Interleukin-17 alleviates erastin-induced alveolar bone loss by suppressing ferroptosis via interaction between NRF2 and p-STAT3.

AIM: To investigate the relationship between interleukin-17 (IL-17), ferroptosis and osteogenic differentiation. MATERIALS AND METHODS: We first analysed the changes in ferroptosis-related molecules in experimental periodontitis models. The effects of erastin, a small-molecule ferroptosis inducer, and IL-17 on alveolar bone loss and repair in animal models were then investigated. Primary mouse mandibular osteoblasts were exposed to erastin and IL-17 in vitro. Ferroptosis- and osteogenesis-related genes and proteins were detected. Further, siRNA, immunofluorescence co-localization and immunoprecipitation were used to confirm the roles of the nuclear factor erythroid-2-related factor 2 (NRF2) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), as well as their interaction. RESULTS: The levels of NRF2, glutathione peroxidase 4 and solute carrier family 7 member 11 were lower in the ligated tissues than in normal periodontal tissues. Alveolar bone loss in an in vivo experimental periodontitis model was aggravated by erastin and alleviated by IL-17. In vitro, IL-17 ameliorated erastin-inhibited osteogenic differentiation by reversing ferroptosis. Altered NRF2 expression correlated with changes in ferroptosis-related molecules and osteogenesis. Furthermore, the physical interaction between NRF2 and p-STAT3 was confirmed in the nucleus. In IL-17 + erastin-stimulated osteoblasts, the p-STAT3-NRF2 complex might actively participate in the downstream transcription of ferroptosis- and osteogenesis-related genes. CONCLUSIONS: IL-17 administration conferred resistance to erastin-induced osteoblast ferroptosis and osteogenesis. The possible mechanism may involve p-STAT3 directly interacting with NRF2.

Research progress on roles of iron metabolism in the occurrence and development of periodontitis. / é“ä»£è°¢åœ¨æ ¢æ€§ç‰™å‘¨ç‚Žå‘ç”Ÿå‘å±•ä¸­çš„ä½œç”¨ç ”ç©¶è¿›å±•.

Iron metabolism refers to the process of absorption, transport, excretion and storage of iron in organisms, including the biological activities of iron ions and iron-binding proteins in cells. Clinical research and animal experiments have shown that iron metabolism is associated with the progress of periodontitis. Iron metabolism can not only enhance the proliferation and toxicity of periodontal pathogens, but also activate host immune- inflammatory response mediated by macrophages, neutrophils and lymphocytes. In addition, iron metabolism is also involved in regulating the cellular death sensitivity of gingival fibroblasts and osteoblasts and promoting the differentiation of osteoclasts to play a regulatory role in the regeneration and repair of periodontal tissue. This article reviews the research progress on the pathogenesis of periodontitis from the perspective of iron metabolism, aiming to provide new ideas for the treatment of periodontitis.

Polysaccharide-Based Injectable Hydrogels with Fast Gelation and Self-Strengthening Mechanical Kinetics for Oral Tissue Regeneration.

Oral defects lead to a series of function disorders, severely threatening the patients' health. Although injectable hydrogels are widely studied in tissue regeneration, their mechanical performance is usually stationary after implant, without further self-adaption toward the microenvironment. Herein, an injectable hydrogel with programmed mechanical kinetics of instant gelation and gradual self-strengthening along with outstanding biodegradation ability is developed. The fast gelation is realized through rapid Schiff base reaction between biodegradable chitosan and aldehyde-modified sodium hyaluronate, while self-strengthening is achieved via slow reaction between redundant amino groups on chitosan and epoxy-modified hydroxyapatite. The resultant hydrogel also possesses multiple functions including (1) bio-adhesion, (2) self-healing, (3) bactericidal, (4) hemostasis, and (5) X-ray in situ imaging, which can be effectively used for oral jaw repair. We believe that the strategy illustrated here will provide new insights into dynamic mechanical regulation of injectable hydrogels and promote their application in tissue regeneration.

Original and liposome-modified indocyanine green-assisted fluorescence study with animal models.

Medical diagnosis heavily relies on the use of bio-imaging techniques. One such technique is the use of ICG-based biological sensors for fluorescence imaging. In this study, we aimed to improve the fluorescence signals of ICG-based biological sensors by incorporating liposome-modified ICG. The results from dynamic light scattering and transmission electron microscopy showed that MLM-ICG was successfully fabricated with a liposome diameter of 100-300 nm. Fluorescence spectroscopy showed that MLM-ICG had the best properties among the three samples (Blank ICG, LM-ICG, and MLM-ICG), as samples immersed in MLM-ICG solution achieved the highest fluorescence intensity. The NIR camera imaging also showed a similar result. For the rat model, the best period for fluorescence tests was between 10 min and 4 h, where most organs reached their maximum fluorescence intensity except for the liver, which continued to rise. After 24 h, ICG was excreted from the rat's body. The study also analyzed the spectra properties of different rat organs, including peak intensity, peak wavelength, and FWHM. In conclusion, the use of liposome-modified ICG provides a safe and optimized optical agent, which is more stable and efficient than non-modified ICG. Incorporating liposome-modified ICG in fluorescence spectroscopy could be an effective way to develop novel biosensors for disease diagnosis.

Interferometric plasmonic imaging and detection of single exosomes.

Exosomes play an important role in numerous cellular processes. Fundamental study and practical use of exosomes are significantly constrained by the lack of analytical tools capable of physical and biochemical characterization. In this paper, we present an optical approach capable of imaging single exosomes in a label-free manner, using interferometric plasmonic microscopy. We demonstrate monitoring of the real-time adsorption of exosomes onto a chemically modified Au surface, calculating the image intensity, and determining the size distribution. The sizing capability enables us to quantitatively measure the membrane fusion activity between exosomes and liposomes. We also report the recording of the dynamic interaction between exosomes and antibodies at the single-exosome level, and the tracking of hit-stay-run behavior of exosomes on an antibody-coated surface. We anticipate that the proposed method will contribute to clinical exosome analysis and to the exploration of fundamental issues such as the exosome-antibody binding kinetics.

Characteristic changes of traumatic dental injuries in a teaching hospital of Wuhan under transmission control measures during the COVID-19 epidemic.

BACKGROUND/AIMS: In December 2019, a novel coronavirus emerged in Wuhan City, and a retrospective analysis is necessary to provide clinicians with the characteristics of traumatic dental injuries (TDIs) during the epidemic. The aim of this study was to evaluate the changes in the characteristics of TDIs under the transmission control measures in Wuhan City utilizing an epidemiologic investigation. MATERIALS AND METHOD: In this retrospective study, epidemiologic information, including the number of patients, gender, age, and TDI parameters such as time since injury to the clinic visit, etiology, tooth location, and the type of injury was extracted from the records of patients in the hospital from two periods: period 1 (between January 23, 2020, and April 7, 2020) and period 2 (between January 23, 2019, and April 7, 2019). The data from the two periods were compared and analyzed. RESULT: A total of 158 patients were treated for TDIs (120 in 2019 and 38 in 2020). Males were more likely to suffer from TDIs than females with a ratio of 1.5:1, both in 2020 and 2019. Other than that, there were characteristic changes in TDIs during the transmission control measures in the COVID-19 epidemic, which included the number of patients, age, time since injury to the clinic visit, etiology, tooth location and the type of TDI. CONCLUSION: The transmission control measures during the COVID-19 epidemic had a significant impact on the epidemiology and etiology of TDIs in Wuhan City.

Enhanced chemo-immunotherapy against melanoma by inhibition of cholesterol esterification in CD8+ T cells.

Cholesterol facilitated the formation of T cell receptor on cytotoxic CD8+ T lymphocytes (CTLs). However, the activation of CD8+ T cells always resulted in the upregulation of acetyl-CoA acetyltransferase-1 (ACAT-1) and enhanced the esterification of cholesterol. To relieve the suppression on CD8+ T cells, an ACAT-1 inhibitor avasimibe was combined with chemo-immunotherapy. Paclitaxel and immunoadjuvant αGC were co-encapsulated in liposomes modified with pH sensitive TH peptide (PTX/αGC-TH-Lip). After intravenous injections, the combination of avasimibe significantly elevated the free cholesterol level and relieved the inhibition of CD8+ T cells caused by PTX/αGC-TH-Lip, leading to enhanced CTL responses and anti-tumor effects of PTX/αGC-TH-Lip in B16F10 melanoma xenograft and lung metastasis models. The adoptive immunotherapy further confirmed the enhanced anti-tumor immune responses of the combined strategy. The combination of avasimibe and PTX/αGC-TH-Lip was proven as a feasible approach to enhance the antitumor effects of chemo-immunotherapy by relieving the inhibition of CD8+ T cells.

Nanopolystyrene size effect and its combined acute toxicity with halogenated PAHs on Daphnia magna.

Nanoplastics (NPs, diameter <1 µm) not only have toxicity but also change the toxicity of other pollutants in water. To date, the nanopolystyrene (nano-PS) size effect and its combined toxicity with halogenated polycyclic aromatic hydrocarbons (HPAHs) remain unclear. In this study, the single toxicity, combined toxicity, and mode of action of the binary mixture of polystyrene (PS) and HPAH were examined. At the same time, the nano-PS size effect on combined toxicity was also discussed. According to our results, the 48 h acute toxicity test results showed that 30 nm PS was highly toxic (EC50-48 h = 1.65 mg/L), 200 nm PS was moderately toxic (EC50-48 h = 17.8 mg/L), and 1 µm PS was lowly toxic (EC50-48 h = 189 mg/L). The NP toxicity decreased with increasing size. HPAHs were highly toxic substances to Daphnia magna (EC50-48 h = 0.12-0.22 mg/L). The mode of action of PS and HPAHs was antagonistic according to the toxicity unit method (TU), additive index method (AI), and mixture toxicity index method (MTI). The size effect of nano-PS operates via two mechanisms: the inherent toxicity of nano-PS and the sorption of pollutants by nano-PS. The former impacts the combined toxicity more than the latter. In the binary mixed system, the larger the particle size and the higher the proportion of NPs in the system, the less toxic the system was. Linear interpolation analysis can be used to predict the combined toxicity of a mixed system with any mixing ratio.

Unveiling the impact of microplastics with distinct polymer types and concentrations on tidal sediment microbiome and nitrogen cycling.

Microplastics (MPs) are distributed widely in the ocean surface waters and sediments. Increasing MPs contamination in intertidal zone profoundly impacts microbial ecosystem services and biogeochemical process. Little is known about the response of tidal sediment microbiome to MPs. We conducted a 30-day laboratory microcosm study using five polymers (PE, PBS, PC, PLA and PET) at three concentrations (1 %, 2 % and 5 %, w/w). High throughput sequencing of 16 S rRNA, qPCR and enzyme activity test were applied to demonstrate the response of microbial community and nitrogen cycling functional genes to MPs. MPs reduced the microbial alpha diversity and the microbial dissimilarity while the effects of PLA-MPs were concentration dependent. LEfSe analysis indicated that the Proteobacteria predominated for all MP treatments. Mantel's test, RDA and correlation analysis implied that pH may be the key environmental factor for causing microbial alterations. MPs enhanced nitrogen fixation in tidal sediment. PLA levels of 1 % but not 5 % produced the most significant effects in nitrogen cycling functional microbiota and genes. PLS-PM revealed that impacts of MPs on tidal sediment microbial communities and nitrogen cycling were dominated by indirect effects. Our study deepened understanding and filled the knowledge gap of MP contaminants affecting tidal sediment microbial nitrogen cycling.

Endoscopic Balloon Dilatation of the Eustachian Tube via the Soft Palate Approach in Miniature Pigs.

The eustachian tube (ET) is one of the most complex organs in the human body, and its dysfunction may lead to a variety of diseases. In recent years, an increasing number of scholars have opted to conduct ET-related studies using large experimental animals such as miniature pigs or sheep, yielding promising results. Typically, conventional endoscopic procedures are performed through the nasal approach for large experimental animals. However, due to the elongated and narrow nasal cavity in these animals, transnasal surgeries are challenging. To address this issue, we explored an ET surgery approach via the soft palate. The animal was placed in a supine position. After endotracheal intubation under general anesthesia, a mouth opener was used to fully expose the upper palate. Local infiltration with diluted adrenal fluid was performed for anesthesia of the area. A sickle knife was then used to make a longitudinal soft palate incision at the junction of the soft and hard palates. After hemostasis, an endoscope was inserted into the nasopharynx cavity, allowing the visualization of the pharyngeal opening of the ET on the posterior lateral wall of the nasal cavity. Subsequently, a specialized pusher was used to insert a balloon into ET. The balloon was inflated, maintained at 10 bar for 2 min, and then removed. The incision in the soft palate was then sutured to ensure proper alignment. The soft palate healed well after the operation. This surgical approach is suitable for ET-related procedures in large experimental animals (e.g., miniature pigs, sheep, and dogs). The surgical procedure is simple, with a short surgical time, and wound healing is rapid. Under endoscopy, the pharyngeal opening of the ET is visible, and it is thus a good choice for procedures such as balloon dilation of the ET.

Laboratory tidal microcosm deciphers responses of sediment archaeal and bacterial communities to microplastic exposure.

Microplastics (MPs) are 1-5 mm plastic particles that are serious global contaminants distributed throughout marine ecosystems. However, their impact on intertidal sediment microbial communities is poorly understood. In this study, we conducted a 30-day laboratory tidal microcosm experiment to investigate the effects of MPs on microbial communities. Specifically, we used the biodegradable polymers polylactic acid (PLA) and polybutylene succinate (PBS), as well as the conventional polymers polyethylene terephthalate (PET), polycarbonate (PC), and polyethylene (PE). Treatments with different concentrations (1-5%, w/w) of PLA- and PE-MPs were also included. We analyzed taxonomic variations in archaeal and bacterial communities using 16S rRNA high-throughput sequencing. PLA-MPs at concentrations of 1% (w/w) rapidly altered microbiome composition. Total organic carbon and nitrite nitrogen were the key physicochemical factors and urease was the major enzyme shaping MP-exposed sediment microbial communities. Stochastic processes predominated in microbial assembly and the addition of biodegradable MPs enhanced the contribution of ecological selections. The major keystone taxa of archaea and bacteria were Nitrososphaeria and Alphaproteobacteria, respectively. MPs exposure had less effect on archaeal functions while nitrogen cycling decreased in PLA-MPs treatments. These findings expanded the current understanding of the mechanism and pattern that MPs affect sediment microbial communities.

Application of antimicrobial photodynamic therapy to treat subgingival multidrug-resistant bacterial infections in ICU patients.

BACKGROUND: Drug-resistant bacterial infections have received much attention in recent years. Antimicrobial photodynamic therapy (aPDT) is an effective antimicrobial strategy. This study aimed to evaluate the therapeutic effect of methylene blue (MB)-mediated aPDT against subgingival multidrug-resistant (MDR) bacterial infections in intensive care unit (ICU) patients. METHODS: Eighty-three patients who were hospitalized in the ICU of the Second Affiliated Hospital of Nanchang University from July 2019 to June 2021 were selected. The intraoral partitioned control test was conducted. Teeth that met the criteria were selected from different quadrants of the same patient, randomly divided into three groups, namely, A, B, and C, and treated with aPDT, chlorhexidine gargle, or normal saline. The counts of MDR bacteria in the gingival crevicular fluid were assessed in the different groups at different time points before and after treatment. RESULTS: The MDR bacterial count decreased immediately after aPDT and was significantly different from that in the chlorhexidine gargle rinse group and the normal saline rinse group (P<0.05). There was no significant difference among the three groups at 6, 12, and 24 hours after treatment (P>0.05). CONCLUSION: aPDT can be used to treat subgingival MDR bacterial infections, but the long-term effects of treatment need to be further studied.

Mechanisms of polystyrene microplastic degradation by the microbially driven Fenton reaction.

Natural hydroxyl radical (·OH) production, which partially occurs through the microbially driven Fenton reaction, can enhance the degradation of polystyrene microplastics (PS-MPs). However, ·OH causes damage to microorganisms, which might in turn restrain the microbially driven Fenton reaction. Thus, whether PS-MPs can be continuously degraded by the microbially driven Fenton reaction and how they are degraded are still unknown. A pure-culture system using Shewanella putrefaciens 200 was set up to explore the effect and mechanism of microbially driven Fenton reaction on PS-MP degradation. In a 14-day operation, ·OH produced by the microbially driven Fenton reaction could degrade PS-MPs with a weight loss of 6.1 ± 0.6% and an O/C ratio of 0.6 (v.s. 0.6 ± 0.1% and 0.1, respectively, in the ·OH quenched group). Benzene ring derivatives such as 2-isopropyl-5-methyl-1-heptanol and nonahexacontanoic acid were the main soluble products of PS-MP degradation. The ·OH-induced oxidative damage on microorganisms did not affect ·OH production significantly when there was timely replenishment of organic carbon sources to promote reproduction of microorganisms. Thus, PS-MPs can be continuously degraded by microbially driven Fenton reactions in natural alternating anaerobic-aerobic environments. This study also provides a new microbial technique for MP degradation that is different from previous technologies based on microbial plastic-degrading enzymes.

Tuning Ambipolarity of the Conjugated Polymer Channel Layers of Floating-Gate Free Transistors: From Volatile Memories to Artificial Synapses.

Three-terminal synaptic transistor has drawn significant research interests for neuromorphic computation due to its advantage of facile device integrability. Lately, bulk-heterojunction-based synaptic transistors with bipolar modulation are proposed to exempt the use of an additional floating gate. However, the actual correlation between the channel's ambipolarity, memory characteristic, and synaptic behavior for a floating-gate free transistor has not been investigated yet. Herein, by studying five diketopyrrolopyrrole-benzotriazole dual-acceptor random conjugated polymers, a clear correlation among the hole/electron ratio, the memory retention characteristic, and the synaptic behavior for the polymer channel layer in a floating-gate free transistor is described. It reveals that the polymers with balanced ambipolarity possess better charge trapping capabilities and larger memory windows; however, the high ambipolarity results in higher volatility of the memory characteristics, namely poor memory retention capability. In contrast, the polymer with a reduced ambipolarity possesses an enhanced memory retention capability despite showing a reduced memory window. It is further manifested that this enhanced charge retention capability enables the device to present artificial synaptic characteristics. The results highlight the importance of the channel's ambipolarity of floating-gate free transistors on the resultant volatile memory characteristics and synaptic behaviors.

Wnt signaling: An attractive target for periodontitis treatment.

Periodontitis is the most common chronic inflammatory disease, and a leading cause of tooth loss. Characterized by resorption of alveolar process and destruction of periodontal ligaments, periodontitis can impact not only periodontal tissues but also systemic diseases, such as diabetes, cardiovascular diseases, and respiratory infections. Currently, it is a hotspot to manage destruction and gain regeneration of periodontal tissues. Increasing evidence indicates that the Wnt signaling plays an important role in homeostasis of periodontal tissues, functions of periodontal derived cells, and progression of periodontitis. Its molecule expressions were abnormal in periodontitis. As such, modulators targeting the Wnt signaling may be an adjuvant therapy for periodontitis treatment. This review elucidates the role of Wnt signaling and its molecules, with a view to develop a potential application of drugs targeting the Wnt signaling for periodontitis treatment.

Enhanced aging of polystyrene microplastics in sediments under alternating anoxic-oxic conditions.

Aging of microplastics (MPs) (i.e., degradation and weathering) is ubiquitous in the environment. The MP aging process is thought to be limited to light and static areas, while aging in dark and fluctuating anoxic-oxic areas is poorly understood. Here, we provide initial evidence for aging of polystyrene microplastics (PS-MPs) under different anoxic/oxic conditions in sediments, and we further explored these mechanisms using sediment column experiments and pure-culture experiments. The results showed that PS-MPs in alternating anoxic-oxic sediments displayed the highest degree of aging. In the in-situ experiment, both the weight losses and O/C ratios of PS-MPs aged under alternating anoxic-oxic conditions were ∼2 times higher than those aged under static oxic and static anoxic conditions during 2-month experiments. In a 2-month column experiment, the PS-MPs in the alternating anoxic-oxic group showed weight losses and O/C ratios that were, respectively, triple and double the corresponding values for the static oxic and static anoxic groups. Column and pure-culture experiments demonstrated that dark production of ·OH which showed a positive correlation with a Fe redox process could explain enhanced MP aging under the alternating anoxic-oxic conditions. These findings provide a basis for risk assessment and management of MPs in the natural environment, such as in intertidal zones and paddy fields, and also have implications for engineering of optimized MP degradation processes.

Mussel-Inspired Polymeric Coatings to Realize Functions from Single and Dual to Multiple Antimicrobial Mechanisms.

Numerous efforts to fabricate antimicrobial surfaces by simple yet universal protocols with high efficiency have attracted considerable interest but proved to be particularly challenging. Herein, we designed and fabricated a series of antimicrobial polymeric coatings with different functions from single to multiple mechanisms by selectively utilizing diethylene glycol diglycidyl ether (PEGDGE), polylysine, and poly[glycidylmethacrylate-co-3-(dimethyl(4-vinylbenzyl)ammonium)propyl sulfonate] (poly(GMA-co-DVBAPS)) via straightforward mussel-inspired codeposition techniques. Bactericidal polylysine endowed the modified surfaces with a high ability (∼90%) to kill attached bacteria, while PEGDGE components with unique surface hydration prevented bacterial adhesion, avoiding the initial biofilm formation. Moreover, excellent salt-responsive poly(GMA-co-DVBAPS) enabled reactant polymeric coatings to change chain conformations from shrinkable to stretchable state and subsequently release >90% attached bacteria when treated with NaCl solution, even after repeated cycles. Therefore, the obtained polymeric coatings, polydopamine/poly(GMA-co-DVBAPS) (PDA/PDV), polydopamine/polylysine/poly(GMA-co-DVBAPS) (PDA/l-PDV), and polydopamine/polylysine/poly(GMA-co-DVBAPS)/diethylene glycol diglycidyl ether (PDA/l-PDV-PEGDGE), controllably realized functions from single and dual to multiple antimicrobial mechanisms, as evidenced by long-term antifouling activity to bacteria, high bactericidal efficiency, and salt-responsive bacterial regeneration performance with several bacterial killing-release cycles. This study not only contributes to mussel-inspired chemistry for polymeric coatings with controllable functions but also provides a series of reliable and highly efficient antimicrobial surfaces for potential biomedical applications.

The Role of Acid-sensing Ion Channel 3 in the Modulation of Tooth Mechanical Hyperalgesia Induced by Orthodontic Tooth Movement.

This study aimed to explore the role of acid-sensing ion channel 3 (ASIC3) in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement. In male Sprague-Dawley rats, closed coil springs were ligated between mandibular incisors and molars to mimic orthodontic tooth movement. Bite force was assessed to evaluate tooth mechanical hyperalgesia. The alveolar bone, trigeminal ganglia, and trigeminal nucleus caudalis underwent immunohistochemical staining and immunoblotting for ASIC3. The inferior alveolar nerves were transected to explore the interaction between the periodontal sensory endings and trigeminal ganglia. The role of ASIC3 in trigeminal ganglia was further explored with lentivirus-mediated ASIC3 ribonucleic acid interference. Results showed that ASIC3 was expressed in the periodontal Ruffini endings and expression of ASIC3 protein was elevated in periodontal tissues, trigeminal ganglia, and trigeminal nucleus caudalis, following orthodontic tooth movement. ASIC3 agonists and antagonists significantly aggravated and mitigated tooth mechanical hyperalgesia, respectively. ASIC3 expression decreased after inferior alveolar nerve transection in periodontal tissues. Both in vitro and vivo, the lentivirus vector carrying ASIC3 shRNA inhibited ASIC3 expression and relieved tooth mechanical hyperalgesia. To conclude, ASIC3 is important in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement. Further, the role of ASIC3 in the modulation of pain in periodontal tissues is regulated by trigeminal ganglia. An adjuvant analgesic therapy targeting ASIC3 could alleviate orthodontic movement-associated mechanical hyperalgesia in rats.

A New Concept of Enhancing Immuno-Chemotherapeutic Effects Against B16F10 Tumor via Systemic Administration by Taking Advantages of the Limitation of EPR Effect.

The enhanced permeability and retention (EPR) effect has been comfortably accepted, and extensively assumed as a keystone in the research on tumor-targeted drug delivery system. Due to the unsatisfied tumor-targeting efficiency of EPR effect being one conspicuous drawback, nanocarriers that merely relying on EPR effect are difficult to access the tumor tissue and consequently trigger efficient tumor therapy in clinic. In the present contribution, we break up the shackles of EPR effect on nanocarriers thanks to their universal distribution characteristic. We successfully design a paclitaxel (PTX) and alpha-galactosylceramide (αGC) co-loaded TH peptide (AGYLLGHINLHHLAHL(Aib)HHIL-Cys) -modified liposome (PTX/αGC-TH-Lip) and introduce a new concept of immuno-chemotherapy combination via accumulation of these liposomes at both spleen and tumor sites naturally and simultaneously. The PTX-initiated cytotoxicity attacks tumor cells at tumor sites, meanwhile, the αGC-triggered antitumor immune response emerges at spleen tissue. Different to the case that liposomes are loaded with sole drug, in this concept two therapeutic processes effectively reinforce each other, thereby elevating the tumor therapy efficiency significantly. The data demonstrates that the PTX/αGC-TH-Lip not only possess therapeutic effect against highly malignant B16F10 melanoma tumor, but also adjust the in vivo immune status and induce a more remarkable systemic antitumor immunity that could further suppress the growth of tumor at distant site. This work exhibits the capability of the PTX/αGC-TH-Lip in improving immune-chemotherapy against tumor after systemic administration.

Suppression for lung metastasis by depletion of collagen I and lysyl oxidase via losartan assisted with paclitaxel-loaded pH-sensitive liposomes in breast cancer.

Tumor metastasis would seriously impair the efficacy of chemotherapy. Our previous studies showed losartan combined with paclitaxel-loaded pH-sensitive cleavable liposomes (PTX-Cl-Lip) facilitated paclitaxel accumulation and led to enhanced antitumor efficacy in 4T1 bearing mice. Since losartan could inhibit the level of collagen I which was related to tumor metastasis, this strategy was further applied to suppress tumor metastasis this time. Our in vivo anti-metastatic study manifested losartan could lower the colonies occupied in lungs by 76.4% compared with that of saline group. When losartan and PTX-Cl-Lip were combined, anti-metastatic efficiency reached to 88.2%, which was the best among all the groups. In vitro 3D tumor spheroids studies proved losartan could significantly suppress the invasion of tumor cells. Losartan plus PTX-Cl-Lip could further weaken the metastasis of tumor cells. Mechanism study showed the declination of collagen I level via losartan was caused by inhibition of active transforming growth factor-ß1. Western-blot study showed losartan could decrease the level of lysyl oxidase, then inhibit the cross-linking of collagen I, finally weakened the cell signaling transmit via integrin and the metastasis of tumor cells was restrained. All above studies illustrated this combined tactic could achieve favorable effect on suppression of lung tumor metastasis.