Background: Paclitaxel-based intraperitoneal chemotherapy (IPC) is a cornerstone strategy for treating gastric cancer peritoneal metastasis (GCPM). However, a subset of patients exhibit resistance to this therapy. Our study revealed that glucose transporter type 3 (GLUT3) is a key mediator of paclitaxel resistance in GCPM, although its precise mechanism of action remains to be fully elucidated. Methods: Single-cell (nucleus) sequencing and immunohistochemical staining were used to analyze paclitaxel-resistant and paclitaxel-sensitive GCPM tissue samples. GLUT3 was knocked down in AGS and HGC27 cells and overexpressed in MKN45 cells to establish the corresponding experimental models. The CUT&Tag and ChIP-qPCR techniques were utilized to elucidate the GLUT3-histone H3 lysine 18 lactylation (H3K18la)-mitogen-activated protein kinase associated protein 1 (MAPKAP1) regulatory axis. A mouse peritoneal metastasis model was used to evaluate the ability of GLUT3 targeting to reverse ferroptosis resistance and paclitaxel chemoresistance. Results: GLUT3, glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) expression was significantly upregulated in paclitaxel-resistant GCPM tissues. Elevated GLUT3 expression correlated with poor prognosis in GC patients. Functionally, GLUT3 knockdown sensitized GC cells to both Erastin and paclitaxel, whereas GLUT3 overexpression conferred therapeutic resistance. Mechanistically, GLUT3 upregulated hexokinase 3 (HK3) expression, increasing glucose-6-phosphate (G6P) and lactate production. Elevated lactate levels supported E1A binding protein p300 (p300)-mediated H3K18la enrichment at the MAPKAP1 promoter, thereby activating its transcription. Rescue assays indicated that depletion of MAPKAP1 restored ferroptosis sensitivity in GC cells. In vivo, compared with paclitaxel monotherapy, the combination of GLUT3 inhibition and paclitaxel not only reduced tumor weight by 75.47% (P<0.05) but also significantly suppressed the expression of MAPKAP1, GPX4, and SLC7A11. Conclusion: Targeting GLUT3-H3K18la-MAPKAP1 reverses paclitaxel resistance by inducing ferroptosis, providing a novel combination strategy for treating refractory GCPM.

Intrahepatic cholangiocarcinoma (ICC) is notoriously resistant to treatment, largely due to a "cold" microenvironment shaped by the Warburg effect. This metabolic signature leads to excessive lactate buildup, which acts as a physical and chemical shield against T-cell infiltration. To breach this barrier, we developed ultrasound-activated GdMnO3 (GMO) perovskite nanozymes that forcibly reverse the Warburg effect by accelerating the lactate-to-pyruvate metabolic switch. Through Gd-incorporating, we optimized the Mn-based electronic structure to achieve high-efficiency lactate catabolism, which is pulsed by ultrasound to maximize enzymatic turnover. This intervention does not merely deplete lactate; it reshapes the tumor's "bioenergetic engine" from glycolytic acidification toward mitochondrial oxidation. When cloaked in M1 macrophage membranes (GMO@M), these nanozymes selectively accumulate in ICC tissues. The subsequent Mn2+ release triggers the cGAS-STING pathway, synergizing with the metabolic shift to flip the immunological status of the tumor. Combined with αPD-L1, this ultrasound-driven metabolic recalibration yields potent systemic immunity and durable tumor regression. Our findings demonstrate that targeting the Warburg effect via responsive nanozymes is a decisive strategy for sensitizing recalcitrant ICC to immunotherapy.

Chiral plasmonic gold nanomaterials held significant promise for tumor photothermal therapy, with their helical pitch depth playing a critical role in determining both chirality and photothermal performance. However, precise pitch depth control remained a major challenge. Herein, we reported a Br--chiral ligand cooperative strategy to synthesize near-infrared-responsive helical chiral Au nanorods (Au NRs) with finely tunable pitch depths. Systematic investigations revealed distinct ion-regulation mechanisms: Br- selectively passivated [100] facets to promote [111] anisotropic growth of; I-/Cu2+ strongly adsorbed onto [111] to suppress helical development, Fe3+ only altered ligand adsorption without impeding [111] growth. These findings established directional [111] growth as a fundamental for both pitch-depth engineering and chiral structure formation. Optimized chiral Au NRs exhibited a high g-factor of 0.026, a >3-fold stronger localized electromagnetic field, and 16% higher photothermal conversion efficiency with reversibility. In vitro studies show 94% cellular uptake in HepG2 and near-complete cancer ablation under 808 nm irradiation, and high normal cell viability. This work elucidated ion-specific modulation roles, established a "pitch depth-chirality-performance-outcome" correlation, and provided design principles for precision photothermal therapy and chiral sensing.

Ephrin-B2 (EB2) signaling plays a crucial role in regulating memory and synaptic plasticity. Comprehensive identification of cell-type-specific transcriptomic changes in EB2 knockout mice is expected to shed light on potential mechanisms associated with EB2 signaling in cognitive functions. Our study captures changes in cell populations in response to EB2 manipulation and reveals previously uncharacterized cell types (CPA6 + inhibitory neurons) in the mPFC. We validated the differential transcriptomic activity of Pbx1 and Meis1 in CPA6 + neurons using fluorescence in situ hybridization (ISH) in EB2-vGATCre mice. The aberrant presence of CPA6 + neurons in the mPFC may correlate with cognitive impairments induced by EB2 deletion in vGAT + neurons. Analyzing differentially expressed genes (DEGs) in individual cell clusters, we identified alterations related to synapse organization and development, cognition, amyloid-beta formation, and locomotor behavior. Additionally, our DEGs overlapped with human genome-wide association study (GWAS) candidate genes related to cognition and anxiety, underscoring the relevance of our mouse model to human disease. We present a comprehensive atlas of cell-type-specific gene expression changes in this synaptic deficiency model and identify novel cell-type-specific targets implicated in cognitive deficits. Our investigation provides a detailed map of the cell types, genes, and pathways altered in this inhibitory synaptic deficiency model.

BACKGROUND:Social anxiety disorder (SAD) is one of the most prevalent anxiety disorders in adolescents but remains underdiagnosed due to the lack of objective diagnostic tools. This study aimed to identify serum metabolomic alterations in adolescent SAD patients and to develop an interpretable diagnostic model. METHODS:In this cross-sectional study, serum samples were collected from 78 adolescents, including 42 drug-naive, first-episode SAD patients and 36 matched healthy controls. Untargeted metabolomic profiling was performed, and feature selection was conducted via least absolute shrinkage and selection operator regression, followed by logistic regression for model construction. RESULTS:Among the 661 detected metabolites, 46 differed significantly between groups, mainly within amino acid and energy metabolism pathways. Five key metabolites, 2-hydroxybutanoic acid, L-alanine, L-asparagine, glutamine and beta-tocopherol, were selected for model construction. The diagnostic model achieved an area under the curve of 0.934 in the training set, but external validation is still lacking, and the findings should be interpreted as hypothesis-generating. CONCLUSIONS:Adolescents with SAD exhibit distinct metabolic profiles, and a preliminary diagnostic model was developed. Exploratory microbiota-related observations suggested potential links between gut microbial activity, host metabolism, and anxiety phenotypes, but these findings remain preliminary and outside the scope of the present study. Overall, these findings provide hypothesis-generating support for further investigation of gut-metabolism-brain interactions and highlight the need for larger, externally validated studies to advance biomarker development.

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.

Hydrogen therapy has emerged as a promising agent for cancer treatment. Earlier research demonstrated that hydrogen (H2) possesses anti-angiogenic effects across multiple tumor types. However, no studies have yet investigated the anti-angiogenic effects of H2 in sunitinib-resistant clear cell renal cell carcinoma (ccRCC) or elucidated the mechanism involved. Besides, both Hypoxia-inducible factor 2α (HIF-2α) and lncRNA Activated in RCC with sunitinib resistance (lncARSR) play essential roles in mediating ccRCC sunitinib resistance. Nevertheless, traditional multidrug combination strategy fails to achieve precise and effective suppression of drug-resistance related targets in conjunction with gas therapy. Therefore, we engineered a tumor-targeted nanocomplex, enabling localized H2 generation and efficient PT2385 and small interfering RNA targeting lncARSR (silncARSR) delivery to inhibit molecular targets associated with sunitinib resistance in ccRCC. Mechanistically, in situ generated hydrogen and lncARSR knockdown effectively suppresses tumor angiogenesis by downregulating vascular endothelial growth factor A(VEGFA) secretion from sunitinib-resistant cancer cells and M2-like tumor-associated macrophages (TAMs). Thus, the anti-angiogenic activity of PT2385 (HIF-2α inhibitor) was potentiated by H2 and silncARSR significantly. Moreover, the combination of H2, silncARSR and PT2385 exerts significantly potentiated efficacy in modulating apoptosis-related protein expression and ultimately enhancing cancer cell mitochondrial apoptosis. The demonstrated high therapeutic efficacy and great biocompatibility of this Hydrogen-PT2385-silncARSR nanocomplex underscore the clinical translation potential for overcoming ccRCC sunitinib resistance.

In this study, natural polysaccharides were first modified to synthesize natural functional monomers (NFMs). Subsequently, a natural novel NFM-based imprinted hydrogel microsphere was prepared for the specific recognition and enrichment of 7-xylulose-10-deacetylpaclitaxel (7-X-10-DTA). Molecular dynamics computational simulations were employed to screen and compare the functional monomers. Subsequently, the optimal preparation and application conditions of NMIHM were determined, with a maximum adsorption capacity of 71.77 mg mL- 1. The adsorption behavior of NMIHM for 7-X-10-DTA conforms to the pseudo-second-order kinetic model and the Langmuir model for monolayer adsorption, representing a spontaneous exothermic process. When used as a solid-phase extraction filler, NMIHM increased the content of 7-X-10-DTA by 13.36 times after enrichment in Taxus x media Rehde. The 7-X-10-DTA extracted in this study exhibited low half-maximal inhibitory concentration (IC50) values of 0.3205 mu M and 0.7636 mu M against cervical cancer Hela cells and prostate cancer PC-3 cells, respectively, demonstrating a more potent killing effect on these two types of cancer cells. This research is expected to accelerate the research and development of natural functional monomers and the advancement of molecular imprinting technology, thereby promoting the rapid development of practical separation applications.

Introduction: Psoriasis, a chronic inflammatory skin disease, is traditionally classified as ''leukoderma'' or ''tinea cruris'' in Traditional Chinese Medicine (TCM). Dang Gui Yinzi (Dang Gui Drink, DGD), a classic TCM formula, is prescribed to nourish blood, dispel wind, and alleviate dryness, aligning with TCM pathogenesis theories of psoriasis. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) focusing on the efficacy and safety of Dang Gui Drink combined with topical medications for psoriasis was conducted. This meta-analysis was performed based on a protocol registered in PROSPERO (CRD42025637050). The outcomes were reported as mean differences (MDs) with corresponding 95 % confidence intervals (CI) or risk ratio (RR) with 95 % CI. Results: A total of 13 RCTs, involving 918 participants, were included. The MD for Psoriasis Area and Severity Index (PASI) score improvement was −3.26 (95 % CI [−4.13 to −2.39]), indicating a significant improvement in the combination therapy group compared to the control group. The RR for clinical efficacy was 1.27 (95 % CI [1.19 to 1.36]), suggesting higher efficacy in the combination therapy group. There was no significant difference in the incidence of adverse events (RR = 0.51, 95 % CI [0.16 to 1.62]). Discussion: Dang Gui Drink combined with topical therapies demonstrates enhanced efficacy for psoriasis with a favorable safety profile. However, further high-quality RCTs are needed to enhance the robustness and reliability of these findings.© 2012 Published by Elsevier Ltd. Selection and/or peer-review under responsibility of Global Science and Technology Forum Pte Ltd

BACKGROUND:Social anxiety disorder (SAD) is a prevalent and burdensome neuropsychiatric disorder characterised by pronounced and persistent fear and anxiety in social situations. While evidence links gut microbiota to neuropsychiatric disorders, its role in SAD remains poorly understood. AIM:In this study, we aimed to investigate the potential involvement of gut microbiota in SAD pathophysiology through fecal microbiota transplantation. METHOD:We collected demographic data and fecal samples from 40 first-episode, comorbidity-free, and drug-naive adolescent patients with SAD, along with 32 demographically matched healthy controls. Fecal samples underwent 16S rDNA amplicon sequencing and were pooled for transplantation into neonatal rats from postnatal day 1 through late adolescence. Recipient rats were evaluated with behavioral tests, microbiota detection, and non-targeted metabolomics of the medial prefrontal cortex. RESULT:Patients with SAD displayed alterations in gut microbiota composition. Rats colonized with SAD-associated microbiota exhibited anxiety-like behaviors and reduced social novelty preference, alongside microbial profiles partially overlapping with those of patients. These behavioral changes were correlated with microbiota differences, and distinct metabolic alterations were detected in the medial prefrontal cortex of SAD-colonized rats. CONCLUSION:Gut microbiota from adolescents with SAD is associated with behavioral and metabolic alterations in a rodent model, suggesting a potential role of the gut-brain axis in SAD. Further studies are warranted to establish causality and elucidate underlying mechanisms.

Background: Second-generation antipsychotics (SGAs) frequently cause metabolic syndrome (MetS), which raises the risk of heart disease, type 2 diabetes, morbid obesity, atherosclerosis, and hypertension. MetS also impairs cognitive function in patients with schizophrenia. However, the fundamental reasons of MetS caused by SGAs are not yet fully understood. Thus, we aimed to identify potential therapeutic targets for MetS induced by SGAs. Methods: The serum biochemical parameters and the RNA-sequencing of peripheral blood mononuclear cells were measured in three groups (healthy controls and patients with schizophrenia with and without MetS taking SGAs). The study of the weighted gene co-expression network was utilized to pinpoint modules that were significantly connected to clinical markers. Results: Statistical analysis showed significant differences in triglyceride and high-density lipoprotein among the three groups. The TNF signaling pathway, TGF-β signaling pathway, fatty acid metabolism, NF-kappa B signaling pathway, MAPK signaling pathway, and Toll-like receptor signaling pathway were the pathways that were primarily enriched in the two unique co-expression network modules that were found. Finally, five specific genes (TNF, CXCL8, IL1B, TIMP1, and ESR1) associated with metabolism and immunity pathways were identified. Conclusions: This study indicated that SGAs differentially induced MetS of patients with schizophrenia through metabolic and inflammation-related pathways. Therefore, the potential side effects of drugs on inflammatory processes need to be considered when using SGAs for the treatment of schizophrenia.

BackgroundCervical intraepithelial neoplasia (CIN) encompasses a range of cervical lesions that are closely linked to cervical invasive carcinoma. Early detection and timely treatment of CIN are crucial for preventing the progression of the disease. However, no bibliometric analysis has been conducted in this area. This research aimed to employ bibliometric analysis to summarize the current research hotspots and estimate future research trends in the CIN field.MethodsPublications related to CIN (2013–2023) were retrieved from the Science-Citation-Index-Expanded-of-Web-of-Science-Core-Collection. CiteSpace, VOSviewer, and the bibliometric-Online-Analysis-Platform-of-Literature-Metrology were employed to analyze the yearly research output, collaborating institutions or countries, leading researchers, principal journals, co-referenced sources, and emerging keywords.ResultsIn total, 4677 articles on CIN that were published from 2013 to 2023 and met our criteria were extracted. Major publishing platforms were predominantly USA until 2017 when China emerged as the leading source of publications about CIN. The USA was the leading nation in international collaborations. The National-Cancer-Institute (NCI) was the institution with the most publications. Schiffman Mark produced the highest number of articles, with a total of 92. Ten major clusters were identified through co-cited keyword clustering, including prevalence, human papillomavirus, DNA methylation, p16, methylation, conization, HPV genotyping tests (VALGENT), deep learning, vaginal microbiome, and immunohistochemistry. Keyword burst analysis showed that photodynamic therapy and deep learning emerged as prominent research focal points with significant impact in resent three years.ConclusionGlobal publications on CIN research showed a relatively stable trend over the past eleven years. Current research hotspots are deep learning and photodynamic therapy. This research offered organized data and insightful guidance for future studies, which may help better prevent, screen, and treat CIN.

Advanced hepatocellular carcinoma (HCC) is one of the most prevalent malignancies, and the clinical treatment outcomes are not satisfactory. Due to the complexity, heterogeneity, and immunosuppressive microenvironment of HCC, monotherapies have limited effects. Therefore, combined therapy may effectively enhance antitumor treatment by remodeling the tumor immune microenvironment. This study reports an injectable thermosensitive microsphere-hydrogel composite system for local co-delivery of the targeted drug sorafenib (SOR) and immunomodulatory cytokines for the combined therapy of HCC. The delivery system exhibited superior properties such as dual-drug delivery, sustained and slow release, local injectability, thermosensitivity, and low side effects. Moreover, it successfully remodeled the immune microenvironment of HCC by increasing the infiltration of CD8+ T cells and natural killer cells while decreasing the infiltration of immunosuppressive Treg cells, thereby achieving a potent synergistic effect with SOR. This safe composite delivery system can remodel the tumor microenvironment and enhance anti-tumor treatment, providing a valuable option for the treatment of HCC.

For genitourinary cancers, renal cell carcinoma (RCC) is the third leading cause of death, while target drug resistance has always been a difficult problem. Integrin alpha 1 (ITGA1) is a member of the integrin family, which is significant for the pathogenesis, development, and drug resistance of various malignant tumors. However, it remains unclear for the ITGA1 functions in renal cell carcinoma sunitinib resistance. In this study, we found that the ITGA1 gene facilitates renal cell carcinoma sunitinib resistance through the PI3K/Akt/Bcl-2 signaling pathway. Based on this, we developed a co-delivery system designated as Su/Si-PEAL NPs for the synergistic delivery of ITGA1 small interfering RNA (siRNA) and sunitinib using monomethoxy polyethylene glycol-polylactic acid/glycolic acid-poly-L-lysine triblock copolymer (mPEG-PLGA-PLL, PEAL) as the backbone material. Furthermore, the results of a series of functional experiments confirmed that this codelivery system was capable of downregulating the expression of ITGA1 and enhancing the sensitivity of 786-O-R cells to sunitinib. This co-delivery system could be an efficient approach for reversing sunitinib resistance in renal cell carcinoma.

BackgroundNeuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown.PurposeThis study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP.MethodsThe analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro.ResultsNetwork pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission.ConclusionIn conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.

CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of therapeutic agents remains largely incomplete. Here, patients with liver cancer co-expressing CD47 and CDC7 (cell division cycle 7, a negative senescence-related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual-targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy-resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.

Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably Apoa1, Apoc3, and Apoh. These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.

The challenge of drug resistance in intrahepatic cholangiocarcinoma (ICC) is intricately linked with lipid metabolism reprogramming. The hepatic lipase (HL) and the membrane receptor CD36 are overexpressed in BGJ398-resistant ICC cells, while they are essential for lipid uptake, further enhancing lipid utilization in ICC. Herein, a metal-organic framework-based drug delivery system (OB@D-pMOF/CaP-AC, DDS), has been developed. The specifically designed DDS exhibits a successive targeting property, enabling it to precisely target ICC cells and their mitochondria. By specifically targeting the mitochondria, DDS produces reactive oxygen species (ROS) through its sonodynamic therapy effect, achieving a more potent reduction in ATP levels compared to non-targeted approaches, through the impairment of mitochondrial function. Additionally, the DDS strategically minimizes lipid uptake through the incorporation of the anti-HL drug, Orlistat, and anti-CD36 monoclonal antibody, reducing lipid-derived energy production. This dual-action strategy on both mitochondria and lipids can hinder energy utilization to restore drug sensitivity to BGJ398 in ICC. Moreover, an orthotopic mice model of drug-resistant ICC was developed, which serves as an exacting platform for evaluating the multifunction of designed DDS. Upon in vivo experiments with this model, the DDS demonstrated exceptional capabilities in suppressing tumor growth, reprogramming lipid metabolism and improving immune response, thereby overcoming drug resistance. These findings underscore the mitochondria-targeted DDS as a promising and innovative solution in ICC drug resistance.

Breast cancer has become the most common form of cancer worldwide. Chemotherapy failure, primarily due to drug resistance, necessitates the development of new therapeutic strategies. In this study, ultrathin Ti3C2 nanosheets are utilized as photothermal agents and nanocarriers. We developed a multifunctional Ti3C2-based nanoplatform (214.7 nm) through layer-by-layer absorption of HSP90 antisense oligonucleotide (ASO) and doxorubicin (DOX), with surface modification using hyaluronic acid (HA). In a simulated acidic tumor microenvironment in vitro, 90 % of the drug was released within 36 hours. Additionally, Under 808 nm irradiation (2.0 W/cm(2)), MCF-7/ADM cell viability assays revealed the following results: HA-Ti3C2 (57 %), HA-Ti3C2@ASO (HT@A) (41 %), and HA-Ti3C2@ASO/DOX (HT@AD) (26 %), which shown the synergistic inhibitory effects of this multifunctional nanoplatform. Herein, this nanosystem exhibits enhanced biocompatibility, superior photothermal performance, and stimuli-responsive drug release behavior, making it a promising candidate for effective inhibition of cancer cell proliferation and migration.

Conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family proteins leads to the accumulation of 5hmC in the central nervous system; however, the role of 5hmC in the postnatal brain and how its levels and target genes are regulated by TETs remain elusive. We have generated mice that lack all three Tet genes specifically in postnatal excitatory neurons. These mice exhibit significantly reduced 5hmC levels, altered dendritic spine morphology within brain regions crucial for cognition, and substantially impaired spatial and associative memories. Transcriptome profiling combined with epigenetic mapping reveals that a subset of genes, which display changes in both 5hmC/5mC levels and expression patterns, are involved in synapse-related functions. Our findings provide insight into the role of postnatally accumulated 5hmC in the mouse brain and underscore the impact of 5hmC modification on the expression of genes essential for synapse development and function.