Explore the vast range of titles available.

Currently, molecular docking is becoming a key tool in drug discovery and molecular modeling applications. The reliability of molecular docking depends on the accuracy of the adopted scoring function, which can guide and determine the ligand poses when thousands of possible poses of ligand are generated. The scoring function can be used to determine the binding mode and site of a ligand, predict binding affinity and identify the potential drug leads for a given protein target. Despite intensive research over the years, accurate and rapid prediction of protein–ligand interactions is still a challenge in molecular docking. For this reason, this study reviews four basic types of scoring functions, physics-based, empirical, knowledge-based, and machine learning-based scoring functions, based on an up-to-date classification scheme. We not only discuss the foundations of the four types scoring functions, suitable application areas and shortcomings, but also discuss challenges and potential future study directions.

Mitochondrial dysfunction is a major and common mechanism in developing non-alcoholic fatty liver disease (NAFLD). Replacement of dysfunctional mitochondria by functional exogenous mitochondria may attenuate intrahepatic excessive lipid and recover hepatocyte function. However, no data shows that mitochondria can be systemically administrated to animals to date. Here we suggest that mitochondria isolated from hepatoma cells are used as a mitotherapy agent to treat mouse fatty liver induced by high-fat diets. When the mitochondria were intravenously injected into the mice, serum aminotransferase activity and cholesterol level decreased in a dose-dependent manner. Also, the mitotherapy reduced lipid accumulation and oxidation injury of the fatty liver mice, improved energy production, and consequently restored hepatocyte function. The mitotherapy strategy offers a new potential therapeutic approach for treating NAFLD.

Glioma is the most aggressive and lethal brain tumor in humans, it comprises about 30 per cent of all brain tumors and central nervous system tumors. The objective of this study was to create novel brain-targeting nanoliposomes to encapsulate curcumin as a promising option for glioma therapy. Human glioma cells (U251MG) were used to determine cell uptake efficiency and possible internalization mechanism of the curcumin-loaded nanoliposomes modified by a brain-targeting peptide RDP. In addition, intracranial glioma mice model was prepared by transplantation of U251MG cells into the mice striatum, and then the liposomes were intravenously administered into the glioma-bearing mice to evaluate the anti-glioma activity. RDP-modified liposomes (RCL) could enter the brain and glioma region, and were internalized by the glioma cells perhaps through acetylcholine receptor-mediated endocytosis pathway. Furthermore, the RCL prolonged the survival time of the glioma-bearing mice from 23 to 33 days, and the inhibition mechanism of the RCL on glioma cell was partly due to cell cycle arrest at the S phase and induction of cell apoptosis. This study would provide a potential approach for targeted delivery of drug-loaded liposomes for glioma treatment.

In the original publication [...]

In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPR mt ), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPR mt , various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPR mt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPR mt pathways and its crucial role in targeted therapy of metastasis tumors.

Carbon tetrachloride (CCl4)‐induced liver injury is predominantly caused by free radicals, in which mitochondrial function of hepatocytes is impaired, accompanying with the production of ROS and decreased ATP energy supply in animals intoxicated with CCl4. Here we explored a novel therapeutic approach, mitochondrial transplantation therapy, for treating the liver injury. The results showed that mitochondria entered hepatocytes through macropinocytosis pathway, and thereby cell viability was recovered in a concentration‐dependent manner. Mitochondrial therapy could increase ATP supply and reduce free radical damage. In liver injury model of mice, mitochondrial therapy significantly improved liver function and prevented tissue fibrogenesis. Transcriptomic data revealed that mitochondrial unfold protein response (UPRmt), a protective transcriptional response of mitochondria‐to‐nuclear retrograde signaling, would be triggered after mitochondrial administration. Then the anti‐oxidant genes were up‐regulated to scavenge free radicals. The mitochondrial function was rehabilitated through the transcriptional activation of respiratory chain enzyme and mitophage‐associated genes. The protective response re‐balanced the cellular homeostasis, and eventually enhanced stress resistance that is linked to cell survival. The efficacy of mitochondrial transplantation therapy in the animals would suggest a novel approach for treating liver injury caused by toxins.

Glioma is the most aggressive and lethal brain tumor in humans. Mutations of mitochondrial DNA (mtDNA) are commonly found in tumor cells and are closely associated with tumorigenesis and progress. However, glioma-specific inhibitors that reflect the unique feature of tumor cells are rare. Here we uncover RC-7, a ruthenium complex with strong red fluorescence, could bind with glioma mtDNA and then inhibited the growth of human glioma cells but not that of neuronal cells, liver, or endothelial cells. RC-7 significantly reduced energy production and increased the oxidative stress in the glioma cells. Administration of RC-7 into mice not only could be observed in the glioma mass of brain by fluorescence imaging, but also obviously prevented the growth of xenograft glioma and prolonged mouse survival days. The findings suggested the theranostic application of a novel type of complex through targeting the tumor mtDNA.

Non-alcoholic liver injury (NLI) is a common disease worldwide. Since free radical damage in the liver is a crucial initiator leading to diseases, scavenging excess free radicals has become an essential therapeutic strategy. To enhance the antioxidant capacity of histidine, we synthesized a protonated dimeric histidine, H-bihistidine, and investigated its anti-free radical potential in several free-radical-induced NLI. Results showed that H-bihistidine could strongly scavenge free radicals caused by H2O2, fatty acid, and CCl4, respectively, and recover cell viability in cultured hepatocytes. In the animal model of nonalcoholic fatty liver injury caused by high-fat diet, H-bihistidine reduced the contents of transaminases and lipids in serum, eliminated the liver’s fat accumulation, and decreased the oxidative damage. Moreover, H-bihistidine could rescue CCl4-induced liver injury and recover energy supply through scavenging free radicals. Moreover, liver fibrosis prepared by high-fat diet and CCl4 administration was significantly alleviated after H-bihistidine treatment. This study suggests a novel nonenzymatic free radical scavenger against NLI and, potentially, other free-radical-induced diseases.

Much effort has been devoted to the discovery of effective biomaterials for nerve regeneration. Here, we reported a novel application of gold nanoparticles (AuNPs) modified with 6-mercaptopurine (6MP) and a neuron-penetrating peptide (RDP) as a neurophic agent to promote proliferation and neurite growth of human neuroblastoma (SH-SY5Y) cells. When the cells were treated with 6MP-AuNPs-RDP conjugates, they showed higher metabolic activity than the control. Moreover, SH-SY5Y cells were transplanted onto the surface coated with 6MP-AuNPs-RDP to examine the effect of neurite development. It can be concluded that 6MP-AuNPs-RDP attached to the cell surface and then internalized into cells, leading to a significant increase of neurite growth. Even though 6MP-AuNPs-RDP-treated cells were recovered from frozen storage, the cells still maintained constant growth, indicating that the cells have excellent tolerance to 6MP-AuNPs-RDP. The results suggested that the 6MP-AuNPs-RDP had promising potential to be developed as a neurophic nanomaterial for neuronal growth.

To date, Alzheimer’s disease (AD) has grown to be a predominant health challenge that disturbs the elderly population. Studies have shown that mitochondrial dysfunction is one of the most significant features of AD. Transplantation therapy of healthy mitochondria (mitotherapy), as a novel therapeutic strategy to restore mitochondrial function, is proposed to treat the mitochondria−associated disease. Also, the molecular mechanism of mitotherapy remains unclear. Here, we applied the mitotherapy in AD model mice induced by amyloid−β (Aβ) plaque deposition and suggested that autophagy would be an important mechanism of the mitotherapy. After the healthy mitochondria entered the defective neuronal cells damaged by the misfolded Aβ protein, autophagy was activated through the NAD+−dependent deacetylase sirtuin 1 (SIRT1) signal. The damaged mitochondria and Aβ protein were eliminated by autophagy, which could also decrease the content of radical oxygen species (ROS). Moreover, the levels of brain−derived neurotrophic factor (BDNF) and extracellular−regulated protein kinases (ERK) phosphorylation increased after mitotherapy, which would be beneficial to repair neuronal function. As a result, the cognitive ability of AD animals was ameliorated in a water maze test after the healthy mitochondria were administrated to the mice. The study indicated that mitotherapy would be an effective approach to AD treatment through the mechanism of autophagy activation.