Progress of Astrocyte-Neuron Crosstalk in Central Nervous System Diseases.

Neurons are the primary cells responsible for information processing in the central nervous system (CNS). However, they are vulnerable to damage and insult in a variety of neurological disorders. As the most abundant glial cells in the brain, astrocytes provide crucial support to neurons and participate in synapse formation, synaptic transmission, neurotransmitter recycling, regulation of metabolic processes, and the maintenance of the blood-brain barrier integrity. Though astrocytes play a significant role in the manifestation of injury and disease, they do not work in isolation. Cellular interactions between astrocytes and neurons are essential for maintaining the homeostasis of the CNS under both physiological and pathological conditions. In this review, we explore the diverse interactions between astrocytes and neurons under physiological conditions, including the exchange of neurotrophic factors, gliotransmitters, and energy substrates, and different CNS diseases such as Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis. This review sheds light on the contribution of astrocyte-neuron crosstalk to the progression of neurological diseases to provide potential therapeutic targets for the treatment of neurological diseases.

Trifarotene alleviates skin photoaging injury by inhibition of JNK/c-Jun/MMPs.

Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 µmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway.

Progress on the effects and underlying mechanisms of evodiamine in digestive system diseases, and its toxicity: A systematic review and meta-analysis.

BACKGROUND: Evodiamine (EVO) is one of the primary components of Evodia rutaecarpa and has been found to have a positive therapeutic effect on various digestive system diseases. However, no systematic review has been conducted on the research progress and mechanisms of EVO in relation to digestive system diseases, and its toxicity. PURPOSE: This study aimed to provide a reference for future research in this field. STUDY DESIGN: A systematic review and meta-analysis of the research progress, mechanisms, and toxicity of EVO in the treatment of digestive system diseases. METHODS: Five electronic databases were utilized to search for relevant experiments. We conducted a comprehensive review and meta-analysis of the pertinent literature following the guidelines of Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). RESULTS: EVO's animal experiments in digestive system diseases primarily focus on colorectal cancer, gastric ulcers, liver cancer, liver fibrosis, ulcerative colitis, colitis-associated cancer, and functional gastrointestinal disorders. EVO also has positive effects on pancreatic cancer, radiation enteritis, gastric cancer, tongue squamous cancer, hepatitis B, oral cancer, and esophageal cancer in vivo. EVO's in cellular experiments primarily focus on SGC7901, HT29, HCT-116, and HepG2 cells. EVO also exhibits positive effects on SW480, LoVo, BGC-823, AGS, COLO-205, MKN45, SMMC-7721, Bel-7402, QGY7-701, PANC-1, SW1990, BxPC-3, HSC4, MC3, HONE1, and CNE1 cells in vitro. The potential common pathways include TGF-ß, PI3K-AKT, Wnt, ErbB, mTOR, MAPK, HIF-1, NOD-like receptor, NF-κB, VEGF, JAK-STAT, AMPK, Toll-like receptor, EGFR, Ras, TNF, AGE-RAGE, Relaxin, FoxO, IL-17, Hippo, and cAMP. The mechanisms of EVO on ulcerative colitis, gastric cancer, and HCT116 cells are still controversial in vivo. EVO may have a bidirectional regulatory effect on functional gastrointestinal disorders through calcium signaling. The mechanisms of EVO on HCT116, HT29, SW480, AGS, COLO-205, and SW1990 cells are still controversial in vitro. The question of whether EVO has obvious toxicity is controversial. CONCLUSION: In both cellular and animal experiments, EVO has demonstrated positive impacts on digestive system diseases. Nevertheless, additional in vivo and in vitro research is required to confirm the beneficial effects and mechanisms of EVO on digestive system diseases, as well as its potential toxicity.

Myeloid Cell Trim59 Deficiency Worsens Experimental Ischemic Stroke and Alters Cerebral Proteomic Profile.

Background: Tripartite motif containing 59 (TRIM59) is a ubiquitin ligase and is involved in the pathogenesis of various diseases, including cancers, sepsis, and other immune-related diseases. However, it has not been defined whether TRIM59 plays a role in ischemic stroke in mice. Methods: This study determined the influence of Trim59 deficiency on experimental stroke outcomes and the cerebral proteomic profile using myeloid cell Trim59 conditional knockout (Trim59-cKO) mice and a label-free quantitative proteomic profiling technique. The possible mechanisms by which TRIM59 affected stroke onset were elucidated by in vivo and in vitro experiments. Results: Immunofluorescence staining results showed that TRIM59 expression was up-regulated after cerebral ischemia and co-localized with macrophages. Myeloid cell Trim59 deficiency exacerbated ischemic injury on day 3 after experimental stroke. In proteomic analysis, 23 differentially expressed proteins were identified in ischemic brain of Trim59-cKO mice as compared to Trim59flox/flox mice. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the differentially expressed proteins were enriched in complement and coagulation cascades. Protein-protein interaction analysis suggested the central role of clusterin in the interaction network. ELISA and Western blot assays confirmed the reduced levels of clusterin protein in the ischemic brains of Trim59-cKO mice. Further experimental results showed that clusterin was expressed in neurons. Conditional co-culture experiments of primary neurons and bone marrow-derived macrophages demonstrated that LPS stimulated macrophages to secrete complement C3. In addition, TRIM59 may affect the changes in clusterin expression in an indirect manner by influencing the secretion of complement C3 in macrophages. In vivo experiments also proved a significant increase in C3 levels in the brains of Trim59-cKO mice after ischemia. Conclusion: Myeloid cell Trim59 deficiency aggravated ischemic stroke outcomes in conjunction with a distinct cerebral proteomic profile, and the underlying mechanism may be related to the regulation of macrophage C3 expression by TRIM59.

Research progress on prediction of RNA-protein binding sites in the past five years.

Accurately predicting RNA-protein binding sites is essential to gain a deeper comprehension of the protein-RNA interactions and their regulatory mechanisms, which are fundamental in gene expression and regulation. However, conventional biological approaches to detect these sites are often costly and time-consuming. In contrast, computational methods for predicting RNA protein binding sites are both cost-effective and expeditious. This review synthesizes already existing computational methods, summarizing commonly used databases for predicting RNA protein binding sites. In addition, applications and innovations of computational methods using traditional machine learning and deep learning for RNA protein binding site prediction during 2018-2023 are presented. These methods cover a wide range of aspects such as effective database utilization, feature selection and encoding, innovative classification algorithms, and evaluation strategies. Exploring the limitations of existing computational methods, this paper delves into the potential directions for future development. DeepRKE, RDense, and DeepDW all employ convolutional neural networks and long and short-term memory networks to construct prediction models, yet their algorithm design and feature encoding differ, resulting in diverse prediction performances.

Stage-specific regulation of undifferentiated spermatogonia by AKT1S1-mediated AKT-mTORC1 signaling during mouse spermatogenesis.

Undifferentiated spermatogonia are composed of a heterogeneous cell population including spermatogonial stem cells (SSCs). Molecular mechanisms underlying the regulation of various spermatogonial cohorts during their self-renewal and differentiation are largely unclear. Here we show that AKT1S1, an AKT substrate and inhibitor of mTORC1, regulates the homeostasis of undifferentiated spermatogonia. Although deletion of Akt1s1 in mouse appears not grossly affecting steady-state spermatogenesis and male mice are fertile, the subset of differentiation-primed OCT4+ spermatogonia decreased significantly, whereas self-renewing GFRα1+ and proliferating PLZF+ spermatogonia were sustained. Both neonatal prospermatogonia and the first wave spermatogenesis were greatly reduced in Akt1s1-/- mice. Further analyses suggest that OCT4+ spermatogonia in Akt1s1-/- mice possess altered PI3K/AKT-mTORC1 signaling, gene expression and carbohydrate metabolism, leading to their functionally compromised developmental potential. Collectively, these results revealed an important role of AKT1S1 in mediating the stage-specific signals that regulate the self-renewal and differentiation of spermatogonia during mouse spermatogenesis.

Progress of Ferroptosis in Ischemic Stroke and Therapeutic Targets.

Ferroptosis is an iron-dependent form of programmed cell death (PCD) and ischemic stroke (IS) has been confirmed to be closely related to ferroptosis. The mechanisms of ferroptosis were summarized into three interrelated aspects: iron metabolism, lipid peroxide metabolism, as well as glutathione and amino acid metabolism. What's more, the causal relationship between ferroptosis and IS has been elucidated by several processes. The disruption of the blood-brain barrier, the release of excitatory amino acids, and the inflammatory response after ischemic stroke all lead to the disorder of iron metabolism and the antioxidant system. Based on these statements, we reviewed the reported effects of compounds and drugs treating IS by modulating key molecules in ferroptosis. Through detailed analysis of the roles of these key molecules, we have also more clearly demonstrated the essential effect of ferroptosis in the occurrence of IS so as to provide new targets and ideas for the therapeutic targets of IS.

CDS-DB, an omnibus for patient-derived gene expression signatures induced by cancer treatment.

Patient-derived gene expression signatures induced by cancer treatment, obtained from paired pre- and post-treatment clinical transcriptomes, can help reveal drug mechanisms of action (MOAs) in cancer patients and understand the molecular response mechanism of tumor sensitivity or resistance. Their integration and reuse may bring new insights. Paired pre- and post-treatment clinical transcriptomic data are rapidly accumulating. However, a lack of systematic collection makes data access, integration, and reuse challenging. We therefore present the Cancer Drug-induced gene expression Signature DataBase (CDS-DB). CDS-DB has collected 78 patient-derived, paired pre- and post-treatment transcriptomic source datasets with uniformly reprocessed expression profiles and manually curated metadata such as drug administration dosage, sampling time and location, and intrinsic drug response status. From these source datasets, 2012 patient-level gene perturbation signatures were obtained, covering 85 therapeutic regimens, 39 cancer subtypes and 3628 patient samples. Besides data browsing, download and search, CDS-DB also supports single signature analysis (including differential gene expression, functional enrichment, tumor microenvironment and correlation analyses), signature comparative analysis and signature connectivity analysis. This provides insights into drug MOA and its heterogeneity in patients, drug resistance mechanisms, drug repositioning and drug (combination) discovery, etc. CDS-DB is available at http://cdsdb.ncpsb.org.cn/.

A comprehensive quality evaluation for Huangqi Guizhi Wuwu decoction by integrating UPLC-DAD/MS chemical profile and pharmacodynamics combined with chemometric analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Guizhi Wuwu Decoction (HGWD), a classical Chinese formula originally recorded in Jin Kui Yao Lue, was used for the treatment of human "blood impediment" (a type of "Bi" syndrome). In clinical practice, HGWD has been applied to treat rheumatoid arthritis (RA). AIM OF THE STUDY: The characterization of chemical markers reflecting both efficacy and chemical characteristics is of great significance for TCM quality control. With the anti-RA effects of HGWD as an example, the aim of this study was to develop a comprehensive strategy combining the overall chemical profile and biological activity data to identify chemical markers. MATERIALS AND METHODS: First, an ultra-performance liquid chromatography-diode array detector (UPLC-DAD) fingerprint was established and validated to evaluate the holistic quality of HGWD of different origins. Characteristic markers associated with HGWD from different geographical origins were screened by a combination of UPLC-DAD fingerprint and chemometrics methods. Second, the chemical profiles of the 15 batches of HGWD samples were characterized by UPLC coupled tohybrid linear ion trap-Orbitrap mass spectrometry (UPLC-HRMS). The in vitro anti-RA activities of the 15 HGWD samples were then evaluated. Third, spectrum-effect relationship analysis was performed to identify bioactive compounds that could potentially be used as quality markers. Finally, a UPLC-triple quadrupole tandem mass spectrometry approach was optimized and established for quantitative analysis of the characteristic and quality markers in 15 batches of HGWD. RESULTS: In total, 30 common peaks were assigned in the UPLC-DAD fingerprint. Nine peaks were recognized and considered characteristic markers: protocatechuic acid, coumarin, cinnamic acid, oxypaeoniflorin, paeoniflorin, calycosin, formononetin, catechin, and albiflorin. Furthermore, ninety-five common compounds were identified in the UPLC-HRMS chemical profile. The pharmacological analysis indicated that the anti-RA activities of the 15 HGWD samples were vastly different. The spectrum-effect relationship analysis revealed 30 potential bioactive constituents positively correlated with anti-RA activity. Among them, five compounds with relative amounts >1%, paeoniflorin, astragaloside IV, hexahydrocurcumin, formononetin and calycosin-7-glucoside, were selected as quality markers, and their activity was verified in LPS-induced RAW264.7 macrophages. Finally, the above 12 representative components were simultaneously quantified in the 15 batches of HGWD samples. CONCLUSION: Combining a holistic chemical profile with representative component evaluation, this systematic strategy could be a reliable and effective method to improve quality evaluations of HGWD.

The combination of astragalus injection and ambroxol hydrochloride in the adjuvant treatment of COPD: a systematic review and meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a severe condition that leads to premature mortality and places a significant financial burden on healthcare systems. An adjunctive therapy in COPD includes the simultaneous administration of astragalus injection and ambroxol hydrochloride. Despite its widespread use, the effectiveness of this combined approach in COPD treatment has not been systematically evaluated. Thus, we conducted a systematic review and meta-analysis to assess the efficacy of combining astragalus injection with ambroxol hydrochloride as an adjuvant treatment for COPD. Six electronic databases were used to search for relevant randomized controlled trials, and data analysis was conducted using Review Manager 5.4. A total of 14 randomized controlled trials were included, involving 1070 patients who met the criteria. The results of the meta-analysis indicated that the combination of astragalus injection with ambroxol hydrochloride as an adjuvant treatment can improve various clinical parameters in patients with COPD compared to conventional treatment alone. These parameters include the clinical effective rate (OR = 5.44, 95% CI 3.51-8.43, I2 = 0%), partial pressure of oxygen in artery (MD = 1.12, 95% CI 0.87-1.36, I2 = 5%), partial pressure of carbon dioxide in artery (MD = - 1.43, 95% CI - 1.65 to - 1.21, I2 = 0%), forced expiratory volume in one second (MD = 0.30, 95% CI 0.18-0.42, I2 = 0%), percentage of forced expiratory volume in one second (MD = 16.18, 95% CI 12.60-19.76, I2 = 82%), forced vital capacity (MD = 0.33, 95% CI 0.21-0.45, I2 = 36%), hemoglobin (MD = - 16.17, 95% CI - 20.84 to - 11.51, I2 = 29%), and the ratio of forced expiratory volume in one second to forced vital capacity (MD = 2.51, 95% CI - 0.05 to 5.06, I2 = 0%). The combination of astragalus injection and ambroxol hydrochloride could be a selection of COPD patients as an adjuvant treatment. However, further validation is required to evaluate the effectiveness of combining astragalus injection and ambroxol hydrochloride as an adjunctive treatment for patients with COPD.

P-Glycoprotein Exacerbates Brain Injury Following Experimental Cerebral Ischemia by Promoting Proinflammatory Microglia Activation.

Microglia are activated following cerebral ischemic insult. P-glycoprotein (P-gp) is an efflux transporter on microvascular endothelial cells and upregulated after cerebral ischemia. This study evaluated the effects and possible mechanisms of P-gp on microglial polarization/activation in mice after ischemic stroke. P-gp-specific siRNA and adeno-associated virus (p-AAV) were used to silence and overexpress P-gp, respectively. Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) were performed in mice and cerebral microvascular endothelial cells (bEnd.3) in vitro, respectively. OGD/R-injured bEnd.3 cells were cocultured with mouse microglial cells (BV2) in Transwell. Influences on acute ischemic stroke outcome, the expression of inflammatory cytokines, and chemokines and chemokines receptors, microglial polarization, glucocorticoid receptor (GR) nuclear translocation, and GR-mediated mRNA decay (GMD) activation were evaluated via reverse transcription real-time polymerase chain reaction, western blot, or immunofluorescence. Silencing P-gp markedly alleviated experimental ischemia injury as indicated by reduced cerebral infarct size, improved neurological deficits, and reduced the expression of interleukin-6 (IL-6) and IL-12 expression. Silencing P-gp also mitigated proinflammatory microglial polarization and the expression of C-C motif chemokine ligand 2 (CCL2) and its receptor CCR2 expression, whereas promoted anti-inflammatory microglia polarization. Additionally, P-gp silencing promoted GR nuclear translocation and the expression of GMD relative proteins in endothelial cells. Conversely, overexpressing P-gp via p-AAV transfection offset all these effects. Furthermore, silencing endothelial GR counteracted all effects mediated by silencing or overexpressing P-gp. Elevated P-gp expression aggravated inflammatory response and brain damage after ischemic stroke by augmenting proinflammatory microglial polarization in association with increased endothelial CCL2 release due to GMD inhibition by P-gp.

Network pharmacology: a bright guiding light on the way to explore the personalized precise medication of traditional Chinese medicine.

Network pharmacology can ascertain the therapeutic mechanism of drugs for treating diseases at the level of biological targets and pathways. The effective mechanism study of traditional Chinese medicine (TCM) characterized by multi-component, multi-targeted, and integrative efficacy, perfectly corresponds to the application of network pharmacology. Currently, network pharmacology has been widely utilized to clarify the mechanism of the physiological activity of TCM. In this review, we comprehensively summarize the application of network pharmacology in TCM to reveal its potential of verifying the phenotype and underlying causes of diseases, realizing the personalized and accurate application of TCM. We searched the literature using "TCM network pharmacology" and "network pharmacology" as keywords from Web of Science, PubMed, Google Scholar, as well as Chinese National Knowledge Infrastructure in the last decade. The origins, development, and application of network pharmacology are closely correlated with the study of TCM which has been applied in China for thousands of years. Network pharmacology and TCM have the same core idea and promote each other. A well-defined research strategy for network pharmacology has been utilized in several aspects of TCM research, including the elucidation of the biological basis of diseases and syndromes, the prediction of TCM targets, the screening of TCM active compounds, and the decipherment of mechanisms of TCM in treating diseases. However, several factors limit its application, such as the selection of databases and algorithms, the unstable quality of the research results, and the lack of standardization. This review aims to provide references and ideas for the research of TCM and to encourage the personalized and precise use of Chinese medicine.

Au-Catalyzed Asymmetric Polyene Cyclization and Its Application in the Total Synthesis of (+)-2-Ketoferruginol, (+)-Fleuryinol B, (+)-Salviol, and (-)-Erythroxylisin A.

A catalytic asymmetric 1,3-acyloxy shift/polyene cyclization cascade has been achieved with good enantioselectivities under the catalysis of the chiral Au(I) reagent. The synthetic utility of this method has been showcased by the catalytic asymmetric total syntheses of (+)-2-ketoferruginol, (+)-fleuryinol B, and (+)-salviol. Notably, the first enantioselective total synthesis of (-)-erythroxylisin A has also been realized in 15 steps.

Selenium-integrated conjugated oligomer nanoparticles with high photothermal conversion efficiency for NIR-II imaging-guided cancer phototheranostics in vivo.

Second near-infrared (NIR-II) fluorescence imaging in the range of 1000-1700 nm has great prospects for in vivo imaging and theranostics monitoring. At present, few NIR-II probes with theranostics properties have been developed, especially the high-performance organic theranostics material remains underexploited. Herein, we demonstrate a selenium (Se)-tailoring method to develop high-efficient NIR-II imaging-guided material for in vivo cancer phototheranostics. Via Se-tailoring strategy, conjugated oligomer TPSe-based nanoparticles (TPSe NPs) achieve bright NIR-II emission up to 1400 nm and exhibit a relatively high photothermal conversion efficiency of 60% with good stability. Moreover, the TPSe NPs demonstrate their photothermal ablation of cancer cells in vitro and tumor in vivo with the guidance of NIR-II imaging. It is worth noting that the TPSe NPs have good biocompatibility without obvious side effects. Thus, this work provides new insight into the development of NIR-II theranostics agents.

Black Phosphorus for Photonic Integrated Circuits.

Black phosphorus gives several advantages and complementarities over other two-dimensional materials. It has drawn extensive interest owing to its relatively high carrier mobility, wide tunable bandgap, and in-plane anisotropy in recent years. This manuscript briefly reviews the structure and physical properties of black phosphorus and targets on black phosphorus for photonic integrated circuits. Some of the applications are discussed including photodetection, optical modulation, light emission, and polarization conversion. Corresponding recent progresses, associated challenges, and future potentials are covered.

Identification of potential quality markers of Zishen Yutai pill based on spectrum-effect relationship analysis.

Introduction: The current quality evaluation of traditional Chinese medicine (TCM) is difficult to attribute to clinical efficacy due to the complexity of TCM. Zishen Yutai pill (ZYP), a well-known traditional Chinese patent medicine, has been widely used to prevent recurrent miscarriage and treat threatened abortion. However, the chemical components of ZYP are unknown, and there is no convincing quality control method applied on ZYP. Although ZYP has been found to promote endometrial receptivity and treat impending abortion, the substantial basis of the therapeutic effects is unclear. The aim of this study was to clarify the quality markers correlated with the potential medicinal activities and provide a theoretical foundation for scientific quality control and product quality improvement of ZYP. Methods: The chemical constituents of ZYP were comprehensively analyzed by offline two-dimensional liquid chromatography-mass spectrometry (2DLC-LTQ-Orbitrap-MS). The efficacy of the 27 ZYP orthogonal groups was investigated using the HTR-8/SVneo oxidative damage model and migration model in vitro, as well as the endometrial receptivity disorder mouse model and premature ovarian failure mouse model in vivo. Based on the efficacy and mass spectral results, spectrum-effect relationship analysis was used to identify the chemical components with corresponding pharmacological activities. Results: A total of 589 chemical components were found in ZYP, of which 139 were not identified in the literature. The potential quality markers for ZYP were successfully identified through orthogonal design and spectrum-effect relationship analysis. By combining mass spectrum data and pharmacological results of 27 orthogonal groups, 39 substances were identified as potential quality markers. Conclusion: The approaches used in this study will provide a feasible strategy for the discovery of quality markers with bioactivity and further investigation into the quality evaluation of TCM.

An integrated computational strategy to predict personalized cancer drug combinations by reversing drug resistance signatures.

Drug resistance currently poses the greatest barrier to cancer treatments. To overcome drug resistance, drug combination therapy has been proposed as a promising treatment strategy. Herein, we present Re-Sensitizing Drug Prediction (RSDP), a novel computational strategy, for predicting the personalized cancer drug combination A + B by reversing the resistance signature of drug A. The process integrates multiple biological features using a robust rank aggregation algorithm, including Connectivity Map, synthetic lethality, synthetic rescue, pathway, and drug target. Bioinformatics assessments revealed that RSDP achieved a relatively accurate prediction performance for identifying personalized combinational re-sensitizing drug B against cell line-specific intrinsic resistance, cell line-specific acquired resistance, and patient-specific intrinsic resistance to drug A. In addition, we developed the largest resource of cell line-specific cancer drug resistance signatures, including intrinsic and acquired resistance, as a byproduct of the proposed strategy. The findings indicate that personalized drug resistance signature reversal is a promising strategy for identifying personalized drug combinations, which may guide future clinical decisions regarding personalized medicine.

Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response.

Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with CGA. Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis. However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response.

Nitrogen-phosphorous co-doped carbonized chitosan nanoparticles for chemotherapy and ROS-mediated immunotherapy of intracellular Staphylococcus aureus infection.

Staphylococcus aureus (S. aureus) residing in host macrophages is hard to clear because intracellular S. aureus has evolved mechanisms to hijack and subvert the immune response to favor intracellular infection. To overcome this challenge, nitrogen-phosphorous co-doped carbonized chitosan nanoparticles (NPCNs), which possess the polymer/carbon hybrid structures, were fabricated to clear intracellular S. aureus infection through chemotherapy and immunotherapy. Multi-heteroatom NPCNs were fabricated through the hydrothermal method, where chitosan and imidazole were used as the C and N sources and phosphoric acid as the P source. NPCNs can not only be used as a fluorescent probe for bacteria imaging but also kill extracellular and intracellular bacteria with low cytotoxicity. NPCNs could generate ROS and polarize macrophages into classically activated (M1) phenotypes to increase antibacterial immunity. Furthermore, NPCNs could accelerate intracellular S. aureus-infected wound healing in vivo. We envision that these carbonized chitosan nanoparticles may provide a new platform for clearing intracellular bacterial infection through chemotherapy and ROS-mediated immunotherapy.

Calcium dobesilate attenuates renal ischemia-reperfusion injury in a mouse model.

BACKGROUND: Calcium dobesilate (CaD) is a microvascular protective agent that can significantly improve kidney function by reducing urinary protein, serum creatinine, and urea nitrogen levels. The effects of CaD on ischemia-reperfusion-induced acute kidney injury (AKI) were investigated in this study. METHOD: In this study, The Balb/c mice were randomly divided into (1) sham group, (2) I/R group, (3) I/R group + CaD (50 mg/kg) and (4) I/R group + CaD (500 mg/kg). After treatment, serum creatinine and urea nitrogen were detected. The levels of superoxide dismutase (SOD) and malonaldehyde (MDA) were examined. Then, the effects of CaD H2O2-damaged HK-2 cells were investigated, as reflected by the results of cell viability, reactive oxygen species (ROS) level, apoptosis and markers of kidney injury. RESULTS: The results showed that CaD treatment effectively attenuated the renal functions, pathological changes, and oxidative stress in I/R-induced AKI mice. It effectively reduced ROS production and improved MMP and apoptosis in H2O2-damaged HK-2 cells. The increased expression of apoptosis-related proteins and kidney injury biomarkers were significantly ameliorated after CaD treatment. CONCLUSION: Overall, CaD effectively ameliorated renal injury by eliminating ROS and demonstrated in vivo and in vitro for I/R-induced AKI. CaD has been shown to be a promising therapeutic agent for the treatment of I/R-induced AKI.