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Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Alpha-ketoglutarate (α-KG), an endogenous intermediate of the tricarboxylic acid cycle, is involved in a variety of cellular metabolic pathways. It serves as an energy...
Alpha-ketoglutarate (α-KG), an endogenous intermediate of the tricarboxylic acid cycle, is involved in a variety of cellular metabolic pathways. It serves as an energy donor, a precursor of amino acid biosynthesis, and an epigenetic regulator. α-KG plays physiological functions in immune regulation, oxidative stress, and anti-aging as well. In recent years, it has been reported that the level of α-KG in the body is closely associated with metabolic syndrome, including obesity, hyperglycemia, and other pathological factors. Exogenous supplementation of α-KG improves obesity, blood glucose levels, and cardiovascular disease risks associated with metabolic syndrome. Furthermore, α-KG regulates the common pathological mechanisms of metabolic syndrome, suggesting the potential application prospect of α-KG in metabolic syndrome. In order to provide a theoretical basis for further exploration of the application of α-KG in metabolic syndrome, we focused on α-KG and metabolic syndrome in this article and summarized the latest research progress in the role of α-KG in improving the pathological condition and disease progression of metabolic syndrome. For the next step, researchers may focus on the co-pathogenesis of metabolic syndrome and investigate whether α-KG can be used to achieve the therapeutic goal of "homotherapy for heteropathy" in the treatment of metabolic syndrome.
PubMed: 38948289
DOI: 10.12182/20240560302 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Endometriosis (EMT), a common benign gynecological disease, is a leading cause of infertility in women. EMT affects female fertility in various aspects. However, the...
Endometriosis (EMT), a common benign gynecological disease, is a leading cause of infertility in women. EMT affects female fertility in various aspects. However, the underlying mechanisms have not been fully elucidated. Mitochondria are known as the "powerhouse" of a cell. They play pivotal roles in the physiological processes of cellular energy metabolism, calcium homeostasis, oxidative stress, autophagy, the regulation of cell cycle, and cell death, and are involved in the pathophysiology of many diseases. Cellular mitochondria are highly dynamic, continuously undergoing cyclic fission and fusion to meet the demands of cellular activities. Balanced mitochondrial dynamics are critical for maintaining normal reproductive function in women. In addition, mitochondria are the major source of reactive oxygen species (ROS). Cell damage, cell death, and fibrosis mediated by the imbalance in the oxidative-antioxidant system in EMT patients lead to decreased oocyte quality and ovarian reserve. Currently, the treatment of EMT-associated infertility remains a challenging and controversial topic. We herein reviewed the latest findings on the role of mitochondrial dysfunction in EMT-associated infertility and the potential therapeutic targets.
PubMed: 38948278
DOI: 10.12182/20240560404 -
MethodsX Jun 2024Chromatography combined with mass spectrometry is a gold standard technique for steroid measurement, however the type of sample preparation, the dynamic range and...
Chromatography combined with mass spectrometry is a gold standard technique for steroid measurement, however the type of sample preparation, the dynamic range and reliability of the calibration curve, the chromatographic separation and mass spectrometry settings ultimately determine the success of the method. The steroid biosynthetic pathway is conserved in higher mammals and literature demonstrates that the concentration ranges of different steroid groups are relatively comparable across species. We sought to develop a robust and reliable multi steroid targeted analysis method for blood that would have wide application across higher mammals. The method was developed following bioanalytical method validation guidelines to standards typically applied to human clinical studies, including isotopically labelled internal standards where at all possible. Here we describe the practical approach to a 96-well supported liquid extraction (SLE) method of extraction from plasma (200 µL) using an Extrahera liquid handling robot (Biotage, Sweden), including quality control samples, followed by a comprehensive separation and targeted LC-MS/MS analysis of 18 steroids in plasma (pregnenolone, progesterone, 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycortisol, 21-deoxycortisol, cortisol, cortisone, androstenedione, testosterone, 5α-dihydrotestosterone, dehydroepiandrosterone, estrone, 17β-estradiol and estriol). •SLE in a 96-well format of up to 74 biological plasma samples, enriched with multiple isotopically labelled internal standards, a 12-point aqueous calibration curve, and 6 serum quality controls, designed to monitor long-term performance of the method•Chromatographic separation of multiple steroids along the gradient, with ammonium fluoride mobile phase additive to improve sensitivity, followed by electrospray ionisation and constant polarity switching•Aqueous calibration standards that cover physiologically relevant ranges - high nanomolar glucocorticoids, low nanomolar androgens and picomolar ranges for estrogens and steroid intermediates.
PubMed: 38948242
DOI: 10.1016/j.mex.2024.102728 -
Frontiers in Network Physiology 2024Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable)...
Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable) deviation from healthy physiology. In contrast, a substantial diversity of bodily responses to SARS-CoV-2 infection have been reported in the clinical milieu. This raises the question of how to characterize the diversity of illness manifestations, and whether such characterization could reveal meaningful relationships across different illness manifestations. Here, we present a framework motivated by information theory to generate quantified maps of illness presentation, which we term "manifestations," as resolved by continuous physiological data from a wearable device (Oura Ring). We test this framework on five physiological data streams (heart rate, heart rate variability, respiratory rate, metabolic activity, and sleep temperature) assessed at the time of reported illness onset in a previously reported COVID-19-positive cohort (N = 73). We find that the number of distinct manifestations are few in this cohort, compared to the space of all possible manifestations. In addition, manifestation frequency correlates with the rough number of symptoms reported by a given individual, over a several-day period prior to their imputed onset of illness. These findings suggest that information-theoretic approaches can be used to sort COVID-19 illness manifestations into types with real-world value. This proof of concept supports the use of information-theoretic approaches to map illness manifestations from continuous physiological data. Such approaches could likely inform algorithm design and real-time treatment decisions if developed on large, diverse samples.
PubMed: 38948084
DOI: 10.3389/fnetp.2024.1211413 -
Theranostics 2024Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer...
Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both and . Our findings provide an important theoretical basis for clinical prostate cancer treatment. Our and results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.
PubMed: 38948069
DOI: 10.7150/thno.92119 -
Theranostics 2024PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their...
PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P and PI(3,5)P into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.
PubMed: 38948056
DOI: 10.7150/thno.93127 -
Theranostics 2024Radiopharmaceutical therapy (RPT) is a rapidly developing field of nuclear medicine, with several RPTs already well established in the treatment of several different... (Review)
Review
Radiopharmaceutical therapy (RPT) is a rapidly developing field of nuclear medicine, with several RPTs already well established in the treatment of several different types of cancers. However, the current approaches to RPTs often follow a somewhat inflexible "one size fits all" paradigm, where patients are administered the same amount of radioactivity per cycle regardless of their individual characteristics and features. This approach fails to consider inter-patient variations in radiopharmacokinetics, radiation biology, and immunological factors, which can significantly impact treatment outcomes. To address this limitation, we propose the development of theranostic digital twins (TDTs) to personalize RPTs based on actual patient data. Our proposed roadmap outlines the steps needed to create and refine TDTs that can optimize radiation dose to tumors while minimizing toxicity to organs at risk. The TDT models incorporate physiologically-based radiopharmacokinetic (PBRPK) models, which are additionally linked to a radiobiological optimizer and an immunological modulator, taking into account factors that influence RPT response. By using TDT models, we envisage the ability to perform virtual clinical trials, selecting therapies towards improved treatment outcomes while minimizing risks associated with secondary effects. This framework could empower practitioners to ultimately develop tailored RPT solutions for subgroups and individual patients, thus improving the precision, accuracy, and efficacy of treatments while minimizing risks to patients. By incorporating TDT models into RPTs, we can pave the way for a new era of precision medicine in cancer treatment
PubMed: 38948052
DOI: 10.7150/thno.93973 -
Heliyon Jun 2024Microbes are a worthwhile organism of the earth that could be formulated as consortium which can be utilized as biofertilizers. Consortium-based bioinoculants or...
Microbes are a worthwhile organism of the earth that could be formulated as consortium which can be utilized as biofertilizers. Consortium-based bioinoculants or biofertilizers are superior to single strain-based inoculants for sustainable agricultural productivity and increased micronutrient content in yield. The aim of present study was to evaluate the effect of different combinations of beneficial bacteria that are more effective than single-based bioinoculants. The current work focuses on the isolation of rhizospheric microorganisms from various cereals and pseudocereal crops and the development of a single inoculum as well as a bacterial consortium which were evaluated on wheat crop. A total 214 rhizospheric bacteria were sorted out and, screened for mineral solubilizing attributes i.e., phosphorus, potassium, zinc and selenium solubilization. Among all the bacterial isolates, four potential strains exhibiting P, K, Zn and Se-solubilizing attributes were identified with the help of 16S rRNA gene sequencing as EU-A3Rb1, EU-A2RNL1, EU-C3SK2, and EU-WRSe4, respectively. The identified strains formulated as a consortium which were found to improve the plant growth and physiological parameters in comparison to single culture inoculants and control. To the best of our knowledge, the present investigation is the first report that has developed the consortium from bacterial strains EU-A3Rb1, EU-A2RNL1, EU-C3SK2, and EU-WRSe4. A combination of bacterial strains could be used as liquid inoculants for cereal crops growing in mountainous regions.
PubMed: 38948031
DOI: 10.1016/j.heliyon.2024.e33167 -
Biologics : Targets & Therapy 2024
Gene Expression, Morphology, and Electrophysiology During the Dynamic Development of Human-Induced Pluripotent Stem Cell-Derived Atrial- and Ventricular-Like Cardiomyocytes [Response to Letter].
PubMed: 38948007
DOI: 10.2147/BTT.S480422 -
Frontiers in Sports and Active Living 2024Hamstring strain injuries (HSIs) remain one of the most burdensome injuries in soccer. Current recommendations to prevent sports injuries suggest the importance for...
INTRODUCTION
Hamstring strain injuries (HSIs) remain one of the most burdensome injuries in soccer. Current recommendations to prevent sports injuries suggest the importance for coaches and medical staff to consider psychological and contextual risk factors and to specify them according to the injury type and context. HSI risk factors in soccer have been widely investigated, mainly from physiological and biomechanical perspectives. However, psychological and health-related risk factors are still unexplored. Therefore, the objective of this study was to determine the psychological and health-related risk factors for a first HSI in male competitive soccer.
METHOD
Individual semi-structured interviews were conducted with ten male competitive soccer players, who had recently sustained a HSI. Based on multifactorial models of sports injury causation, soccer players' individual, contextual, and situational risk factors at the time of their first HSI were investigated. Interviews were analyzed using thematic analysis with deductive and inductive approaches.
RESULTS
Individual psychological risk factors included common at-risk personality traits, obsessive passion for soccer with competitive motivational goals, strong athletic identity, and poor health literacy. The injured players were exposed to a controlling coaching style, with a fear of negative staff evaluations, and had recently experienced life stressors. They were injured during matches or overload periods and were highly engaged in the activity.
DISCUSSION
Previously injured soccer players exhibit a lack of perspective concerning the repercussions of their actions on their health. From a preventive viewpoint, these results suggest enhancing the players' health literacy, supporting their autonomy, and moderating the controlling coaching style.
PubMed: 38947866
DOI: 10.3389/fspor.2024.1377045