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Chemodynamic therapy (CDT)-activated apoptosis is a potential anticancer strategy. However, CDT encounters a bottleneck in clinical translation due to its serious side effects and low efficacy. Here, we first reveal that surface engineering of ginsenoside Rg3 dramatically alters the organ distribution and tumor enrichment of systematically administered nanocatalysts using the orthotopic pancreatic tumor model while avoiding toxicity and increasing efficacy in vivo to address the key and universal toxicity problems encountered in nanomedicine. Compared with nanocatalysts alone, Rg3-sheltered dynamic nanocatalysts form hydrophilic nanoclusters, prolonging their circulation lifespan in the blood, protecting the internal nanocatalysts from leakage while allowing their specific release at the tumor site. Moreover, the nanoclusters provide a drug-loading platform for Rg3 so that more Rg3 reaches the tumor site to achieve obvious synergistic effect with nanocatalysts. Rg3-sheltered dynamic nanocatalysts can simultaneously activate ferroptosis and apoptosis to significantly improve anticancer efficacy. Systematic administration of ginsenoside Rg3-sheltered nanocatalysts inhibited 86.6% of tumor growth without toxicity and prolonged the survival time of mice. This study provides a promising approach of nanomedicine with high biosafety and a new outlook for catalytic ferroptosis-apoptosis combined antitumor therapies. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) has limited clinical efficacy in cancer. In this study, we developed Rg3-sheltered dynamic nanocatalysts, which could simultaneously activate ferroptosis based on CDT-activated apoptosis, and ultimately form a combined therapy of ferroptosis-apoptosis to kill tumors. Studies have shown that the nanocatalysts after Rg3 surface engineering dramatically alters the pharmacokinetics and organ distribution of the nanocatalysts after being systematically administered, resulting in avoiding the toxicity of the nanocatalysts. Nanocatalysts also act as a drug-loading platform, guiding more Rg3 into the tumor site. This study emphasizes that nanocatalysts after Rg3 surface engineering improve the safety and effectiveness of ferroptosis-apoptosis combined therapy, providing an effective idea for clinical practices.

Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well‐established to have antitumour and anti‐fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF‐LA@DSPE‐PEG and MMF‐LA@PEG‐PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG5k‐PLA8k and DSPE‐ PEG2k, respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti‐HCC efficacy of nanoparticles (NPs), whereas NIH‐3T3 fibroblasts and highly‐fibrotic HCC models were used to explore the anti‐fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF‐LA@DSPE‐PEG achieved significantly higher anti‐HCC efficacy than free MMF and MMF‐LA@PEG‐PLA both in C57BL/6 HCC model and highly‐fibrotic HCC models. Immunohistochemistry further confirmed that MMF‐LA@DSPE‐PEG dramatically reduced cancer‐associated fibroblast (CAF) density in tumours, as the expression levels of alpha‐smooth muscle actin (α‐SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF‐LA@DSPE‐PEG might act as a rational therapeutic strategy in treating HCC and preventing post‐transplant HCC recurrence.

Nanosecond pulsed electric field (nsPEF) has emerged as a promising tool for hepatocellular carcinoma ablation recently. However, little is known about how nsPEF affects liver regeneration while being applied to eliminate liver lesions. Besides, the impact of nsPEF ablation on liver function should also be taken into consideration in the process. In this paper, we study the impact of nsPEF ablation on liver function by the measurement of serum levels of AST and ALT as well as liver regeneration and relevant molecular mechanisms in vivo. We found that mouse liver function exhibited a temporary injury without weight loss after ablation. In addition, local hepatic nsPEF ablation promoted significant proliferation of hepatocytes of the whole liver with an increase in HGF level. Moreover, the proliferation of hepatocytes was dramatically inhibited by the inhibitor of c-Met. Of interest, the periablational area is characterized by high level of PDGF and a large amount of activated hepatic stellate cells. Furthermore, neutralizing PDGF was able to significantly inhibit liver regeneration, the increased HGF level, and the accumulation of activated HSCs. Our findings demonstrated that nsPEF not only was a safe ablation approach but also could stimulate the regeneration of the whole liver through the activation of the HGF/c-Met pathway by upregulation of PDGF within the periablational zone.

The coupling of nanozymes with ginsenoside Rg3 to form a nanodrug completely compensates for their respective defects and results in obvious anticancer synergistic effects, which provides a clear direction for the subsequent clinical application.

Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.

Objective To establish a nude mouse model of photoaging and study the therapeutic effect of a concentrated growth factor preparation (CGF) on skin photoaging. Methods CGF was prepared from blood from Sprague–Dawley rats. A skin photoaging nude mouse model was developed using UV irradiation combined with the photosensitizer, 8-methoxypsoralen. Mice were divided randomly into seven groups (n = 6 per group): normal control, photoaging, mock treatment, saline treatment, CGF treatment, Filoca 135HA treatment, and plasma skin regeneration system irradiation (the latter two were positive controls). Body weight and skin appearance were observed and pathological changes were determined by hematoxylin and eosin staining. Fiber elasticity was evaluated by Weigert staining. Expression levels of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase 1 (MMP1) were determined by immunohistochemistry. Results A mouse model with typical features of photoaging skin was successfully developed. CGF significantly improved the skin appearance, wrinkle scores, pathological changes, and fiber elasticity, and increased PCNA and decreased MMP1 expression levels in photoaging mice, comparable to the two positive controls. Conclusion CGF can improve the symptoms of skin photoaging in mice, suggesting that it may have applications in the treatment of skin aging in humans.

As a promising method for local tumor treatment, nanosecond pulsed electric field (nsPEF) ablation elicits a potent anti-tumor immune response. However, the mechanism of the nsPEF-mediated anti-tumor immune response and its effects on the tumor microenvironment remains unclear. Here, we demonstrated that nsPEF treatment increased the level of membrane PD-L1 in liver cancer cells. Furthermore, nsPEF induced the release of PD-L1-associated extra-cellular vesicles, leading to the dysfunction of CD8

Background: Intrahepatic cholangiocarcinoma (ICC) is a high malignant tumor arising from the bile ducts in the liver with a poor prognosis. As current molecular targeted therapies and systemic chemotherapies had limited success in ICC, novel therapeutic targets are needed. In this study, we attempted to investigate the expression and the role of the intermediate conductance calcium-activated potassium channel (KCa3.1) in ICC. Methods: The expression levels of KCa3.1 channel were measured in 81 resected ICC tumor specimens and the clinicopathological significance of these levels were determined. KCa3.1 channel inhibitor and siRNA were used to study the role of KCa3.1 in proliferation, migration, and invasion of ICC cell lines. The effect of KCa3.1 channel blockade on tumor growth in vivo was also studied using xenograft model in nude mice. Results: The protein expression of KCa3.1 channel was upregulated in ICC tissues and was correlated with age, lymph node metastasis and TNM stage. And high KCa3.1 expression indicated a worse prognosis in ICC patients. Blocking KCa3.1 channel with a specific inhibitor TRAM-34 reduced the proliferation and invasion of ICC cells. Knockdown of KCa3.1 could achieve the same effects through decreasing NF-κB activation. Further in vivo studies demonstrated that KCa3.1 channel blockade suppressed ICC tumor growth. Conclusions: Our observations suggested KCa3.1 might be a promising novel therapeutic target in intrahepatic cholangiocarcinoma.

Aim How irreversible electroporation (IRE) affect immune status is still kept unknown. This preclinical study is to investigate its local and systemic immune reaction both on tumor-bearing and tumor free animals. Methods Liver ablation was performed by a standard IRE instrument and proposal. Altogether 57 tumor bearing mice and 10 tumor-free porcine livers were ablated. The reaction of survival, radiology image, pathologically and immunologically were followed up. The detailed cytokines and chemokines responses were recorded dynamically post IRE ablation. Results IRE ablation induced coagulation and necrosis in liver. It caused macrophages infiltration, in ablation zone. IRE ablation caused cellular inflammation. It, corrected the abnormal drifted Th2 in HCC back to Th1 status, promoting tumor eradication and host survival. The quantified cytokines and chemokines indicate IRE can stimulate both local immune reaction and systemic immune reaction. Conclusion Local IRE ablation changes the abnormal drifted Th2 in HCC back to Th1 status, facilitating tumor eradication and host survival.

BACKGROUND Predicting the development of early allograft dysfunction (EAD) following liver transplantation (LT) remains challenging for transplant clinicians. The objectives of this study are to investigate the potential relationship between the protein profiles of pretransplant grafts and the onset of EAD, and then combine with clinical parameters to construct a mathematically predictive model. METHODS Clinical data of 121 LT procedures from donation after circulatory death at the authors' center were analyzed. The expression levels of 7 studied proteins were determined by immunohistochemistry. Another independent cohort of 37 subjects was designed for further validation of the predictive model. RESULTS With an incidence of 43.0% (52/121), EAD was linked to significantly increased risk of acute kidney injury and renal replacement therapy, as well as reduced 6-month patient and liver graft survival. Allograft weight and high intrahepatic vascular endothelial growth factor (VEGF) expression were identified as independent risk factors of EAD and survival outcomes. Liver grafts with high VEGF expression exhibited delayed functional recovery within the first postoperative week. The combination of VEGF overexpression and EAD yielded the highest frequency of renal dysfunction and the worst survival. Based on allograft weight and intrahepatic VEGF expression, an EAD risk assessment model was developed. The incidence of EAD differed significantly between grafts with risk scores ≥-1.72 and

Background Biliary tract obstruction is a common clinical problem. In this study, we attempted to understand the change in intestinal glucose absorption after biliary tract obstruction. Methods Experimental models of murine biliary duct ligation and external biliary drainage were established. Murine intestinal mucosal glucose absorption was examined with Ussing chambers according to the increase in the short-circuit current in vitro and blood glucose measurement after oral glucose in vivo. The protein expression of the sodium-glucose cotransporter (SGLT1) and the facilitated glucose transporter, member 2 (GLUT2) was analyzed by Western blot and immunohistochemistry. Results The results from Ussing chamber experiments showed that duodenal mucosal glucose absorption levels were significantly higher in biliary duct ligation and biliary drainage mice than those in normal control mice at 1 and 2 weeks after the operation. Gastrointestinal bile acid administration almost reversed the elevated duodenal mucosal glucose absorption to the normal level in biliary drainage mice. The results from the experiments in vivo further confirmed that the glucose absorption increased in biliary duct ligation and biliary drainage mice. The protein expression levels of SGLT1 in the duodenal mucosae of both biliary duct ligation and biliary drainage mice were markedly higher than those in control mice, and the protein expression of GLUT2 was not significantly altered, compared with control mice. Conclusion Bile deficiency in the intestine upregulates the expression of intestinal mucosal SGLT1 and enhances intestinal mucosal glucose absorption capacity, which contributes to the understanding of intestinal physiologic function for patients with biliary duct obstruction and external biliary drainage.