5-Hydroxytryptophan acts as a gap junction inhibitor to limit the spread of chemotherapy-induced cardiomyocyte injury and mitochondrial dysfunction.

Anthracycline chemotherapeutics like doxorubicin (DOX) are widely used against various cancers but are accompanied by severe cardiotoxic effects that can lead to heart failure. Through whole transcriptome sequencing and pathological tissue analysis in a murine model, our study has revealed that DOX impairs collagen expression in the early phase, causing extracellular matrix anomalies that weaken the mechanical integrity of the heart. This results in ventricular wall thinning and dilation, exacerbating cardiac dysfunction. In this work, we have identified 5-hydroxytryptophan (5-HTP) as a potent inhibitor of gap junction communication. This inhibition is key to limiting the spread of DOX-induced cardiotoxicity. Treatment with 5-HTP effectively countered the adverse effects of DOX on the heart, preserving ventricular structure and ejection fraction. Moreover, 5-HTP enhanced mitochondrial respiratory function, as shown by the O2k mitochondrial function assay, by improving mitochondrial complex activity and ATP production. Importantly, the cardioprotective benefits of 5-HTP did not interfere with DOX's ability to combat cancer. These findings shed light on the cardiotoxic mechanisms of DOX and suggest that 5-HTP could be a viable strategy to prevent heart damage during chemotherapy, offering a foundation for future clinical development. This research opens the door for 5-HTP to be considered a dual-purpose agent that can protect the heart without compromising the oncological efficacy of anthracycline chemotherapy.

Precise diagnosis and risk stratification of prostate cancer by comprehensive serum metabolic fingerprints: a prediction model study.

OBJECTIVES: Prostate cancer (PCa) is one of the most common malignancies in men worldwide and has caused increasing clinical morbidity and mortality, making timely diagnosis and accurate staging crucial. The authors introduced a novel approach based on mass spectrometry for precise diagnosis and stratification of PCa to facilitate clinical decision-making. METHODS: Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis of trace blood samples was combined with machine learning algorithms to construct diagnostic and stratification models. A total of 367 subjects, comprising 181 with PCa and 186 with non-PCa were enrolled. Additional 60 subjects, comprising 30 with PCa and 30 with non-PCa were enrolled as an external cohort for validation. Subsequent metabolomic analysis was carried out using Autoflex MALDI-TOF, and the mass spectra were introduced into various algorithms to construct different models. RESULTS: Serum metabolic fingerprints were successfully obtained from 181 patients with PCa and 186 patients with non-PCa. The diagnostic model based on the eight signals demonstrated a remarkable area under curve of 100% and was validated in the external cohort with the area under curve of 87.3%. Fifteen signals were selected for enrichment analysis, revealing the potential metabolic pathways that facilitate tumorigenesis. Furthermore, the stage prediction model with an overall accuracy of 85.9% precisely classified subjects with localized disease and those with metastasis. The risk stratification model, with an overall accuracy of 89.6%, precisely classified the subjects as low-risk and high-risk. CONCLUSIONS: Our study facilitated the timely diagnosis and risk stratification of PCa and provided new insights into the underlying mechanisms of metabolic alterations in PCa.

Nanotechnology for brain tumor imaging and therapy based on π-conjugated materials: state-of-the-art advances and prospects.

In contemporary biomedical research, the development of nanotechnology has brought forth numerous possibilities for brain tumor imaging and therapy. Among these, π-conjugated materials have garnered significant attention as a special class of nanomaterials in brain tumor-related studies. With their excellent optical and electronic properties, π-conjugated materials can be tailored in structure and nature to facilitate applications in multimodal imaging, nano-drug delivery, photothermal therapy, and other related fields. This review focuses on presenting the cutting-edge advances and application prospects of π-conjugated materials in brain tumor imaging and therapeutic nanotechnology.

Engineering the MoS2 /MXene Heterostructure for Precise and Noninvasive Diagnosis of Prostate Cancer with Clinical Specimens.

High-throughput metabolic fingerprinting has been deemed one of the most promising strategies for addressing the high false positive rate of prostate cancer (PCa) diagnosis in the prostate-specific antigen (PSA) gray zone. However, the current metabolic fingerprinting remains challenging in achieving high-precision metabolite detection in complex biological samples (e.g., serum and urine). Herein, a novel self-assembly MoS2 /MXene heterostructure nanocomposite with a tailored doping ratio of 10% is presented as a matrix for laser desorption ionization mass spectrometry analysis in clinical biosamples. Notably, owing to the two-dimensional architecture and doping effect, MoS2 /MXene demonstrates favorable laser desorption ionization performance with low adsorption energy, which is evidenced by efficient urinary metabolic fingerprinting with an enhanced area under curve (AUC) diagnosis capability of 0.959 relative to that of serum metabolic fingerprinting (AUC = 0.902) for the diagnosis of PCa in the PSA gray zone. Thus, this MoS2 /MXene heterostructure is anticipated to offer a novel strategy to precisely and noninvasively diagnose PCa in the PSA gray zone.

Liquiritigenin reverses skin aging by inhibiting UV-induced mitochondrial uncoupling and excessive energy consumption.

BACKGROUND: The accumulation of reactive oxygen species (ROS) generated by UV radiation can lead to lipid, protein, nucleic acid, and organelle damage, one of the core mechanisms mediating skin aging. In the photoaging process, how ROS drives the imbalance of the body's complex repair system to induce senescence-like features is not fully understood. METHODS: We irradiated human epidermal keratinocytes with 12 J/cm2 of UVA to establish an in vitro photoaging model. Then we employed whole-transcriptome sequencing and O2K mitochondrial function assay to reveal the photoprotective mechanisms of liquiritigenin (LQ). DISCUSSION: We found that skin reduces endogenous ROS by promoting mitochondrial oxidative phosphorylation uncoupling in response to UVA-induced damage. However, this also causes excessive consumption and idling of nutrients, leading to the inhibition of cell proliferation, and ultimately accelerating the skin aging process. Here, we demonstrated that LQ can reduce stress in keratinocytes, increase oxidative phosphorylation and ATP production efficiency, and block the massive loss of skin nutrients and net energy stress. Furthermore, LQ can promote collagen synthesis and keratinocyte proliferation through the PI3K-AKT pathway, thereby reversing photoaging. CONCLUSION: This work provides a new skin aging mechanism and solution strategy with high clinical translation value.

Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity.

Aims: The broad-spectrum anticancer drug doxorubicin (Dox) is associated with a high incidence of cardiotoxicity, which severely affects the clinical application of the drug and patients' quality of life. Here, we assess how Dox modulates myocardial energy and contractile function and this could aid the development of relevant protective drugs. Methods: Mice were subjected to doxorubicin and breviscapine treatment. Cardiac function was analyzed by echocardiography, and Dox-mediated signaling was assessed in isolated cardiomyocytes. The dual cardio-protective and anti-tumor actions of breviscapine were assessed in mouse breast tumor models. Results: We found that Dox disrupts myocardial energy metabolism by decreasing glucose uptake and increasing fatty acid oxidation, leading to a decrease in ATP production rate, an increase in oxygen consumption rate and oxidative stress, and further energy deficits to enhance myocardial fatty acid uptake and drive DIC development. Interestingly, breviscapine increases the efficiency of ATP production and restores myocardial energy homeostasis by modulating the serotonin-glucose-myocardial PI3K/AKT loop, increasing glucose utilization by the heart and reducing lipid oxidation. It enhances mitochondrial autophagy via the PINK1/Parkin pathway, eliminates damaged mitochondrial accumulation caused by Dox, reduces the degree of cardiac fibrosis and inflammation, and restores cardiac micro-environmental homeostasis. Importantly, its low inflammation levels reduce myeloid immunosuppressive cell infiltration, and this effect is synergistic with the anti-tumor effect of Dox. Conclusion: Our findings suggest that disruption of the cardiac metabolic network by Dox is an important driver of its cardiotoxicity and that serotonin is an important regulator of myocardial glucose and lipid metabolism. Myocardial energy homeostasis and timely clearance of damaged mitochondria synergistically contribute to the prevention of anthracycline-induced cardiotoxicity and improve the efficiency of tumor treatment.

Advances in Trop2-targeted therapy: Novel agents and opportunities beyond breast cancer.

Trop2 is a transmembrane glycoprotein and calcium signal transducer with limited expression in normal human tissues. It is consistently overexpressed in a variety of malignant tumors and participates in several oncogenic signaling pathways that lead to tumor development, invasion, and metastasis. As a result, Trop2 has become an attractive therapeutic target in cancer treatment. The anti-Trop2 antibody-drug conjugate (Trodelvy™, sacituzumab govitecan) has been approved to treat metastatic triple-negative breast cancer. However, it is still unclear whether the success observed in Trop2-positive breast cancer could be replicated in other tumor types, owing to the differences in the expression levels and functions of Trop2 across cancer types. In this review, we summarize the recent progress on the structures and functions of Trop2 and highlight the potential diagnostic and therapeutic value of Trop2 beyond breast cancer. In addition, the promising novel Trop2-targeted agents in the clinic were discussed, which will likely alter the therapeutic landscape of Trop2-positive tumors in the future.

New insights into bacterial mechanisms and potential intestinal epithelial cell therapeutic targets of inflammatory bowel disease.

The global incidence of inflammatory bowel disease (IBD) has increased rapidly in recent years, but its exact etiology remains unclear. In the past decade, IBD has been reported to be associated with dysbiosis of gut microbiota. Although not yet proven to be a cause or consequence of IBD, the common hypothesis is that at least some alterations in the microbiome are protective or pathogenic. Furthermore, intestinal epithelial cells (IECs) serve as a protective physical barrier for gut microbiota, essential for maintaining intestinal homeostasis and actively contributes to the mucosal immune system. Thus, dysregulation within the intestinal epithelium increases intestinal permeability, promotes the entry of bacteria, toxins, and macromolecules, and disrupts intestinal immune homeostasis, all of which are associated with the clinical course of IBD. This article presents a selective overview of recent studies on bacterial mechanisms that may be protective or promotive of IBD in biological models. Moreover, we summarize and discuss the recent discovery of key modulators and signaling pathways in the IECs that could serve as potential IBD therapeutic targets. Understanding the role of the IECs in the pathogenesis of IBD may help improve the understanding of the inflammatory process and the identification of potential therapeutic targets to help ameliorate this increasingly common disease.

Metabolic Control by Heat Stress Determining Cell Fate to Ferroptosis for Effective Cancer Therapy.

Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe3O4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe3O4-containing nanoformulation (GBP@Fe3O4). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe3O4in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress.

Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma.

Despite significant progression in the study of hepatocellular carcinoma (HCC), the role of the proteasome in regulating cross talk between mTOR signaling and glycolysis in liver cancer progression is not fully understood. Here, we demonstrate that deficiency of REGγ, a proteasome activator, in mice significantly attenuates DEN-induced liver tumor formation. Ablation of REGγ increases the stability of PP2Ac (protein phosphatase 2 catalytic subunit) in vitro and in vivo, which dephosphorylates PRAS40 (AKT1 substrate 1) and stabilizes the interaction between PRAS40 and Raptor to inactive mTORC1-mediated hyper-glycolytic metabolism. In the DEN-induced animal model and clinical hepato-carcinoma samples, high levels of REGγ in HCC tumor regions contribute to reduced expression of PP2Ac, leading to accumulation of phosphorylated PRAS40 and mTORC1-mediated activation of HIF1α. Interestingly, mTORC1 enhances REGγ activity in HCC, forming a positive feedback regulatory loop. In conclusion, our study identifies REGγ-PP2Ac-PRAS40 axis as a new layer in regulating mTORC1 activity and downstream glycolytic alterations during HCC development, highlighting the REGγ-proteasome as a potential target for personalized HCC therapy.

Sequential PDT and PTT Using Dual-Modal Single-Walled Carbon Nanohorns Synergistically Promote Systemic Immune Responses against Tumor Metastasis and Relapse.

Immune responses stimulated by photodynamic therapy (PDT) and photothermal therapy (PTT) are a promising strategy for the treatment of advanced cancer. However, the antitumor efficacy by PDT or PTT alone is less potent and unsustainable against cancer metastasis and relapse. In this study, Gd3+ and chlorin e6 loaded single-walled carbon nanohorns (Gd-Ce6@SWNHs) are developed, and it is demonstrated that they are a strong immune adjuvant, and have high tumor targeting and penetration efficiency. Then, three in vivo mouse cancer models are established, and it is found that sequential PDT and PTT using Gd-Ce6@SWNHs synergistically promotes systemic antitumor immune responses, where PTT stimulates dendritic cells (DCs) to secrete IL-6 and TNF-α, while PDT triggers upregulation of IFN-γ and CD80. Moreover, migration of Gd-Ce6@SWNHs from the targeted tumors to tumor-draining lymph nodes sustainably activates the DCs to generate a durable immune response, which eventually eliminates the distant metastases without using additional therapeutics. Gd-Ce6@SWNHs intervened phototherapies also generate durable and long-term memory immune responses to tolerate and prevent cancer rechallenge. Therefore, this study demonstrates that sequential PDT and PTT using Gd-Ce6@SWNHs under moderate conditions elicits cooperative and long-lasting antitumor immune responses, which are promising for the treatment of patients with advanced metastatic cancers.

GE11-PDA-Pt@USPIOs nano-formulation for relief of tumor hypoxia and MRI/PAI-guided tumor radio-chemotherapy.

Radio-chemo combination therapy has synergetic therapeutic effects on tumors. However, the tumor microenvironment, e.g. hypoxia and elevated H2S levels, limits its treatment efficacy. In this study, we developed a cisplatin-loaded, poly dopamine-coated and GE11 peptide-conjugated multi-functional theranostic system (GE11-PDA-Pt@USPIOs) based on poly acrylic acid-coated ultra-small superparamagnetic iron oxide nanoparticles (PAA@USPIOs) for modulation of the tumor hypoxic microenvironment and magnetic resonance imaging/photoacoustic imaging (MRI/PAI) guided radio-chemotherapy of tumors. The thick PAA coating on the USPIOs allowed highly efficient cisplatin loading by complexing the carboxylic groups on PAA with activated cisplatin. A subsequent thin layer of polydopamine (PDA) encapsulation following drug loading provided a means of further surface functionalization; it endowed the particles with photo-thermal properties but did not impede release of the drug or iron ions. GE11-PDA-Pt@USPIOs had high specificity for EGFR-positive tumor cells, could catalyze decomposition of H2O2 to oxygen and exhibited radio-chemo synergetic therapeutic effects under hypothermia conditions in vitro. Once administered intravenously, MRI and PA imaging revealed that the probes were able to accumulate in tumors with high efficiency; this relieved the tumor hypoxic conditions, sensitizing the tumors to radiation therapy. As a result, radio-chemo combination therapy significantly inhibited tumor growth. Our study illustrates for the first time that USPIOs can relieve tumor hypoxia and that GE11-PDA-Pt@USPIOs are highly effective for radio-chemotherapy of EGFR-positive tumors.

Dual Chemodrug-Loaded Single-Walled Carbon Nanohorns for Multimodal Imaging-Guided Chemo-Photothermal Therapy of Tumors and Lung Metastases.

Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases. Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection. Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules. Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site.