ABSTRACT
Spins confined to point defects in atomically thin semiconductors constitute well-defined atomic-scale quantum systems that are being explored as single-photon emitters and spin qubits. Here, we investigate the in-gap electronic structure of individual sulfur vacancies in molybdenum disulfide (MoS2) monolayers using resonant tunneling scanning probe spectroscopy in the Coulomb blockade regime. Spectroscopic mapping of defect wave functions reveals an interplay of local symmetry breaking by a charge-state-dependent Jahn-Teller lattice distortion that, when combined with strong (≃100 meV) spin-orbit coupling, leads to a locking of an unpaired spin-1/2 magnetic moment to the lattice at low temperature, susceptible to lattice strain. Our results provide new insights into the spin and electronic structure of vacancy-induced in-gap states toward their application as electrically and optically addressable quantum systems.
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Oxidative DNA damage-related diseases, such as incurable inflammation, malignant tumors, and age-related disorders, present significant challenges in modern medicine due to their complex molecular mechanisms and limitations in identifying effective treatment targets. Recently, 8-oxoguanine DNA glycosylase 1 (OGG1) has emerged as a promising multifunctional therapeutic target for the treatment of these challenging diseases. In this review, we systematically summarize the multiple functions and mechanisms of OGG1, including pro-inflammatory, tumorigenic, and aging regulatory mechanisms. We also highlight the potential of OGG1 inhibitors and activators as potent therapeutic agents for the aforementioned life-limiting diseases. We conclude that OGG1 serves as a multifunctional hub; the inhibition of OGG1 may provide a novel approach for preventing and treating inflammation and cancer, and the activation of OGG1 could be a strategy for preventing age-related disorders. Furthermore, we provide an extensive overview of successful applications of OGG1 regulation in treating inflammatory, cancerous, and aging-related diseases. Finally, we discuss the current challenges and future directions of OGG1 as an emerging multifunctional therapeutic marker for the aforementioned challenging diseases. The aim of this review is to provide a robust reference for scientific researchers and clinical drug developers in the development of novel clinical targeted drugs for life-limiting diseases, especially for incurable inflammation, malignant tumors, and age-related disorders.
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OBJECTIVE: Erxian Decoction (EXD) is traditionally employed in the treatment of menopausal syndromes, although its underlying mechanisms remain largely undefined. Given that the senescence of bone marrow mesenchymal stem cells (BMSCs) is intertwined with organismal aging and associated diseases, this study endeavored to elucidate the influence of EXD on aging BMSCs and uncover the mechanisms through which EXD impedes BMSC senescence. METHODS: Initially, we probed the anti-senescent mechanisms of EXD on BMSCs via network pharmacology. We subsequently isolated and identified exosomes from the serum of EXD-fed rats (EXD-Exos) and administered these to H2 O2 -induced aging BMSC. Assays were conducted to assess BMSC senescence indicators and markers pertinent to mitochondrial autophagy. Treatments with mitophagy inhibitors and activators were then employed to substantiate our findings. RESULTS: Protein-protein interaction (PPI) network analyses spotlighted AKT1, TP53, TNF, JUN, VEGFA, IL6, CASP3 and EGFR as focal targets. Gene Ontology and Kyoto Encylcopedia of Genes and Genomes pathway analyses underscored oxidative stress, mitophagy and cell proliferation as pivotal processes. Our cellular assays ascertained that EXD-Exos mitigated H2 O2 -induced senescence phenotypes in BMSCs. Moreover, EXD-Exos ameliorated disrupted mitophagy in BMSCs, as evidenced by enhanced cellular membrane potential and diminished reactive oxygen species levels. Intriguingly, EXD-Exos also preserved the osteogenic differentiation potential of BMSCs while curtailing their adipogenic propensity. CONCLUSION: Our findings compellingly suggest that EXD counteracts BMSC senescence by fostering mitophagy.
Subject(s)
Disulfides , Drugs, Chinese Herbal , Exosomes , Mesenchymal Stem Cells , Thiones , Rats , Animals , Osteogenesis , Mitophagy , Exosomes/metabolism , Mesenchymal Stem Cells/metabolismABSTRACT
Background: Recent studies have indicated that heart failure (HF) with preserved ejection fraction (HFpEF) within different left ventricular ejection fraction (LVEF) ranges presents distinct morphological and pathophysiological characteristics, potentially leading to diverse prognoses. Methods: We included chronic HF patients hospitalized in the Department of Cardiology at Hebei General Hospital from January 2018 to June 2021. Patients were categorized into four groups based on LVEF: HF with reduced ejection fraction (HFrEF, LVEF ≤ 40%), HF with mildly reduced ejection fraction (HFmrEF, 41% ≤ LVEF ≤ 49%), low LVEF-HFpEF (50% ≤ LVEF ≤ 60%), and high LVEF-HFpEF (LVEF > 60%). KaplanâMeier curves were plotted to observe the occurrence rate of endpoint events (all-cause mortality and cardiovascular mortality) within a 2-year period. Cox proportional hazards regression models were employed to predict the risk factors for endpoint events. Sensitivity analyses were conducted using propensity score matching (PSM), and Fine-Gray tests were used to evaluate competitive risk. Results: A total of 483 chronic HF patients were ultimately included. KaplanâMeier curves indicated a lower risk of endpoint events in the high LVEF-HFpEF group than in the low LVEF-HFpEF group. After PSM, there were still statistically significant differences in endpoint events between the two groups (all-cause mortality p = 0.048, cardiovascular mortality p = 0.027). Body mass index (BMI), coronary artery disease, cerebrovascular disease, hyperlipidemia, hypoalbuminemia, and diuretic use were identified as independent risk factors for all-cause mortality in the low LVEF-HFpEF group (p < 0.05). Hyperlipidemia, the estimated glomerular filtration rate (eGFR), and ß -blocker use were independent risk factors for cardiovascular mortality (p < 0.05). In the high LVEF-HFpEF group, multivariate Cox regression analysis revealed that age, smoking history, hypoalbuminemia, and the eGFR were independent risk factors for all-cause mortality, while age, heart rate, blood potassium level, and the eGFR were independent risk factors for cardiovascular mortality (p < 0.05). After controlling for competitive risk, cardiovascular mortality risk remained higher in the low LVEF-HFpEF group than in the high LVEF-HFpEF group (Fine-Gray p < 0.01). Conclusions: Low LVEF-HFpEF and high LVEF-HFpEF represent two distinct phenotypes of HFpEF. Patients with high LVEF-HFpEF have lower risks of both all-cause mortality and cardiovascular mortality than those with low LVEF-HFpEF. The therapeutic reduction in blood volume may not be the best treatment option for patients with high LVEF-HFpEF.
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BACKGROUND: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. METHODS: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. RESULTS: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome. CONCLUSIONS: Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy.
Subject(s)
Disease Models, Animal , Microglia , Neurons , Receptors, Purinergic P2X7 , Seizures , Animals , Microglia/metabolism , Receptors, Purinergic P2X7/metabolism , Receptors, Purinergic P2X7/genetics , Male , Mice , Seizures/metabolism , Seizures/genetics , Neurons/metabolism , Female , Mice, Inbred C57BL , Kainic Acid , Epilepsies, Myoclonic/metabolism , Epilepsies, Myoclonic/genetics , Hippocampus/metabolism , Status Epilepticus/metabolism , Status Epilepticus/genetics , Mice, Knockout , Pentylenetetrazole , Signal Transduction , GABAergic Neurons/metabolism , Epilepsy/metabolism , Epilepsy/genetics , Brain/metabolismABSTRACT
Heterotopic bone occurs after burns, trauma and major orthopedic surgery, which cannot be completely cured by current treatments. The development of new treatments requires more in-depth research into the mechanism of HO. Available evidence suggests that miR-21-5p plays an important role in bone formation. However, its mechanism in traumatic HO is still unclear. First, we identified exosomes extracted from L6 cells using TEM observation of the structure and western blotting detection of the surface marker CD63. Regulation effect of HIF-1α to miR-21-5p was confirmed by q-PCR assay. Then we co-cultured L6 cells with ASCs and performed alizarin red staining and ALP detection. Overexpression of miR-21-5p upregulated BMP4, p-smad1/5/8, OCN and OPN, which suggests the BMP4-smad signaling pathway may be involved in miR-21-5p regulation of osteogenic differentiation of ASCs. Finally inâ vivo experiments showed that miR-21-5p exosomes promoted ectopic formation in traumatized mice. This study confirms that HIF-1α could modulate miR-21-5p exosomes to promote post-traumatic ectopic bone formation by inducing ASCs cell differentiation. Our study reveals the mechanisms of miR-21-5p in ectopic ossification formation after trauma.
Subject(s)
Exosomes , MicroRNAs , Mice , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Osteogenesis , Exosomes/metabolism , Cell Differentiation , Cells, CulturedABSTRACT
As the Internet of Things (IoT) becomes more widespread, wearable smart systems will begin to be used in a variety of applications in people's daily lives, not only requiring the devices to have excellent flexibility and biocompatibility, but also taking into account redundant data and communication delays due to the use of a large number of sensors. Fortunately, the emerging paradigms of near-sensor and in-sensor computing, together with the proposal of flexible neuromorphic devices, provides a viable solution for the application of intelligent low-power wearable devices. Therefore, wearable smart systems based on new computing paradigms are of great research value. This review discusses the research status of a flexible five-sense sensing system based on near-sensor and in-sensor architectures, considering material design, structural design and circuit design. Furthermore, we summarize challenging problems that need to be solved and provide an outlook on the potential applications of intelligent wearable devices.
Subject(s)
Internet of Things , Wearable Electronic Devices , Humans , Communication , Intelligence , PerceptionABSTRACT
Epilepsy is one of the most common neurological diseases worldwide. Anti-seizure medications (ASMs) with anticonvulsants remain the mainstay of epilepsy treatment. Currently used ASMs are, however, ineffective to suppress seizures in about one third of all patients. Moreover, ASMs show no significant impact on the pathogenic mechanisms involved in epilepsy development or disease progression and may cause serious side-effects, highlighting the need for the identification of new drug targets for a more causal therapy. Compelling evidence has demonstrated a role for purinergic signalling, including the nucleotide adenosine 5'-triphosphate (ATP) during the generation of seizures and epilepsy. Consequently, drugs targeting specific ATP-gated purinergic receptors have been suggested as promising treatment options for epilepsy including the cationic P2X7 receptor (P27XR). P2X7R protein levels have been shown to be increased in the brain of experimental models of epilepsy and in the resected brain tissue of patients with epilepsy. Animal studies have provided evidence that P2X7R blocking can reduce the severity of acute seizures and the epileptic phenotype. The current review will provide a brief summary of recent key findings on P2X7R signalling during seizures and epilepsy focusing on the potential clinical use of treatments based on the P2X7R as an adjunctive therapeutic strategy for drug-refractory seizures and epilepsy.
Subject(s)
Anticonvulsants , Drug Resistant Epilepsy , Purinergic P2X Receptor Antagonists , Receptors, Purinergic P2X7 , Receptors, Purinergic P2X7/metabolism , Humans , Animals , Anticonvulsants/therapeutic use , Anticonvulsants/pharmacology , Purinergic P2X Receptor Antagonists/therapeutic use , Purinergic P2X Receptor Antagonists/pharmacology , Drug Resistant Epilepsy/drug therapy , Drug Resistant Epilepsy/metabolism , Signal Transduction/drug effects , Molecular Targeted Therapy , Epilepsy/drug therapy , Epilepsy/metabolism , Seizures/drug therapy , Seizures/metabolismABSTRACT
Recently, food safety issues caused by contaminants have aroused great public concern. The development of innovative and efficient sensing techniques for contaminants detection in food matrix is in urgent demand. As fluorescent nanomaterials, noble metal nanoclusters have attracted much attention because of their ease of synthesis, enhanced catalytic activity and biocompatibility, and most importantly, excellent photoluminescence property that provides promising analytical applications. This review comprehensively introduced the synthesis method of noble metal nanoclusters, and summarized the application of metal nanoclusters as fluorescent sensing materials in the detection of pollutants, including pesticides, heavy metal, mycotoxin, food additives, and other contaminants in food. The detection mechanism of pesticide residues mostly relies on the inhibition of natural enzymes. For heavy metals, the detection mechanism is mainly related to the interaction between metal ions and nanoclusters or ligands. It is evidenced that metal nanoclusters have great potential application in the field of food safety monitoring. Moreover, challenges and future trends of nanoclusters were discussed. We hope that this review can provide insights and directions for the application of nanoclusters in contaminants detection.
Subject(s)
Metals, Heavy , Nanostructures , Pesticides , Food Safety/methods , Nanostructures/chemistry , Coloring AgentsABSTRACT
Huangqi Guizhi Wuwu decoction (HGWD), as a classical formula, has been used for thousands of years in China. In this work, a comprehensive strategy was proposed for characterizing the chemical profile of HGWD based on online two-dimensional hydrophilic interaction and reversed-phase liquid chromatography coupled with hybrid linear ion trap-Orbitrap mass spectrometry (online HILIC × RP-ESI/HRMS/MSn). The compounds in HGWD were first separated by the combined use of an XBridge amide column (150 × 4.6 mm, 3.5 µm) and Accucore C18 column (50 mm × 4.6 mm, 2.6 µm). Modulation with assistant technology, including trap columns and online dilution, was optimized and developed to decrease potential analyte loss and improve the resolution of the system. Subsequently, the accurate mass was determined by high-resolution Orbitrap and MSn fragment data by a hybrid linear ion trap (LTQ). In total, 170 chemical constituents were unambiguously identified or tentatively characterized in both positive and negative ion modes. Our study demonstrated that the proposed online HILIC × RP system coupled to the LTQ-Orbitrap MS platform is an efficient analytical technique for characterizing the chemical profile of multicomponent systems.
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Ulcerative colitis (UC) has emerged as a global healthcare issue due to high prevalence and unsatisfying therapeutic measures. 20(S)- Protopanaxadiol saponins (PDS) from Panax notoginseng with anti-inflammatory properties is a potential anti-colitis agent. Herein, we explored the effects and mechanisms of PDS administration on experimental murine UC. Dextran sulfate sodium-induced murine UC model was employed to investigate anti-colitis effects of PDS, and associated mechanisms were further verified in HMGB1-exposed THP-1 macrophages. Results indicated that PDS administration exerted ameliorative effects against experimental UC. Moreover, PDS administration remarkably downregulated mRNA expressions and productions of related pro-inflammatory mediators, and reversed elevated expressions of proteins related to NLRP3 inflammasome after colitis induction. Furthermore, administration with PDS also suppressed the expression and translocation of HMGB1, interrupting the downstream TLR4/NF-κB pathway. In vitro, ginsenoside CK and 20(S)-protopanaxadiol, the metabolites of PDS, exhibited greater potential in anti-inflammation, and intervened with the TLR4-binding domain of HMGB1 predictably. Expectedly, ginsenoside CK and 20(S)-protopanaxadiol administrations inhibited the activation of TLR4/NF-κB/NLRP3 inflammasome pathway in HMGB1-exposed THP-1 macrophages. Summarily, PDS administration attenuated inflammatory injury in experimental colitis by blocking the binding of HMGB1 to TLR4, majorly attributed to the antagonistic efficacies of ginsenoside CK and 20(S)-protopanaxadiol.
Subject(s)
Colitis, Ulcerative , Colitis , HMGB1 Protein , Panax notoginseng , Saponins , Mice , Animals , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Saponins/pharmacology , Panax notoginseng/chemistry , Toll-Like Receptor 4/metabolism , NF-kappa B/metabolism , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Inflammation/drug therapy , Inflammation/metabolism , Colitis/chemically induced , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Dextran Sulfate/adverse effectsABSTRACT
A biomimetic mineralization method was used in the facile and rapid preparation of nanoflowers for immobilizing alcohol dehydrogenase (ADH). The method mainly uses ADH as an organic component and zinc phosphate as an inorganic component to prepare flower-like ADH/Zn3(PO4)2 organic-inorganic hybrid nanoflowers (HNFs) with the high specific surface area through a self-assembly process. The synthesis conditions of the ADH HNFs were optimized and its morphology was characterized. Under the optimum enzymatic reaction conditions, the Michaelis-Menten constant (Km) of ADH HNFs (ß-NAD+ as substrate) was measured to be 3.54 mM, and the half-maximal inhibitory concentration (IC50) of the positive control ranitidine (0.2-0.8 mM) was determined to be 0.49 mM. Subsequently, the inhibitory activity of natural medicine Penthorum chinense Pursh and nine small-molecule compounds on ADH was evaluated using ADH HNFs. The inhibition percentage of the aqueous extract of P. chinense is 57.9%. The vanillic acid, protocatechuic acid, gallic acid, and naringenin have obvious inhibitory effects on ADH, and their percentages of inhibition are 55.1%, 68.3%, 61.9%, and 75.5%, respectively. Moreover, molecular docking analysis was applied to explore the binding modes and sites of the four most active small-molecule compounds to ADH. The results of this study can broaden the application of immobilized enzymes through biomimetic mineralization, and provide a reference for the discovery of ADH inhibitors from natural products.
Subject(s)
Alcohol Dehydrogenase , Nanostructures , Nanostructures/chemistry , Biomimetics , Molecular Docking SimulationABSTRACT
Breast cancer is a common cancer in women worldwide. The existing clinical treatment strategies have been able to limit the progression of breast cancer and cancer metastasis, but abnormal metabolism, immunosuppression, and multidrug resistance involving multiple regulators remain the major challenges for the treatment of breast cancer. Adenosine 5'-monophosphate (AMP)-Activated Protein Kinase (AMPK) can regulate metabolic reprogramming and reverse the "Warburg effect" via multiple metabolic signaling pathways in breast cancer. Previous studies suggest that the activation of AMPK suppresses the growth and metastasis of breast cancer cells, as well as stimulating the responses of immune cells. However, some other reports claim that the development and poor prognosis of breast cancer are related to the overexpression and aberrant activation of AMPK. Thus, the role of AMPK in the progression of breast cancer is still controversial. In this review, we summarize the current understanding of AMPK, particularly the comprehensive bidirectional functions of AMPK in cancer progression; discuss the pharmacological activators of AMPK and some specific molecules, including the natural products (including berberine, curcumin, (-)-epigallocatechin-3-gallate, ginsenosides, and paclitaxel) that influence the efficacy of these activators in cancer therapy; and elaborate the role of AMPK as a potential therapeutic target for the treatment of breast cancer.
Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , AMP-Activated Protein Kinases/metabolism , Breast , Signal Transduction , Plant Extracts/therapeutic useABSTRACT
The tuberous root of Ophiopogon japonicus (Thunb.) Ker-Gawl. is a well-known Chinese medicine also called Maidong (MD) in Chinese. It could be divided into "Chuanmaidong" (CMD) and "Zhemaidong" (ZMD), according to the geographic origins. Meanwhile, the root of Liriope spicata (Thunb.) Lour. var. prolifera Y. T. Ma (SMD) is occasionally used as a substitute for MD in the market. In this study, a reliable pressurized liquid extraction and HPLC-DAD-ELSD method was developed for the simultaneous determination of nine chemical components, including four steroidal saponins (ophiopojaponin C, ophiopogonin D, liriopesides B and ophiopogonin D'), four homoisoflavonoids (methylophiopogonone A, methylophiopogonone B, methylophiopogonanone A and methylophiopogonanone B) and one sapogenin (ruscogenin) in CMD, ZMD and SMD. The method was validated in terms of linearity, sensitivity, precision, repeatability and accuracy, and then applied to the real samples from different origins. The results indicated that there were significant differences in the contents of the investigated compounds in CMD, ZMD and SMD. Ruscogenin was not detected in all the samples, and liriopesides B was only found in SMD samples. CMD contained higher ophiopogonin D and ophiopogonin D', while the other compounds were more abundant in ZMD. Moreover, the anticancer effects of the herbal extracts and selected components against A2780 human ovarian cancer cells were also compared. CMD and ZMD showed similar cytotoxic effects, which were stronger than those of SMD. The effects of MD may be due to the significant anticancer potential of ophiopognin D' and homoisoflavonoids. These results suggested that there were great differences in the chemical composition and pharmacological activity among CMD, ZMD and SMD; thus, their origins should be carefully considered in clinical application.
Subject(s)
Drugs, Chinese Herbal , Ophiopogon , Ovarian Neoplasms , Saponins , Spiro Compounds , Humans , Female , Ophiopogon/chemistry , Cell Line, Tumor , Saponins/pharmacology , Saponins/chemistry , Drugs, Chinese Herbal/chemistryABSTRACT
The resin ethanol extract of Gegen Qinlian Decoction(GGQLD) has been found to significantly alleviate the intestinal toxicity caused by Irinotecan, but further research is needed to establish its overall quality and clinical medication standards. This study aimed to establish an HPLC characteristic fingerprint of the resin ethanol extract of GGQLD, predicted the targets and signaling pathways of its pharmacological effects based on network pharmacology, identified core compounds with pharmacological relevance, and analyzed potential quality markers(Q-markers) of the resin eluate of GGQLD for relieving Irinotecan-induced toxicity. By considering the uniqueness, measurability, and traceability of Q-markers based on the "five principles" of Q-markers and combining them with network pharmacology techniques, the overall efficacy of the resin ethanol extract of GGQLD can be characterized. Preliminary predictions suggested that the four components of puerarin, berberine, baicalin, and baicalein might serve as potential Q-markers for the resin etha-nol extract of GGQLD. This study provides a basis and references for the quality control and clinical mechanism of the resin ethanol extract of GGQLD.
Subject(s)
Drugs, Chinese Herbal , Network Pharmacology , Irinotecan , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic useABSTRACT
Immunotherapy sheds new light to cancer treatment and is satisfied by cancer patients. However, immunotoxicity, single-source antibodies, and single-targeting stratege are potential challenges to the success of cancer immunotherapy. A huge number of promising lead compounds for cancer treatment are of natural origin from herbal medicines. The application of natural products from herbal medicines that have immunomodulatory properties could alter the landscape of immunotherapy drastically. The present study summarizes current medication for cancer immunotherapy and discusses the potential chemicals from herbal medicines as immune checkpoint inhibitors that have a broad range of immunomodulatory effects. Therefore, this review provides valuable insights into the efficacy and mechanism of actions of cancer immunotherapies, including natural products and combined treatment with immune checkpoint inhibitors, which could confer an improved clinical outcome for cancer treatment.
Subject(s)
Biological Products , Neoplasms , Biological Products/pharmacology , Biological Products/therapeutic use , Humans , Immune Checkpoint Inhibitors , Immunomodulation , Immunotherapy , Neoplasms/therapyABSTRACT
The bile acid (BA) submetabolome can partially reflect either physiological or pathological status of vertebrates. The structural diversity, however, extensively hinders BA submetabolome clarification. Here, efforts were primarily devoted to enhance structural annotation confidences of BAs, in particular the conjugated BAs, through fortifying a new technology, namely, squared energy-resolved mass spectrometry (ER2-MS), to traditional liquid chromatography with tandem mass spectrometry (LC-MS/MS). Because of possessing two tandem-in-space collision cells, namely, q2 and linear ion trap (LIT) chambers, Qtrap-MS was employed as the fit-for-purpose tool to conduct ER2-MS measurements. The first ER-MS was undertaken in a q2 cell to gain first-generation breakdown graphs to disclose conjugation sites via applying the multiple-reaction monitoring (MRM) program, and the second ER-MS was accomplished in a LIT chamber through programming MRM cubed to acquire second-generation breakdown graphs of concerned ions for scaffold characterization. An authentic BA library consisting of commercial BAs together with their in vitro metabolites was built to record a reference breakdown graph set. Moreover, the so-called universal metabolome standard sample that was prepared by pooling diverse BA-enriched matrices was applied for structural deciphering potential evaluation and quasi-quantitative analysis of all detected BAs as well, according to applying a well-defined quasi-content concept. High-confidence structural analysis was achieved for as many as 201 BAs, and significant impacts occurred for the BA submetabolome of HepG2 cells after lithocholic acid treatment. Together, ER2-MS provides a promising tool to promote, although not limited to, LC-MS/MS-based BA-targeted metabolomics.
Subject(s)
Bile Acids and Salts , Tandem Mass Spectrometry , Animals , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Metabolomics/methods , MetabolomeABSTRACT
This paper is dedicated to the lifetime prediction of Type II modifications (i.e., nanogratings) written in silica glass using an infrared femtosecond laser. Herein we report accelerated aging experiments of such nanogratings through the monitoring of their characteristic linear birefringence signature. Based on the master curve formalism, we demonstrate that these laser-induced nanostructures can survive for 200 hours at 1100°C. Under the reported processing conditions and after a dedicated passivation treatment, the estimated lifetime of the birefringent optical elements is beyond 10 years at 800°C with a minor erasure of 7%.
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Inflammatory bowel disease (IBD) refers to a gamut of disorders that are characterized by chronic intestinal inflammation, including ulcerative colitis (UC) and Crohn's disease (CD), which often leads to mucosal ulceration and progressive loss of intestinal function. The etiopathogenesis of IBD has not been completely clarified, although multiple factors involving genetic modifications, host immune dysfunction, intestinal dysbiosis and environmental effects have been implicated. Currently, pharmacotherapies including both non-targeted and targeted biological agents are widely used for the clinical treatment of IBD. In addition, novel therapeutic approaches that target the intestinal microorganisms, such as fecal microbiota transplantation, antibiotics, probiotics and microbial metabolite inhibitors, are also under development. However, these treatments are either accompanied by side effects or cannot achieve complete clinical remission when used alone. The efficacy and safety of drugs are currently a clinical challenge. Thus, advanced drug delivery systems are needed for targeted delivery of drugs to the inflammatory sites and avoid absorption by healthy tissues. In this review, we have summarized the latest research on the pathogenesis of IBD and the emerging pharmacotherapies, and discussed potential therapeutic targets for innovative therapies.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Colitis, Ulcerative/complications , Crohn Disease/complications , Dysbiosis/complications , Fecal Microbiota Transplantation , Humans , Inflammation/complications , Inflammatory Bowel Diseases/drug therapyABSTRACT
Long noncoding RNAs (lncRNAs) are known to play a crucial role in the onset and progression of cervical cancer (CC). Here, the results of RNA microarray and RNA-sequencing dataset analysis showed that lncRNA DLEU2 was significantly upregulated in CC tissues. Clinicopathologic analysis indicated that lncRNA DLEU2 was closely related to tumor topography. Functional experiments and bioinformatics analysis revealed that lncRNA DLEU2 promoted CC cell proliferation and accelerated the cell cycle. Mechanistically, lncRNA DLEU2 promoted the progression of the cell cycle and inhibited the activity of the Notch signaling pathway by inhibiting p53 expression. Additionally, lncRNA DLEU2 probably interacted with ZFP36 Ring Finger Protein (ZFP36) to inhibit the expression of p53. In conclusion, this study revealed the function of lncRNA DLEU2 in CC tumorigenesis, suggesting new therapeutic targets in CC.