Repurposing disulfiram with CuET nanocrystals: Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases.

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs. Recently, disulfiram (DSF), a drug primarily used for alcohol addiction treatment, has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis, a form of programmed cell death. The therapeutic activity of DSF can be further enhanced by the presence of Cu2+, although the underlying mechanism of this enhancement remains unclear. In this study, we investigated the mechanistic basis of Cu2+-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate (CuET) complex. CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action. However, despite its potent activity, CuET suffered from poor solubility and limited permeability, as revealed by our druggability studies. To overcome these intrinsic limitations, we developed a scalable method to prepare CuET nanocrystals (CuET NCs) using a metal coordination-driven self-assembly approach. Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability. Notably, CuET NCs exhibited high biodistribution in the intestine, suggesting their potential application for the treatment of inflammatory bowel diseases (IBDs). To evaluate their therapeutic efficacy in vivo, we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms. Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent, and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

Cholecystohepatic shunt pathway reduces secondary bile acid accumulation to enhance natural killer T cell-mediated anti-hepatocellular carcinoma immunity.

BACKGROUND AND AIM: The impact of cholecystectomy, which blocks the cholecystohepatic shunt pathway (CHSP), on the prognosis of patients with hepatocellular carcinoma (HCC) is unclear. Hepatic secondary bile acids (BAs) inhibit natural killer T (NKT) cell-mediated immunity against HCC, and the regulation of homeostasis of hepatic secondary BAs is controlled by the CHSP. However, the influence of CHSP on NKT cell-mediated immunity against HCC remains unclear. METHODS: The clinical data of hospitalized patients undergoing HCC resection were collected. Meanwhile, an in situ HCC mouse model was established, and the CHSP was augmented using oleanolic acid (OA). RESULTS: After 1:1 propensity score matching, Cox regression analysis revealed that cholecystectomy was an independent risk factor for HCC recurrence after hepatectomy (P = 0.027, hazard ratio: 1.599, 95% confidence interval: 1.055-2.422). Experimentally, when OA enhanced CHSP, a significant decrease was observed in the accumulation of secondary BAs in the livers of mice. Additionally, a significant increase was observed in the levels of C-X-C ligand 16 and interferon γ in the serum and tumor tissues. Further, the percentage of C-X-C receptor 6 (+) NKT cells in the tumor tissues increased significantly, and the growth of liver tumors was inhibited. CONCLUSIONS: This clinical study revealed that cholecystectomy promoted the recurrence after radical hepatectomy in patients with HCC. Preserving the normal-functioning gallbladder as much as possible during surgery may be beneficial to the patient's prognosis. Further investigation into the mechanism revealed that CHSP enhanced NKT cell-mediated immunity against HCC by reducing the hepatic accumulation of secondary BAs.

Protein nanogels with enhanced pH-responsive dynamics triggered by remote NIR for systemic protein delivery and programmable controlled release.

Therapeutic proteins represent promising treatments in medical applications; however, direct administration of native proteins frequently suffers from in vivo enzymatic degradation or denaturation in hostile environments. Engineering proteins into biocompatible formulations can be used to solve these problems. Despite years of effort, efficient systemic delivery followed by successful release from the formulation remains a challenge. Herein, we describe a pH-responsive nanogel (PI825@PDC/protein NGs) formed by host-guest recognition of 6-arm PEGylated crystalline ß-cyclodextrin (ß-CD) and near-infrared IR825 dye, which affords highly efficient encapsulation of proteins during their self-assembly. PI825@PDC/protein NGs are robust enough to withstand hostile physiological conditions both in vitro and in vivo and could be slightly disassociated from protein release in acidic environments due to the anchored pH-responsive 2,3-dimethylmaleic anhydride (DMA) linker. Furthermore, the pH-responsive dynamics can be greatly enhanced by elevated temperature upon remote (Near-infrared spectroscopy) NIR irradiation of the IR825 within NGs, generating programmable release of loaded proteins for enhanced cancer treatment. This study describes a general method to load proteins with high efficiency for systemic delivery, followed by programmable protein release by remote NIR irradiation and offers new insights for protein engineering and potential medical applications.

pH-Sensitive Biomaterials for Drug Delivery.

The development of precise and personalized medicine requires novel formulation strategies to deliver the therapeutic payloads to the pathological tissues, producing enhanced therapeutic outcome and reduced side effects. As many diseased tissues are feathered with acidic characteristics microenvironment, pH-sensitive biomaterials for drug delivery present great promise for the purpose, which could protect the therapeutic payloads from metabolism and degradation during in vivo circulation and exhibit responsive release of the therapeutics triggered by the acidic pathological tissues, especially for cancer treatment. In the past decades, many methodologies, such as acidic cleavage linkage, have been applied for fabrication of pH-responsive materials for both in vitro and in vivo applications. In this review, we will summarize some pH-sensitive drug delivery system for medical application, mainly focusing on the pH-sensitive linkage bonds and pH-sensitive biomaterials.

Clinical efficacy of laparoscopic modified loop cholecystojejunostomy for the treatment of malignant obstructive jaundice.

OBJECTIVE: This study was performed to summarize our experience and investigate the safety and efficacy of laparoscopic modified loop cholecystojejunostomy for the treatment of malignant obstructive jaundice. METHODS: Thirteen patients with malignant obstructive jaundice who underwent laparoscopic modified loop cholecystojejunostomy from March 2015 to March 2016 were retrospectively reviewed. The patients' characteristics, operation time, postoperative intestinal recovery time, length of hospital stay, postoperative bilirubin level, and complications were analyzed. RESULTS: The patients were followed up as outpatients for 2 years. Nine patients with pancreatic head carcinoma, one patient with periampullary carcinoma, and three patients with distal bile duct carcinoma successfully underwent laparoscopic modified loop cholecystojejunostomy. The mean operation time was 176 ± 45 minutes, and the mean length of hospital stay was 9.5 ± 2.8 days. The serum total bilirubin concentration and gamma-glutamyl transferase concentration significantly decreased on postoperative day 7. The median follow-up time was 7 months. No patients developed bile leakage or required a reoperation. CONCLUSIONS: Laparoscopic modified loop cholecystojejunostomy is not only safe and minimally invasive, but it is also feasible for patients with malignant obstructive jaundice.