Roles of heat shock protein A12A in the development of diabetic cardiomyopathy.

Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not been fully elucidated. Heat shock protein A12A (HSPA12A) is the atypic member of the Heat shock 70kDa protein family. In the present study, we found that the expression of HSPA12A was upregulated in the hearts of mice with streptozotocin-induced diabetes, while ablation of HSPA12A improved cardiac systolic and diastolic dysfunction and increased cumulative survival of diabetic mice. An increased expression of HSPA12A was also found in H9c2 cardiac cells following treatment with high glucose (HG), while overexpression of HSPA12A-enhanced the HG-induced cardiac cell death, as reflected by higher levels of propidium iodide cells, lactate dehydrogenase leakage, and caspase 3 cleavage. Moreover, the HG-induced increase of oxidative stress, as indicated by dihydroethidium staining, was exaggerated by HSPA12A overexpression. Further studies demonstrated that the HG-induced increases of protein kinase B and forkhead box transcription factors 1 phosphorylation were diminished by HSPA12A overexpression, while pharmacologically inhibition of protein kinase B further enhanced the HG-induced lactate dehydrogenase leakage in HSPA12A overexpressed cardiac cells. Together, the results suggest that hyperglycemia upregulated HSPA12A expression in cardiac cells, by which induced cell death to promote DCM development. Targeting HSPA12A may serve as a potential approach for DCM management.

Self-Assembled Corrole/Chitosan Photothermal Nanoparticles for Accelerating Infected Diabetic Wound Healing.

Microvascular dysfunction caused by hyperglycemia leads to slow healing of diabetic wounds and significantly increases the risk of bacterial infection. The misuse of antibiotics can also lead to bacterial resistance, making the management of diabetic wounds more challenging. Thus, developing new antibacterial agents or strategies to overcome antibiotic resistance is highly pursued. Herein, novel supramolecular photothermal nanoparticles (MCC/CS NPs), assembled from mono-carboxyl corrole (MCC) and chitosan via hydrogen bonding and π-π stacking, are developed and used for treating bacterial wound infection. The MCC molecules possess good photothermal performance and the chitosan with inherent bioactivity can exert moderate antibacterial effects. The aggregation of MCC in MCC/CS NPs induced by chitosan-templated self-assembly further quenches molecular fluorescence and realizes an extraordinary photothermal conversion efficiency of 66.4%. Moreover, the highly positively charged MCC/CS NPs can selectively target bacteria via electrostatic interactions. Under near-infrared laser irradiation, the MCC/CS NPs achieve potent photothermal and inherent antimicrobial synergistic effects against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) in vitro. Furthermore, the bacteria-infected diabetic wound model confirms that the MCC/CS NPs can effectively kill drug-resistant bacteria, accelerate wound healing and angiogenesis, and show good biocompatibility, representing a novel and efficient photothermal antibacterial nanoplatform.

Efficient oral insulin delivery enabled by transferrin-coated acid-resistant metal-organic framework nanoparticles.

Oral protein delivery is considered a cutting-edge technology to improve patients' quality of life, offering superior patient compliance and convenience compared with injections. However, oral protein formulation has stagnated because of the instability and inefficient penetration of protein in the gastrointestinal tract. Here, we used acid-resistant metal-organic framework nanoparticles (UiO-68-NH2) to encapsulate sufficient insulin and decorated the exterior with targeting proteins (transferrin) to realize highly efficient oral insulin delivery. The UiO-68-NH2 nanocarrier with proper pore size achieved high insulin loading while protecting insulin from acid and enzymatic degradation. Through receptor-mediated transcellular pathway, the transferrin-coated nanoparticles realized efficient transport across the intestinal epithelium and controlled insulin release under physiological conditions, leading to a notable hypoglycemic effect and a high oral bioavailability of 29.6%. Our work demonstrates that functional metal-organic framework nanoparticles can protect proteins from the gastric environment and overcome the intestinal barrier, thus providing the possibility for oral biomacromolecule delivery.

Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer.

Combination chemotherapy is a promising strategy for cancer treatment in clinics especially when multidrug-resistant cancer is emerging. One significant challenge remains in achieving sufficient multi-drug delivery into tumor cells to maximize the synergetic therapeutic effect, as it is hard to concentrate drugs in drug-resistant cancer. Therefore herein, metal-organic framework (MOF)-based polymer-coated hybrid nanoparticles (NPs) were devised and constructed for the co-delivery of doxorubicin and cisplatin to enhance combination therapy of multidrug-resistant cancer. The MOF@polymer nanocarrier combined the merits of high multi-drug loading capacity, physiological stability, and tumor microenvironment pH-responsiveness, facilitating simultaneous delivery of drugs into cancer cells and making the most of synergistic antitumor effect. Remarkably, this hybrid nanocarrier maintains a negative surface charge during circulation to guarantee a stable and prolonged process in vivo, and then exposes inner positive MOF after degradation of the outer polymer in the acidic tumor microenvironment to promote multi-drug release, cellular internalization, nuclear localization, and tumor penetration. In vitro and in vivo studies with drug-resistant MCF-7/ADR cancer suggested that the nanocarrier could achieve increased accumulation of drugs in solid tumors, remarkable tumor elimination results as well as minimized side effects, indicating an improved efficacy and safety of combination chemotherapy. MOF@polymer hybrid nanocarriers provide new insights into the development of stimuli-responsive co-delivery systems of multiple drugs.

Autophagy and Ubiquitin-Proteasome System Coordinate to Regulate the Protein Quality Control of Neurodegenerative Disease-Associated DCTN1.

Motor neuron diseases are neurodegenerative diseases that are characterized by degeneration of the upper and lower motor neurons in the central nervous system. Mutations in Dynactin 1 (DCTN1), a component in the Dynein/Dynactin motor complex, have been previously identified to cause motor neuron diseases and other neurodegenerative disorders. Recent studies showed that motor neuron disease-linked mutation, such as G59S mutation, could lead to dysfunction and protein aggregation of DCTN1. However, the cellular pathway involved in the clearance of DCTN1 aggregates is still not fully elucidated. In this study, we employed a culture cell model of DCTN1-linked neurodegeneration and explored the role of cellular protein control systems in the regulation of wild type and mutant DCTN1. We find that the ubiquitin-proteasome system, but not autophagy, is the primary protein degradation system for the turnover of both wild type and G59S DCTN1 under normal conditions. However, it turns out that autophagy can play a role in the clearance of protein aggregates of G59S DCTN1 when the proteasome activity is inhibited. Importantly, overexpression of TFEB, a master regulator of autophagy, promotes the autophagic clearance of G59S DCTN1 aggregates and ameliorates G59S DCTN1-induced cytotoxicity when the proteasomes are impaired. In conclusion, autophagy may play as a backup system to protect cells against the cytotoxicity induced by aggregate-prone DCTN1 when proteasomal function is damaged.

Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases.

Autophagy is an important cellular protein control process, which plays a key role in the regulation of cell homeostasis and pathogenesis of many human diseases including neurodegenerative diseases. Reduced autophagic activity and abnormal protein aggregation are common features of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Therefore, pharmacological regulation of overall autophagy may be helpful for effective treatment of neurodegenerative diseases. In the present study, we find Dynasore, a potent inhibitor of dynamin, can repress the lysosomal localization of mTOR and block the activity of mTORC1, which in turn enhances the nuclear translocation of the master regulators of autophagy including TFE3 and TFEB. We find that autophagic flux is upregulated in Dynasore-treated cells. Moreover, treatment of Dynasore significantly promotes the clearance of protein aggregates formed by mutant huntingtin protein containing expanded polyglutamine (polyQ), but not damaged mitochondria. In contrast, treatment with Dynasore has no effect on the clearance of polyQ aggregates of mutant huntingtin in ATG5-depleted cells, in which autophagy is defective. Taken together, our results indicate that Dynasore affects autophagic degradation of neurodegenerative disease-associated proteins by regulating mTORC1-TFEB signaling.