Mechanism study of ubiquitination in T cell development and autoimmune disease.

T cells play critical role in multiple immune processes including antigen response, tumor immunity, inflammation, self-tolerance maintenance and autoimmune diseases et. Fetal liver or bone marrow-derived thymus-seeding progenitors (TSPs) settle in thymus and undergo T cell-lineage commitment, proliferation, T cell receptor (TCR) rearrangement, and thymic selections driven by microenvironment composed of thymic epithelial cells (TEC), dendritic cells (DC), macrophage and B cells, thus generating T cells with diverse TCR repertoire immunocompetent but not self-reactive. Additionally, some self-reactive thymocytes give rise to Treg with the help of TEC and DC, serving for immune tolerance. The sequential proliferation, cell fate decision, and selection during T cell development and self-tolerance establishment are tightly regulated to ensure the proper immune response without autoimmune reaction. There are remarkable progresses in understanding of the regulatory mechanisms regarding ubiquitination in T cell development and the establishment of self-tolerance in the past few years, which holds great potential for further therapeutic interventions in immune-related diseases.

Extracellular Vesicles and Ischemic Cardiovascular Diseases.

Characterized by coronary artery obstruction or stenosis, ischemic cardiovascular diseases as advanced stages of coronary heart diseases commonly lead to left ventricular aneurysm, ventricular septal defect, and mitral insufficiency. Extracellular vesicles (EVs) secreted by diverse cells in the body exert roles in cell-cell interactions and intrinsic cellular regulations. With a lipid double-layer membrane and biological components such as DNA, protein, mRNA, microRNAs (miRNA), and siRNA inside, the EVs function as paracrine signaling for the pathophysiology of ischemic cardiovascular diseases and maintenance of the cardiac homeostasis. Unlike stem cell transplantation with the potential tumorigenicity and immunogenicity, the EV-based therapeutic strategy is proposed to satisfy the demand for cardiac repair and regeneration while the circulating EVs detected by a noninvasive approach can act as precious biomarkers. In this chapter, we extensively summarize the cardioprotective functions of native EVs and bioengineered EVs released from stem cells, cardiomyocytes, cardiac progenitor cells (CPCs), endothelial cells, fibroblast, smooth muscle cells, and immune cells. In addition, the potential of EVs as robust molecule biomarkers is discussed for clinical diagnosis of ischemic cardiovascular disease, attributed to the same pathology of EVs as that of their origin. Finally, we highlight EV-based therapy as a biocompatible alternative to direct cell-based therapy for ischemic cardiovascular diseases.

Polydopamine-guarded metal-organic frameworks as co-delivery systems for starvation-assisted chemo-photothermal therapy.

Cutting off glucose provision by glucose oxidase (GOx) to famish tumors can be an assistance with chemotherapy to eliminate cancer cells. Co-encapsulation of GOx and chemotherapeutics (doxorubicin) within pH-sensitive metal-organic frameworks (MOFs) could disorder metabolic pathways of cancer cells and generate excessive intracellular reactive oxygen species (ROS), together. To prevent premature leach of GOx from the porous channels of MOFs, polydopamine (PDA) was deposited on the surface of MOFs, which endowed the delivery system with photothermal conversion ability. Our nanoscaled co-delivery system (denoted as DGZPNs) remains stable with low amount of drug leakage under simulated physiological conditions in vitro and internal environment, while they are triggered to release doxorubicin (DOX) and GOx in acid tumor microenvironment and at high temperature for reinforced chemotherapy. NIR laser irradiation also activates superior photothermal conversion efficiency of PDA (36.9 %) to initiate hyperthermia to ablate tumor tissue. After being phagocytized by 4 T1 cells (breast cancer cells), the DGZPNs delivery system showed a superior therapeutic efficacy with a tumor growth inhibition of 88.9 ± 6.6 % under NIR irradiation, which indicated that the starvation-assisted chemo-photothermal therapy prompts the significant advance of synergistic therapy in a parallelly controlled mode.

Insight into Heart-Tailored Architectures of Hydrogel to Restore Cardiac Functions after Myocardial Infarction.

With permanent heart muscle injury or death, myocardial infarction (MI) is complicated by inflammatory, proliferation and remodeling phases from both the early ischemic period and subsequent infarct expansion. Though in situ re-establishment of blood flow to the infarct zone and delays of the ventricular remodeling process are current treatment options of MI, they fail to address massive loss of viable cardiomyocytes while transplanting stem cells to regenerate heart is hindered by their poor retention in the infarct bed. Equipped with heart-specific mimicry and extracellular matrix (ECM)-like functionality on the network structure, hydrogels leveraging tissue-matching biomechanics and biocompatibility can mechanically constrain the infarct and act as localized transport of bioactive ingredients to refresh the dysfunctional heart under the constant cyclic stress. Given diverse characteristics of hydrogel including conductivity, anisotropy, adhesiveness, biodegradability, self-healing and mechanical properties driving local cardiac repair, we aim to investigate and conclude the dynamic balance between ordered architectures of hydrogels and the post-MI pathological milieu. Additionally, our review summarizes advantages of heart-tailored architectures of hydrogels in cardiac repair following MI. Finally, we propose challenges and prospects in clinical translation of hydrogels to draw theoretical guidance on cardiac repair and regeneration after MI.

Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment.

Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, is non-apoptotic programmed cell death highly relevant to tumor development. It was found to manipulate oncogenes and resistant mutations of cancer cells via lipid metabolism pathways converging on phospholipid glutathione peroxidase (GPX4) that squanders lipid peroxides (L-OOH) to block the iron-mediated reactions of peroxides, thus rendering resistant cancer cells vulnerable to ferroptotic cell death. By accumulating ROS and lipid peroxidation (LPO) products to lethal levels in tumor microenvironment (TME), ferroptosis-driven nanotherapeutics show a superior ability of eradicating aggressive malignancies than traditional therapeutic modalities, especially for the drug-resistant tumors with high metastasis tendency. Moreover, Fenton reaction, inhibition of GPX-4, and exogenous regulation of LPO are three major therapeutic strategies to induce ferroptosis in cancer cells, which were generally applied in ferroptosis-driven nanotherapeutics. In this review, we elaborate current trends of ferroptosis-driven nanotherapeutics to reverse drug resistance of tumors in anticancer fields at the intersection of cancer biology, materials science, and chemistry. Finally, their challenges and perspectives toward feasible translational studies are spotlighted, which would ignite the hope of anti-resistant cancer treatment.

An Efficient Carbon-Based Drug Delivery System for Cancer Therapy through the Nucleus Targeting and Mitochondria Mediated Apoptotic Pathway.

The emergence of nanocarriers solves the problems of antitumor drugs such as non-targeting, huge side effects, etc., and has been widely used in tumor therapy. Some kinds of antitumor drugs such as doxorubicin (DOX) mainly act on the nucleic acid causing DNA damage, interfering with transcription, and thereby disrupting or blocking the process of cancer cell replication. Herein, a new nanodrug delivery system, the carbon-based nanomaterials (CBNs)-Pluronic F127-DOX (CPD), is designed by using CBNs as a nanocarrier for DOX. As a result, the tumor growth inhibition rate of CPD group is as high as 79.42 ± 2.83%, and greatly reduces the side effects. The targeting rate of the CPD group of DOX in the tumor nucleus is 36.78%, and the %ID/g in tumor tissue is 30.09%. The CPD regulates the expression levels of Caspase-3, p53, and Bcl-2 genes by increasing intracellular reactive oxygen species (ROS) levels and reducing mitochondrial membrane potential, which indicates that mitochondrial-mediated pathways are involved in apoptosis. The CPD nanodrug delivery system increases the effective accumulation of DOX in tumor cell nuclei and tumor tissues, and generates massive ROS, thereby inhibiting tumor growth in vivo, representing a promising agent for anticancer applications.

Improved Stability and Targeted Cytotoxicity of Epigallocatechin-3-Gallate Palmitate for Anticancer Therapy.

Although with high antioxidant activity, epigallocatechin-3-gallate (EGCG) was restricted by its poor chemical stability in practical applications. One of EGCG derivatives, EGCG palmitate, was synthesized with EGCG and palmitoyl chloride to overcome instability of EGCG. However, uncertainties still exist in chemical stability and cytotoxicity of EGCG palmitate, which are essential for further exploration in anticancer therapy. Our work aims to analyze the resistance of EGCG palmitate to oxidation and summarize its targeted inhibition efficiency on cancerous cells and normal cells. High-performance liquid chromatography analysis confirmed that EGCG palmitate remained stable in air and Dulbecco's modified eagle medium (DMEM) for a longer time than EGCG. Antioxidative and pro-oxidative effects of EGCG palmitate on treated cells are proposed through reactive oxygen species (ROS) detection, respectively. It reveals that pro-oxidants by H2O2 production can exert antiproliferative and proapoptotic effects on cancerous cells and stimulate autophagy, while an antioxidant relieves oxidative stress caused by superoxide as compared to normal cells. Consequently, targeted cytotoxicity is adopted by EGCG palmitate-treated cancerous cells. Results above manifest that EGCG palmitate possesses potential to serve as a promising prodrug in anticancer treatment.

Orchestration of biomimetic membrane coating and nanotherapeutics in personalized anticancer therapy.

Nanoparticle-based therapeutic and detectable modalities can augment anticancer efficiency, holding potential in capable target and suppressive metastases post administration. However, the individual discrepancies of the current "one-size-fits-all" strategies for anticancer nanotherapeutics have heralded the need for "personalized therapy". Benefiting from the special inherency of various cells, diverse cell membrane-coated nanoparticles (CMCNs) were established on a patient-by-patient basis, which would facilitate the personalized treatment of individual cancer patients. CMCNs in a complex microenvironment can evade the immune system and target homologous tumors with a suppressed immune response, as well as a prolonged circulation time, consequently increasing the drug accumulation at the tumor site and anticancer therapeutic efficacy. This review focuses on the emerging strategies and advances of CMCNs to synergistically integrate the merit of source cells with nanoparticulate delivery systems for the orchestration of personalized anticancer nanotherapeutics, thus discussing their rationalities in facilitating chemotherapy, imaging, immunotherapy, phototherapy, radiotherapy, sonodynamic, magnetocaloric, chemodynamic and gene therapy. Furthermore, the mechanism, challenges and opportunities of CMCNs in personalized anticancer therapy were highlighted to further boost cooperation from different fields, including materials science, chemistry, medicine, pharmacy and biology for the lab-to-clinic translation of CMCNs combined with the individual advantages of source cells and nanotherapeutics.

Duo of (-)-epigallocatechin-3-gallate and doxorubicin loaded by polydopamine coating ZIF-8 in the regulation of autophagy for chemo-photothermal synergistic therapy.

To achieve highly systemic therapeutic efficacy, chemotherapy is combined with photothermal therapy for chemo-photothermal synergistic therapy; however, this strategy suffers from high toxicity and unsatisfactory sensitivity for cancer cells. Herein, we developed a pH- and photothermal-responsive zeolitic imidazolate framework (ZIF-8) compound for loading a dual-drug in the tumor site and improving their curative effects. Since autophagy always accompanies tumor progression and metastasis, there is an unmet need for an anticancer treatment related to the regulation of autophagy. Green tea polyphenols, namely, (-)-epigallocatechin-3-gallate (EGCG) and doxorubicin (DOX), both of which exhibit anticancer activity, were dual-loaded via polydopamine (PDA) coating ZIF-8 (EGCG@ZIF-PDA-PEG-DOX, EZPPD for short) through hierarchical self-assembly. PDA could transfer photothermal energy to increase the temperature under near-infrared (NIR) laser irradiation. Due to its pH-response, EZPPD released EGCG and DOX in the tumor microenvironment, wherein the temperature increased with the help of PDA and NIR laser irradiation. The duo of DOX and EGCG induced autophagic flux and accelerated the formation of autophagosomes. In a mouse HeLa tumor model, photothermal-chemotherapy could ablate the tumor with a significant synergistic effect and potentiate the anticancer efficacy. Thus, the results indicate that EZPPD renders the key traits of a clinically promising candidate to address the challenges associated with synergistic chemotherapy and photothermal utilization in antitumor therapy.

FA-PEG decorated MOF nanoparticles as a targeted drug delivery system for controlled release of an autophagy inhibitor.

A zeolitic imidazolate framework (ZIF-8) with high loading capacity and pH-responsive properties, an important subclass of metal-organic frameworks (MOFs), has become a promising material for drug delivery. A multifunctional drug delivery system (DDS) was designed in this work for effective targeting delivery of chloroquine diphosphate (CQ) as an autophagy inhibitor. The ZIF-8 nanoparticles encapsulating CQ (CQ@ZIF-8 NPs) were fabricated by a simple one-pot method and were then decorated with methoxy poly(ethylene glycol)-folate (FA-PEG), a special identifier of cancer cells, to form FA-PEG/CQ@ZIF-8. The target identification of FA-PEG/CQ@ZIF-8 NPs, compared with CQ@ZIF-8 NPs, leads to an increasing number of NPs being internalized into HeLa cells, which decreases the loss of drugs and results in high cytotoxicity of CQ for cancer cells. The lower viabilities of HeLa cells (cancer cells) and higher viabilities of HEK293 cells (healthy cells) treated with FA-PEG/CQ@ZIF-8 NPs show that the special target for cancer cells results from the combinations of folic acid and folate receptors on the surface of HeLa cells. The quantitative measurements of autophagy-related proteins and the detection of autophagy flux in HeLa cells suggest that the autophagosome formation and autophagy flux are appreciably blocked after the cells are treated with FA-PEG/CQ@ZIF-8 NPs. The ZIF-8 can disintegrate only under low pH conditions, resulting in fast and full release of CQ. The pH-responsive and tumor-targeted properties of the NPs can control the drug release and enhance the efficiency of autophagy inhibition. It indicates that the FA-PEG/CQ@ZIF-8 NPs combining target identification with controlled drug release can be used as a novel model for discussing targeted cancer therapy and inhibiting the autophagy of cancer cells.

Spermidine­induced growth inhibition and apoptosis via autophagic activation in cervical cancer.

Cervical cancer is the most common malignancy of the female reproductive tract, and the poor response to prophylactic vaccines and the toxicity of high­dose chemotherapeutic drugs have limited their clinical application. Spermidine, a natural polyamine detected in all eukaryotic organisms, exhibits functions that promote longevity in multiple model systems and may constitute a promising agent for cancer treatment. However, the potential effectiveness of spermidine in cervical cancer has not yet been fully elucidated, and the underlying molecular mechanisms remain unclear. In the present study, we aimed to assess the effects of spermidine on proliferation and apoptosis of HeLa cells (a cervical cancer cell line). Firstly, CCK­8 and flow cytometric assays revealed that spermidine reduced the proliferation of HeLa cells in a dose­dependent fashion by arresting the cell cycle at the S phase. Secondly, flow cytometry incorporating Annexin V­FITC/PI­staining revealed that spermidine promoted the apoptosis of HeLa cells, and western blot analysis revealed that spermidine activated autophagy. Finally, spermidine­activated autophagy mediated the inhibition of cell proliferation by spermidine and spermidine­induced apoptosis in HeLa cells. Collectively, these results revealed a novel function for spermidine in inhibiting cellular proliferation and inducing apoptosis of HeLa cells by activating autophagy, which may have important implications for the use of spermidine in cervical cancer therapy.

Derivative of Epigallocatechin-3-gallatea Encapsulated in ZIF-8 with Polyethylene Glycol-Folic Acid Modification for Target and pH-Responsive Drug Release in Anticancer Research.

Epigallocatechin-3-gallatea (EGCG), a key component of tea, has been found to have anticancer activity but poor stability. To improve its antioxidative stability and widen the application of EGCG in anticancer therapy, a kind of EGCG derivative, EGCG palmitate (PEGCG), was synthesized and encapsulated in ZIF-8 nanoparticles with functionalization of folic acid (FA), which is commonly used as pH-responsive drug carrier. PEGCG encapsulated in polyethylene glycol (PEG)-FA/ZIF-8 nanoparticles (PEG-FA/PEGCG@ZIF-8 NPs) exhibits sixfold improvement of stability compared to that of free PEGCG. With target recognition between folic acid (FA) on the surface of NPs and overexpressed FA receptor (FR) in cancer cells, the NPs can be efficiently internalized into cells and present targeted effects of inhibition growth on HeLa cells (cancer cells) compared with HEK 293 cells (normal cells), consistent with the regulation of reactive oxygen species (ROS) level and the induction of autophagy. The detection of autophagy flux and the measurement of autophagy marked proteins in cells suggest that autophagy flux and the autophagosome formation are appreciably induced when the cells were treated with PEG-FA/PEGCG@ZIF-8 NPs. It indicates that pH-responsive PEG-FA/PEGCG@ZIF-8 NPs with target identification for cancer cells can be used as highly efficient drug carriers in targeting cancer chemotherapy.

MOF Nanoparticles with Encapsulated Autophagy Inhibitor in Controlled Drug Delivery System for Antitumor.

High porosities, large surface areas, and tunable functionalities made metal-organic frameworks (MOFs) as effective carriers for drug delivery. One of the most promising MOFs is the zeolitic imidazolate framework (ZIF-8) crystal, an advanced functional material for small-molecule delivery, due to its high loading ability and pH-sensitive degradation. As a novel carrier, ZIF-8 nanoparticles were used in this work to control the release of an autophagy inhibitor, 3-methyladenine (3-MA), and prevent it from dissipating in a large quantity before reaching the target. The cellular uptake in HeLa cells of 3-MA encapsulated in ZIF-8 (3-MA@ZIF-8 NPs) is facilitated through the nanoparticle internalization with reference to TEM observations and the quantitative analyses of zinc by ICP-MS. The autophagy-related proteins and autophagy flux in HeLa cells treated with 3-MA@ZIF-8 NPs show that the autophagosome formation is significantly blocked, which reveals that the pH-sensitive dissociation increases the efficiency of autophagy inhibition at the equivalent concentration of 3-MA. In vivo experiments, when compared to free 3-MA, 3-MA@ZIF-8 NPs show a higher antitumor efficacy and repress the expression of autophagy-related markers, Beclin 1 and LC3. It follows that ZIF-8 is an efficient drug delivery vehicle in antitumor therapy, especially in inhibiting autophagy of cancer cells.

Hydrophobic fractal surface from glycerol tripalmitate and the effects on C6 glioma cell growth.

To provide a biomimic environment for glial cell culture, glycerol tripalmitate (PPP) has been used as a raw material to prepare fractal surfaces with different degrees of hydrophobicity. The spontaneous formation of the hydrophobic fractal surfaces was monitored by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The surface morphologies were observed by a scanning electron microscope (SEM), and then the fractal dimension (FD) values of the surfaces were determined with the box-counting method. C6 glioma cells were cultured and compared on different hydrophobic PPP surfaces and poly-L-lysine (PLL)-coated surface. The cell numbers as a function of incubation time on different surfaces during the cell proliferation process were measured, and the cell morphologies were observed under a fluorescence microscope. Influences of hydrophobic fractal surfaces on the cell number and morphology were analyzed. The experimental results show that the cell proliferation rates decrease while the cell morphology complexities increase with the growth of the fractal dimensions of the PPP surfaces.

Antibacterial Activity, in Vitro Cytotoxicity, and Cell Cycle Arrest of Gemini Quaternary Ammonium Surfactants.

Twelve gemini quaternary ammonium surfactants have been employed to evaluate the antibacterial activity and in vitro cytotoxicity. The antibacterial effects of the gemini surfactants are performed on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with minimum inhibitory concentrations (MIC) ranging from 2.8 to 167.7 µM. Scanning electron microscopy (SEM) analysis results show that these surfactants interact with the bacterial cell membrane, disrupt the integrity of the membrane, and consequently kill the bacteria. The data recorded on C6 glioma and HEK293 human kidney cell lines using an MTT assay exhibit low half inhibitory concentrations (IC50). The influences of the gemini surfactants on the cell morphology, the cell migration ability, and the cell cycle are observed through hematoxylin-eosin (HE) staining, cell wound healing assay, and flow cytometric analyses, respectively. Both the values of MIC and IC50 decrease against the growth of the alkyl chain length of the gemini surfactants with the same spacer group. In the case of surfactants 12-s-12, the MICs and IC50s are found to decrease slightly with the spacer chain length changing from 2 to 8 and again to increase at higher spacer length (s = 10-12). All of the gemini surfactants show great antibacterial activity and cytotoxicity, and they might exhibit potential applications in medical fields.