Targeted Theranostic of Cryptococcal Encephalitis by a Novel Polypyridyl Ruthenium Complex.

Cryptococcus neoformans (C. neoformans) is one of the most well-known zoonotic fungal pathogens. Cryptococcal encephalitis remains a major cause of morbidity and mortality in immunocompromised hosts. Effective and targeting killing of C. neoformans in the brain is an essential approach to prevent and treat cryptococcal encephalitis. In this study, a fluorescent polypyridyl ruthenium complex RC-7, {[phen2Ru(bpy-dinonyl)](PF6)2 (phen = 1,10-phenanthroline, bpy-dinonyl = 4,4'-dinonyl-2,2'-bipyridine)}, was screened out, which showed a highly fungicidal effect on C. neoformans. The values of minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) in antifungal activities were significantly lower than fluconazole as the control. Moreover, RC-7 was prepared as a brain-targeting nanoliposome (RDP-liposome; RDP is a peptide derived from rabies virus glycoprotein) for in vivo application. The results revealed that the liposomes could accumulate in the encephalitis brain and play an antifungal role. Compared with the cryptococcal encephalitis model mice, the RDP-liposomes remarkably prolonged the survival days of the encephalitis-bearing mice from 10 days to 24 days. Here, we introduce a polypyridyl ruthenium complex that could be used as a novel antifungal agent, and this study may have a broad impact on the development of targeted delivery based on ruthenium complex-loaded liposomes for theranostics of cryptococcal encephalitis.

Discovery of a Ruthenium Complex for the Theranosis of Glioma through Targeting the Mitochondrial DNA with Bioinformatic Methods.

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.

A pH-Sensitive Nanocarrier for Tumor Targeting : Delivery of Ruthenium Complex for Tumor Theranostic by pH-Sensitive Nanocapsule.

PURPOSE: Ruthenium complex is a potentially theranostic agent for cancer imaging and therapy, however its application is limited due to poor water-solubility and lack of tumor selectivity. To overcome the above drawbacks, pH-sensitive nanocapsule as a novel targeting carrier was designed to deliver ruthenium complex for treating xenograft tumor of mice. METHODS: The core/shell structured nanocapsule with ruthenium complex tris(1,10-phenanthroline) ruthenium(II) complex (3P-Ru) as the core and a pH-sensitive polymeric material poly (2-diisopropylaminoethyl methacrylate)-block poly(2-aminoethyl methacrylate hydrochloride) (PbPS) as the shell was synthesized and characterized. Meanwhile, the nanocapsule was used to investigate cell viability and evaluate tissue distribution as well as preventing tumor growth efficacy in U251 stem cells tumor-bearing mouse model. RESULTS: The nanocapsule had a size of 103.1 ± 11.3 nm, zeta potential of -40 ± 5.3 mV, EE of 76.7 ± 0.9%, LE of 25.4 ± 0.6% and it could control drug release under different pH conditions. The results of cell uptake showed that the fluorescent 3P-Ru loaded in the nanocapsule could be delivered into cells with high efficiency, and then significantly inhibited U251 proliferation in a concentration-dependent manner. After U251 stem cells were transplanted subcutaneously into mice, the 3P-Ru/PbPS nanocapsule (PbPS-Ru-NC) via intravenous administration could concentrate in tumor area and obviously prevent tumor growth. CONCLUSIONS: The pH-sensitive nanocapsule as a antitumor agent carrier was able to effectively deliver 3P-Ru into gliomas cells, and cell growth was significantly inhibited both in vitro and in vivo. Such pH-sensitive nanocapsule for ruthenium complex delivery would have great potential application in tumor theranostics.

Promises and pitfalls of intracellular delivery of proteins.

The direct delivery of functional proteins into the cell cytosol is a key issue for protein therapy, with many current strategies resulting in endosomal entrapment. Protein delivery to the cytosol is challenging due to the high molecular weight and the polarity of therapeutic proteins. Here we review strategies for the delivery of proteins into cells, including cell-penetrating peptides, virus-like particles, supercharged proteins, nanocarriers, polymers, and nanoparticle-stabilized nanocapsules. The advantages and disadvantages of these approaches including cytosolar delivery are compared and contrasted, with promising pathways forward identified.

Alleviating binary toxicity of polystyrene nanoplastics and atrazine to Chlorella vulgaris through humic acid interaction: Long-term toxicity using environmentally relevant concentrations.

In this study, microalgae Chlorella vulgaris (C. vulgaris) were simultaneously exposed to environmental concentrations of amino-functionalized polystyrene nanoplastics (PS-NH2; 0.05, 0.1, 0.2, 0.3 and 0.4 mg/L) and the world's second most used pesticide, the herbicide atrazine (ATZ; 10 µg/L), in the absence and presence of humic acid (HA; 1 mg/L) for 21 days. Due to the low concentrations of PS-NH2, the majority of them could not cause a significant difference in the end-points of biomass, chlorophylls a and b, total antioxidant, total protein, and superoxide dismutase and malondialdehyde compared to the control group (p > 0.05). On the other hand, by adding ATZ to the PS-NH2, all the mentioned end-point values showed a considerable difference from the control (p < 0.05). The exposure of PS-NH2+ATZ treatments to the HA could remarkably reduce their toxicity, additionally, HA was able to decrease the changes in the expression of genes related to oxidative stress (e.g., superoxide dismutase, glutathione reductase, and catalase) in the C. vulgaris in the most toxic treatment group (e.g., PS-NH2+ATZ). The synergistic toxicity of the PS-NH2+ATZ group could be due to their enhanced bioavailability for algal cells. Nevertheless, the toxicity alleviation in the PS-NH2+ATZ treatment group after the addition of HA could be due to the eco-corona formation, and changes in their zeta potential from positive to negative value, which would increase their electrostatic repulsion with the C. vulgaris cells, in such a way that HA also caused a decrease in the formation of C. vulgaris-NPs hetero-aggregates. This research underscores the complex interplay between PS-NH2, ATZ, and HA in aquatic environments and their collective impact on microalgal communities.

Presence of humic acid in the environment holds promise as a potential mitigating factor for the joint toxicity of polystyrene nanoplastics and herbicide atrazine to Chlorella vulgaris: 96-H acute toxicity.

Increasing amounts of amino-functionalized polystyrene nanoplastics (PS-NH2) are entering aquatic ecosystems, raising concerns. Hence, this study investigated 96-h acute toxicity of PS-NH2 and its combination with the pesticide atrazine (ATZ) in the absence/presence of humic acid (HA) on the microalgae Chlorella vulgaris (C. vulgaris). Results showed that both PS-NH2 and PS-NH2+ATZ reduced algal growth, photosynthetic pigments, protein content, and antioxidant capacity, while increasing enzymatic activities. Gene expression related to oxidative stress was altered in C. vulgaris exposed to these treatments. Morphological and intracellular changes were also observed. The combined toxicity of PS-NH2+ATZ demonstrated a synergistic effect, but the addition of environmentally relevant concentration of HA significantly alleviated its toxicity to C. vulgaris, indicating an antagonistic effect due to the emergence of an eco-corona, and entrapment and sedimentation of PS-NH2+ATZ particles by HA. This study firstly highlights the role of HA in mitigating the toxicity of PS-NH2 when combined with other harmful compounds, enhancing our understanding of HA's presence in the environment.

Cellular uptake mechanism and therapeutic utility of a novel peptide in targeted-delivery of proteins into neuronal cells.

PURPOSE: The peptide-based delivery system constitutes a potent approach to overcome the limitations of drug delivery in vitro and in vivo. We recently proposed a novel peptide RDP, which enables brain-targeting delivery of proteins into neuronal cells. Here we investigate the possible internalization mechanism of RDP, and identify the therapeutic effects of functional proteins when linked with RDP in brain disease. METHODS: The RDP fusion proteins are produced through recombinant DNA technology, and cell culture is used to investigate the uptake mechanism of RDP and its fusion protein. Experimental Parkinson's disease (PD) model is prepared in mice by intra-striatal injection of 6-hydroxydopamine, and is tested by apomorphine- and amphetamine-induced rotation. RESULTS: The results suggest that the possible route for RDP cellular uptake might involve GABA receptor-dependent, clathrin-mediated endocytosis pathway. Additionally, the conjugate of RDP and glial cell-derived neurotrophic factor (GDNF) exhibits the neuroprotective effect in experimental PD animals, including reduction of apomorphine- and amphetamine-induced rotation following toxin administration. CONCLUSIONS: RDP may become an effective tool for the targeted delivery of proteins into brain for disease treatment.

Discovery of the Effects of the Hemiprotonic Phenanthroline-Phenanthroline+ against Trichophyton rubrum by Inducing Fungal Apoptosis.

Trichophyton rubrum (T. rubrum) is the most common causative agent of dermatophytosis worldwide. The development of antifungal drugs will contribute to treating the disease. In this study, we suggest that a hemiprotonic compound phenanthroline-phenanthroline+ (ph-ph+) is active in inhibiting the growth and reproduction of T. rubrum, and the minimum inhibitory concentration and minimum fungicidal concentration values were 2 µg/ml and 8 µg/ml, respectively. In an in vitro onychomycosis model, ph-ph+ killed T. rubrum by inducing apoptosis, which was evaluated by transmission electron microscopy and Annexin V-FITC/propidium iodide staining. Transcriptomic analysis and biochemical assay showed that ph-ph+ elevated iron ion content in T. rubrum cells and reduced glutathione antioxidant system level, leading to an increase in the contents of ROS and malondialdehyde. Therefore, the antifungal mechanism of ph-ph+ would be associated with iron ion-induced cell apoptosis, which is different from other known antifungal drugs. Furthermore, ph-ph+ was prepared into gel for application in guinea pigs with dermatophytosis caused by T. rubrum. The results showed that the ph-ph+ gel eliminated the fungus in the animals without causing skin irritation or other adverse reactions. The study would not only provide a potential compound to treat dermatophytosis, but also suggest that iron ion-induced cell apoptosis might be a new approach to killing fungi.

Improvement Effect of Mitotherapy on the Cognitive Ability of Alzheimer's Disease through NAD+/SIRT1-Mediated Autophagy.

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-ß (Aß) 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 Aß protein, autophagy was activated through the NAD+-dependent deacetylase sirtuin 1 (SIRT1) signal. The damaged mitochondria and Aß 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.

Treatment of colorectal cancer by anticancer and antibacterial effects of hemiprotonic phenanthroline-phenanthroline+ with nanomicelle delivery.

Colorectal cancer (CRC) is a common digestive tract tumor worldwide. Specific microorganisms, including Fusobacterium nucleatum (F. nucleatum) and Escherichia coli (E. coli), are abundant in colonic mucosa and can promote the cancer progression and malignancy. Therefore, a therapeutic strategy is proposed to deliver effective drugs to colorectum for both anticancer and antibacteria. Here we used thin-film dispersion method to encapsulate hemiprotonic phenanthroline-phenanthroline+ (ph-ph+) into nanomicelle. The results showed that the drug-loading nanomicelle had good dispersion, and the particle size was about 28 nm. In vitro assay indicated that the nanomicelle was active against CRC-related obligate and facultative anaerobes. In human CRC cells, the nanomicelle could effectively inhibit cell proliferation and induce apoptosis. In vivo distribution showed that the nanomicelle could release ph-ph+ mainly in the colorectum. In CRC model mice, the nanomicelle significantly reduced tumor number and volume, and decreased the bacteria load and colorectal inflammation. Together, the study identifies that the ph-ph+nanomicelle has the potential to apply in treating CRC, and also suggests that anticancer combined with antimicrobial therapy would be a feasible way for CRC therapy.

Targeted delivery of proteins into the central nervous system mediated by rabies virus glycoprotein-derived peptide.

PURPOSE: Delivery of therapeutic proteins across the blood-brain barrier (BBB) is severely limited by their size and biochemical properties. Here we showed that a 39-amino acid peptide derived from the rabies virus glycoprotein (RDP) was exploited as an efficient protein carrier for brain-targeting delivery. METHODS: Three proteins with different molecular weight and pI, ß-galactosidase (ß-Gal), luciferase (Luc) and brain-derived neurotrophic factor (BDNF), were fused to RDP and intravenously injected into the mice respectively. The slices of different tissues with X-Gal staining were used to examine whether RDP could deliver ß-Gal targeted into the CNS. The time-course relationship of RDP-Luc was studied to confirm the transport efficiency of RDP. The neuroprotective function of RDP-BDNF was examined in mouse experimental stroke to explore the pharmacological effect of RDP fusion protein. RESULTS: The results showed that the fusion proteins rapidly and specific entered the nerve cells in 15 min, and the t(1/2) was about 1 hr. Furthermore, RDP-BDNF fusion protein showed the neuroprotective properties in mouse experimental stroke including reduction of stroke volume and neural deficit. CONCLUSIONS: RDP provides an effective approach for the targeted delivery of biological active proteins into the central nervous system.

[Zebrafish as a model animal for the study of blood-brain barrier permeability by biomolecules].

Blood-brain barrier (BBB) is the major obstacle for drug delivery into the central nervous system (CNS). However, there is no ideal model animal for the study of BBB permeability till now. Currently zebrafish (Danio rerio) has emerged as a powerful model organism for the study of vertebrate biology. In this study, the feasibility of using zebrafish as model animal was investigated for BBB permeability by comparing the results of administration of BBB-penetrating peptide and protein to mouse and zebrafish. The results showed that the BBBs of mouse and zebrafish were similar in molecular permeability. Additionally, zebrafish has advantageous features as a model animal, such as small size, fertile and easy to breed. Therefore, it is suggested that zebrafish may be a favored model for the study of BBB permeability.

Association of psychological symptoms with job burnout and occupational stress among coal miners in Xinjiang, China: A cross-sectional study.

Objective: The study aimed to investigate the influencing factors of psychological symptoms in relation to job burnout and occupational stress among coal miners in Xinjiang, so as to provide data support for enterprises in an effort to help them identify internal psychological risk factors and improve the mental health of coal miners. Methods: A cross-sectional study was carried out. A total of 12 coal mines were selected using the stratified cluster random sampling method and 4,109 coal miners were investigated by means of online electronic questionnaires. The Symptoms Check List-90 (SCL-90), Chinese Maslach Burnout Inventory (CMBI), and Job Demand-Control (JDC) model were respectively used to measure the status of psychological symptoms, job burnout, and occupational stress among coal miners. The mediation analysis was performed through structural equation modeling (SEM) by using Analysis of Moment Structure (AMOS). Results: The prevalence of psychological symptoms was higher in the occupational stress group than in the non-occupational stress group, and increased with job burnout (P < 0.05). The multivariate logistic regression analysis results showed that mild (OR = 1.401, 95% CL: 1.165, 1.685), moderate (OR = 2.190, 95% CL: 1.795, 2.672), or severe levels of burnout (OR = 6.102, 95% CL: 3.481, 10.694) and occupational stress (OR = 1.462, 95% CL: 1.272, 1.679) were risk factors for psychological symptoms in coal miners. The results of structural equation modeling indicated that occupational stress (ß = 0.11, P = 0.002) and job burnout (ß = 0.46, P = 0.002) had significant positive direct effects on psychological symptoms, and job burnout was an intermediate variable between occupational stress and psychological symptoms. Conclusion: High levels of job burnout and occupational stress were risk factors for psychological symptoms. Both occupational stress and job burnout had direct effects on psychological symptoms, and occupational stress could also have an indirect effect on coal miners' psychological symptoms through the intermediate variable of job burnout.

Mitochondrial transplantation therapy inhibits the proliferation of malignant hepatocellular carcinoma and its mechanism.

Mitochondrial dysfunction plays a vital role in growth and malignancy of tumors. In recent scenarios, mitochondrial transplantation therapy is considered as an effective method to remodel mitochondrial function in mitochondria-related diseases. However, the mechanism by which mitochondrial transplantation blocks tumor cell proliferation is still not determined. In addition, mitochondria are maternal inheritance in evolution, and mitochondria obtained from genders exhibit differences in mitochondrial activity. Therefore, the study indicates the inhibitory effect of mitochondria from different genders on hepatocellular carcinoma and explores the molecular mechanism. The results reveal that the healthy mitochondria can retard the proliferation of the hepatocellular carcinoma cells in vitro and in vivo through arresting cell cycle and inducing apoptosis. The molecular mechanism suggests that mitochondrial transplantation therapy can decrease aerobic glycolysis, and down-regulate the expression of cycle-related proteins while up-regulate apoptosis-related proteins in tumor cells. In addition, the antitumor activity of mitochondria from female mice (F-Mito) is relatively higher than that of mitochondria from male mice (M-Mito), which would be related to the evidence that the F-Mito process higher activity than the M-Mito. This study clarifies the mechanism of exogenous mitochondria inhibiting the proliferation of hepatocellular carcinoma and contributes a new biotechnology for therapy of mitochondria-related diseases from different genders.

Synthesis of Hemiprotonic Phenanthroline-Phenanthroline+ Compounds with both Antitumor and Antimicrobial Activity.

Currently, cancer patients with microbial infection are a severe challenge in clinical treatment. To address the problem, we synthesized hemiprotonic compounds based on the unique structure of hemiprotonic nucleotide base pairs in a DNA i-motif. These compounds were produced from phenanthroline (ph) dimerization with phenanthroline as a proton receptor and ammonium as a donor. The biological activity shows that the compounds have a selective antitumor effect through inducing cell apoptosis. The molecular mechanism could be related to specific inhibition of transcription factor PLAGL2 of tumor cells, assessed by transcriptomic analysis. Moreover, results show that the hemiprotonic ph-ph+ has broad-spectrum antibacterial and antifungal activities, and drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, are sensitive to the compound. In animal models of liver cancer with fungal infection, the ph-ph+ retards proliferation of hepatoma cells in tumor-bearing mice and remedies pneumonia and encephalitis caused by Cryptococcus neoformans. The study provides a novel therapeutic candidate for cancer patients accompanied by infection.

Receptor-mediated abeta amyloid antibody targeting to Alzheimer's disease mouse brain.

The goal of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimer's disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. An anti-Abeta amyloid antibody (AAA) was re-engineered as a fusion protein with a blood-brain barrier (BBB) molecular Trojan horse. The AAA was engineered as a single chain Fv (ScFv) antibody, and the ScFv was fused to the heavy chain of a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), and this fusion protein was designated cTfRMAb-ScFv. The cTfRMAb-ScFv protein penetrates mouse brain from blood via transport on the BBB TfR, and the brain uptake is 3.5% of injected dose/gram brain following an intravenous administration. Double transgenic APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have extensive Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3-4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 mg/kg for 12 consecutive weeks. The brain A߹⁻4² concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma A߹⁻4² concentration. No cerebral microhemorrhage was observed in the treated mice. These results show that brain-penetrating antibody pharmaceutics can be developed for brain disorders such as AD following the re-engineering of the antibody as a fusion protein that is transported across the BBB via receptor-mediated transport.

[Mitochondrial therapy: a new strategy for treating mitochondrion-associated diseases].

Mitochondrion is a multifunctional organelle in cells and responsible for energy production, cell apoptosis and various life processes. Dysfunctional mitochondria are associated with hundreds of diseases. Increasing evidences have shown that extracellular mitochondria can be endocytosed by cells, directly into cells, and then play roles in cells. Mitochondria are the organelles that are extremely sensitive to oxygen content and pH of microenvironment that induces the adverse effect based on the cellular environment: mitochondria will increase cell survival and viability when they arrive in cells of physiological environment, but mitochondria will cause cell death when they enter the hypoxic and acidic tumor tissues, because they can produce a large amounts of oxygen free radicals. The pharmacological feature of environmental responsiveness of mitochondria could make them as a potential biological drug to kill cancer cells and restore the function of damaged tissues. Currently, mitochondria are used in the treatment of central nervous system diseases (Parkinson's disease, depression, schizophrenia, etc.), peripheral system diseases (ischemic myocardial injury, fatty liver, emphysema, etc.) and tumor. In this review, we summarize the research progress, medical application and challenges of mitochondrial therapy.

Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor.

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 (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, 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 UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.

Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury.

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.

Mitochondrial transplantation therapy inhibit carbon tetrachloride-induced liver injury through scavenging free radicals and protecting hepatocytes.

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.