Persistent luminescence nanoparticles with high intensity for colorectal cancer surgery navigation and precision resection.

Surgical resection remains the main treatment for malignant tumors. Image-guided surgery aims to remove tumor tissue completely while preserving normal tissue, thereby reducing tumor recurrence rates and injury. However, challenges like tissue autofluorescence, limited probe penetration and low contrast restrict its use. Near-infrared (NIR) persistent luminescent nanoparticles (PLNPs) provide a solution by emitting persistent luminescence (PersL) even after excitation ceases, thus circumventing autofluorescence and enabling deep tumor imaging. In this study, we prepared nano-sized (140 nm hydrodynamic size) Cr3+ doped zinc gallogermanate (ZGC) using a removable template method and modified it with folate acid to obtain ZGC-FA, which exhibits NIR (695 nm) PersL with a signal-to-noise ratio of 23.9 in vivo. We utilized a colon cancer model that selectively expressed luciferase for the first time to validate the guiding efficacy of ZGC-FA in precision surgical resection. Post-intraperitoneal injection at 50 minutes, the PersL closely matched the tumor boundaries, achieving an overlap rate of approximately 98%. Complete tumor resection was achieved under PersL guidance, with only 2.3% of healthy tissue removed. This research underscores the potential of ZGC-FA in the field of surgical oncology. The precision of the ZGC-FA guided surgical approach holds promise to enhance surgical outcomes and facilitate postoperative recovery in patients.

Pomegranate seeds: a comprehensive review of traditional uses, chemical composition, and pharmacological properties.

Pomegranate seeds (PS) are the dried seeds derived from pomegranate fruit, accounting for approximately 20% of the fruit's total weight, and are a by-product of pomegranate juice extraction. These seeds hold significance in traditional medicine among Uyghurs and Tibetan cultures, featuring diverse clinical applications within traditional Chinese medicine. These applications include management of gastric coldness and acidity, abdominal distension, liver and gallbladder fever, and pediatric enteritis. PS demonstrates properties such as stomach tonicity, qi regulation, analgesia, and anti-inflammatory effects. Extensive research underscores the richness of PS in various phytochemical compounds and metabolites, notably unsaturated fatty acids (particularly linolenic acid and linoleic acid), phenolic compounds tocopherols, proteins, and volatile oils. Notably, among these bioactive compounds, punicic acid (PA), found within PS, demonstrates potential in the prevention and treatment of cancers, diabetes, obesity, and other ailments. Despite extensive literature on pomegranate as a botanical entity, a comprehensive review focusing specifically on the chemical composition and pharmacological effects of PS remains elusive. Therefore, this review aimed to consolidate knowledge regarding the medicinal properties of PS, summarizing its chemical composition, traditional uses, and pharmacological effects in treating various diseases, thereby laying a foundation for the advancement and application of PS in the field of pharmacology.

Enhancing Persistent Luminescence through Synergy between Optimal Electron Traps and Dye Sensitization.

Due to their unique afterglow ability, long-wavelength-light rechargeable persistent luminescence (PersL) nanoparticles (PLNPs) have been emerging as an important category of imaging probes. Among them, ZnGa2O4:0.6% Cr3+ (ZGC) PLNPs have gained widespread recognition due to the ease of synthesis and uniform morphology. Unfortunately, the limited absorption arising from the low molar extinction coefficient of Cr3+ results in relatively low afterglow intensity and rapid decay after long-wavelength LED light irradiation. Herein, we discovered a strategy that boosting dye-sensitization performance was able to effectively amplify the PersL signal under white LED light. Specifically, Dil served as a highly efficient sensitizer for Cr3+, promoting the absorption of the excitation light. By adjusting the Pr dopant concentrations, ZGCP0.5 PLNPs with optimal trap densities were obtained, which showed the highest PersL intensity and dye-sensitized performance. Strikingly, ZGCP0.5-Dil PLNPs exhibited a 24.3-fold enhancement in intensity and a 2-fold prolongation of decay time over bare ZGC PLNPs through the synergy effect of optimal electron traps and dye sensitization. Photostable ZGCP0.5-Dil PLNPs enabled imaging of the HepG2 tumor and effectively guided tumor surgical resection verified by the H&E staining analysis. This strategy could be a significant reference in other dye-sensitization PLNPs to enhance longer-wavelength rechargeable PersL.

Bergapten attenuates human papillary thyroid cancer cell proliferation by triggering apoptosis and the GSK-3ß, P13K and AKT pathways.

BACKGROUND: Over the past few decades, thyroid cancer (TC) incidence has steadily increased globally. The most common TC is human papillary thyroid carcinoma (PTC), which is poorly responsive to the current treatments. Hence, finding a successful therapeutic is urgently required. OBJECTIVES: Bergapten (BG) is a furanocoumarin, a natural psoralen derivative isolated from numerous species of citrus and bergamot oil that has demonstrated anti-tumor activity. However, there are no reports available on the efficacy of BG on PTC cells. MATERIAL AND METHODS: The current research investigated the anti-cancer activity of BG on human BCPAP cells, with cytotoxicity and apoptosis evaluated using MTT assay, AO/EB, DAPI, PI, ELISA, mRNA, and western blot. RESULTS: Bergapten (control group, 10 µM/mL and 15 µM/mL) inhibited PTC cell proliferation and stimulated apoptosis by enhancing Bax and caspase and reducing Bcl-2, cyclin-D1, c-myc, and survivin in a dose-dependent manner. Furthermore, BG expressively attenuated PI3K/AKT/GSK-3ß signaling, creating an uneven Bax/Bcl-2 ratio that triggered Cyt-c, caspase cascade and apoptosis in human PTC cells. CONCLUSIONS: Our findings emphasize that BG has the potential to be used as a protective natural remedy for human PTC cells.

pH-Responsive Plasmon-Enhanced Persistent Luminescent ZnGa2O4:Cr3+ Nanopomegranate for Tumor Imaging.

Noble metal compositing is a promising method to enhance radiance intensity of persistent luminescent (PersL) nanoparticles (NPs) via surface plasmon resonance (SPR) for better tumor imaging, but it rarely unites with the pH-response strategy due to the challenge of realizing rigorous pH-responsive spatial distance control as a "button switch" of SPR. Here, ZnGa2O4:Cr3+ (ZGC) NPs as "pomegranate seeds" are cladded with sodium alginate to form nanoclusters (ZGC-SA), subsequently coated with carboxyl-rich polymers to acquire "pomegranate rind" (ZSPB) and finally decorated with 10 nm gold NPs (AuNPs) on the surface to obtain nanopomegranate structure (ZSPB@AuNPs). Though without deliberate distance control, there are plenty of "seeds" inside ZSPB@AuNPs fortunately at appropriate positions, which could be plasmon-enhanced by AuNPs. Furthermore, triggered by carboxyl protonation in subacid tumor, ZSPB@AuNPs aggregate and subsequently facilitate such plasmon enhancement effect, resulting in 4.4-fold PersL promotion at pH 5.5 (tumor microenvironment, TME) over pH 7.4 and in a maximum "tumor to normal tissue ratio" of PersL imaging signals of 125.9. Under surgical navigation of ZSPB@AuNPs, intramuscular tumors of mice could be resected without residue signals left. This nanopomegranate achieves TME pH-responsive plasmon-enhanced PersL for the first time and broadens the way for designing plasmon-enhanced PersL nanosystems.

A novel removable template method for the preparation of persistent luminescence nanoparticles with biocompatible size and high intensity.

NIR persistent luminescence nanoparticles (PLNPs) are appealing for bio-imaging because of the properties of extremely low autofluorescence interference and deep tissue penetrating ability. However, current preparation methods can hardly simultaneously endow PLNPs with nano-scale size, long persistent luminescence (PersL) life, and high luminescence intensity, which can hardly meet the requirements of bio-imaging. Herein, we report a new synthetic route to nano-sized chromium-doped zinc gallate (ZGC) via a removable MOF template, i.e., one-pot hydrothermal synthesis of an intermediate followed by its calcination at 1100 °C in air. By exploiting the regulatory effect of the intermediate on Zn and Ga, the depth of traps in 170 nm-sized ZGC nanoparticles was enhanced to above 0.8 eV, and the PersL duration to more than 24 h, with an average lifetime of up to 216 s. An in vivo experiment shows that tumors can be accurately delineated for more than 3 hours. This strategy largely resolves the conflict between the particle size and PersL properties of PLNPs, and expands the application of PLNPs in bio-imaging.

M1 polarization enhances the antitumor activity of chimeric antigen receptor macrophages in solid tumors.

BACKGROUND: Chimeric antigen receptor macrophage (CAR-M) therapy is a novel cancer immunotherapy approach that integrates CAR structure and macrophage functions. CAR-M therapy has shown unique and impressive antitumor effects in immunotherapy for solid tumors. However, the polarization state of macrophages can affect the antitumor effect of CAR-M. We hypothesized that the antitumor activity of CAR-Ms may be further improved after inducing M1-type polarization. METHODS: In this report, we constructed a novel HER2-targeting CAR-M, which was composed of humanized anti-HER2 scFv, CD28 hinge region and FcγRI transmembrane domain and intracellular domain. Phagocytosis, tumor-killing capacities, and cytokine release of CAR-Ms were detected with or without M1-polarization pretreatment. Several syngeneic tumor models were used to monitor the in vivo antitumor activity of M1-polarized CAR-Ms. RESULTS: After polarization with LPS combined with interferon-γ in vitro, we found that the phagocytic and tumor-killing capacities of CAR-Ms against target cells were significantly enhanced. The expression of costimulatory molecules and proinflammatory cytokines was also significantly increased after polarization. By establishing several syngeneic tumor models in vivo, we also demonstrated that infusing polarized M1-type CAR-Ms could effectively suppress tumor progression and prolong the survival of tumor-bearing mice with enhanced cytotoxicity. CONCLUSIONS: We demonstrated that our novel CAR-M can effectively eliminate HER2-positive tumor cells both in vitro and in vivo, and M1 polarization significantly enhanced the antitumor ability of CAR-M, resulting in a stronger therapeutic effect in solid cancer immunotherapy.

Association between olfactory pathway gene variants and obesity in Chinese Han population: A case-control study based on genetic score.

BACKGROUND: Our previous bivariate genome-wide association study in dizygotic twins suggested that the olfactory transduction pathway genes were associated with obesity in Northern Han Chinese adults. In this study, we attempted to verify the associations of the olfactory transduction pathway genes score with obesity in population with the same genetic background, and to estimate the interaction between gene variants and potential environment factors. METHODS: A case-control study was conducted in Qingdao, China in 2019-2021, which enrolled 301 obesity cases and 307 controls. Based on the candidate gene selection method, 29 single nucleotide polymorphisms (SNPs) in 7 olfactory pathway genes were selected. Genomic deoxyribonucleic acid (DNA) was isolated and purified from the peripheral blood leukocytes by using DNA extraction kits and was genotyped by the MassArray system. The weighted genetic score of each gene was calculated to analyze the effect of whole gene. The effect of gene scores on obesity and the gene-environment interaction were estimated by logistic regression. RESULTS: After adjusting for age, sex, smoking, alcohol drinking, physical activity, we observed positive associations of OR4D1 (OR = 1.531, 95% CI = 1.083-2.164, P = 0.016) and OR52K1 (OR = 1.437, 95% CI = 1.055-1.957, P = 0.022) gene scores with obesity, as well as negative associations of OR2L8 (OR = 0.708, 95% CI = 0.504-0.995, P = 0.046) and CALML3 (OR = 0.601, 95% CI = 0.410-0.881, P = 0.009) gene scores with obesity. Significant multiplicative model interaction between OR4D1 and smoking (Pinteraction = 0.041) as well as CALML3 and smoking (Pinteraction = 0.026) on obesity were identified. Stratified analysis showed that in smokers, OR4D1 gene score was positively associated with obesity (OR = 2.673, 95% CI = 1.348-5.299, P = 0.005) and CALML3 gene score was negatively correlated with obesity (OR = 0.252, 95% CI = 0.103-0.618, P = 0.003). The relationships were not statistically significant in non-smokers (OR4D1: OR = 1.216, 95% CI = 0.806-1.836, P = 0.351; CALML3: OR = 0.764, 95% CI = 0.492-1.188, P = 0.232). CONCLUSIONS: Genetic variations in the olfactory pathway were associated with obesity in Northern Han Chinese adults. Smoking modified the effect of OR4D1 and CALML3 gene variants on obesity.

Improving the Performance of Perovskite Solar Cells with Insulating Additive-Modified Hole Transport Layers.

Invert perovskite solar cells (PSCs) present a great potential for next-generation photovoltaics for their flexibility and tandem adaptability. In order to improve the conductivity of the hole transport layer (HTL), such as poly(triarylamine), highly conductive additives (e.g., F4TCNQ, Li-TFSI) were generally applied to achieve a power conversion efficiency (PCE) exceeding 21%. However, these additives significantly affect the long-term stability of the devices due to their humidity sensitivity. In this work, the HTL was counterintuitively optimized with insulating additives, such as polyphenylene sulfide, which enhanced PCE from 19.1 to 21.5% along with a noticeable improvement in device stability with T50 of 574 h under double 85 aging conditions. The performance enhancement is attributed to larger grain sizes in perovskite films on the HTL and better energy-level alignment between the HTL and perovskite after introducing the insulating additives, which compensate negative influence caused by additive-induced reduction in conductivity. Our work demonstrates that low-conductivity additives, rather than the commonly used high-conductivity counterparts, can also contribute to improving the photovoltaic performance in PSCs.

Tumor acid microenvironment-activated self-targeting & splitting gold nanoassembly for tumor chemo-radiotherapy.

Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy. Herein, a pH-responsive gold nanoassembly is designed to overcome these problems. Polyethylene glycol linked raltitrexed (RTX, target ligand and chemotherapy drug) and two tertiary amine molecules (1-(2-aminoethyl) pyrrolidine and N, N-dibutylethylenediamine) are modified on the surface of the 6-nm gold nanoparticles by lipoic acid to form gold nanoassembly defined as Au-NNP(RTX). The Au-NNP (RTX) nanoassembly could remain at about 160 nm at the blood circulation (pH 7.4), while split into 6-nm gold nanoparticles due to tertiary amine protonation at tumor extracellular pH (pH 6.8). This pH-responsive disassembly behavior endows Au-NNP(RTX) better tumor tissue permeability through the better diffusion brought by the size reduction. Meanwhile, after disassembly, more RTXs on the surface of gold nanoparticles are exposed from the shielded state of assembly along with 2.25-fold augment of cellular uptake capability. Most importantly, the results show that Au-NNP(RTX) possesses of high tumor accumulation and effective tumor penetration, thereby enhancing the tumor chemo-radiotherapy efficiency.

NuMA regulates mitotic spindle assembly, structural dynamics and function via phase separation.

A functional mitotic spindle is essential for accurate chromosome congression and segregation during cell proliferation; however, the underlying mechanisms of its assembly remain unclear. Here we show that NuMA regulates this assembly process via phase separation regulated by Aurora A. NuMA undergoes liquid-liquid phase separation during mitotic entry and KifC1 facilitates NuMA condensates concentrating on spindle poles. Phase separation of NuMA is mediated by its C-terminus, whereas its dynein-dynactin binding motif also facilitates this process. Phase-separated NuMA droplets concentrate tubulins, bind microtubules, and enrich crucial regulators, including Kif2A, at the spindle poles, which then depolymerizes spindle microtubules and promotes poleward spindle microtubule flux for spindle assembly and structural dynamics. In this work, we show that NuMA orchestrates mitotic spindle assembly, structural dynamics and function via liquid-liquid phase separation regulated by Aurora A phosphorylation.

Nanomaterials as Smart Immunomodulator Delivery System for Enhanced Cancer Therapy.

Immunomodulatory therapeutics, which is conducive to overcoming tumor tolerance and restoring normal immune responses, has been proposed as a promising approach for enhanced cancer therapy and clinical advancement. However, issues including cytokine syndrome, inefficient delivery, hepatic dysfunction, and severe adverse reactions remain to be resolved. It is particularly critical to develop delivery technologies to overcome these limitations and further improve antitumor efficacy. With the continuous development of materials science, biomaterials have been widely used in the field of cancer treatment and have also provided exciting solutions to overcome the bottleneck of immunomodulatory therapeutics. A range of biomaterials, especially nanomaterials, has been developed as a local immunomodulatory platform to enhance targeted delivery, maintain drug stability, and reduce toxicity and side effects. In addition to single immunomodulatory therapeutics, nanomaterials have been demonstrated to possess significant potential in immunomodulatory therapeutics-based synergistic therapies, especially in combination with phototherapy, radiotherapy, chemotherapy, and immune checkpoint blockade. In this review, as background to the discussion of immunomodulatory therapeutics, we first described the mechanisms of action of multiple immunomodulators and discussed their current targeting agents. On this basis, we highlighted the latest advances in the use of nanomaterials-assisted immunomodulatory therapeutics and combination therapy to enhance anticancer immunity. In addition, current challenges and further promises for immunomodulatory therapeutics were also presented.

Gastric environment-stable oral nanocarriers for in situ colorectal cancer therapy.

Colorectal cancer (CRC) is a prevalent and fatal cancer. Oral administration provided the potential for in situ treatment of the colorectal cancer. However, drugs couldn't be well-absorbed mainly due to its degradation in the gastric area and poor intestinal permeability. In this study, we synthesized deoxycholic acid and hydroxybutyl decorated chitosan nanoparticles (DAHBC NPs) as oral curcumin (CUR) delivery system for colorectal cancer treatment. DAHBC with lower critical solution temperature (LCST) below 37 °C (27-33 °C) was obtained. DAHBC NPs were correspondingly stable in simulated gastric conditions (pH 1.2, 37 °C), due to the offset of size change between pH-responsive expansion and thermo-responsive shrinkage. In simulated intestinal tract (pH 7.0-7.4, 37 °C), DAHBC NPs exhibited burst release of CUR owing to the onefold effect of thermo-responsive shrinkage. DAHBC27 NPs showed the minimum CUR leakage (~10%) in simulated gastric conditions, because a furthest temperature-sensitive shrinkage caused by the lowest LCST offset the expansion in acid environment. DAHBC27 NPs induced ~10-fold increased (P < 0.05) CUR absorption by paracellular transport pathway, compared to the free CUR. Thus, DAHBC NPs stabilized in the gastric environment may be a promising oral drugs delivery system for effective in situ colorectal cancer therapy.

Tissue distribution study of periplocin and its two metabolites in rats by a validated LC-MS/MS method.

Periplocin is a cardiac glycoside and has been used widely in the clinic for its cardiotonic, anti-inflammatory and anti-tumor effects. Although it is taken frequently by oral administration in the clinic, there have been no reports demonstrating that periplocin could be detected in vivo after an oral administration, so there is an urgen need to determine the characteristics of periplocin in vivo after oral administration. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry method was developed and validated to identify and quantify periplocin and its two metabolites in rat tissue after a single dosage of perplocin at 50 mg/kg. The results demonstrated that periplocin and its two metabolites were detected in all of the selected tissues; periplocin could reach peak concentration quickly after administration, while periplocymarin and periplogenin reached maximum concentration > 4.83 h after administration. The tissue distribution of analytes tended to be mostly in the liver, and higher analyte concentrations were found in the heart, liver, spleen, lung and kidney, but a small amount of chemical constituents was distributed into the brain. The consequences obtained using this method might provide a meaningful insight for clinical investigations and applications.

Activation of P2X7 receptors in the midbrain periaqueductal gray of rats facilitates morphine tolerance.

Opiates such as morphine exhibit analgesic effect in various pain models, but repeated and chronic morphine administration may develop resistance to antinociception. The purinergic signaling system is involved in the mechanisms of pain modulation and morphine tolerance. This study aimed to determine whether the P2X7 receptor in the ventrolateral midbrain periaqueductal gray (vlPAG) is involved in morphine tolerance. Development of tolerance to the antinociceptive effect of morphine was induced in normal adult male Sprague-Dawley (SD) rats through subcutaneous injection of morphine (10mg/kg). The analgesic effect of morphine (5mg/kg, i.p.) was assessed by measuring mechanical withdrawal thresholds (MWTs) in rats with an electronic von Frey anesthesiometer. The expression levels and distribution of the P2X7 receptor in the vlPAG was evaluated through Western blot analysis and immunohistochemistry. The acute effects of intra-vlPAG injection of the selective P2X7 receptor agonist Bz-ATP, the selective P2X7 receptor antagonist A-740003, or antisense oligodeoxynucleotide (AS ODN) targeting the P2X7 receptor on morphine-treated rats were also observed. Results demonstrated that repeated morphine administration decreased the mechanical pain thresholds. By contrast, the expression of the P2X7 receptor protein was up-regulated in the vlPAG in morphine tolerant rats. The percent changes in MWT were markedly but only transiently attenuated by intra-vlPAG injection of Bz-ATP (9nmol/0.3µL) but elevated by A-740003 at doses of 10 and 100nmol/0.3µL. AS ODN (15nmol/0.3µL) against the P2X7 receptor reduced the development of chronic morphine tolerance in rats. These results suggest that the development of antinociceptive tolerance to morphine is partially mediated by activating the vlPAG P2X7 receptors. The present data also suggest that the P2X7 receptors may be a therapeutic target for improving the analgesic effect of morphine in treatments of pain when morphine tolerance occurs.