodrug system for treating multidrug-resistant bacteria-infected pressure ulcers

Adenosine triphosphate (ATP)-activated prodrug approaches demonstrate potential in antibacterial uses. However, their efficacy frequently faces obstacles due to uncontrolled premature activation and spatiotemporal distribution differences under physiological circumstances. Herein, we present an endogenous ATP-activated prodrug system (termed ISD3) consisting of nanoparticles (indole-3-acetic acid/zeolitic imidazolate framework-8@polydopamine@platinum, IZPP) embedded in a silk fibroin-based hydrogel, aimed at treating multidrug-resistant (MDR) bacteria-infected pressure ulcers. Initially, an ultraviolet-triggered adhesive ISD3 barrier is formed over the pressure ulcer wound by a simple local injection. Subsequently, the bacteria-secreted ATP prompts the degradation of IZPP, allowing the loaded IAA prodrug and nanozyme to encounter spatiotemporally on a single carrier, thereby efficiently generating reactive oxygen species (ROS). Exposure to 808 nm near-infrared light enhances the catalytic reaction speed, boosting ROS levels for stronger antibacterial action. Once optimal antibacterial action is reached, ISD3 switches to a dormant state, halting any further ROS production. Moreover, the bioactive components in ISD3 can exert anti-inflammatory functions, aiding in pressure ulcer recovery. Overall, our research introduces a hydrogel prodrug strategy activated by bacterial endogenous ATP, which precisely manages ROS generation and accelerates the recovery of MDR bacteria-infected pressure ulcers.

Magnetic poly(phages) encoded probes-based dual-mode assay for rapid determination of live Escherichia coli and Hafnia paralvei based on microfluidic chip and ATP bioluminescence meter.

Adual-mode assay was developedfor screening and detecting live Escherichia coli (E. coli) and Hafnia paralvei (H. paralvei) (as two typical pathogens in aquatic environments) based on magnetic poly(phages) encoded probes (MPEP). The probes were prepared by grafting a large number of phages targeting different target bacteria on a long-chain DNA structure, respectively. They could specifically capture and enrich E. coli and H. paralvei by magnetic separation. Then, different DNA signal tags with different lengths conjugate with the corresponding MPEP-bacteria complex and form two kinds of sandwich structures, respectively. After that, the captured E. coli and H. paralvei were lysed to release both adenosine triphosphate (ATP) and DNA signal tags. The measurement includes two steps. Firstly, a portable ATP bioluminescence meter was employed to rapidly screen the positive samples that contain either of the two target bacteria. Secondly, only positive samples were injected into the microfluidic chip which could detect various DNA signal tags for accurate quantification of the target bacteria. The assay demonstrated high sensitivity (3 CFU/mL for E. coli and 5 CFU/mL for H. paralvei), high specificity (strain identification), signal amplification (20-fold), and short time (≤ 35 min). It can be applied to detect other pathogens solelyby changing the relative phage in MPEP. Furthermore, the proposed dual-mode assay provides a wide prospect for rapid screening and accurate determination of live foodborne pathogens. Clinical Trial Number: nbdxms-20240322.

Unraveling Potential Causative Components for the Deleterious Effect of Atmospheric Fine Particulate Matter on Red Blood Cells.

Atmospheric fine particulate matter (PM2.5) poses threats to the cardiovascular system. Red blood cells (RBCs) are the most abundant cells in blood, which are actively involved in multiple hematological diseases, such as blood clot formation and thrombosis. Exploring how PM2.5 with spatiotemporal heterogeneity influences the hematological system by targeting RBCs would help gain insights into the deleterious effects of PM2.5 and provide clues for finding the causative components therein. Herein, the PM2.5 samples collected from 3 urban sites in Beijing (i.e., Chaoyang, Shunyi, and Yanqing districts) during 4 seasons of 2022 were studied for their toxicities to mouse RBCs, and the main contributing components were further explored through chemical analysis and correlation measure. The results showed that exposure to PM2.5 samples decreased adenosine triphosphate (ATP) levels and increased phosphatidylserine (PS) externalization of RBCs, causing cell morphological deformity. The Pearson correlation analysis showed that the aromaticity of the dissolved organic matter (DOM) in PM2.5 samples was positively correlated with PS exposure of RBCs, showing that the lignin-like compounds were the potential contributors. The negative correlation of zeta potentials of PM2.5 samples with PS exposure of RBCs showed the particle-derived bioactivities of this airborne pollutant. The simulative test based on artificial nanomaterials of carbon black (CB) and oxidized CB (OCB) confirmed the crucial role of particulate carbon in PM2.5-induced effects on RBCs, and soot with a certain oxidation degree was, thus, recognized as another contributor, given its ubiquitous existence in PM2.5 samples. This study, for the first time, revealed PM2.5-induced PS exposure of RBCs, and the causative components of DOM and soot were unraveled. Considering the inevitable contact of airborne PM2.5 with RBCs in the blood circulatory system, the findings obtained herein would help bridge the gap between PM2.5 exposure and the risk of cardiovascular diseases, like thrombogenesis.

Distinguishing Wolff-Parkinson-White Syndrome From Fasciculoventricular Pathway Using QRS-T Angle Analysis.

Wolff-Parkinson-White (WPW) syndrome and fasciculoventricular pathway (FVP) present electrocardiographic manifestations characterized by delta waves, differentiating these two is challenging. Specifically, WPW type B with QRS width ≤120ms, resembles typical FVP features. Because of the presence of repolarization abnormalities in WPW syndrome, our hypothesis centered on the potential utility of the QRS-T angle for distinguishing WPW syndrome from FVP. To determine the discriminative value of the QRS-T angle for delineating WPW syndrome from FVP. We included cases of WPW syndrome treated with catheter ablation and FVP diagnosed via adenosine triphosphate administration between 2007 and 2023. We excluded cases with WPW type A, QRS width >120ms, intermittent WPW, congenital heart disease or myocardial damage, ablation history, tachycardia, palpitations within 3 months, and WPW syndrome featuring an accessory pathway on the left lateral wall. Eventually, we identified 40 and 54 patients from the WPW and FVP groups, respectively. The QRS-T angle was compared between the WPW and FVP cohorts. The QRS-T angle in the WPW group was significantly larger than in the FVP group (45.7 ± 46.3° vs. 17.8 ± 13.9°, p < 0.001). Receiver operating characteristic curve analysis with a sensitivity and specificity of 65.0% and 72.6%, respectively, demonstrated that the optimal cut-off value for the QRS-T angle was 22° for distinguishing WPW from FVP. Remarkably, all cases with a QRS-T angle >65° were within the WPW group. The QRS-T angle can offer promising utility in differentiating WPW syndrome from FVP.

Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364.

Almost 30% of survivors of myocardial infarction (MI) develop heart failure (HF), in part due to damage caused by the accumulation of dysfunctional mitochondria. Organelle quality control through Parkin-mediated mitochondrial autophagy (mitophagy) is known to play a role in mediating protection against HF damage post-ischaemic injury and remodelling of the subsequent deteriorated myocardium. This study has shown that a single i.p. dose (2 h post-MI) of the selective small molecule Parkin activator PR-364 reduced mortality, preserved cardiac ejection fraction, and mitigated the progression of HF. To reveal the mechanism of PR-364, a multi-omic strategy was deployed in combination with classical functional assays using in vivo MI and in vitro cardiomyocyte models. In vitro cell data indicated that Parkin activation by PR-364 increased mitophagy and mitochondrial biogenesis, enhanced adenosine triphosphate production via improved citric acid cycle, altered accumulation of calcium localization to the mitochondria, and initiated translational reprogramming with increased expression of mitochondrial translational proteins. In mice, PR-364 administered post-MI resulted in widespread proteome changes, indicating an up-regulation of mitochondrial metabolism and mitochondrial translation in the surviving myocardium. This study demonstrates the therapeutic potential of targeting Parkin-mediated mitophagy using PR-364 to protect surviving cardiac tissue post-MI from progression to HF.

Proteomic analysis of adenosine, thiamine, niacin and cyanocobalamin synergetic neuroprotective effect in pathophysiology of diabetic polyneuropathy

Background. Neurotransmitter adenosine and B-group vitamins are characterized by neuroprotective, remyelinizing and anti-neuroinflammatory properties. Despite the studies of these molecules for decades, the molecular mechanisms of their synergistic effect on neuroinflammation processes are unexplored and not systematized.Objective: To establish the molecular mechanisms of synergism of adenosine, thiamine, niacin and cyanocobalamin in counteracting the pathology of diabetic polyneuropathy (DPN).Material and methods. The molecular mechanisms of action of adenosine, thiamine (vitamin B1), niacin (vitamin PP) and cyanocobalamin (vitamin B12) in the pathophysiology of DPN were determined using functional analysis of genomic and proteomic databases.Results. As a result of the analysis of 20,180 annotated proteins of the human proteome, 504 vitamin-PP-dependent, 22 vitamin-B1-dependent, 24 vitamin-B12-dependent and 50 adenosine-dependent proteins were identified. The proteins of the human proteome were identified, the activity or levels of which are important for reducing neuroinflammation, remyelination, neurogenesis, biosynthesis of neuronal adenosine triphosphate, myelin homeostasis, neuroplasticity, neutralization of homocysteine, regeneration of nerve fibers and support of the endothelium of the microvascular bed.Conclusion. The established molecular mechanisms of synergism of the studied molecules are of fundamental importance for understanding the processes of neuroinflammation regulation and remyelination to prevent diabetic polyneuropathy and other neurodegenerative diseases.

Microbial response to deliquescence of nitrate-rich soils in the hyperarid Atacama Desert

Abstract. Life in hyperarid regions has adapted to extreme water scarcity through mechanisms like salt deliquescence. While halite (NaCl) crusts have been intensively studied and identified as one of the last habitats under hyperarid conditions, other less common hygroscopic salt crusts remain unexplored. Here, we investigated newly discovered deliquescent soil surfaces in the Atacama Desert, containing substantial amounts of nitrates, to evaluate their habitability for microorganisms. We characterized the environment with respect to water availability and biogeochemistry. Microbial abundances and composition were determined by cell cultivation experiments, 16S rRNA gene sequencing, and membrane phospholipid fatty acid (PLFA) analysis, while microbial activity was assessed by analyzing adenosine triphosphate (ATP) and the molecular composition of organic matter. Our findings reveal that, while the studied hygroscopic salts provide temporary water, microbial abundances and activity are lower in the studied soil surfaces than in non-deliquescent soil surfaces. Intriguingly, the deliquescent crusts are enriched in geochemically degraded organic matter, indicated by the molecular composition. We conclude that high nitrate concentrations in the hyperarid soils suppress microbial activity but preserve eolian-derived biomolecules. These insights are important for assessing the habitability and searching for life in hyperarid environments on Earth and beyond.

Deep learning-enhanced automated mitochondrial segmentation in FIB-SEM images using an entropy-weighted ensemble approach.

Mitochondria are intracellular organelles that act as powerhouses by breaking down nutrition molecules to produce adenosine triphosphate (ATP) as cellular fuel. They have their own genetic material called mitochondrial DNA. Alterations in mitochondrial DNA can result in primary mitochondrial diseases, including neurodegenerative disorders. Early detection of these abnormalities is crucial in slowing disease progression. With recent advances in data acquisition techniques such as focused ion beam scanning electron microscopy, it has become feasible to capture large intracellular organelle volumes at data rates reaching 4Tb/minute, each containing numerous cells. However, manually segmenting large data volumes (gigapixels) can be time-consuming for pathologists. Therefore, there is an urgent need for automated tools that can efficiently segment mitochondria with minimal user intervention. Our article proposes an ensemble of two automatic segmentation pipelines to predict regions of interest specific to mitochondria. This architecture combines the predicted outputs from both pipelines using an ensemble learning-based entropy-weighted fusion technique. The methodology minimizes the impact of individual predictions and enhances the overall segmentation results. The performance of the segmentation task is evaluated using various metrics, ensuring the reliability of our results. We used four publicly available datasets to evaluate our proposed method's effectiveness. Our proposed fusion method has achieved a high score in terms of the mean Jaccard index and dice coefficient for all four datasets. For instance, in the UroCell dataset, our proposed fusion method achieved scores of 0.9644 for the mean Jaccard index and 0.9749 for the Dice coefficient. The mean error rate and pixel accuracy were 0.0062 and 0.9938, respectively. Later, we compared it with state-of-the-art methods like 2D and 3D CNN algorithms. Our ensemble approach shows promising segmentation efficiency with minimal intervention and can potentially aid in the early detection and mitigation of mitochondrial diseases.

Catalpol improved energy metabolism and inflammation through the SIRT5-mediated signaling pathway to ameliorate myocardial injury

Background and purpose: Catalpol (CAT) has diverse pharmacological functions, including cellular homeostasis maintenance and anti-inflammatory effects. Sirtuin 5 (SIRT5) plays a considerable role in regulating cellular homeostasis in cardiac diseases. Our research explores the therapeutic potential of CAT against myocardial injury and its underlying mechanism. Methods: The H9c2 cells were pretreated with different CAT concentrations for 24 h, or CAT for 24 h followed by CoCl2 stimulation. Cell viability was determined with MTT assay. Biochemical assays, western blotting, and quantitative real-time PCR (qRT-PCR), combined with bioinformatic analysis, were used to examine the impact of CAT on CoCl2-induced myocardial injury in H9c2 cells and further explore its molecular mechanisms. Results: CAT ameliorated levels of myocardial enzymes, increased nicotinamide adenine dinucleotide (NAD+/NADH) ratio and adenosine triphosphate (ATP), while inhibited lactic acid (LD), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 in CoCl2-induced H9c2 cells. Mechanistically, SIRT5 knockdown inhibited Lin28a expression and negated the effects of CAT on ATP level, LD content, and the expression of inflammatory factors in cells. CAT likely exerted its protective effects on myocardial function through the SIRT5-mediated signaling pathway. Conclusions: CAT regulates energy metabolism and inflammation via the SIRT5-mediated signaling pathway, exerting a protective effect in myocardial injury.

Contamination of Disposable Distal Cap Duodenoscopes and Detachable Elevator Duodenoscopes After Reprocessing: A Randomized Trial.

To reduce bacterial contamination after reprocessing, various new designs of duodenoscopes have been developed to better expose the elevator complex for cleaning. We compared the rates of bacterial contamination and organic residue in disposable distal cap duodenoscopes and detachable elevator duodenoscopes after manual cleaning and high-level disinfection (HLD), as well as their cost-effectiveness. A total of 162 duodenoscopes were randomly assigned to either Group A (disposable distal caps; n = 81) or Group B (detachable elevator; n = 81). A total of 324 samples from the elevator were collected for culture following manual cleaning (n = 81 in each group) and HLD (n = 81 in each group), followed by the adenosine triphosphate (ATP) testing for organic residue. After manual cleaning, there was no difference in bacterial contamination rates (8.6% vs. 8.6%; p = 1.00) and mean ATP levels (164.6 ± 257.5 vs. 158.1 ± 286.1 RLUs; p = 0.88) between Groups A and B. After HLD, no bacterial contamination was observed in either group and the mean ATP levels were very low with no significant difference between the two groups (30.1 ± 45.3 vs. 37.5 ± 51.9 RLUs; p = 0.68). The expense in reprocessing (excluding the scope cost) for Group A was lower (2099 USD) than Group B (3854 USD) in providing comparable scope cleanliness. After manual cleaning, the bacterial contamination rate and organic residue levels in detachable elevator duodenoscopes and disposable distal caps duodenoscopes were comparable. No bacterial contamination was detected in either type of duodenoscope after reprocessing. Apart from the initial differences in scope cost, the disposable distal cap duodenoscope had lower cost on disposable items to have comparable disinfection result.

KIF18A inhibition: the next big player in the search for cancer therapeutics.

Kinesin-like protein 18A (KIF18A) is a member of the kinesin family of molecular motor proteins, which utilise energy from the hydrolysis of adenosine triphosphate (ATP) to regulate critical cellular processes such as chromosome movement and microtubule dynamics. KIF18A plays a vital role in controlling microtubule length, which is crucial for maintaining proper cell function and division. Notably, increased expression levels of KIF18A have been observed in various types of cancer, indicating its potential involvement in tumour progression. Although preclinical studies have demonstrated that KIF18A is not essential for normal somatic cell division, it appears to be crucial for the survival and division of cancer cells, particularly those exhibiting chromosomal instability. This dependency makes KIF18A a promising target for developing new therapeutic strategies aimed at treating chromosomally unstable cancers. This review delves into the structural and functional aspects of KIF18A, and its role in cancer development, and evaluates current and emerging approaches to targeting KIF18A with innovative cancer treatments.

Detecting structural and functional mitochondrial abnormalities in periodontal tissues using an experimental periodontitis model

Background: Recent research indicates that mitochondrial dysfunction plays a significant role in the development and progression of oral inflammation, such as periodontitis and pulpitis. Aim: To assess structural and functional mitochondrial abnormalities in periodontal tissues using an experimental periodontitis model in rats. Materials and methods: The study used male Wistar rats aged 4 months, with a body weight of 221.0±7.5 g. Simple randomization was used to divide the animals into two groups (n=10 each). Group 1 (control) consisted of intact animals, while Group 2 consisted of animals with experimentally induced periodontitis. A ligature-induced periodontitis model was used, with a non-absorbable polyfilament thread sutured into the gum near the mandibular incisors. Histological examinations were used to validate the experimental periodontitis model. The following molecular genetic and biochemical parameters were assessed: nuclear DNA and mitochondrial DNA (mtDNA) damage, abundance and heteroplasmy of mtDNA, mitochondrial gene expression, and levels of hydrogen peroxide (H2O2), malondialdehyde, and reduced glutathione. Results: The resulting experimental periodontitis model revealed histological changes in periodontal tissues, indicating periodontitis in the animals. On day 14 after ligation, histological findings showed that Group 2 had more significant mtDNA damage and heteroplasmy in periodontal tissues than Group 1 (control). Moreover, Group 2 showed a decrease in the expression of mtDNA genes involved in adenosine triphosphate synthesis. This group also had lower glutathione levels and higher H2O2 and malondialdehyde levels than the control group. Conclusion: The experimental periodontitis model in rats revealed structural and functional mitochondrial abnormalities in periodontal tissues. New approaches to assessing mitochondrial function in periodontitis may facilitate the diagnosis and treatment of the disease and its complications.

Upregulation of CD244 promotes CD8+ T cell exhaustion in patients with alveolar echinococcosis and a murine model

BackgroundIn patients with alveolar echinococcosis (AE), CD8+ T cells undergo functional exhaustion, which accelerates the malignant progression of AE. However, the role of inhibitory receptor CD244 in mediating CD8+ T cell exhaustion remains elusive.MethodsCD244 expression on exhausted CD8+ T cells in the close liver tissue (CLT) of AE patients was analyzed using single-cell RNA sequencing data. Immunohistochemistry and immunofluorescence were employed to detect CD244 expression. Flow cytometry was used to assess the impact of CD244 on differentiation and effector function of CD8+ T cells in patients with AE, in vitro and in vivo models. Reactive oxygen species (ROS) and oxygen consumption rate (OCR) were measured to evaluate the influence of CD244 on mitochondrial function of CD8+ T cells.ResultsCD244+CD8+ T cells in the CLT of AE patients exhibit a more terminal differentiation phenotype, with reduced secretion of IFN-γ and TNF-α. In vitro studies revealed that CD8+ T cells from CD244-deficient mice produced higher levels of IFN-γ, TNF-α and Granzyme B. In vivo studies revealed that CD244 deficiency enhanced the secretion capacity of IFN-γ and TNF-α by CD8+ T cells, inhibiting the growth of metacestodes. Moreover, CD244 deficiency leads to a decrease in ROS levels in liver CD8+ T cells, while significantly increasing their adenosine triphosphate (ATP)-linked oxygen consumption rate.ConclusionsCD244 facilitates AE disease progression by mediating immune exhaustion in CD8+ T cells.Graphical abstract

Intermittent episodes of acute severe encephalomyopathy and early death in two siblings caused by biallelic likely pathogenic variants in FASTKD2: Expanding phenotype and literature review.

Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine-threonine kinase domain 2 (FASTKD2) (MIM# 612322). COXPD44 is characterized by variable clinical features-developmental delay, chronic epileptic encephalopathy, seizure disorder/status epilepticus and cerebellar ataxia. We ascertained one sibwith episodic acute encephalomyopathy triggered by acute gastroenteritis and associated with haematological abnormalities, rhabdomyolysis leading to acute kidney injury, hypotensive shock leading to early death and a similarly affected sib with early death. Both siblings were normal neurologically in between the acute episodes. Whole exome sequencing (WES) was performed in the elder sibling. Mitochondrial respiratory chain enzyme activity assaywas performed in fibroblast cells and muscle tissue of the elder sibling. Also, Adenosine triphosphate (ATP) determination assay was done in fibroblast cells of the elder sibling. WES revealed compound heterozygous missense likely pathogenic variants in FASTKD2. Mitochondrial respiratory chain enzyme activity in muscle tissue showed reduced complex IV activity and ATP determination assay showed a reduction of ATP in skin fibroblasts. Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in FASTKD2 associated with the variable phenotypes and mitochondrial OXPHOS defect.

Interplay of Reactive Oxygen Species (ROS) and Epigenetic Remodelling in Cardiovascular Diseases Pathogenesis: A Contemporary Perspective.

Cardiovascular diseases (CVDs) continue to be the leading cause of mortality worldwide, necessitating the development of novel therapies. Despite therapeutic advancements, the underlying mechanisms remain elusive. Reactive oxygen species (ROS) show detrimental effects at high concentrations but act as essential signalling molecules at physiological levels, playing a critical role in the pathophysiology of CVD. However, the link between pathologically elevated ROS and CVDs pathogenesis remains poorly understood. Recent research has highlighted the remodelling of the epigenetic landscape as a crucial factor in CVD pathologies. Epigenetic changes encompass alterations in DNA methylation, post-translational histone modifications, adenosine triphosphate (ATP)-dependent chromatin modifications, and noncoding RNA transcripts. Unravelling the intricate link between ROS and epigenetic changes in CVD is challenging due to the complexity of epigenetic signals in gene regulation. This review aims to provide insights into the role of ROS in modulating the epigenetic landscape within the cardiovascular system. Understanding these interactions may offer novel therapeutic strategies for managing CVD by targeting ROS-induced epigenetic changes. It has been widely accepted that epigenetic modifications are established during development and remain fixed once the lineage-specific gene expression pattern is achieved. However, emerging evidence has unveiled its remarkable dynamism. Consequently, it is now increasingly recognized that epigenetic modifications may serve as a crucial link between ROS and the underlying mechanisms implicated in CVD.

Olaparib promotes FABP4 expression and reduces antitumor effect in ovarian cancer cells with a BRCA1 mutation.

Olaparib (AZD2281) is used as a first-line maintenance treatment for patients with ovarian cancer (OC) with a breast cancer susceptibility gene (BRCA) mutation. Fatty acid binding protein 4 (FABP4) may serve an important role in cancer, but its role in olaparib-treated OC with a BRCA mutation requires further clarification. To explore the function of FABP4 and enhance the efficacy of AZD2281 in OC, cell counting kit-8, cell apoptosis, cell cycle, colony formation, cell transfection, western blotting, reverse transcription-quantitative polymerase chain reaction, chromatin immunoprecipitation, seahorse and reactive oxygen species assays were performed. In the present study, AZD2281 significantly promoted cell apoptosis, and inhibited cell cycle progression and colony formation in COV362 cells. In addition, AZD2281 significantly upregulated the levels of CCAAT enhancer binding protein α (CEBPα), peroxisome proliferator activated receptor γ (PPARγ) and FABP4. AZD2281 markedly promoted fold enrichment of CEBPα in the promoters of PPARγ and FABP4. Furthermore, FABP4 overexpression significantly decreased cell apoptosis and promoted cell cycle progression and colony formation. In contrast, FABP4 knockdown demonstrated the opposite effects. In addition, FABP4 significantly regulated levels of reactive oxygen species, adenosine triphosphate, aerobic glycolysis, basal respiration rate and fatty acid oxidation. The combination of AZD2281 with the FABP4 inhibitor BM S309403 further significantly increased cell apoptosis and decreased colony formation. In conclusion, the findings of the present study demonstrated that AZD2281 significantly enhanced FABP4 expression, leading to diminished antitumor efficacy in OC cells with a BRCA mutation by regulating CEBPα-PPARγ. Conversely, the combination of AZD2281 and FABP4 inhibitor BM S309403 demonstrated heightened antitumor effectiveness, presenting a promising therapeutic strategy for treating patients with OC with a BRCA mutation.

Cinnamon Polyphenols Ameliorate the Dysregulation of Cardiac Energy and Autophagic Homeostasis in Rats with Diabetic Cardiomyopathy via the mTOR/PGC1α Pathway

Background Inflammation mediated by hyperglycemia, lipid metabolism disorders, abnormal myocardial energy metabolism, myocardial cell damage, and changes in ventricular structure are important mechanisms in the occurrence and development of diabetic cardiomyopathy (DCM). Cinnamon polyphenols (CP) are extracted from the traditional Chinese medicine cinnamon, which is believed to have cardioprotective effects and has been used in China for hundreds of years. Purpose This study aimed to investigate the therapeutic effects of CP on DCM and its possible mechanisms. Methods The DCM model was established by a single intraperitoneal injection of 85 mg/kg 1% streptozotocin in rats. The treatment group was orally administered 135 mg/kg CP for 28 consecutive days, a dosage verified by experiments on AC16 myocardial cells and detecting liver and kidney injury markers. Results CP could reduce high blood sugar, high blood lipids, left ventricular mass index, levels of myocardial injury markers, adenosine diphosphate (ADP), and cyclic adenosine monophosphate (cAMP) in the model group. It also improved weight loss, and increased myocardial adenosine triphosphate (ATP), adenosine monophosphate (AMP), phosphocreatine (PCr), and ATP/ADP, AMP/ATP, and PCr/ATP ratios. The expression of p-mTOR/mammalian target of rapamycin (mTOR), p62, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in the myocardium of the CP group was enhanced, while the expression of LC3II/LC3I was inhibited. Conclusion CPs can alleviate myocardial damage by reducing blood sugar, blood lipids, and abnormal autophagy levels while promoting the restoration of myocardial energy metabolism homeostasis.

The mechanism of allosteric regulation of calcium-independent phospholipase A2 by ATP and calmodulin binding to the ankyrin domain

Group VIA calcium-independent phospholipase A2 (iPLA2) is a member of the PLA2 superfamily that exhibits calcium-independent activity in contrast to the other two major types, secreted phospholipase A2 (sPLA2) and cytosolic phospholipase A2 (cPLA2), which both require calcium for their enzymatic activity. Adenosine triphosphate (ATP) has been reported to allosterically activate iPLA2, and this has now been verified with a lipidomics-based mixed-micelle assay, but its mechanism of action has been unknown. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) was employed to identify ATP interaction peptide regions located within the ankyrin repeat domain at which ATP interacts. Molecular dynamics simulations revealed the mechanism by which ATP binds to its site and the main residues that interact. Site-directed mutagenesis was used to verify the importance of these residues in the role of ATP in regulating iPLA2 activity. Importantly, calcium was found to abolish the enhancing regulatory function of ATP and to promote the inhibitory activity by calmodulin. Given previous evidence that calcium does not bind directly to iPLA2, its effect appears to be indirect via association with ATP and/or calmodulin. Using HDX-MS, we found that calmodulin interacts with the N terminus peptide region of iPLA2 consisting of residues 20 to 28. These two regulatory iPLA2 sites open the road to the development of potential targets for therapeutic intervention.

The High Millimolar Concentration of ATP: A Fundamental & Foundational Feature of Eukaryotic, Archaeotic, and Prokaryotic Domains.

Measurement of the adenosine triphosphate (ATP) concentration among different cells, tissues and organs and even across the phylogenetic tree ordinarily yields exceedingly high concentrations at the millimolar (mM) level. This represents a conundrum in that ATP-driven cellular functions only require micromolar (μM) values. Considering that nature is ordinarily conservative in the generation of high-energy phosphatic metabolites such as ATP, a potential major role for ATP has been completely overlooked and may be of paramount importance because ATP is a hydrotrope. In all phylogenetic domains, reports have established that the excessively high mM concentration of ATP is present in studies of eukaryotic cellular and tissue homogenates, living tissues, and a living organ as well as archaeotic and prokaryotic organisms. These ATP concentrations are also present in contemporary relatives of microorganisms having progenitors existing in the Precambrian Era. This feature is fundamental to cell biology across taxonomic domains. These features are interpreted as serving a foundational molecular function for maintaining organismal homeostasis. We hypothesize that ATP prevents pathological protein aggregation and maintains protein solubility through its hydrotropic feature in cells, tissues, and organs.

An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety.

Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.