Alkylated EDTA potentiates antibacterial photodynamic activity of protoporphyrin.

Antibiotic resistance has garnered significant attention due to the scarcity of new antibiotics in development. Protoporphyrin IX (PpIX)-mediated photodynamic therapy shows promise as a novel antibacterial strategy, serving as an alternative to antibiotics. However, the poor solubility of PpIX and its tendency to aggregate greatly hinder its photodynamic efficacy. In this study, we demonstrate that alkylated EDTA derivatives (aEDTA), particularly C14-EDTA, can enhance the solubility of PpIX by facilitating its dispersion in aqueous solutions. The combination of C14-EDTA and PpIX exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus) when exposed to LED light irradiation. Furthermore, this combination effectively eradicates S. aureus biofilms, which are known to be strongly resistant to antibiotics, and demonstrates high therapeutic efficacy in an animal model of infected ulcers. Mechanistic studies reveal that C14-EDTA can disrupt PpIX crystallization, increase bacterial membrane permeability and sequester divalent cations, thereby improving the accumulation of PpIX in bacteria. This, in turn, enhances reactive oxygen species (ROS) production and the antibacterial photodynamic activity. Overall, this effective strategy holds great promise in combating antibiotic-resistant strains.

Global research and emerging trends in autophagy in lung cancer: a bibliometric and visualized study from 2013 to 2022.

Purpose: To highlight the knowledge structure and evolutionary trends in research on autophagy in lung cancer. Methods: Research publications on autophagy in lung cancer were retrieved from the Web of Science Core Collection database. VOSviewer and CiteSpace data analysis software were used for the bibliometric and visualization analysis of countries, institutions, authors, journals, and keywords related to this field. Results: From 2013 to 2022, research on autophagy in lung cancer developed rapidly, showing rising trends in annual publications and citations. China (1,986 papers; 48,913 citations), Shandong University (77 publications; 1,460 citations), and Wei Zhang (20 publications; 342 citations) were the most productive and influential country, institution, and author, respectively. The journal with the most publications and citations on autophagy in lung cancer was the International Journal of Molecular Sciences (93 publications; 3,948 citations). An analysis of keyword co-occurrence showed that related research topics were divided into five clusters: 1) Mechanisms influencing autophagy in lung cancer and the role of autophagy in lung cancer; 2) Effect of autophagy on the biological behavior of lung cancer; 3) Regulatory mechanisms of 2 cell death processes: autophagy and apoptosis in lung cancer cells; 4) Role of autophagy in lung cancer treatment and drug resistance; and 5) Role of autophagy-related genes in the occurrence and development of lung cancer. Cell proliferation, migration, epithelial-mesenchymal transition, and tumor microenvironment were the latest high-frequency keywords that represented promising future research directions. Conclusion: This is the first comprehensive study describing the knowledge structure and emerging frontiers of research on autophagy in lung cancer from 2013 to 2022 by means of a bibliometric analysis. The study points to promising future research directions focusing on in-depth autophagy mechanisms, clinical applications, and potential therapeutic strategies, providing a valuable reference for researchers in the field. Systematic Review Registration: [https://systematicreview.gov/], identifier [registration number].

Case Report: First attempt by off-label use of tenecteplase to treat acute extensive portal venous system thrombosis.

Acute extensive portal venous system thrombosis (PVST) can cause lethal complications. Herein, we have for the first time reported the use of anticoagulation combined with systemic thrombolysis by tenecteplase in a male patient with a diagnosis of acute extensive PVST but without liver cirrhosis. After thrombolytic therapy, abdominal pain obviously alleviated. However, urinary bleeding developed, which was reversible by stopping thrombolytic drugs. Finally, this case developed cavernous transformation of the portal vein without portal venous recanalization. In future, the efficacy and safety of tenecteplase should be explored in acute extensive PVST cases.

Ginsenoside Rg3 overcomes tamoxifen resistance through inhibiting glycolysis in breast cancer cells.

Tamoxifen (TAM) resistance poses a significant clinical challenge in human breast cancer and exhibits high heterogeneity among different patients. Rg3, an original ginsenoside known to inhibit tumor growth, has shown potential for enhancing TAM sensitivity in breast cancer cells. However, the specific role and underlying mechanisms of Rg3 in this context remain unclear. Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM-resistant MCF-7/TamR and T-47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF-7/TamR and T-47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF-7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM-resistant MCF-7 cell proliferation in an in vivo model. In conclusion, this study highlights the contribution of Rg3 in enhancing the therapeutic efficacy of TAM in breast cancer, and suggests that targeting TAM-resistant PFKFB3 overexpression may represent a promising strategy to improve the response to combination therapy in breast cancer.

High-Throughput Screening of Surface Engineered Cyanine Nanodots for Active Transport of Therapeutic Antibodies into Solid Tumor.

The successful delivery of therapeutic biomacromolecules into solid tumor holds great challenge due to their high resistance to penetrate through the complex tumor microenvironments. Here, active-transporting nanoparticles are harnessed to efficiently deliver biomacromolecular drugs into solid tumors through cell transcytosis. A series of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids (G5-AA) is prepared. The capability of these positively charged nanodots to induce cell endocytosis, exocytosis, and transcytosis is evaluated via fluorescence-based high-throughput screen. The optimized nanodots (G5-R) are conjugated with αPD-L1 (a therapeutic monoclonal antibody binding to programmed-death ligand 1) (αPD-L1-G5-R) to demonstrate the nanoparticle-mediated tumor active transport. The αPD-L1-G5-R can greatly enhance the tumor-penetration capability through adsorption-mediated transcytosis (AMT). The effectiveness of αPD-L1-G5-R is tested in treating mice bearing partially resected CT26 tumors, mimicking the local immunotherapy of residual tumors post-surgery in clinic. The αPD-L1-G5-R embedded in fibrin gel can efficiently mediate tumor cell transcytosis, and deliver αPD-L1 throughout the tumor, thereby enhancing immune checkpoint blockade, reducing tumor recurrence, and significantly prolonging the survival time. The active-transporting nanodots are promising platforms for efficient tumor delivery of therapeutic biomacromolecules.

Active Breathing Coordinator reduces radiation dose to the stomach in patients with left breast cancer.

BACKGROUND/PURPOSE: Gastric dose parameters comparison for deep inspiration breath-hold (DIBH) or free breathing (FB) mode during radiotherapy (RT) for left-sided breast cancer patients (LSBCPs) has not been investigated before. This study aimed to analyze the impact of Active Breath Coordinator (ABC)-DIBH technique on the dose received by the stomach during RT for LSBCPs and to provide organ-specific dosimetric parameters. MATERIALS AND METHODS: The study included 73 LSBCPs. The dosimetric parameters of the stomach were compared between FB and DIBH mode. The correlation between the stomach volume and dosimetric parameters was analyzed. RESULTS: Compared to FB mode, statistically significant reductions were observed in gastric dose parameters in ABC-DIBH mode, including Dmax (46.60 vs 17.25, p < 0.001), D1cc (38.42 vs 9.60, p < 0.001), Dmean (4.10 vs 0.80, p < 0.001), V40Gy (0.50 vs 0.00, p < 0.001), V30Gy (6.30 vs 0.00, p < 0.001), V20Gy (20.80 vs 0.00, p < 0.001), V10Gy (51.10 vs 0.77, p < 0.001), and V5Gy (93.20 vs 9.60, p < 0.001). ABC-DIBH increased the distance between the stomach and the breast PTV when compared to FB, from 1.3 cm to 2.8 cm (p < 0.001). Physiologic decrease in stomach volume was not found from FB to ABC-DIBH (415.54 cm3 vs 411.61 cm3, p = 0.260). The stomach volume showed a positive correlation with V40Gy (r2 = 0.289; p < 0.05), V30Gy (r2 = 0.287; p < 0.05), V20Gy (r2 = 0.343; p < 0.05), V10Gy (r2 = 0.039; p < 0.001), V5Gy (r2 = 0.439; p < 0.001), Dmax (r2 = 0.269; p < 0.05) and D1cc (r2 = 0.278; p < 0.05) in FB mode. While in ABC-DIBH mode, most stomach dosimetric parameters were not correlated with gastric volume. CONCLUSIONS: The implementation of ABC-DIBH in LSBCPs radiotherapy resulted in lower irradiation of the stomach. Larger stomach volume was associated with statistically significantly higher dose irradiation in FB mode. To reduce radiotherapy related side effects in FB mode, patients should be fast for at least 2 hours before the CT simulation and treatment.

Cell-Selective Binding Zwitterionic Polymeric Micelles Boost the Delivery Efficiency of Antibiotics.

Effective accumulation and penetration of antibiotics in the biofilm are critical issues for bacterial infection treatment. Red blood cells (RBCs) have been widely utilized to hitchhike nanocarriers for drug delivery. It is vital and challenging to find a nanocarrier with an appropriate affinity toward RBCs and bacteria for selective hitchhiking and release that determines the drug delivery efficiency and specificity. Herein, we report a zwitterionic polymer poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) (OPDEA)-based micelle, which can hitchhike on RBCs in blood and preferentially release in the infection site. We found that OPDEA could bind to the RBCs cell membrane via phospholipid-related affinity and transfer to Gram-positive bacteria due to nearly an order of magnitude stronger interaction with the bacteria cell wall. The zwitterionic surface and cell-wall affinity of OPDEA-based micelles also promote their penetration in biofilm. The clarithromycin-loaded OPDEA micelles show efficient drug delivery into the infection site, resulting in excellent therapeutic performance in both peritonitis and pneumonia models by intravenous or spray administration. This simple RBC-selective hitchhiking and releasing antibiotic delivery system provides a promising strategy for the design of antibacterial nanomedicines.

Electrical stimulation induces anti-tumor immunomodulation via a flexible microneedle-array-integrated interdigital electrode.

Immunotherapy has revolutionized cancer therapy, using chemical or biological agents to reinvigorate the immune system. However, most of these agents have poor tumor penetration and inevitable side effects that complicate therapeutic outcomes. Electrical stimulation (ES) is a promising alternative therapy against cancers that does not involve chemical or biological agents but is limited in the fabrication and operation of complex micrometer-scale ES devices. Here, we present an optically microprinted flexible interdigital electrode with a gold-plated polymer microneedle array to generate alternating electric fields for cancer treatment. A flexible microneedle-array-integrated interdigital electrode (FMIE) was fabricated by combining optical 3D microprinting and electroless plating processes. FMIE-mediated ES of cancer cells induced necrotic cell death through mitochondrial Ca2+ overload and increased intracellular reactive oxygen species (ROS) production. This led to the release of damage-associated molecular patterns that activated the immune response and potentiated immunogenic cell death (ICD). FMIE-based ES has an excellent safety profile and systemic anti-tumor effects, inhibiting the growth of primary and distant tumors as well as melanoma lung metastasis. FMIE-based ES-driven cancer immunomodulation provides a new pathway for drug-free cancer therapy.

Tumor Abnormality-Oriented Nanomedicine Design.

Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.

Dual Synergistic Tumor-Specific Polymeric Nanoparticles for Efficient Chemo-Immunotherapy.

Chemo-immunotherapy has made significant progress in cancer treatment. However, the cancer cell self-defense mechanisms, including cell cycle checkpoint and programmed cell death-ligand 1 (PD-L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)-platinum (Pt) codelivery nanoparticles (NC-NP) with tumor-sensitive release profiles are designed to overcome the self-defense mechanisms via synergistic chemo-immunotherapy. NC-NP remains stable under normal physiological conditions but quickly releases 1,2-diaminocyclohexane-platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD-L1 expression to disrupt the programmed cell death-1 (PD-1)/PD-L1 interaction, synergistically enhancing Pt-based chemotherapy and immunogenic cell death-induced immunotherapy. As a result, NC-NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo-immunotherapy paradigm for cancer treatment.

Esterase-Labile Quaternium Lipidoid Enabling Improved mRNA-LNP Stability and Spleen-Selective mRNA Transfection.

Ionizable cationic lipids are recognized as an essential component of lipid nanoparticles (LNPs) for messenger RNA (mRNA) delivery but can be confounded by low lipoplex stability with mRNA during storage and in vivo delivery. Herein, the rational design and combinatorial synthesis of esterase-triggered decationizable quaternium lipid-like molecules (lipidoids) are reported to develop new LNPs with high delivery efficiency and improved storage stability. This top lipidoid carries positive charges at the physiological condition but promptly acquires negative charges in the presence of esterase, thus permitting stable mRNA encapsulation during storage and in vivo delivery while balancing efficient mRNA release in the cytosol. An optimal LNP formulation is then identified through orthogonal optimization, which enables efficacious mRNA transfection selectively in the spleen following intravenous administration. LNP-mediated delivery of ovalbumin (OVA)-encoding mRNA induces efficient antigen expression in antigen-presenting cells and elicits robust antigen-specific immune responses against OVA-transduced tumors. The work demonstrates the potential of decationizable quaternium lipidoids for spleen-selective RNA transfection and cancer immunotherapy.

Role of Micelle Size in Cell Transcytosis-Based Tumor Extravasation, Infiltration, and Treatment Efficacy.

Transcytosis-based active transport of cancer nanomedicine has shown great promise for enhancing its tumor extravasation and infiltration and antitumor activity, but how the key nanoproperties of nanomedicine, particularly particle size, influence the transcytosis remains unknown. Herein, we used a transcytosis-inducing polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), and fabricated stable OPDEA-based micelles with different sizes (30, 70, and 140 nm in diameter) from its amphiphilic block copolymer, OPDEA-block-polystyrene (OPDEA-PS). The study of the micelle size effects on cell transcytosis, tumor extravasation, and infiltration showed that the smallest micelles (30 nm) had the fastest transcytosis and, thus, the most efficient tumor extravasation and infiltration. So, the 7-ethyl-10-hydroxyl camptothecin (SN38)-conjugated OPDEA micelles of 30 nm had much enhanced antitumor activity compared with the 140 nm micelles. These results are instructive for the design of active cancer nanomedicine.

A Bispecific Peptide-Polymer Conjugate Bridging Target-Effector Cells to Enhance Immunotherapy.

Peptide-based immune checkpoint inhibitors exhibit remarkable therapeutic benefits although their application is hindered by quick blood clearance and low affinity with receptors. The modification of the peptides into artificial antibodies is an ideal platform to solve these problems, and one of the optional pathways is the conjugation of peptides with a polymer. More importantly, the bridging effect, mediated by bispecific artificial antibodies, could promote the interaction of cancer cells and T cells, which will benefit cancer immunotherapy. Herein, a bispecific peptide-polymer conjugate (octa PEG-PD1-PDL1) is prepared by simultaneously conjugating PD1-binding and PDL1-binding peptides onto 8-arm-PEG. octa PEG-PD1-PDL1 bridges T cells and cancer cells and thus enhances T cell-mediated cytotoxicity against cancer cells. Meanwhile, the tumor-targeting octa PEG-PD1-PDL1 increases the infiltration of cytotoxic T lymphocytes in tumors and reduces their exhaustion. It effectively activates the tumor immune microenvironment and exerts a potent antitumor effect against CT26 tumor models with a tumor inhibition rate of 88.9%. This work provides a novel strategy to enhance tumor immunotherapy through conjugating bispecific peptides onto a hyperbranched polymer to effectively engage target-effector cells.

Highly Sensitive Imaging of Tumor Metastasis Based on the Targeting and Polarization of M2-like Macrophages.

Tumor-associated macrophages, especially M2-like macrophages, are extensively involved in tumor growth and metastasis, suppressing the innate immunity to help tumor cells escape and reshaping the microenvironment to help metastatic cells grow. However, in vivo, real-time visualized migration of M2-like macrophages has never been explored to monitor the tumor metastasis process. Herein, we prepared an M2-like macrophage-targeting nitric oxide (NO)-responsive nanoprobe (NRP@M-PHCQ) consisting of an amphiphilic block copolymer with mannose and hydroxychloroquine (HCQ) moieties (denoted as M-PHCQ) and a NO-responsive NIR-II probe (denoted as NRP). The mannose moieties provided M2-like macrophage-targeting capacity, and the HCQ moieties polarized M2-like macrophages to M1-like ones with enhanced NO secretion. Consequently, NRP@M-PHCQ was lit up by the secreted NO to visualize the migration and polarization of M2-like macrophages in real time. In vivo metastasis imaging with NRP@M-PHCQ successfully tracked early tumor metastasis in the lymph nodes and the lungs with high sensitivity, even superior to Luci-labeled bioluminescence imaging, suggesting the extensive distribution and critical role of M2-like macrophages in tumor metastasis. In general, this work provided a new strategy to sensitively image metastatic tumors by tracking the polarization of M2-like macrophages and visually disclosed the critical role of M2-like macrophages in early tumor metastasis.

Aminopeptidase N-Responsive Conjugates with Tunable Charge-Reversal Properties for Highly Efficient Tumor Accumulation and Penetration.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

Long-term survival outcomes of patients with primary ocular adnexal MALT lymphoma: A large single-center cohort study.

BACKGROUND: Primary ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (OAML) is a rare subtype of non-Hodgkin's lymphoma, and no consensus has been defined concerning the optimal treatment strategies. This study aims to investigate the associations of disease characteristics and different treatments with long-term outcomes of patients with localized OAML. METHODS: A large retrospective cohort study was conducted in a single-center of China, and 166 patients with newly diagnosed primary localized OAML were enrolled. Detailed data of disease characteristics at diagnosis and treatments were collected for all patients. We compared treatment response and progression-free survival (PFS) among patients with different characteristics and treatments. RESULTS: Of the 166 patients, 52 received complete resection of neoplasm, whereas 114 had residual lesion after surgery. Among the 114 patients, 61 underwent watchful waiting and 53 received further treatment including localized radiotherapy, chemotherapy, or combined radiotherapy and chemotherapy. Median follow-up was 49 months. A total of 31 patients had disease progression or relapse, including four patients with such event more than five years after initial treatment. The 5-year PFS was 73.9%, 70.6%, and 85.9%, whereas the 10-year PFS was 69.3%, 59.2%, and 79.3%, among patients with complete resection of neoplasm, patients in the watchful waiting group and patients with further treatment, respectively. Patients with further treatment had longer PFS, compared with patients in the watchful waiting group (p = 0.011). Bilateral involvement at diagnosis was associated with significantly inferior PFS (p = 0.029), whereas age, IPI score, or TNM staging were not associated with PFS. No serious adverse reaction was reported among patients with further treatment. CONCLUSIONS: Bilateral involvement was associated with poor prognosis. Among patients with residual lesions after surgery, further treatment was associated with improved survival. Patients with OAML might experience disease progression or relapse more than five years after initial treatment.

The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives.

Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics. Increasing evidence suggests that the EPR effect is over-represented in human tumors, especially in metastatic tumors. This review covers the evolution of the concept, the heterogeneity and limitation of the EPR effect in clinical realities, and prospects for alternative strategies independent of the EPR effect.

The effect of respiratory capacity for dose sparing in left-sided breast cancer irradiation with active breathing coordinator technique.

Background and aim: A subsequent cardiac toxicity is deemed to be dose-dependent for left-sided breast cancer irradiation. This study aims to demonstrate the effect of respiratory capacity for dose sparing when the deep inspiration breath hold with Active Breathing Coordinator technique (ABC-DIBH) is used in left-sided breast cancer irradiation. Methods: 74 left-sided breast cancer patients, who received whole breast or post-mastectomy chest wall radiotherapy with ABC-DIBH between 2020 and 2021 in our center, were retrospectively reviewed in this study. CT scans of free breath (FB) and ABC-DIBH were done for each patient, and two treatment plans with a prescription dose of 5000 cGy/25 Fr were designed separately. The dose to heart, left anterior descending artery (LAD) and lungs was compared between FB and ABC-DIBH. The correlation between individual parameters (dose to organs at risk (OARs) and minimum heart distance (MHD)) was analyzed, and the effect of respiratory capacity for dose sparing was assessed. Results: The plans with ABC-DIBH achieved lower Dmean for heart (34.80%, P < 0.01) and LAD (29.33%, P < 0.01) than those with FB. Regression analysis revealed that both Dmean and D2 of heart were negatively correlated with MHD in the plans with FB and ABC-DIBH, which decreased with the increase in MHD by 37.8 cGy and 309.9 cGy per 1mm, respectively. Besides, a lower Dmean of heart was related to a larger volume of ipsilateral lung in plans with FB. With the increase in volume of ipsilateral lung, the linear correlation was getting weaker and weaker until the volume of ipsilateral lung reached 1700 cc. Meanwhile, a negative linear correlation between Dmean of LAD and MHD in plans with FB and ABC-DIBH was observed, whose slope was 162.5 and 135.9 cGy/mm, respectively. Furthermore, when the respiratory capacity of ABC-DIBH reached 1L, and the relative ratio (ABC-DIBH/FB) reached 3.6, patients could obtain the benefit of dose sparing. The larger difference in respiratory capacity had no significant effect in the larger difference of MHD, Dmean of heart and Dmean of LAD between FB and ABC-DIBH. Conclusion: This study demonstrates the sufficiently good effect of ABC-DIBH when utilizing for cardiac sparing. It also reveals the correlations among individual parameters and the effect of respiratory capacity for dose sparing. This helps take optimal advantage of the ABC-DIBH technique and predict clinical benefits.

Curcumin treatment attenuates cisplatin-induced gastric mucosal inflammation and apoptosis through the NF- κ B and MAPKs signaling pathway.

To investigate the protective effects of curcumin (Cur) on gastric mucosal injury induced by cisplatin (DDP), and explore possible molecular mechanisms. A mouse of gastric mucosal injury was established by intraperitoneal injection of DDP (27 mg/kg). Thirty mice were randomly divided into control group, DDP group and DDP + Cur group. Serum and gastric mucosal samples were collected on the 7th day after Cur treatment. The index of gastric mucosa injury was calculated, and the expression levels of inflammation, apoptosis and signaling pathway proteins were evaluated using hematoxylin and eosin staining, ELISA and western blotting analysis. These data showed that Cur treatment significantly attenuated DDP-induced decrease in body weight, food intake, fat and muscle ratios, and improved the gross gastric injury, scores of ulcer index, and histopathology changes triggered by DDP (p < .05). Meanwhile, Cur significantly decreased serum IL-23 and IL-17 proteins, reduced the expression levels of gastric mucosal IL-1ß, TNF- α and MPO, and restored the level of IL-10 protein (p < .05). Moreover, Cur treatment significantly inhibited the expression levels of Caspase-3, PARP and Bax, and increased the expression of Bcl-2 protein. Furthermore, Cur treatment significantly decreased the expression levels of IL-1R, MyD88 and TAK1, and also repressed the activation of NF-κB and nuclear translocation of NF-κB p65. And more importantly, Cur treatment significantly inhibited DDP-induced gastric mucosal JNK1/2, ASK1, P38 and JUN phosphorylation, and promoted the phosphorylation of ERK1/2 and C-Myc proteins. Our data suggest that Cur treatment alleviates DDP-induced gastric mucosal inflammation and apoptosis, which may be mediated through the NF- κ B and MAPKs signaling pathway.

Protective effect and mechanism of cannabidiol on myocardial injury in exhaustive exercise training mice.

Cannabinoid diphenol (CBD) is a non-toxic main component extracted from cannabis, which has the effects of anti-inflammatory, anti-apoptosis and anti-oxidative stress. In recent years, exercise-induced myocardial injury has become a research hotspot in the field of sports medicine and sports physiology. Exercise-induced myocardial injury is closely related to oxidative stress, inflammatory response and apoptosis. However, there is no clear evidence of the relationship between CBD and exercise-induced myocardial injury. In this study, by establishing an animal model of exhaustive exercise training in mice, the protective effect of CBD on myocardial injury in mice was elaborated, and the possible molecular mechanism was discussed. After CBD intervention, the arrangement and rupture of myocardial fiber tissue and the degree of inflammatory cell infiltration were reduced, the deposition of collagen fibers in myocardial tissue decreased. CBD can also significantly inhibit cardiac hypertrophy. Meanwhile, the expression of IL-6, IL-10, TNF-α, Bax, Caspase-3, Bcl-2, MDA-5, IRE-1α, NOX-2, SOD-1, Keap1, Nrf2, HO-1, NF-κB and COX-2 was recovered to normal. In addition, after CBD intervention, the protein expression of Keap1 was down-regulated, the translocation of Nrf2 from the cytoplasm to the nucleus was significantly increased, then the transcriptional activity was increased, and the expression of the downstream HO-1 antioxidant protein was increased, indicating that CBD may improve the cardiac function of exhaustive exercise training mice by activating Keap1/Nrf2/HO-1 signaling pathway. Molecular docking results also confirmed that CBD had a good binding effect with Keap1/Nrf2/HO-1 signaling pathway proteins. In conclusion, the protective mechanism of CBD on myocardial injury in exhaustive exercise training mice may be to activate Keap1/Nrf2/HO-1 signaling pathway, and then exert anti-inflammatory, anti-apoptosis and inhibition of oxidative stress.