Guang Ji

Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

Abstract Multidrug resistance is a major challenge to cancer chemotherapy. The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD + to reduce the amount of ATP available for the efflux pumps. The treatment with LSC nanoparticles and NIR laser irradiation also reduces the expression and increases the intracellular distribution of the efflux pumps. Consequently, multidrug-resistant cancer cells lose their multidrug resistance capability for at least 5 days, creating a therapeutic window for chemotherapy. Our in vivo data show that the drug-laden LSC nanoparticles in combination with NIR laser treatment can effectively inhibit the growth of multidrug-resistant tumors with no evident systemic toxicity.

Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.

Chemokines are a large family mediating a lot of biological behaviors including chemotaxis, tumor growth, angiogenesis and so on. As one member of this family, CXC subfamily possesses the same ability. CXC chemokines can recruit and migrate different categories of immune cells, regulate tumor's pathological behaviors like proliferation, invasion and metastasis, activate angiogenesis, etc. Due to these characteristics, CXCL subfamily is extensively and closely associated with tumors and inflammatory diseases. As studies are becoming more and more intensive, CXCLs' concrete roles are better described, and CXCLs' therapeutic applications including biomarkers and targets are also deeply explained. In this review, the role of CXCL family members in various diseases is summarized.

Kaempferol, also known as kaempferol-3 or kaempferide, is a flavonoid compound that naturally occurs in tea, as well as numerous common vegetables and fruits, including beans, broccoli, cabbage, gooseberries, grapes, kale, strawberries, tomatoes, citrus fruits, brussel sprouts, apples and grapefruit. The present review mainly summarizes the application of kaempferol in treating diseases and the underlying mechanisms that are currently being studied. Due to its anti-inflammatory properties, it may be used to treat numerous acute and chronic inflammation-induced diseases, including intervertebral disc degeneration and colitis, as well as post-menopausal bone loss and acute lung injury. In addition, it has beneficial effects against cancer, liver injury, obesity and diabetes, inhibits vascular endothelial inflammation, protects the cranial nerve and heart function, and may be used for treating fibroproliferative disorders, including hypertrophic scar.