Hemiprotonic ph-ph+ with two targets inhibits metastatic breast cancer and concurrent candidiasis.

Concurrent infection in breast cancer patients is the direct cause of the high mortality rate of the disease. However, there is no available method to increase the survival rate until now. To address the problem, we propose one drug with two target strategy to treat the refractory disease. A small chemical, ph-ph+, was attempted to be used in the study to explore the feasibility of the approach in anticancer and antifungus at the same time. The results showed that ph-ph+ could prevent the proliferation and metastasis of breast cancer cells, and kill C. albicans simultaneously. The molecular mechanism was associated with the activation of an evolutionarily conserved protease CLpP in the cancer and C. albicans cells. Also, the signaling pathway mediated by PLAGL2 that highly expressed in cancer cells participated in preventing cell metastasis and inducing apoptosis of ph-ph+. The one drug with dual targets inhibited the growth and metastasis of the cancer cells, and meanwhile eliminated C. albicans in tissues in the experimental animals. The results suggested that ph-ph+ with dual targets of CLpP and PLAGL2 would be a feasible approach to prolong the survival rate in patients with metastatic breast cancer and pathogenic infection.

Water-soluble pillar[6]arene bearing pyrene on alternating methylene bridges for direct spermine sensing.

This paper describes the design and synthesis of a conjugate, which is composed of a percarboxylated water-soluble pillar[6]arene and three fluorescent pyrene chromophores on alternating methylene bridges. The optical characteristics are investigated. This conjugate is capable of encapsulating polycationic guest spermine, which results in an enhancement in the fluorescence intensity of pyrene. This host-pyrene conjugate is used for direct sensing of spermine, which shows selectivity towards a variety of biological analytes. The detection of spermine is demonstrated in live cells.

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.

Discretized butterfly optimization algorithm for variable selection in the rapid determination of cholesterol by near-infrared spectroscopy.

The blood cholesterol level is strongly associated with cardiovascular disease. It is necessary to develop a rapid method to determine the cholesterol concentration of blood. In this study, a discretized butterfly optimization algorithm-partial least squares (BOA-PLS) method combined with near-infrared (NIR) spectroscopy is firstly proposed for rapid determination of the cholesterol concentration in blood. In discretized BOA, the butterfly vector is described by 1 or 0, which represents whether the variable is selected or not, respectively. In the optimization process, four transfer functions, i.e., arctangent, V-shaped, improved arctangent (I-atan) and improved V-shaped (I-V), are introduced and compared for discretization of the butterfly position. The partial least squares (PLS) model is established between the selected NIR variables and cholesterol concentrations. The iteration number, transfer functions and the performance of butterflies are investigated. The proposed method is compared with full-spectrum PLS, multiplicative scatter correction-PLS (MSC-PLS), max-min scaling-PLS (MMS-PLS), MSC-MMS-PLS, uninformative variable elimination-PLS (UVE-PLS), Monte Carlo uninformative variable elimination-PLS (MCUVE-PLS) and randomization test-PLS (RT-PLS). Results show that the I-V function is the best transfer function for discretization. Both preprocessing and variable selection can improve the prediction performance of PLS. Variable selection methods based on BOA are better than those based on statistics. Furthermore, I-V-BOA-PLS has the highest predictive accuracy among the seven variable selection methods. MSC-MMS can further improve the prediction ability of I-V-BOA-PLS. Therefore, BOA-PLS combined with NIR spectroscopy is promising for the rapid determination of cholesterol concentration in blood.

Acyclic cucurbit[n]uril-based nanosponges significantly enhance the photodynamic therapeutic efficacy of temoporfin in vitro and in vivo.

Acyclic cucurbit[n]uril-based nanosponges are prepared based on supramolecular vesicle-templated cross-linking. The nanosponges are capable of encapsulating the clinically approved photodynamic therapeutic (PDT) drug temoporfin. When loaded with nanosponges, the PDT bioactivity of temoporfin is enhanced 7.5-fold for HeLa cancer cells and 20.8 fold for B16-F10 cancer cells, respectively. The reason for the significant improvement in PDT efficacy is confirmed to be an enhanced cell uptake by confocal laser scanning microscopy and flow cytometry. Animal studies show that nanosponges could dramatically increase the tumor suppression effect of temoporfin. In vitro and in vivo experiments demonstrate that nanosponges are nontoxic and biocompatible.

A ratiometric fluorescent probe for the detection of biological thiols based on a new supramolecular design.

A new ratiometric fluorescent probe is designed and prepared based on the concept of supramolecular encapsulation and dye competition. This supramolecular probe is based on two commercially-available dyes, one common guest and a simple-to-synthesize host. Fluorescence spectroscopy confirms that the supramolecular probe is capable of detecting thiols quantitatively with a broad linear region in phosphate buffered saline or fetal bovine serum. Mechanistic study shows a reaction between thiol specie and the guest to alter the distribution of encapsulated dyes. The supramolecular probes are demonstrated to quantitatively detect extracellular biological thiols by plate reader, which shows it keeps its effectiveness in complex buffered systems.

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.

pH-sensing supramolecular fluorescent probes discovered by library screening.

A new design concept for pH-sensing supramolecular fluorescent probes is reported. Supramolecular fluorescent pH probes based on pro-guest are designed and prepared. Pro-guests are designed to degrade under acidic condition and convert to competitive guests to displace encapsulated dyes, which leads to a significant enhancement in fluorescence intensity. A library of potential fluorescent pH probes is generated and screened to discover workable probes. These probes are capable of detecting the acidic pH in solution phase. We confirm that these supramolecular probes could detect the acidic environment in endosomal compartments in live cells.

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.

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.

Self-assembled nanoparticles based on supramolecular-organic frameworks and temoporfin for an enhanced photodynamic therapy in vitro and in vivo.

Water-soluble three-dimensional supramolecular-organic frameworks (SOFs) and temoporfin (mTHPC) are discovered to form uniform self-assembled nanoparticles. These nanoparticles demonstrate an improved 1O2 generation efficiency due to the reduced aggregation-caused quenching effect. SOFs and self-assembled nanoparticles are biocompatible. Self-assembled nanoparticles display an improved photo cytotoxicity toward four types of human cancer cells. The tumor model in mice shows that self-assembled nanoparticles could efficiently suppress tumor growth in vivo.

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.

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.

The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma.

Today mitochondria are considered much more than a energy plant in cells. Mitochondrial transplantation therapy has been an active research area for treating mitochondria-associated diseases from animal studies to clinical trials. However, the specific mechanism involved in the anti-tumor activity of healthy mitochondria remain to be characterized. Here we investigate the signal mechanism and gender difference of mitochondrial transplantation therapy against malignant melanoma. In the study, we administrated intact mitochondria extracted from mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. The results suggested that the mitochondria significantly inhibited the tumor cell proliferation in vitro through cell cycle arrest and induction of cell apoptosis. In the melanoma-bearing mice, the mitochondria retard the tumor growth and lung migration, and the transcriptomic analysis indicated that general chromosome silencing was strongly associated with the mitochondria against melanoma after the mitochondrial transplantation on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice. The study identifies the anti-tumor mechanism of the mitochondrial transplantation therapy, and provides a novel insight into the effect of mitochondria from different gender.

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.

[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.

Photodynamic Nanophotosensitizers: Promising Materials for Tumor Theranostics.

Photodynamic theranostics/therapy (PDT) is a potential strategy for selectively imaging malignant sites and treating cancer via a non-invasive therapeutic method. Photosensitizers, the crucial components of PDT, enable colocalization of photons and light, and photon/light therapy in the therapeutic window of 400-900 nm exhibits photocytotoxicity to tumor cells. Due to their high biostability and photocytotoxicity, nanophotosensitizers (NPSs) are of much interest for malignant tumor theranostics at present. NPS-activated photons transfer energy through the absorption of a photon and convert molecular oxygen to the singlet reactive oxygen species, which leads to apoptosis and necrosis. Moreover, NPSs modified by polymers, including PLGA, PEG-PLA, PDLLA, PVCL-g-PLA, and P(VCL-co-VIM)-g-PLA, exhibit excellent biocompatibility, and a tumor-targeting molecule linked on the nanoparticle surface can precisely deliver NPSs into the tumor region. The development of NPSs will accelerate the progress in tumor theranostics through the photon/light pathway.

Improvement of cognitive and motor performance with mitotherapy in aged mice.

Changes in mitochondrial structure and function are mostly responsible for aging and age-related features. Whether healthy mitochondria could prevent aging is, however, unclear. Here we intravenously injected the mitochondria isolated from young mice into aged mice and investigated the mitotherapy on biochemistry metabolism and animal behaviors. The results showed that heterozygous mitochondrial DNA (mtDNA) of both aged and young mouse coexisted in tissues of aged mice after mitochondrial administration, and meanwhile, ATP content in tissues increased while reactive oxygen species (ROS) level reduced. Besides, the mitotherapy significantly improved cognitive and motor performance of aged mice. Our study, at the first report in aged animals, not only provides a useful approach to study mitochondrial function associated with aging, but also a new insight into anti-aging through mitotherapy.

Microwave-assisted organic acid-base-co-catalyzed tandem Meinwald rearrangement and annulation of styrylepoxides.

A novel organic acid-base-co-catalyzed conversion of styrylepoxides into [1,1'-biaryl]-3-carbaldehydes was realized under microwave irradiation. Styrylepoxides first underwent an acid-catalyzed Meinwald rearrangement followed by a tandem base-catalyzed Michael addition, aldol addition, and aromatization sequence to generate [1,1'-biaryl]-3-carbaldehydes.

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.