SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Ferroptosis boosted oral cancer photodynamic therapy by carrier-free Sorafenib-Ce6 self-assembly nanoparticles.

Oral cancer is a disease with high morbidity and mortality worldwide and greatly impacts the quality of life, especially in patients with advanced stages. Photodynamic therapy (PDT) is one of the most effective clinical treatments for oral cancers. However, most clinically applied photosensitizers have several deficiencies, including oxygen dependence, poor aqueous solubility, and a lack of tumor-targeting ability. Herein, the carrier-free multifunctional Sorafenib (Sor), chlorin e6 (Ce6), and Fe3+ self-assembly co-delivery nanoparticles (Sor-Ce6 NPs) were constructed via combining a ferroptosis inducer Sor and a photosensitizer Ce6 for synergetic therapy. The as-synthesized Sor-Ce6 NPs presented excellent colloidal stability and water dispersity with good in vivo tumor-targeting ability. More significantly, the low dose of Sor-Ce6 NPs had little dark toxicity but produced significantly enhanced ROS and supplied O2 sustainably to increase phototoxicity through ferroptosis pathway. Notably, the Sor-Ce6 NPs showed significantly higher in vitro and in vivo anti-tumor efficacy than the Sor/Ce6 mixture due to the improvement of cellular uptake and the incorporation of foreign Fe ions in the system, which also confer the T1 magnetic resonance-guided imaging ability to the formed Sor-Ce6 NPs. Our study demonstrates a promising self-assembled strategy for overcoming hypoxia-related PDT resistance for oral cancer treatment.

Novel Carrier-Free Nanodrug Enhances Photodynamic Effects by Blocking the Autophagy Pathway and Synergistically Triggers Immunogenic Cell Death for the Efficient Treatment of Breast Cancer.

Photosensitizers have been widely used to cause intratumoral generation of reactive oxygen species (ROS) for cancer therapy, but they are easily disturbed by the autophagy pathway, a self-protective mechanism by mitigating oxidative damage. Hereby, we reported a simple and effective strategy to construct a carrier-free nanodrug, Ce6@CQ namely, based on the self-assembly of the photosensitizer chlorin e6 (Ce6) and the autophagy inhibitor chloroquine (CQ). Specifically, Ce6@CQ avoided the unexpected toxicity caused by the regular nanocarrier and also ameliorated its stability in different conditions. Light-activated Ce6 generated cytotoxic ROS and elicited part of the immunogenic cell death (ICD). Moreover, CQ induced autophagy dysfunction, which hindered self-healing in tumor cells and enhanced photodynamic therapy (PDT) to exert a more potent killing effect and more efficient ICD. Also, Ce6@CQ could effectively accumulate in the xenograft breast tumor site in a mouse model through the enhanced permeability and retention (EPR) effect, and the growth of breast tumors was effectively inhibited by Ce6@CQ with light. Such a carrier-free nanodrug provided a new strategy to improve the efficacy of PDT via the suppression of autophagy to digest ROS-induced toxic substances.

Discovery of dolutegravir-1,2,3-triazole derivatives against prostate cancer via inducing DNA damage.

Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.

A carrier-free supramolecular nano-twin-drug for overcoming irinotecan-resistance and enhancing efficacy against colorectal cancer.

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC.

A Cascade Strategy Boosting Hydroxyl Radical Generation with Aggregation-Induced Emission Photosensitizers-Albumin Complex for Photodynamic Therapy.

Effective photodynamic therapy (PDT) requires photosensitizers (PSs) to massively generate type I reactive oxygen species (ROS) in a less oxygen-dependent manner in the hypoxia tumor microenvironment. Herein, we present a cascade strategy to boost type I ROS, especially hydroxyl radical (OH·-), generation with an aggregation-induced emission (AIE) photosensitizer-albumin complex for hypoxia-tolerant PDT. The cationic AIE PS TPAQ-Py-PF6 (TPA = triphenylamine, Q = anthraquinone, Py = pyridine) contains three important moieties to cooperatively enhance free radical generation: the AIE-active TPA unit ensures the effective triplet exciton generation in aggregate, the anthraquinone moiety possesses the redox cycling ability to promote electron transfer, while the cationic methylpyridinium cation further increases intramolecular charge transfer and electron separation processes. Inserting the cationic TPAQ-Py-PF6 into the hydrophobic domain of bovine serum albumin nanoparticles (BSA NPs) could greatly immobilize its molecular geometry to further increase triplet exciton generation, while the electron-rich microenvironment of BSA ultimately leads to OH·- generation. Both experimental and theoretical results confirm the effectiveness of our molecular cationization and BSA immobilization cascade strategy for enhancing OH·- generation. In vitro and in vivo experiments validate the excellent antitumor PDT performance of BSA NPs, superior to the conventional polymeric encapsulation approach. Such a multidimensional cascade strategy for specially boosting OH·- generation shall hold great potential in hypoxia-tolerant PDT and related antitumor applications.

Photosensitizers with multiple degradation modes for efficient and postoperatively safe photodynamic therapy.

Photodynamic therapy (PDT) is emerging as a powerful tool for cancer treatment due to its unique advantages in terms of noninvasive and spatiotemporal selectivity. However, the residue of photosensitizers (PSs), which usually lead to thorny post-treatment side effects after photodynamic therapy (PDT), is one of bottlenecks for clinical translation. Herein, PSs with multiple degradation modes are developed to solve this issue. Upon 660 nm laser excitation, PSs can produce different types of reactive oxygen species (ROS), in which 1O2 and O2·- could kill the cancer cells, while ·OH could oxide the PSs themselves for photodegradation. After PDT, the residual few number of PSs could be further oxidized by endogenous ROS for biodegradation, and the degradation products could be further excreted by urine. This process therefore solves the slow-metabolism issue of traditional PSs. Among them, SQSe demonstrates the highest killing efficiency with best degradation ability, as confirmed by both in vitro and in vivo results. The postoperative safety of SQSe is further verified by assessment on in vivo artificially induced post-operative side effects.

Supramolecular Cyclic Dinucleotide Nanoparticles for STING-Mediated Cancer Immunotherapy.

Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine to construct a ligand for the STING agonist c-di-GMP (CDG), a hydrophobic nucleotide lipid (3',5'-diOA-dC), which can assemble with CDG into stable cyclic dinucleotide nanoparticles (CDG-NPs) through various supramolecular forces driven by molecular recognition. CDG-NPs are homogeneous and stable spherical nanoparticles with an average diameter of 59.0 ± 13.0 nm. Compared with free CDG, CDG-NPs promote the retention and intracellular delivery of CDG in the tumor site, boost STING activation and TME immunogenicity, and potentiate STING-mediated anti-tumor immunity when administered by either intratumoral or systemic routes in melanoma-bearing mice. We propose a flexible supramolecular nanodelivery system for CDG by using endogenous small molecules, which provides a CDN delivery platform for STING-mediated cancer immunotherapy.

Primary empty sella syndrome-caused rhabdomyolysis misdiagnosed as recurrent sepsis: a case report and literature review.

We reported a case of a 68-year-old man who presented with recurrent fever and multiorgan dysfunction. His significantly elevated procalcitonin and C-reactive protein levels indicated recurrent sepsis. However, no focus of infection and no pathogens were identified through a variety of examinations and tests. Although the increase of creatine kinase was less than five times the upper limit of normal value, the diagnosis of rhabdomyolysis secondary to adrenal insufficiency resulting from primary empty sella syndrome was finally made, as supported by serum myoglobin elevation, serum cortisol, and adrenocorticotropic hormone deficiency, bilateral adrenal atrophy on computed tomography, and empty sella on magnetic resonance imaging. After the glucocorticoid replacement treatment, the patient's myoglobin gradually returned to normal range, and his condition continued to improve. Rhabdomyolysis resulting from a rare cause may be misdiagnosed as sepsis in patients who present with increased procalcitonin levels.

Cell membrane-targeting NIR fluorescent probes with large Stokes shifts for ultralong-term transplanted neural stem cell tracking.

There is an emerging therapeutic strategy to transplant stem cells into diseased host tissue for various neurodegenerative diseases, owing to their self-renewal ability and pluripotency. However, the traceability of long-term transplanted cells limits the further understanding of the mechanism of the therapy. Herein, we designed and synthesized a quinoxalinone scaffold-based near-infrared (NIR) fluorescent probe named QSN, which exhibits ultra-strong photostability, large Stokes shift, and cell membrane-targeting capacity. It could be found that QSN-labeled human embryonic stem cells showed strong fluorescent emission and photostability both in vitro and in vivo. Additionally, QSN would not impair the pluripotency of embryonic stem cells, indicating that QSN did not perform cytotoxicity. Moreover, it is worth mentioning that QSN-labeled human neural stem cells held cellular retention for at least 6 weeks in the mouse brain striatum post transplantation. All these findings highlight the potential application of QSN for ultralong-term transplanted cell tracking.

An aminopeptidase N-based color-convertible fluorescent nano-probe for cancer diagnosis.

Specific cancer diagnosis at an early stage plays a significant role in preventing cancer metastasis and reducing cancer mortality. Thus, exploring specific and sensitive fluorescent probes to realize early cancer diagnosis is an urgent need in clinic. Aminopeptidase N (APN/CD13), overexpressed in numerous malignant tumors, is an important tumor biomarker associated with cancer progression, invasion, and metastasis. In this study, a novel fluorescent molecule APN-SUB, capable of monitoring APN in real time, is encapsulated in a pH-responsive block copolymer (termed APN-SUB nanoprobe) for cancer diagnosis. APN-SUB contains a fluorophore center and a trigger moiety (leucine group), which is covalently conjugated on the fluorophore with an amide bond. The hydrolysis of the amide bond in APN-SUB activated by APN leads to a red shift of maximum fluorescence emission wavelength from 495 nm to 600 nm, realizing dual-color transformation from green to red. Moreover, the APN-SUB nanoprobe with pH-responsiveness is prepared to improve the accumulation and the release rate in the tumor region. It is worth noting that the APN-SUB nanoprobe exhibits good performance for APN imaging, namely, superior limit of detection (0.14 nU mL-1), excellent selectivity and strong photostability. More importantly, the APN-SUB nanoprobe can be successfully employed as a color-convertible fluorescent probe for cancer diagnosis by tracking the activity of APN with high specificity and sensitivity in vivo, demonstrating its potential value for cancer diagnosis.

Self-assembled peptide-paclitaxel nanoparticles for enhancing therapeutic efficacy in colorectal cancer.

Chemotherapy is one of the main treatments for colorectal cancer, but systemic toxicity severely limits its clinical use. Packaging hydrophobic chemotherapeutic drugs in targeted nanoparticles greatly improve their efficacy and reduce side effects. We previously identified a novel colorectal cancer specific binding peptide P-LPK (LPKTVSSDMSLN) from phage display peptide library. Here we designed a self-assembled paclitaxel (PTX)-loaded nanoparticle (LPK-PTX NPs). LPK-PTX NPs displayed a superior intracellular internalization and improved tumor cytotoxicity in vitro. Cy5.5-labeled LPK-PTX NPs showed much higher tumor accumulation in colorectal cancer-bearing mice. Furthermore, LPK-PTX NPs exhibit enhanced antitumor activity and decreased systemic toxicity in colorectal cancer patient-derived xenografts (PDX) model. The excellent in vitro and in vivo antitumor efficacy proves the improved targeting drug delivery, suggesting that peptide P-LPK has potential to provide a novel approach for enhanced drug delivery with negligible systemic toxicity.

Toxicity Analysis of Mesoporous Polydopamine on Intestinal Tissue and Microflora.

As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.

An Activity-Based Photosensitizer to Reverse Hypoxia and Oxidative Resistance for Tumor Photodynamic Eradication.

Photodynamic therapy (PDT) has been a well-accepted clinical treatment for malignant tumors owing to its noninvasiveness and high spatiotemporal selectivity. However, the treatment outcome of current PDT applications is hindered by hypoxia and intracellular oxidative resistance of solid tumors. Recent studies have shown that inhibiting histone deacetylases (HDACs) can induce cell ferroptosis, reverse hypoxia, and elevate oxidative status. Theoretically, the design and synthesis of activity-based photosensitizers that target HDACs can address the bottlenecks of PDT. Herein, the concept of an activity-based photosensitizer is presented for targeting HDACs, which is designed based on a quinoxalinone scaffold through a pharmacophore migration strategy. The developed activity-based photosensitizer can inhibit HDACs, and overcome hypoxia and intracellular oxidative resistance, realizing the full potential of photosensitizers for malignant tumor treatment. The molecular design strategy proposed in this project should provide theoretical guidance for the development of ideal photosensitizers for practical applications.

Effects of the Dectin-2/TNF-α Pathway on Ventricular Arrhythmia after Acute Myocardial Infarction in Mice.

Background: Inflammatory responses are involved in ischemic injuries and cardiac repair after acute myocardial infarction (AMI). Dectin-2 is a C-type lectin receptor that induces cytokine production and promotes local inflammatory responses. Methods: Sixty C57BL/6 mice were randomly assigned to a sham-surgery group, AMI group, or AMI + etanercept group, with 20 mice in each group. Programmed electrical stimulation (PES) was used to anesthetized mice to induce ventricular tachycardia. Real-time polymerase chain reaction (PCR) and western blot analysis were adopted to determine the expression and distribution of dectin-2 in heart tissues. The tumor necrosis factor-α (TNF-α), interferon-gamma (IFN)-γ, interleukin (IL) 4, and IL-5 levels in the serum were determined using ELISAs. Results: The expression of dectin-2 and TNF-α was increased in the myocardium in AMI, and the susceptibility to ventricular arrhythmia (VA) was increased. The induction rate of VA was significantly decreased by etanercept. Compared with those in the sham-surgery group, the AMI group showed significantly higher serum TNF-α and IFN-γ levels and lower IL-4 and IL-5levels. Conclusion: Dectin-2 intensifies the activation of the TNF-α immune reaction through the Th1 differentiation, which may increase vulnerability to VA in AMI.

A Strategy to Design Cu2MoS4@MXene Composite With High Photothermal Conversion Efficiency Based on Electron Transfer Regulatory Effect.

Using photothermal therapy to treat cancer has become an effective method, and the design of photothermal agents determines their performance. However, due to the major radiative recombination of a photogenerated electron in photothermal materials, the photothermal performance is weak which hinders their applications. In order to solve this issue, preventing radiative recombination and accelerating nonradiative recombination, which can generate heat, has been proved as a reasonable way. We demonstrated a Cu2MoS4@MXene nanocomposite with an obviously enhanced photothermal conversion efficiency (η = 87.98%), and this improvement can be attributed to the electron migration. Then, a mechanism is proposed based on the electron transfer regulatory effect and the localized surface plasmon resonance effect, which synergistically promote nonradiative recombination and generate more heat. Overall, our design strategy shows a way to improve the photothermal performance of Cu2MoS4, and this method can be extended to other photothermal agents to let them be more efficient in treating cancer.

LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade.

The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) increased CD8+ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti-CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cell-exclusionary TME to a T cell-enriched TME through mechanisms involving cooperation with innate immune cells.

Sprayable hydrogel for biomedical applications.

Polymeric hydrogels have extraordinary potential to be utilized for biomedical applications. Recently, sprayable hydrogels have received increasing attention for their biocompatibility, degradability, tunable mechanical properties and rapid spray-filming abilities. In this review, hydrogel-based biomaterials, especially those based on natural polymers, such as polysaccharides and proteins, have been explained. The focus of this review lies on illuminating recent advances in sprayable hydrogel systems and highlighting the properties and applications of sprayable hydrogels, such as wound management, postoperative adhesion and cancer therapeutics. In addition, future research directions and challenges are also discussed.

Living Bacteria-Based Immuno-Photodynamic Therapy: Metabolic Labeling of Clostridium butyricum for Eradicating Malignant Melanoma.

Due to the complexity, aggressiveness, and heterogeneity of malignant melanoma, it is difficult to eradicate the whole tumor through conventional treatment. Herein, a strategy of metabolic engineering labeled anaerobic oncolytic bacteria (Clostridium butyricum) is demonstrated to achieve the ablation of melanoma. In this system, the metabolic substrate of C. butyricum d-alanine (d-Ala) is first conjugated with a photosensitizer (TPApy) showing aggregation-induced emission (AIE). The yielded metabolic substrate of d-Ala-TPAPy can be metabolically incorporated into bacterial peptidoglycan to form engineered C. Butyricum. Once the engineered C. butyricum is injected into melanoma, the bacteria can only proliferate in an anaerobic zone, stimulate the tumor immune microenvironment, and ablate the tumor hypoxia region. Following that, the relatively rich oxygen content in the peripheral area can induce the death of C. butyricum. The photosensitizer (PS) on the bacteria can subsequently exert a photodynamic effect in the oxygen-rich region and further remove the melanoma residue under light irradiation. Prominent in vivo melanoma ablation results revealed that the engineering oncolytic bacteria can provide a promising regime for solid tumor eradication.

Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell-Mediated Antitumor Immune Responses.

Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I PRMTs remains uncharacterized. Here, our The Cancer Genome Atlas dataset analysis revealed that expression of type I PRMTs associated with poor clinical response and decreased immune infiltration in patients with melanoma. In cancer cell lines, inhibition of type I PRMTs induced an IFN gene signature, amplified responses to IFN and innate immune signaling, and decreased expression of the immunosuppressive cytokine VEGF. In immunocompetent mouse tumor models, including a model of T-cell exclusion that represents a common mechanism of anti-programmed cell death protein 1 (PD-1) resistance in humans, type I PRMT inhibition increased T-cell infiltration, produced durable responses dependent on CD8+ T cells, and enhanced efficacy of anti-PD-1 therapy. These data indicate that type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade (ICB) to induce durable antitumor responses in a T cell-dependent manner, suggesting that type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.