SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis.

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.

Enzyme-responsive design combined with photodynamic therapy for cancer treatment.

Photodynamic therapy (PDT) is a noninvasive cancer treatment that has garnered significant attention in recent years. However, its application is still hampered by certain limitations, such as the hydrophobicity and low targeting of photosensitizers (PSs) and the hypoxia of the tumor microenvironment. Nevertheless, the fusion of enzyme-responsive drugs with PDT offers novel solutions to overcome these challenges. Utilizing the attributes of enzyme-responsive drugs, PDT can deliver PSs to the target site and selectively release them, thereby enhancing therapeutic outcomes. In this review, we spotlight recent advances in enzyme-responsive materials for cancer treatment and primarily delineate their application in combination with PDT.

Heterocyclic-Modified Imidazoquinoline Derivatives: Selective TLR7 Agonist Regulates Tumor Microenvironment against Melanoma.

Immunotherapy targeting the toll-like receptor 7 (TLR7) is a promising strategy for cancer treatment. Herein, we describe the design and synthesis of a series of imidazoquinoline-based TLR7 agonists and assess NF-κB pathway activation using HEK-Blue hTLR7 cells to identify the most potent small-molecule TLR7 agonist, SMU-L11 (EC50 = 0.024 ± 0.002 µM). In vitro experiments demonstrated that SMU-L11 specifically activated TLR7, resulting in recruitment of the MyD88 adaptor protein and activation of the NF-κB and MAPK signaling pathways. Moreover, SMU-L11 was found to exert immune-enhancing effects by significantly inducing the secretion of proinflammatory cytokines in murine dendritic cells, macrophages, and human peripheral blood mononuclear cells while promoting M1 macrophage polarization. In vivo studies using a B16-F10 mouse tumor model showed that SMU-L11 significantly enhanced immune cell activation and augmented CD4+ T and CD8+ T-cell proliferation, directly killing tumor cells and inhibiting tumor growth.

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Artificial Humic Acid Mediated Carbon-Iron Coupling to Promote Carbon Sequestration.

Fe (hydr)oxides have a substantial impact on the structure and stability of soil organic carbon (SOC) pools and also drive organic carbon turnover processes via reduction-oxidation reactions. Currently, many studies have paid much attention to organic matter-Fe mineral-microbial interactions on SOC turnover, while there is few research on how exogenous carbon addition abiotically regulates the intrinsic mechanisms of Fe-mediated organic carbon conversion. The study investigated the coupling process of artificial humic acid (A-HA) and Fe(hydr)oxide, the mechanism of inner-sphere ligands, and the capacity for carbon sequestration using transmission electron microscopy, thermogravimetric, x-ray photoelectron spectroscopy, and wet-chemical disposal. Furthermore, spherical aberration-corrected scanning transmission electron microscopy-electron energy loss spectroscopy and Mössbauer spectra have been carried out to demonstrate the spatial heterogeneity of A-HA/Fe (hydr)oxides and reveal the relationship between the increase in Fe-phase crystallinity and redox sensitivity and the accumulation of organic carbon. Additionally, the dynamics of soil structures on a microscale, distribution of carbon-iron microdomains, and the cementing-gluing effect can be observed in the constructing nonliving anthropogenic soils, confirming that the formation of stable aggregates is an effective approach to achieving organic carbon indirect protection. We propose that exogenous organic carbon inputs, specifically A-HA, could exert a substantial but hitherto unexplored effect on the geochemistry of iron-carbon turnover and sequestration in anoxic water/solid soils and sediments.

Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.

Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.

Cancer Cell Membrane-Coated Nanoparticle Co-loaded with Photosensitizer and Toll-like Receptor 7 Agonist for the Enhancement of Combined Tumor Immunotherapy.

Tumor immunotherapy has shown considerable therapeutic potential in the past few years, but the clinical response rate of immunotherapy is less than 20%. Encountering the high heterogeneity of tumors, it will be a general trend to apply combined therapy for cancer treatment. Photodynamic therapy (PDT) transiently kills tumor cells by producing reactive oxygen species (ROS), while residual tumor cells are prone to metastasis, leading to tumor recurrence. In combination with tumor immunotherapy, it is hoped to awaken the host immune system and eradicate residual tumor cells. Herein, cancer cell membrane-coated nanoparticles as a platform to combine PDT, TLR7 agonist, and tumor antigen for the enhancement of tumor therapeutic efficacy are designed. The final biomimetic nanoparticles (CCMV/LTNPs) can specifically kill tumor cells through PDT, while strong host antitumor immune responses are elicited to eliminate residue tumor cells under the help of immune adjuvant and tumor antigen from the cancer cell membrane. In summary, a photoimmunotherapy strategy is designed that synergistically enhances the tumor therapeutic effects by killing tumor cells through PDT and activating host antitumor immune responses through the co-delivery of adjuvant and tumor antigen, which may offer a promising strategy for clinical immunotherapy in the future.

Thiol-Chromene "Click" Reaction-Activated Chemiluminescent Probe for Thiol Detection In Vitro and In Vivo.

Biothiols are biomolecules found in a higher content in cancer cells compared to normal cells, marking them useful cancer biomarkers. Chemiluminescence is widely used in biological imaging due to its excellent sensitivity and signal-to-noise ratio (SNR). In this study, we designed and prepared a chemiluminescent probe that is activated by a thiol-chromene "click" nucleophilic reaction. This probe is initially chemiluminescent but turned off and releases extremely strong chemiluminescence in the presence of thiols. It has high selectivity to thiol compared with other analytes. Real-time imaging of mice tumor sites showed significant chemiluminescence after the probe was injected, and the chemiluminescence of osteosarcoma tissues was also significantly stronger than that in adjacent tissues. We conclude that this chemiluminescent probe has potential to detect thiol, diagnose cancer, especially in its early stages, and aid in the development of related cancer drugs.

Remote Activation of M2 Macrophage Polarization via Magneto-Mechanical Stimulation To Promote Osteointegration.

Osteoimmunomodulation has been considered to play a key role in osteointegration of orthopedic biomaterials. However, regulation of the macrophage phenotype in vivo with a spatiotemporal controllable way still remains a challenge. In this study, we designed a novel magnetic-responsive mineralized collagen coating to exert remotely controlled magneto-mechanical stimulation on macrophages using an external magnetic field. The magneto-mechanical stimulation exhibited immunomodulatory capability to activate M2 macrophage polarization via triggering the integrin-related cascade pathway and suppressing the phosphorylation of JNK in the MAPK pathway. The optimized inflammatory microenvironment subsequently promoted the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and the osteointegration in vivo. This work, therefore, provides a remote spatiotemporal controllable strategy to promote the osteointegration of orthopedic biomaterials via regulation of the osteoimmune microenvironment.

Enhanced M2 Polarization of Oriented Macrophages on the P(VDF-TrFE) Film by Coupling with Electrical Stimulation.

Electrical stimulation (ES) has been considered a promising strategy in regulating intracellular communication, membrane depolarization, ion transport, etc. Meanwhile, cell topography, such as the alignment and elongation in anisotropic orientation, also plays a critical role in triggering mechanotransduction as well as the cellular fate. However, coupling of ES and cell orientation to regulate the polarization of macrophages is yet to be explored. In this work, we intended to explore the polarization of macrophages on a poly(vinylidene fluoride-trifluoroethylene [P(VDF-TrFE)] film with intrinsic microstripe roughness, which was covered on indium tin oxide planar microelectrodes. We found that mouse bone marrow-derived macrophages (BMDMs) cultured on a P(VDF-TrFE) film exhibited an elongated morphology aligned with the microstripe crystal whisker, but their polarization behavior was not affected. However, the elongated cells were susceptible to ES and upregulated their M2 polarization, as verified by the related expression of phenotype markers, cytokines, and genes, while not affecting M1 polarization. This is due to the increased expression of the M2 polarization receptor interleukin-4Rα on the surface of elongated BMDMs, while the M1 polarization receptor toll-like receptor 4 was not affected. Thus, M2 polarization was singularly enhanced after activation of polarization by ES. The combination of surface morphology and ES to promote M2 single polarization in this work provides a new perspective for regulating macrophage polarization in the field of immunotherapy.

Design, synthesis and bioactivity evaluation of a series of quinazolinone derivatives as potent PI3Kγ antagonist.

Targeting PI3Kγ would be a useful strategy for treating inflammatory and cancer diseases. However, the development of selective inhibitors of PI3Kγ is very challenging due to the high structural and sequence homology with other PI3K isoforms. A series of quinazolinone derivatives were designed, synthesized and biologically evaluated as PI3Kγ-selective inhibitors. Among all the 28 compounds, compound 9b was found to be the most potent selective inhibitor with IC50 values of 13.11 nM against PI3Kγ kinase. Additionally, compound 9b could generate toxicity on leukemia cells in a panel of 12 different of cancer cell lines with the IC50 value of 2.41 ± 0.11 µM on Jurkat cell. Preliminary mechanism studies indicated that compound 9b through inhibit the activity of PI3K-AKT in human and murine leukemia cells, and activated phosphorylated p38 and phosphorylated ERK presented potent antiproliferative activity, which provided a potent small molecule for further cancer therapy.

Photothermal extracellular matrix based nanocomposite films and their effect on the osteogenic differentiation of BMSCs.

Mild thermal stimulation in vivo could induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In this study, nano-functionalized photothermal extracellular matrix (ECM) nanocomposite films were obtained through adding graphene during cell culture, so that graphene could directly integrate with the ECM secreted by cells. Owing to the similarity of the ECM to the in vivo microenvironment and the apparent photothermal effect of graphene nanoflakes, heat could be generated and transferred at the material-cell interface in a biomimetic way. It was demonstrated that such nanocomposite films achieved an interface temperature rise with light illumination. This could be easily sensed by BMSCs through the ECM. According to alkaline phosphatase, osteogenic related gene expression, mineral deposition, and upregulated expression of heat shock protein (HSP70) and p-ERK, composite films with proper illumination significantly promoted the differentiation of BMSCs into osteoblasts. This work endeavors to study the thermal regulation of BMSC differentiation and provide a new perspective on biocompatible osteo-implant materials which can be remotely controlled.

Electrochemical deposition of Ppy/Dex/ECM coatings and their regulation on cellular responses through electrical controlled drug release.

Bone tissue engineering requires a material that can simultaneously promote osteogenic differentiation and anti-inflammatory effects at specific times in response to a series of problems after bone implantation. In this study, the porous network-like titanium matrix was constructed and polypyrrole/dexamethasone (Ppy/Dex) composite coatings with three-dimensional nano-network structure were prepared by electrochemical deposition. The biocompatibility of the composite coatings was further improved by the composite of the extracellular matrix (ECM). The Ppy/Dex/ECM composite coatings released Dex by changing the redox state of Ppy under the electrical stimulation of negative pulses, achieving a drug release controlled by electric field. In terms of osteogenic differentiation, the Ppy/Dex/ECM composite coatings exhibited the best osteogenic activity under electrical controlled release, indicating the synergistic effect of Dex and ECM on osteogenic differentiation. In terms of anti-inflammatory properties, ECM exhibited simultaneous inhibition of both pro- and anti-inflammatory process, while Dex demonstrated significant promotion of anti-inflammatory processes. In this work, the effect of electrical controlled drug release on osteogenic differentiation and inflammation in the ECM cell microenvironment was achieved by preparing Ppy/Dex/ECM composite coatings, which is of great significance for bone tissue engineering and regenerative medicine.

Solvent-assisted assembly of reduced graphene oxide/MXene-polypyrrole composite film for flexible supercapacitors.

Two-dimensional (2D) materials represented by graphene and MXene have attracted extensive attention in the field of energy storage. However, the automatic stacking and poor stability of 2D materials considerably limit their electrochemical performance. In this article, we apply a design strategy based on combining the ternary components of reduced graphene oxide (rGO), MXene, and polypyrrole (PPy) into one electrode to form a flexible film with a sandwich structure. As a result, the resulting rGO/MXene-PPy composite electrode inherits the characteristics of high conductivity, robust mechanical properties, and pseudocapacitance. In addition to providing capacitive contributions, the PPy serves as a blocker to prevent face-to-face restacking of the 2D nanosheets and also as a coating layer to significantly protect MXene from oxidation. Consequently, the rGO/MXene-PPy electrode exhibits a high specific capacitance of 408.2 F g-1 and a superior rate performance, with 67.3% capacitance retention at an increased current density of 10.0 A g-1. Furthermore, the as-assembled asymmetric supercapacitor possesses a pronounced energy density of 11.3 Wh kg-1 (35.5 Wh L-1) at a power density of 500.0 W kg-1 (1570.0 W L-1) and remarkable cycling stability, with 8.8% capacitance deterioration after 10,000 cycles. This work demonstrates the potential for application of as-prepared rGO/MXene-PPy electrodes in flexible energy storage devices with high volumetric/gravimetric energy and power densities.

Pyogenic Liver Abscesses with an Elevated Carcinoembryonic Antigen Level.

Serological tumor markers are useful for the detection of malignancies and evaluation of disease progression. These markers are not checked as part of a routine examination for patients with benign diseases and without any clinical suspicion of malignancy. However, some markers appear to be elevated in patients with benign diseases and without malignancies. We present a case of pyogenic liver abscesses with an elevated serum carcinoembryonic antigen (CEA) level associated with neither evidence of malignancy nor elevation of other tumor markers such as carbohydrate antigen (CA 19-9) and alpha-fetoprotein (AFP) levels. The serological level of CEA decreased and subsequently became within normal limits with treatment. This case also demonstrates that diabetic patients with a liver abscess may present with no infectious symptoms and that fine-needle aspiration is as effective as catheter drainage in the treatment of pyogenic liver abscess.

Extracellular arginine is required but the arginine transporter CAT3 (Slc7a3) is dispensable for mouse normal and malignant hematopoiesis.

Amino acid-mediated metabolism is one of the key catabolic and anabolic processes involved in diverse cellular functions. However, the role of the semi-essential amino acid arginine in normal and malignant hematopoietic cell development is poorly understood. Here we report that a continuous supply of exogenous arginine is required for the maintenance/function of normal hematopoietic stem cells (HSCs). Surprisingly, knockout of Slc7a3 (CAT3), a major L-arginine transporter, does not affect HSCs in steady-state or under stress. Although Slc7a3 is highly expressed in naïve and activated CD8 T cells, neither T cell development nor activation/proliferation is impacted by Slc7a3 depletion. Furthermore, the Slc7a3 deletion does not attenuate leukemia development driven by Pten loss or the oncogenic Ptpn11E76K mutation. Arginine uptake assays reveal that L-arginine uptake is not disrupted in Slc7a3 knockout cells. These data suggest that extracellular arginine is critically important for HSCs, but CAT3 is dispensable for normal hematopoiesis and leukemogenesis.

Small molecule-based immunomodulators for cancer therapy.

Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to pharmacodynamics (e.g., specificity and efficacy). However, they have limitations in terms of pharmacokinetics including long half-lives, poor tissue/tumor penetration, and little/no oral bioavailability. In addition, therapeutic antibodies are immunogenic, thus may cause unwanted adverse effects. Therefore, researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy, as small molecules may overcome the above disadvantages associated with antibodies. Further, small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment, and may be combined to elicit synergistic effects. Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy. In this review, we describe the current progress in small molecule-based immunomodulators (inhibitors/agonists/degraders) for cancer therapy, including those targeting PD-1/PD-L1, chemokine receptors, stimulator of interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.

Remotely Temporal Scheduled Macrophage Phenotypic Transition Enables Optimized Immunomodulatory Bone Regeneration.

Precise timing of macrophage polarization plays a pivotal role in immunomodulation of tissue regeneration, yet most studies mainly focus on M2 macrophages for their anti-inflammatory and regenerative effects while the essential proinflammatory role of the M1 phenotype on the early inflammation stage is largely underestimated. Herein, a superparamagnetic hydrogel capable of timely controlling macrophage polarization is constructed by grafting superparamagnetic nanoparticles on collagen nanofibers. The magnetic responsive hydrogel network enables efficient polarization of encapsulated macrophage to the M2 phenotype through the podosome/Rho/ROCK mechanical pathway in response to static magnetic field (MF) as needed. Taking advantage of remote accessibility of magnetic field together with the superparamagnetic hydrogels, a temporal engineered M1 to M2 transition course preserving the essential role of M1 at the early stage of tissue healing, as well as enhancing the prohealing effect of M2 at the middle/late stages is established via delayed MF switch. Such precise timing of macrophage polarization matching the regenerative process of injured tissue eventually leads to optimized immunomodulatory bone healing in vivo. Overall, this study offers a remotely time-scheduled approach for macrophage polarization, which enables precise manipulation of inflammation progression during tissue healing.

Near-Infrared Fluorescent and Photoacoustic Dual-Mode Probe for Highly Sensitive and Selective Imaging of Cysteine In Vivo.

Cysteine (Cys) plays an important role in many physiological activities of human beings. Various diseases are always accompanied by abnormal levels of Cys. A series of Cys-responsive probes were recently developed. However, most fluorescent probes have many disadvantages and exhibit poor in vivo imaging. Therefore, a near-infrared fluorescence (NIRF)/photoacoustic (PA) dual-mode probe with high selectivity and sensitivity (limit of detection = 10.6 nM) toward Cys was developed in this study. The new Probe I interacted with Cys to activate NIRF/PA signals, detecting Cys in vitro with a large emission wavelength (851 nm) and Stokes shift (191 nm), monitoring the occurrence of liver cancer in vivo. This work not only presented an effective NIRF/PA dual-mode dicyanoisophorone probe for the first time in the imaging of Cys but also provided a comprehensive and accurate tool for detecting different analytes and tumors in deeper tissues, which could be conducive to the early diagnosis of diseases.

Photo-thermic mineralized collagen coatings and their modulation of macrophages polarization.

Macrophages polarization in bone immune microenvironment is crucial in bone regeneration. In this work, mineralized collagen (MC) coatings with photo-thermal effect were prepared through incorporation of polydopamine (PDA). MC coatings with different thicknesses were deposited on titanium substrate through electrochemical deposition. PDA preformed on the substrate, acting as a photo-thermal agent. The effects of light illumination, i.e., different thermal effects, on the polarization of mouse bone marrow-derived macrophages were explored. It was found that heat can promote the M1 polarization of macrophages and inhibit the M2 polarization. Also, gene expression results revealed that such photo illumination based macrophage modulation is effective and safe. It provides a possible way for the design of functional materials to regulate the bone immune microenvironment.