Phospholipid-inspired alkoxylation induces crystallization and cellular uptake of luminescent COF nanocarriers.

The porous nature and structural variability of covalent organic frameworks (COFs) make them preferred for drug loading and delivery applications. However, most COF materials suffer from poor luminescent properties and inefficiency for cell uptake. Herein, we experimentally demonstrate the crucial role of long alkoxy chains in the synthesis of crystalline COF nanostructures with high cellular uptake efficiency. After luminescence integration through band engineering, the semiconducting COF exhibits an optical bandgap of 2.05 eV, an emission wavelength of 632 nm, a high quantum yield of 37 %, and excellent fluorescence stability (100 % at 3 h). Such excellent optical properties of the designed COF nanocarriers enable quantitative evaluations of cellular uptake and visual tracking of drug delivery. It was demonstrated that the cellular uptake efficiency was enhanced by orders of magnitude for the COF after the introduction of long n-octyloxy chains, which firstly delivered the anticancer camptothecin (CPT) to cell lysosomes, and then underwent "endo/lysosomal escape" to induce cell apoptosis. In vivo assay evidenced a significant enhancement in the therapeutic effect with a 96 % inhibition of tumor growth after 14 days of treatment. This progress sheds light on designing cutting-edge drug delivery nanosystems based on COF materials with integrated diagnostic and therapeutic functions.

Role of Ferroptosis in the Progression of COVID-19 and the Development of Long COVID.

OBJECTIVES: To examine the role of ferroptosis on the pathogenesis and progression of COVID-19. MATERIALS AND METHODS: A total of 127 patients who were hospitalized for COVID-19 were categorized into two groups according to the intensity of oxygen therapy (high-flow or low-flow). Clinical characteristics, laboratory parameters, plasma markers, and peripheral blood mononuclear cell (PBMC) markers were measured at baseline and one or two weeks after treatment. Telephone follow-up was performed 3 months after discharge to assess long COVID. RESULTS: Patients receiving high-flow oxygen therapy had greater levels of neutrophils; D-dimer; C reactive protein; procalcitonin; plasma protein levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-17, and acyl-CoA synthetase long-chain family member 4 (ACSL4); and PBMC mRNA level of TNF-α; but had lower levels of lymphocytes and plasma glutathione peroxidase 4 (GPX4). There were negative correlations of plasma GPX4 and cystine/glutamate transporter-11 (SLC7A11) with TNF-α, IL-6, and IL-17, and positive correlations of ACSL4 with inflammatory markers in plasma and PBMCs. The plasma levels of TNF-α, IL-6, IL-17, and ACSL4 were significantly lower after treatment than at baseline, but there were higher post-treatment levels of lymphocytes, GPX4, and SLC7A11. Patients with long COVID had a lower baseline level of plasma SLC7A11. CONCLUSION: Ferroptosis is activated during the progression of COVID-19, and a low baseline level of a ferroptosis marker (SLC7A11) may indicate an increased risk for long COVID-19. Ferroptosis has potential as a clinical indicator of long COVID and as a therapeutic target.

Red-Fluorescent Covalent Organic Framework Nanospheres for Trackable Anticancer Drug Delivery.

Covalent organic frameworks (COFs) have emerged as promising drug carriers due to their structural variability, inherent porosity, and customizable functions. However, most COFs used in drug delivery suffer from low cellular bioavailability and poor luminescence properties. In this study, we designed a series of size-tunable, crystalline, and red-fluorescent COF nanospheres (COFNSs) for trackable anticancer drug delivery. The semiconducting COFNSs were prepared by condensations of 1,3,5-triformylbenzene (TFB) with various dihydrazide blocks through the Schiff-base reaction, resulting in red emission at 647 nm and excellent fluorescence stability (∼100% for 1 h). Such fluorescence property allowed for systematic investigation of the cellular endocytosis pathway of COFNSs, visualization of drug delivery, and observation of the cell apoptosis process. The COFNSs exhibited high cell viability (>90%), a loading capacity of 183 wt % for the anticancer drug camptothecin (CPT), and significant enhancement in inhibiting 4T1 cancers both in vitro and in vivo as the CPT nanocarrier. This progress presents a valuable approach to design COF nanocarriers with integrated fluorescent and drug delivery functions.

Flower-like porous BCN assembled by nanosheets for paclitaxel delivery.

Developing smart drug delivery systems has become a feasible solution to overcome the challenges in cancer chemotherapeutics. In this work, porous boron carbon nitride (ZBCN) nanomaterials with flower-like structures assembled with BCN nanosheets were synthesized by using ZIF-L as a template. The rich hydroxyl groups on the BCN surfaces make it highly dispersible and stable in aqueous solutions. Additionally, ZBCN exhibits stable photoluminescence properties that can be utilized for cellular uptake and tracking of drug delivery. Furthermore, the flower-like ZBCN structure contributes to a large specific surface area of up to 340 m2 g-1 and a pore volume of 1.03 cm3 g-1; and the presence of rich macropores results in a high drug loading capacity of 116 wt% for paclitaxel. In vitro and in vivo anticancer experiments demonstrated that ZBCN exhibits excellent performance in delivering anticancer drugs, with in vivo tumor inhibition of 58%. This study presents a novel template method for preparing porous BCN nanomaterials, offering a promising platform for high-performance anticancer drug delivery.

New insights into muscularis macrophages in the gut: from their origin to therapeutic targeting.

Muscularis macrophages, as the most abundant immune cells in the intestinal muscularis externa, exhibit tissue protective phenotype in the steady state. Owing to tremendous advances in technology, we now know the fact that muscularis macrophages are a heterogeneous population of cells which could be divided into different functional subsets depending on their anatomic niches. There is emerging evidence showing that these subsets, through molecular interactions with their neighbours, take part in a wide range of physiological and pathophysiological processes in the gut. In this review, we summarize recent progress (particularly over the past 4 years) on distribution, morphology, origin and functions of muscularis macrophages and, where possible, the characteristics of specific subsets in response to the microenvironment they occupy, with particular emphasis on their role in muscular inflammation. Furthermore, we also integrate their role in inflammation-related gastrointestinal disorders, such as post-operative ileus and diabetic gastroparesis, in order to propose future therapeutic strategies.

[Prediction model of recurrence after parathyroidectomy in secondary hyperparathyroidism].

Objective:To quantitatively evaluate the risk of recurrence in patients with secondary hyperparathyroidism after parathyroidectomy. Methods:The clinical data of 168 patients who underwent parathyroidectomy（PTX） from June 2017 to May 2019 were collected. The prediction model was constructed by using Akaike information criterion（AIC） to screen factors. A total of 158 patients treated with PTX from June 2019 to September 2021 were included in the validation set to conduct external validation of the model in three aspects of differentiation, consistency and clinical utility. Results:The prediction model we constructed includes different dialysis methods, ectopic parathyroid gland, the iPTH level at one day and one month after surgery, the number of excisional parathyroid and postoperative blood phosphorus. The C index of external validation of this model is 0.992 and the P value of the Calibration curve is 0.886[KG0.5mm]1. The decision curve analysis also shows that the evaluation effect of this model is perfect. Conclusion:The prediction model constructed in this study is useful for individualized prediction of recurrence after PTX in patients with secondary hyperparathyroidism.

Novel manganese and polyester dendrimer-based theranostic nanoparticles for MRI and breast cancer therapy.

Therapeutic nanoplatforms are widely used in the diagnosis and treatment of breast cancer due to the merits of enabling high soft-tissue resolution and the availability of numerous therapeutic nanoparticles. It is thus vital to develop multifunctional theranostic nanoparticles for the visualization and dynamic monitoring of tumor therapy. In this study, we designed a manganese-based and hypericin-loaded polyester dendrimer nanoparticle (MHD) for magnetic resonance imaging (MRI) and hypericin-based photodynamic therapy (PDT) enhancement. We found that MHD could greatly enhance MRI contrast with a longitudinal relaxivity of 5.8 mM-1 s-1 due to the Mn-based paramagnetic dendrimer carrier. Meanwhile, the MRI-guided PDT inhibition of breast tumors could be achieved by the hypericin-carrying MHD and further improved by Mn2+-mediated alleviation of the hypoxic microenvironment and the enhancement of cellular ROS. Besides, MHD showed excellent biocompatibility and biosafety with liver and kidney clearance mechanisms. Thus, the high efficiency in MRI contrast enhancement and excellent tumor-inhibiting effects indicate MHD's potential as a novel, stable, and multifunctional nanotheranostic agent for breast cancer.

Effects of Ellagic Acid Supplementation on Jejunal Morphology, Digestive Enzyme Activities, Antioxidant Capacity, and Microbiota in Mice.

Ellagic acid (EA), a plant polyphenol mainly found in nuts and fruits, exhibits various biological effects. However, the effects of EA on intestinal health remain poorly understood. Hence, the present study aimed to assess the effects of EA supplementation on jejunal morphology, digestive enzyme activities, antioxidant capacity, and microbiota in C57BL/6J mice. A total of 144 mice were randomly assigned to three treatments groups: the control (CON) group received a standard pellet diet, the 0.1% EA group received a standard pellet diet plus 0.1% EA, and the 0.3% EA group received a standard pellet diet plus 0.3% EA. The mice were killed at the end of the experimental period, and jejunal samples were collected. The results revealed that the mice in the 0.3% EA group had higher (P < 0.05) average daily gain and greater (P < 0.05) jejunal villus height than those in the CON group. In addition, the jejunal lactase and sucrase activities were higher (P < 0.05) in the 0.1% EA and 0.3% EA groups, and the alkaline phosphatase activity was higher (P < 0.05) in the 0.3% EA group than in the CON group. Compared with the CON group, the administration of EA increased (P < 0.05) the superoxide dismutase and catalase activities but decreased (P < 0.05) the malonaldehyde content in the jejunum. Moreover, the jejunal messenger RNA expression levels of nuclear factor-E2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1) were higher (P < 0.05) in the 0.3% EA group than in the CON group. Furthermore, compared with the CON group, the count of Escherichia coli decreased (P < 0.05), and that of Lactobacillus species increased (P < 0.05) in the 0.3% EA group. In general, our findings indicate that the administration of EA can enhance the growth of mice, promote intestinal development, increase the antioxidant capacity, and regulate the intestinal microbiota.

Biodegradable and Peroxidase-Mimetic Boron Oxynitride Nanozyme for Breast Cancer Therapy.

Nanomaterials having enzyme-like activities are recognized as potentially important self-therapeutic nanomedicines. Herein, a peroxidase-like artificial enzyme is developed based on novel biodegradable boron oxynitride (BON) nanostructures for highly efficient and multi-mode breast cancer therapies. The BON nanozyme catalytically generates cytotoxic hydroxyl radicals, which induce apoptosis of 4T1 cancer cells and significantly reduce the cell viability by 82% in 48 h. In vivo experiment reveals a high potency of the BON nanozyme for breast tumor growth inhibitions by 97% after 14-day treatment compared with the control, which are 10 times or 1.3 times more effective than the inert or B-releasing boron nitride (BN) nanospheres, respectively. This work highlights the BON nanozyme and its functional integrations within the BN nanomedicine platform for high-potency breast cancer therapies.

Self-assembly of hyaluronic acid-mediated tumor-targeting theranostic nanoparticles.

Theranostic nanoparticles (NPs) have emerged as promising candidates for cancer diagnosis and treatment. Manganese dioxide (MnO2)-based NPs are potential contrast agents with excellent paramagnetic property and biocompatibility, exhibiting satisfactory magnetic resonance imaging (MRI) effects and biological safety. Recently, hyaluronic acid (HA) has gained increasing interest due to its tumor-targeting ability, which can improve the tumor affinity of manganese dioxide (MnO2)-based NPs. In this study, HA-coated and albumin (BSA)-templated MnO2 and polydopamine hybrid nanoparticles (HMDNs) with tumor-targeting and superior imaging capability were fabricated via modifying the nanoparticles prepared by integrating dopamine polymerization and MnO2 biomineralization. The modification was found to enhance the cellular uptake of HMDNs by cancer cells. The prepared HMDN had high MRI contrasting capability with a longitudinal relaxivity of 22.2 mM-1 s-1 and strong photothermal therapy (PTT) effects with nearly complete tumor ablation under laser irradiation in vivo. HMDNs also showed effective clearance through kidneys, with no toxicity to important tissues. Therefore, HMDNs with superior imaging and PTT capability presented a new method to prepare tumor-targeting multifunctional nanotheranostics.

Pulmonary cryptococcosis coexisting with central type lung cancer in an immuocompetent patient: a case report and literature review.

BACKGROUND: Pulmonary Cryptococcosis is a common fungal infection mainly caused by Cryptococcus neoformans/C.gattii species in immunocompromised patients. Cases of pulmonary cryptococcosis in patients with normal immune function are increasingly common in China. Clinical and radiographic features of pulmonary cryptococcosis are various and without obvious characteristics, so it is often misdiagnosed as pulmonary metastatic tumor or tuberculosis. When coexisting with malignant lung tumors, it was more difficult to differentiate from metastatic lung cancer, although the coexistence of pulmonary cryptococcosis and central type lung cancer is rare. Reviewing the imaging manifestations and diagnosis of the case and the relevant literature will contribute to recognition of the disease and a decrease in misdiagnoses. CASE PRESENTATION: A 72-year-old immunocompetent Han Chinese man had repeated dry cough for more than half a year. CT examination of chest showed an irregular mass at the left hilum of the lung, and two small nodules in the right lung, which were considered as the left central lung cancer with right lung metastasis. However, the patient was diagnosed with pulmonary cryptococcosis coexisting with central type lung cancer based on the results of laboratory examination, percutaneous lung biopsy, fiberoptic bronchoscopy, and surgical pathology. The patient underwent surgical resection of the left central type lung cancer and was placed on fluconazole treatment after a positive diagnosis was made. Five years after the lung cancer surgery, the patient had a recurrence, but the pulmonary cryptococcus nodule disappeared. CONCLUSION: Our case shows that CT findings of central type lung cancer with multiple pulmonary nodules are not necessarily metastases, but may be coexisting pulmonary cryptococcosis. CT images of cryptococcosis of the lung were diverse and have no obvious characteristics, so it was very difficult to distinguish from metastatic tumors. CT-guided percutaneous lung biopsy was a simple and efficient method for identification.

Hypoxia-targeting dendritic MRI contrast agent based on internally hydroxy dendrimer for tumor imaging.

Hypoxia is one of the critical features in solid tumors, and hypoxia-targeting contrast agents (CAs) could greatly enhance the magnetic resonance imaging (MRI) of tumors by increasing its specificity and providing more diagnosis information. In this article, an internally hydroxy dendrimer of high molecular weight was facilely synthesized by "epoxy-amine" and "thiol-ene" reactions with a ß-cyclodextrin (ß-CD) as the core, and a hypoxia-targeting dendritic contrast agent (DCA) was synthesized through conjugating Gd chelates onto the internal hydroxyl groups and grafting the hypoxia-targeting groups sulfonamides and zwitterionic groups onto the exterior groups of the dendrimer. The zwitterionic surface without disturbance from internally conjugated CAs could reduce unspecific cellular uptake by normal cells, while the hypoxia-targeting group mediate the cellular uptake by hypoxic tumor cells. The in vitro and in vivo study showed that the hypoxia-targeting DCA could be selectively uptake by hypoxic cancer cells and greatly enhance the MRI of orthotopic breast tumor in a mouse model.

A Tumor-Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers.

A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of ß-lapachone and a reactive-oxygen-species (ROS)-responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing ß-lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects.

Enhancing MRI of liver metastases with a zwitterionized biodegradable dendritic contrast agent.

Metastasis is the main reason for cancer-associated mortality, and accurate diagnostic imaging of metastases is critical for the clinical administration and tailoring personalized treatments for metastatic tumors. However, magnetic resonance imaging of metastases in the liver is impeded by its low sensitivity because the currently used contrast agents accumulate in hepatocytes and Kupffer cells instead of cancer cells. Herein, a 4th generation zwitterionized biodegradable dendritic contrast agent (DCA) with a size of ca. 9 nm and a longitudinal relaxivity of 15.7 mM-1 s-1 in terms of Gd was synthesized and used to enhance the MRI of liver metastasis. The DCA could remarkably enhance the MRI of metastasized tumors in the liver, because it could simultaneously reduce the background signal in the liver by avoiding uptake by hepatocytes and Kupffer cells through the zwitterionization and increase the signal in tumors through the enhanced permeability and retention effect. Moreover, in contrast to non-biodegradable DCA, this DCA showed minimal long-term Gd3+ retention in all organs and tissues because it could be degraded into small fragments. The significant capability of enhancing the MRI of metastases in the liver plus its excellent biodegradability made this DCA a promising CA for metastatic tumor imaging.