Downregulation of WNK4 expression facilitates the proliferation of gastric cancer cells via activation of the STAT3 signaling pathway.

WNK lysine deficient protein kinase 4 (WNK4) has been shown to be significantly associated with cancer progression. Nevertheless, its involvement in gastric cancer (GC) is unclear. The objective of this work was to investigate the WNK4's regulatory mechanism in GC. Quantitative RT-PCR and immunoblots revealed that WNK4 expression was downregulated in GC and that low expression of WNK4 was strongly linked to poor prognosis. Functional assays including cell counting kit-8 assay and colony formation assay demonstrated that overexpression of WNK4 led to limited tumor proliferation both in vitro and in vivo, while the WNK4 reduction yielded to the opposite results. Gene Set Enrichment Analysis (GSEA) indicated a potential association between WNK4 and the signal transducer and activator of transcription (STAT3). WNK4 suppressed the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in GC cells. The inhibition of the STAT3 pathway with Stattic reversed growth and proliferation induced by WNK4 knockdown in GC cells. These findings provide new insights for identifying key therapeutic targets for GC in the future.

Evaluation of Profile Control and Oil Displacement Effect of Starch Gel and Nano-MoS2 Combination System in High-Temperature Heterogeneous Reservoir.

The Henan Oilfield's medium-permeability blocks face challenges such as high temperatures and severe heterogeneity, making conventional flooding systems less effective. The starch gel system is an efficient approach for deep profile control in high-temperature reservoirs, while the nano-MoS2 system is a promising enhanced oil recovery (EOR) technology for high-temperature low-permeability reservoirs. Combining these two may achieve the dual effects of profile control and oil displacement, significantly enhancing oil recovery in high-temperature heterogeneous reservoirs. The basic performance evaluation of the combination system was carried out under reservoir temperature. Displacement experiments were conducted in target blocks under different permeabilities and extreme disparity core flooding to evaluate the combination system's oil displacement effect. Additionally, the displacement effects and mechanisms of the starch gel and nano-MoS2 combination system in heterogeneous reservoirs were evaluated by simulating interlayer and intralayer heterogeneity models. The results show that the single nano-MoS2 system's efficiency decreases with increased core permeability, and its effectiveness is limited in triple and quintuple disparity parallel experiments. After injecting the starch gel-nano-MoS2 combination system, the enhanced oil recovery effect was significant. The interlayer and intralayer heterogeneous models demonstrated that the primary water flooding mainly affected the high-permeability layers, while the starch gel effectively blocked the dominant channels, forcing the nano-MoS2 oil displacement system towards unswept areas. This coordination significantly enhanced oil displacement, with the combination system improving recovery by 15.33 and 12.20 percentage points, respectively. This research indicates that the starch gel and nano-MoS2 combination flooding technique holds promise for enhancing oil recovery in high-temperature heterogeneous reservoirs of Henan Oilfield, providing foundational support for field applications.

Erratum: PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer: Erratum.

[This corrects the article DOI: 10.7150/jca.66773.].

Epidemiology, characteristics, and prognostic factors of lymphoplasmacyte-rich meningioma: a systematic literature review.

BACKGROUNDS: Lymphoplasmacyte-rich meningioma(LPM) is a rare subtype of meningioma with a low degree of malignancy and an overall preferable prognosis. The purpose of this article is to increase the understanding of the disease, reduce misdiagnosis, and improve prognosis. METHODS: A search was conducted in the PubMed database for English articles published from 1993 to 2023. The keywords were "lymphoplasmacyte-rich (all fields) and meningioma (all fields) and English (lang)" and "lymphoplasmacyte-rich meningioma (title/abstract) and English (lang)".We further analyzed the clinical manifestations, imaging manifestations, pathological features, treatment strategies, and prognosis of LPM.The possible prognostic indicators were analyzed by the log-rank test and Pearson's chi-squared test. RESULTS: Fourteen reports with 95 LPM patients were included in this report, including 47 males and 48 females who were diagnosed between the ages of 9 and 79, with an average age of 45 years. The most common clinical manifestations are headache and limb movement disorders. In most cases, the tumor occurred on the convex portion of the brain. All tumors showed significant enhancement, with homogeneous enhancement being more common, and most patients showed peritumoral edema. Postoperative pathological EMA, LCA, and vimentin positivity were helpful for the final diagnosis of the patient. Log-rank tests showed a correlation between complete resection and better prognosis and recurrence. CONCLUSION: There is a lack of significant differences in the clinical symptoms and imaging manifestations of LPM compared to other diseases that need to be differentiated, and a clear diagnosis requires pathological examination. After standardized surgical treatment, the recurrence rate and mortality rate of LPM are both low. Complete surgical resection of tumors is associated with a better prognosis and lower recurrence rate.

MRPL21 promotes HCC proliferation through TP53 mutation-induced apoptotic resistance.

BACKGROUND AND AIMS: The specific mechanisms underlying the inhibition of hepatocellular carcinoma (HCC) proliferation and metastasis by mitochondrial apoptosis are not yet fully understood. However, it plays a vital role in suppressing HCC's ability to proliferate and spread. The involvement of MRPL21, a member within the family of mitochondrial ribosomal proteins (MRPs), is well-documented in both cellular apoptosis and energy metabolism. This study aims to explore and unravel the underlying mechanisms through which MRPL21 contributes to mitochondrial apoptosis and resistance against apoptosis in HCC. METHODS: To evaluate the level of MRPL21 expression at the gene and protein expression levels, analysis was performed on human liver samples and blood using techniques for quantification. A knockdown plasmid targeting MRPL21 was constructed to investigate its impact on the growth and apoptosis of hepatocellular carcinoma (HCC). To evaluate the impact of MRPL21 knockdown on hepatocellular carcinoma (HCC) cell proliferation and apoptosis, various assays were performed including CCK-8 assays, flow cytometry analysis, detection of reactive oxygen species (ROS), and assessment of mitochondrial membrane potential (MMP). Furthermore, the role of MRPL21 in TP53 mutation was examined using Nutlin-3. RESULTS: In HCC tissues and blood samples, an upregulation of MRPL21 expression was observed when compared to samples obtained from healthy individuals, and it is correlated with a poor prognosis for HCC. Silencing MRPL21 can effectively suppress Hep3B and HCCLM3 cells proliferation by modulating the mitochondrial membrane potential, it triggers the generation of reactive oxygen species (ROS), thereby leading to G0/G1 cell cycle arrest and initiation of early apoptosis. Furthermore, by inhibiting P53 activity, Nutlin-3 treatment can enhance MRPL21-deficiency-mediated apoptosis in Hep3B and HCCLM3 cells. CONCLUSION: Through its influence on TP53 mutation, MRPL21 promotes HCC proliferation and progression while conferring resistance to apoptosis. These findings suggest that MRPL21 holds promise as a valuable biomarker for the treatment of HCC.

Nano-medicine therapy reprogramming metabolic network of tumour microenvironment: new opportunity for cancer therapies.

Metabolic heterogeneity is one of the characteristics of tumour cells. In order to adapt to the tumour microenvironment of hypoxia, acidity and nutritional deficiency, tumour cells have undergone extensive metabolic reprogramming. Metabolites involved in tumour cell metabolism are also very different from normal cells, such as a large number of lactate and adenosine. Metabolites play an important role in regulating the whole tumour microenvironment. Taking metabolites as the target, it aims to change the metabolic pattern of tumour cells again, destroy the energy balance it maintains, activate the immune system, and finally kill tumour cells. In this paper, the regulatory effects of metabolites such as lactate, glutamine, arginine, tryptophan, fatty acids and adenosine were reviewed, and the related targeting strategies of nano-medicines were summarised, and the future therapeutic strategies of nano-drugs were discussed. The abnormality of tumour metabolites caused by tumour metabolic remodelling not only changes the energy and material supply of tumour, but also participates in the regulation of tumour-related signal pathways, which plays an important role in the survival, proliferation, invasion and metastasis of tumour cells. Regulating the availability of local metabolites is a new aspect that affects tumour progress. (The graphical abstract is by Figdraw).

Metabolic heterogeneity is one of the important characteristics of tumour cells, and the metabolites of tumour cells are very different from those of normal cells.Lactate, fatty acids, glutamine, arginine, tryptophan and adenosine are all important metabolites in tumour metabolism.Nano-medicines are used to regulate tumour metabolites, affecting the energy and material supply of tumour cells, thus achieving therapeutic effects.

Central nervous system clear cell meningioma: a systematic literature review.

Clear cell meningiomas are a rare histological subtype of World Health Organization (WHO) grade II meningioma. Despite its relatively low frequency, clear cell meningioma has attracted considerable attention because of its unique pathological characteristics, clinical behavior, and challenging management considerations. The purpose of our systematic review is to provide clinicians with a better understanding of this rare disease. PubMed was searched for articles in the English language published from 1988 to 2023 June. The keywords were as follows: "clear cell meningioma," "clear cell" and "meningioma." We analyzed clinical manifestations, radiological manifestations, pathological features, comprehensive treatment strategies, and prognosis to determine the factors influencing recurrence-free survival (RFS). Recurrence-free survival curves of related factors were calculated by the Kaplan‒Meier method. The log-rank test and Cox univariate analysis were adopted to assess the intergroup differences and seek significant factors influencing prognosis and recurrence. Fifty-seven papers met the eligibility criteria, including 207 cases of clear cell meningioma (CCM), which were confirmed by postoperative pathology. The fifty-seven articles involved 84 (40.6%) males and 123 (59.4%) females. The average age at diagnosis was 27.9 years (range, 14 months to 84 years). Among the symptoms observed, headache, neurologic deficit, and hearing loss were the most commonly reported clinical manifestations. Most tumors (47.8%) were located in the skull base region. Most tumors showed significant enhancement, and homogeneous enhancement was more common. A total of 152 (74.1%) patients underwent gross total resection (GTR), and 53 (25.9%) patients underwent subtotal resection (STR). During the follow-up, the tumor recurred in 80 (39.4%) patients. The log-rank test and the Cox univariate analysis revealed that tumor resection range (GTR vs. STR) and adjuvant treatment (YES vs. NO) were significant predictors of recurrence-free survival (RFS). Clear cell meningioma is a rare type of meningioma with challenging diagnosis and therapy. The prognosis of this disease is different from that of regular meningiomas. Recurrence remains a possibility even after total tumor resection. We found that the surgical resection range and adjuvant treatment affected the recurrence period. This finding provides significant guidance for the treatment of clear cell meningioma.

Tumor Microenvironment Sequential Drug/Gene Delivery Nanosystem for Realizing Multistage Boosting of Cancer-Immunity Cycle on Cancer Immunotherapy.

The antitumor immune response of cancer immunotherapy is a cascade of cancer-immunity cycles (CIC). The immunosuppression of the tumor microenvironment and low immunogenicity of tumor cells, insufficient T lymphocyte activation, trafficking, and infiltration caused the failure to initiate and run the continuous multistage CIC, leading to unsatisfactory cancer immunotherapy outcomes. A doxorubicin/interleukin-12 plasmid DNA/celecoxib (DOX/pIL-12/CXB) combination strategy was designed by targeting the cascade CIC. Then, an intratumoral CXB-detachable nanosystem, or DOX/PAC/pIL-12 micelleplexes, was developed for sequential drug/gene delivery to facilitate the multistage boosting of CIC on synergistic cancer immunotherapy. The DOX/PAC/pIL-12 micelleplexes could program intratumorally sequential release of CXB to remodulate the tumor microenvironment immunosuppression by suppressing the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway. The smaller sizes and surface charge-switched micelleplexes facilitated the codelivery and corelease of DOX and pIL-12 inside 4T1 tumor cells. These micelleplexes exerted a synergistic antitumor immune response using CIC cascade activation and amplification, providing therapeutic antitumor and antimetastasis efficacy. The drug/gene sequential delivery nanosystem provides a complete CIC-boosted combinatory strategy for developing immunotherapy against cancer.

Recent advancements in nanomedicine based lipid metabolism for tumour immunotherapy.

Therapy on lipid metabolism is emerging as a groundbreaking cancer treatment, offering the unprecedented opportunity to effectively treat and in several cases. Tumorigenesis is inextricably linked to lipid metabolism. In this regard, the features of lipid metabolism include lipid synthesis, decomposition, metabolism and lipid storage and mobilisation from intracellular lipid droplets. Most importantly, the regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects. Different cancers and immune cells have different dependence on lipid metabolism, playing a pivotal role in differentiation and function of immune cells. However, what lies before the immunotherapy targeting lipid metabolism is side effects of systemic toxicity and defects of individual drugs, which strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies. This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells and their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.HighlightsThe regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects.Preparations of focusing lipid metabolism have side effects of systemic toxicity and defects of individual drugs. It strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies.This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells as well as their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.

The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity.

While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.

Quercetagetin alleviates zearalenone-induced liver injury in rabbits through Keap1/Nrf2/ARE signaling pathway.

Introduction: This study aimed to assess the alleviative effect of quercetagetin (QG) on zearalenone (ZEN)-induced liver injury in rabbits. Methods: Ninety 41-day-old healthy Hyla rabbits were randomly assigned into three groups, including a control (fed with basic diet), ZEN addition group (fed with basic diet + 600 µg/kg ZEN), and ZEN + QG addition group (fed with basic diet + 600 µg/kg ZEN + 100 mg/kg QG), with 30 rabbits per group. The duration of the experiment was 28 days. Results: The results revealed no significant differences in the average daily gain, average daily feed intake, the gain to feed ratio and the liver, kidney and spleen organ indexes (p > 0.05) between the rabbits across the three groups. However, the sacculus rotundus index of the rabbits in the control group was significantly higher than that in the ZEN + QG group (p < 0.05). The intake of ZEN-contaminated diet also significantly increased the activities or levels of alanine transaminase, alkaline phosphatase, total bile acid (TBA), total bilirubin, malondialdehyde, and interleukin-4 (IL-4) and enhanced the abundance of kelch-like ECH-associated protein 1 (Keap1), heat shock protein 70 (HSP70) and cysteine-aspartic acid protease-3 (Caspase-3) mRNA in the blood or liver tissue in ZEN group, compared to the control group (p < 0.05). On the contrary, the activities or levels of immunoglobulin A, complement 3, total antioxidant capacity, glutathione peroxidase (GSH-Px), superoxide dismutase, interleukin-10, and the abundance of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA were significantly decreased (p < 0.05). Supplementing the diet with QG still maintained significantly higher levels of TBA and IL-4, and the abundance of GSH-Px, HSP70, IL-4, and Caspase-3 mRNA in the blood and liver of rabbits in the ZEN + QG group than in the control group (p < 0.05). At the same time, the other indicators were restored to levels in the control group (p > 0.05). Discussion: In conclusion, QG alleviated the ZEN-induced oxidative damage and liver injury caused by inflammatory reaction through the Keap1-Nrf2-antioxidant response element (ARE) signal pathway, which protected the liver. This study revealed the alleviative effect of QG on the hepatotoxicity of ZEN in rabbits for the first time, providing a new perspective for applying QG and developing a ZEN antidote.

'Social' versus 'asocial' cells-dynamic competition flux balance analysis.

In multicellular organisms cells compete for resources or growth factors. If any one cell type wins, the co-existence of diverse cell types disappears. Existing dynamic Flux Balance Analysis (dFBA) does not accommodate changes in cell density caused by competition. Therefore we here develop 'dynamic competition Flux Balance Analysis' (dcFBA). With total biomass synthesis as objective, lower-growth-yield cells were outcompeted even when cells synthesized mutually required nutrients. Signal transduction between cells established co-existence, which suggests that such 'socialness' is required for multicellularity. Whilst mutants with increased specific growth rate did not outgrow the other cell types, loss of social characteristics did enable a mutant to outgrow the other cells. We discuss that 'asocialness' rather than enhanced growth rates, i.e., a reduced sensitivity to regulatory factors rather than enhanced growth rates, may characterize cancer cells and organisms causing ecological blooms. Therapies reinforcing cross-regulation may therefore be more effective than those targeting replication rates.

Thymol targeting interleukin 4 induced 1 expression reshapes the immune microenvironment to sensitize the immunotherapy in lung adenocarcinoma.

Immune checkpoint blockades are the most promising therapy in lung adenocarcinoma (LUAD). However, the response rate remains limited, underscoring the urgent need for effective sensitizers. Interleukin 4 induced 1 (IL4I1) is reported to have immunoinhibitory and tumor-promoting effects in several cancers. However, the targetable value of IL4I1 in sensitizing the immunotherapy is not clear, and there is a lack of effective small molecules that specifically target IL4I1. Here, we show that silencing IL4I1 significantly remodels the immune microenvironment via inhibiting aryl hydrocarbon receptor (AHR) signaling, thereby enhancing the efficacy of anti-PD-1 antibody in LUAD, which suggests that IL4I1 is a potential drug target for the combination immunotherapy. We then identify thymol as the first small molecule targeting IL4I1 transcription through a drug screening. Thymol inhibits the IL4I1 expression and blocks AHR signaling in LUAD cells. Thymol treatment restores the antitumor immune response and suppresses the progression of LUAD in an orthotopic mouse model. Strikingly, the combination treatment of thymol with anti-PD-1 antibody shows significant tumor regression in LUAD mice. Thus, we demonstrate that thymol is an effective small molecule to sensitize the PD-1 blockade in LUAD via targeting IL4I1, which provides a novel strategy for the immunotherapy of LUAD.

The Application of Nano-drug Delivery System With Sequential Drug Release Strategies in Cancer Therapy.

Currently, multidrug combinations are often used clinically to improve the efficacy of oncology chemotherapy, but multidrug combinations often lead to multidrug resistance and decreased performance, resulting in more severe side effects than monotherapy. Therefore, sequential drug release strategies in time and space as well as nano-carriers that respond to the tumor microenvironment have been developed. First, the advantage of the sequential release strategy is that they can load multiple drugs simultaneously to meet their spatiotemporal requirements and stability, thus exerting synergistic effects of two or more drugs. Second, in some cases, sequential drug delivery of different molecular targets can improve the sensitivity of cancer cells to drugs. Control the metabolism of cancer cells, and remodel tumor vasculature. Finally, some drug combinations with built-in release control are used for sequential administration. This paper focuses on the use of nanotechnology and built-in control device to construct drug delivery carriers with different stimulation responses, thus achieving the sequential release of drugs. Therefore, the nano-sequential delivery carrier provides a new idea and platform for the therapeutic effect of various drugs and the synergistic effect among drugs.

Developmental toxicity in Daphnia magna induced by environmentally relevant concentrations of carbon black: From the perspective of metabolomics and symbiotic bacteria composition.

The level of carbon black (CB) pollution in the environment is rapidly increasing, owing to the increase in natural and industrial emissions. The water environment has become an important sink for CB. However, studies on CB mainly focused on its impact on air pollution and phytoremediation applications, and the toxicity mechanism of CB in aquatic organisms is relatively limited. Thus, Daphnia magna was used as a model organism to explore the developmental toxicity of environmentally relevant concentrations of CB under a full life-cycle exposure. The toxicity mechanism of CB in aquatic organisms was investigated based on metabolomic and symbiotic microbial analyses. It was found that compared with the control group, the body length of exposed D. magna decreased, while the mortality and intestinal inflammation increased with increasing concentration of CB. The normal reproductive regularity of D. magna was disturbed, and the deformity and body length of the offspring increased and decreased, respectively, after CB exposure. Metabolomic analysis showed that the urea cycle metabolic pathway of exposed D. magna was increased significantly, suggesting a perturbation of N metabolism. In addition, two eicosanoids were increased, suggesting possible inflammation in D. magna. The levels of seven phospholipid metabolites decreased that might be responsible for offspring malformations. Microbiological analysis showed that the composition of the symbiotic microbial community of D. magna was disturbed, including microorganisms involved in carbon cycling, nitrogen cycling, and biodegradation of pollutants, as well as pathogenic microorganisms. Overall, this study found that the inflammatory related metabolites and symbiotic bacterial, as well as reproductive related metabolites, were disrupted after D. magna exposed to different concentrations of CB, which revealed a possible developmental toxicity mechanism of CB in D. magna. These findings provide a scientific basis for analyzing the risks of CB in aquatic environments.

Virtual reality psychological intervention helps reduce preoperative anxiety in patients undergoing carotid artery stenting: a single-blind randomized controlled trial.

Objective: This study aimed to explore the effectiveness and applicability of a psychological intervention using virtual reality (VR) to reduce preoperative anxiety in patients undergoing carotid artery stenting (CAS). Methods: A total of 114 patients aged 18-86 years who were scheduled to undergo CAS were randomized to the VR and control groups. Patients in the VR group used a VR headset to view a 16-min psychological intervention video, while those in the control group used a tablet for viewing. The primary assessment instrument was the State Anxiety Inventory (S-AI), which was given 20 min before and after the intervention and 24 h after surgery. Secondary assessment tools were the Self-efficacy for Managing Chronic Disease (SEMCD-6) scale, which was completed before the intervention and 24 h after the operation, a smart bracelet to assess sleep quality, monitored in the evening before the operation, and the VR Suitability and Satisfaction Questionnaire, completed 24 h after the operation. Results: The two groups were similar in terms of demographic information, preintervention STAI scores and preintervention SEMCD-6 scores (p > 0.05). S-AI scores were lower in both groups after the intervention and surgery, and the scores of the VR group were lower than those of the control group (p = 0.036, p = 0.014). SEMCD-6 scores post-surgery had improved in both groups, but the VR group had significantly higher scores than the control group (p = 0.005). Smart bracelet measurements showed no significant differences in postintervention sleep quality between the two groups (p = 0.540). For satisfaction, the VR group scored higher in all aspects except scheduling. A total of 47 (85.45%) patients reported having a comfortable experience, and only 5 (9.09%) experienced mild adverse effects. Conclusion: The use of a virtual reality psychological intervention was beneficial to reduce the anxiety of patients before CAS and improved their self-efficacy. As virtual reality devices evolve and demonstrate better comfort and safety, more comprehensive and in-depth research of the use of VR to reduce patient anxiety should be performed in the future.Clinical trial registration:https://www.chictr.org.cn/showproj.aspx?proj=186412, identifier ChiCTR2200066219.

WITHDRAWN: The Application of Nanodrug Delivery System with Sequential Drug Release Strategies in Cancer Therapy

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Blue-ringed octopus-inspired microneedle patch for robust tissue surface adhesion and active injection drug delivery.

Intratissue topical medication is important for the treatment of cutaneous, mucosal or splanchnic diseases. However, penetrating surface barriers to providing adequate and controllable drug delivery while guaranteeing adhesion in bodily fluids remains challenging. Here, the predatory behavior of the blue-ringed octopus inspired us with a strategy to improve topical medication. For effective intratissue drug delivery, the active injection microneedles were prepared in a manner inspired by the teeth and venom secretion of blue-ringed octopus. With on demand release function guided by temperature-sensitive hydrophobic and shrinkage variations, these microneedles can supply adequate drug delivery at an early stage and then achieve the long-term release stage. Meanwhile, the bionic suction cups were developed to facilitate microneedles to stay firmly in place (>10 kilopascal) when wet. With wet bonding ability and multiple delivery mode, this microneedle patch achieved satisfactory efficacy, such as accelerating the ulcers' healing speed or halting early tumor progression.

Simultaneous assaying of NLG919, tryptophan and kynurenine by ultra-high performance LC-MS in pharmacokinetics and biodistribution studies.

Background: Indocyanine2,3-dioxygenase (IDO) is an enzyme that can catalyze the metabolism of tryptophan (Trp) into kynurenine (Kyn), thus inhibiting the tumor immune microenvironment. Method: Based on its inhibitor, NLG919 (NLG), the authors developed a new immunomodulatory polymer micelle and established and verified an ultrahigh performance liquid chromatography-mass spectrometry method for the simultaneous determination of NLG, Trp and Kyn in mouse tumors through the ratio determination of Trp/Kyn tissue distribution and pharmacokinetics. The linear range of the method was 0.001-10 µg/ml. Results: Compared with NLG solution, the immunomodulatory polymeric drug-loaded micelles based on polystyrene-arginine showed higher Trp/Kyn ratio, more tumor aggregation and good pharmacokinetics. Conclusion: This method has been successfully applied to the simultaneous determination of Trp/Kyn and NLG in tumor tissues of mice.

Janus-Inspired Core-Shell Structure Hydrogel Programmatically Releases Melatonin for Reconstruction of Postoperative Bone Tumor.

At present, surgery is one of the main treatments for bone tumor. However, the risk of recurrence and the large area of bone defects after surgery pose a great challenge. Therefore, a Janus-inspired core-shell structure bone scaffold was designed to achieve the self-programmed release of melatonin at different concentrations, clearing the residual tumor cells at early stage after resection and promoting bone repair later. The layered differential load designs inspired by Janus laid the foundation for the differential release of melatonin, where sufficient melatonin inhibited tumor growth as low dose promoted osteogenesis. Then, the automatically programmed delivery of melatonin is achieved by the gradient degradation of the core-shell structure. In the material characterization, scanning electron microscopy revealed the core-shell structure. The drug release experiment and in vivo degradation experiment reflected the programmed differential release of melatonin. In the biological experiment part, in vivo and in vitro experiments not only confirmed the significant inhibitory effect of the core-shell hydrogel scaffold on tumor but also confirmed its positive effect on osteogenesis. Our Janus-inspired core-shell hydrogel scaffold provides a safe and efficient means to inhibit tumor recurrence and bone repair after bone tumor, and it also develops a new and efficient tool for differential and programmed release of other drugs.