Journal of advanced research最新文献

Introduction: Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome.

Objectives: To assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms.

Methods: Untargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs.

Results: The baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.

Conclusions: The disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.

Background: Surface coating of dental implants with a bioactive biomaterial is one of the distinguished approaches to improve the osseointegration potential, antibacterial properties, durability, and clinical success rate of dental implants. Carbon-based bioactive coatings, a unique class of biomaterial that possesses excellent mechanical properties, high chemical and thermal stability, osteoconductivity, corrosion resistance, and biocompatibility, have been utilized successfully for this purpose.

Aim: This review aims to present a comprehensive overview of the structure, properties, coating techniques, and application of the various carbon-based coatings for dental implant applicationswith a particular focuson Carbon-based nanomaterial (CNMs), which is an advanced class of biomaterials.

Key scientific concepts of review: Available articles on carbon coatings for dental implants were reviewed using PubMed, Science Direct, and Google Scholar resources. Carbon-based coatings are non-cytotoxic, highly biocompatible, chemically inert, and osteoconductive, which allows the bone cells to come into close contact with the implant surface and prevents bacterial attachment and growth. Current research and advancements are now more focused on carbon-based nanomaterial (CNMs), as this emerging class of biomaterial possesses the advantage of both nanotechnology and carbon and aligns closely with ideal coating material characteristics. Carbon nanotubes, graphene, and its derivatives have received the most attention for dental implant coating. Various coating techniques are available for carbon-based materials, chosen according to substrate type, application requirements, and desired coating thickness. Vapor deposition technique, plasma spraying, laser deposition, and thermal spraying techniques are most commonly employed to coat the carbon structures on the implant surface. Longer duration trials and monitoring are required to ascertain the role of carbon-based bioactive coating for dental implant applications.

Introduction: Environmental and occupational exposure to cadmium (Cd) has been shown to cause acute kidney injury (AKI). Previous studies have demonstrated that autophagy inhibition and lysosomal dysfunction are important mechanisms of Cd-induced AKI.

Objectives: Transcription factor EB (TFEB) is a critical transcription regulator that modulates autophagy-lysosome function, but its role in Cd-induced AKI is yet to be elucidated. Thus, in vivo and in vitro studies were conducted to clarify this issue.

Methods and results: Data firstly showed that reduced TFEB expression and nuclear translocation were evident in Cd-induced AKI models, accompanied by autophagy-lysosome dysfunction. Pharmacological and genetic activation of TFEB improved Cd-induced AKI via alleviating autophagy inhibition and lysosomal dysfunction, whereas Tfeb knockdown further aggravated this phenomenon, suggesting the key role of TFEB in Cd-induced AKI by regulating autophagy. Mechanistically, Cd activated mechanistic target of rapamycin complex 1 (mTORC1) to enhance TFEB phosphorylation and thereby inhibiting TFEB nuclear translocation. Cd also activated chromosome region maintenance 1 (CRM1) to promote TFEB nuclear export. Meanwhile, Cd activated general control non-repressed protein 5 (GCN5) to enhance nuclear TFEB acetylation, resulting in the decreased TFEB transcriptional activity. Moreover, inhibition of CRM1 or GCN5 alleviated Cd-induced AKI by enhancing TFEB activity, respectively.

Conclusion: In summary, these findings reveal that TFEB phosphorylation, nuclear export and acetylation independently suppress TFEB activity to cause Cd-induced AKI via regulating autophagy-lysosome function, suggesting that TFEB activation might be a promising treatment strategy for Cd-induced AKI.

Introduction: Sleep deprivation (SD) is a common disorder in modern society. Hippocampus is an important region of the brain for learning, memory, and emotions. Dysfunction of hippocampus can lead to severe learning and memory disorder, significantly affecting quality of life. SD is accompanied by hippocampal microglia activation and a surge in inflammatory factors, but the precise mechanism remains unclear. Moreover, the ongoing unknown persists regarding how activated microglia in SD lead to neuronal damage. Topoisomerase 1 (TOP1) plays an essential role in the inflammatory process, including the tumor system and viral infection. In this study, we observed a significant elevation in TOP1 levels in the hippocampus of mice subjected to SD. Therefore, we hypothesize that TOP1 may be implicated in SD-induced microglia activation and neuronal damage.

Objectives: To investigate the role of TOP1 in SD-induced microglial activation, neuronal damage, and neurobehavioral impairments, and the molecular basis of SD-induced elevated TOP1 levels.

Methods: TOP1-specific knockout mice in microglia were used to study the effects of TOP1 on microglial activation and neuronal damage. Transcription factor prediction, RNA interference, ChIP-qPCR, ChIP-seq database analysis, and luciferase reporter assays were performed to explore the molecular mechanisms of YY1 transcriptional activation. Untargeted metabolic profiling was employed to investigate the material basis of YY1 transcriptional activation.

Results: Knockdown of TOP1 in hippocampal microglia ameliorates SD-induced microglial activation, inflammatory response, and neuronal damage. Mechanistically, TOP1 mediates the release of IL-6 from microglia, which consequently leads to neuronal dysfunction. Moreover, elevated TOP1 due to SD were associated with neopterin, which was attributed to its promotion of elevated levels of H3K27ac in the TOP1 promoter region by disrupting the binding of YY1 and HDAC1.

Conclusion: The present study reveals that TOP1-mediated microglial activation is critical for SD induced hippocampal neuronal damage and behavioral impairments.

Introduction: The intestine, frequently subjected to pelvic or abdominal radiotherapy, is particularly vulnerable to delayed effects of acute radiation exposure (DEARE) owing to its high radiation sensitivity. Radiation-induced intestinal senescence, a result of DEARE, profoundly affects the well-being and quality of life of radiotherapy patients. However, targeted pharmaceutical interventions for radiation-induced senescence are currently scarce. Our findings showcase that nicotinamide riboside(NR) effectively alleviates radiation-induced intestinal senescence, offering crucial implications for utilizing NR as a pharmacological agent to combat intestinal DEARE.

Objectives: The aim of this study was to investigate the ability of NR to reduce radiation induced intestinal senescence and explore its related mechanisms.

Methods: Male C57BL/6J mice were randomly divided into CON, IR, and IR + NR groups. The mice in the IR and IR + NR groups were subjected to a 6.0 Gy γ-ray total body exposure. After 8 weeks, the mice in the IR + NR group received NR via gavage at a dose of 400 mg/kg/d for 21 days. Then the mice were used for sample collection.

Results: Our results demonstrate that NR can significantly mitigate radiation-induced intestinal senescence. Furthermore, our findings indicate that NR can mitigate oxidative damage, restore the normal function of intestinal stem cells, regulate the disruption of the intestinal symbiotic ecosystem and address metabolic abnormalities. In addition, the underlying mechanisms involve the activation of SIRT6, SIRT7 and the inhibition of the mTORC1 pathway by NR.

Conclusion: In conclusion, our results reveal the substantial inhibitory effects of NR on radiation-induced intestinal senescence. These findings offer valuable insights into the potential therapeutic use of NR as a pharmacological agent for alleviating intestinal DEARE.

Introduction: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified.

Objectives: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD).

Methods: We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches.

Results: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy.

Conclusion: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.

Introduction: Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses.

Objective: This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment.

Methods: In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed.

Results: In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC.

Conclusion: This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.

Introduction: The antidepressant properties of Hypericum species are known. Hyperibone J, a principal component found in the flowers of Hypericum bellum, exhibited in vitro anti-inflammatory effects. However, the antidepressant effects and mechanisms of Hyperibone J remain to be elucidated. Adenosine kinase (ADK) is upregulated in epilepsy and depression and has been implicated in promoting neuroinflammation.

Objectives: This study aimed to explore the impact of Hyperibone J on neuroinflammation-mediated depression and the mechanism underlying this impact.

Methods: This study employed acute and chronic in vivo depression models and an in vitro LPS-induced depression model using BV-2 microglia. The in vivo antidepressant efficacy of Hyperibone J was assessed through behavioral assays. Techniques such as RNA-seq, western blot, qPCR and ELISA were utilized to elucidate the direct target and mechanism of action of Hyperibone J.

Results: Compared with the model group, depression-like behaviors were significantly alleviated in the Hyperibone J group. Furthermore, Hyperibone J mitigated hippocampal neuroinflammation and neuronal damage. RNA-seq suggested that Hyperibone J predominantly influenced inflammation-related pathways. In vitro experiments revealed that Hyperibone J reversed the LPS-induced overexpression and release of inflammatory factors. Network pharmacology and various molecular biology experiments revealed that the potential binding of Hyperibone J at the ASN-312 site of ADK diminished the stability and protein expression of ADK. Mechanistic studies revealed that Hyperibone J attenuated the ADK/ATP/P2X7R/Caspase-1-mediated maturation and release of IL-1β. The study also revealed a significant correlation between Tlr4 expression and depression-like behaviors in mice. Hyperibone J downregulated ADK, inhibiting Tlr4 transcription, which in turn reduced the phosphorylation of NF-κB and the subsequent transcription of Nlrp3, Il-1b, Tnf, and Il-6.

Conclusion: Hyperibone J exerted antineuroinflammatory and antidepressant effects by binding to ADK in microglia, reducing its expression and thereby inhibiting the ATP/P2X7R/Caspase-1 and TLR4/NF-κB pathways. This study provides experimental evidence for the therapeutic potential of Hypericum bellum.

Introduction: Since the outbreak of COVID-19, microplastics (MPs) and triclosan in pharmaceuticals and personal care products (PPCPs) are markedly rising. MPs and triclosan are co-present in the environment, but their interactions and subsequent implications on the fate of triclosan in plants are not well understood.

Objective: This study aimed to investigate effects of charged polystyrene microplastics (PS-MPs) on the fate of triclosan in cabbage plants under a hydroponic system.

Methods: ¹⁴C-labeling method and liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (LC-QTOF-MS) analysis were applied to clarify the bioaccumulation, distribution, and metabolism of triclosan in hydroponics-cabbage system. The distribution of differentially charged PS-MPs in cabbage was investigated by confocal laser scanning microscopy and scanning electron microscopy.

Results: The results showed that MPs had a significant impact on bioaccumulation and metabolism of triclosan in hydroponics-cabbage system. PS-COO^-, PS, and PS-NH₃⁺ MPs decreased the bioaccumulation of triclosan in cabbage by 69.1 %, 81.5 %, and 87.7 %, respectively, in comparison with the non-MP treatment (control). PS-MPs also reduced the translocation of triclosan from the roots to the shoots in cabbage, with a reduction rate of 15.6 %, 28.3 %, and 65.8 % for PS-COO^-, PS, and PS-NH₃⁺, respectively. In addition, PS-NH₃⁺ profoundly inhibited the triclosan metabolism pathways such as sulfonation, nitration, and nitrosation in the hydroponics-cabbage system. The above findings might be linked to strong adsorption between PS-NH₃⁺ and triclosan, and PS-NH₃⁺ may also potentially inhibit the growth of cabbage. Specially, the amount of triclosan adsorbed on PS-NH₃⁺ was significantly greater than that on PS and PS-COO^-. The cabbage biomass was reduced by 76.9 % in PS-NH₃⁺ groups, in comparison with the control.

Conclusion: The uptake and transformation of triclosan in hydroponics-cabbage system were significantly inhibited by charged PS-MPs, especially PS-NH₃⁺. This provides new insights into the fate of triclosan and other PPCPs coexisted with microplastics for potential risk assessments.

Introduction: Motor neurons differ from sensory neurons in aspects including origins and surrounding environment. Understanding the similarities and differences in molecular response to peripheral nerve injury (PNI) and regeneration between sensory and motor neurons is crucial for developing effective drug targets for CNS regeneration. However, genome-wide comparisons of molecular changes between sensory and motor neurons following PNI remains limited.

Objectives: This study aims to investigate genome-wide convergence and divergence of injury response between sensory and motor neurons to identify novel drug targets for neural repair.

Methods: We analyzed two large-scale RNA-seq datasets of in situ captured sensory neurons (SNs) and motoneurons (MNs) upon PNI, retinal ganglion cells and spinal cord upon CNS injury. Additionally, we integrated these with other related single-cell level datasets. Bootstrap DESeq2 and WGCNA were used to detect and explore co-expression modules of differentially expressed genes (DEGs).

Results: We found that SNs and MNs exhibited similar injury states, but with a delayed response in MNs. We identified a conserved regeneration-associated module (cRAM) with 274 shared DEGs. Of which, 47% of DEGs could be changed in injured neurons supported by single-cell resolution datasets. We also identified some less-studied candidates in cRAM, including genes associated with transcription, ubiquitination (Rnf122), and neuron-immune cells cross-talk. Further in vitro experiments confirmed a novel role of Rnf122 in axon growth. Analysis of the top 10% of DEGs with a large divergence suggested that both extrinsic (e.g., immune microenvironment) and intrinsic factors (e.g., development) contributed to expression divergence between SNs and MNs following injury.

Conclusions: This comprehensive analysis revealed convergent and divergent injury response genes in SNs and MNs, providing new insights into transcriptional reprogramming of sensory and motor neurons responding to axonal injury and subsequent regeneration. It also identified some novel regeneration-associated candidates that may facilitate the development of strategies for axon regeneration.