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.

Rational Design of pH-Responsive DNA Motifs with General Sequence Compatibility.

Reconfigurable molecular events are key to molecular machines. In response to external cues, molecular machines rearrange/change their structures to perform certain functions. Such machines exist in nature, for example cell surface receptors, and have been artificially engineered. To be able to build sophisticated and efficient molecular machines for an increasing range of applications, constant efforts have been devoted to developing new mechanisms of controllable structural reconfiguration. Herein, we report a general design principle for pH-responsive DNA motifs for general DNA sequences (not limited to triplex or i-motif forming sequences). We have thoroughly characterized such DNA motifs by polyacrylamide gel electrophoresis (PAGE) and fluorescence spectroscopy and demonstrated their applications in dynamic DNA nanotechnology. We expect that it will greatly facilitate the development of DNA nanomachines, biosensing/bioimaging, drug delivery, etc.

Systematic Analysis of tRNA-Derived Small RNAs Reveals Novel Potential Therapeutic Targets of Traditional Chinese Medicine (Buyang-Huanwu-Decoction) on Intracerebral Hemorrhage.

Although Buyang-Huanwu-Decoction (BYHWD), a famous traditional Chinese medicine, has been utilized to promote the recovery of neurological function in intracerebral hemorrhage (ICH) for centuries, its therapeutic mechanisms remain unclear. tRNA-derived small RNA (tsRNA) is a novel class of short non-coding RNA, possessing potential regulating functions. In the current study, we explored the novel therapeutic targets of BYHWD by tsRNA-sequencing. Rats were randomly divided into three groups: sham, ICH, and BYHWD-treated groups. The modified neurological severity score, corner turn test, foot-fault test, and weight change were used to assess neurological injury. After BYHWD treatment, these behavioral tests were obviously meliorated compared with ICH group in the recovery phase. In the rat brain tissues surrounding the hemorrhagic region, a total of 350 tsRNAs for exact match were identified. 12 of tRNAs (fold change >1.3 and P-value <0.05) were significantly changed in ICH group compared to sham group. Among them, 3 of tRNAs (rno-tRFi-Ser-25a, rno-tRF5-Ala-16a and rno-tRF5-Glu-29a) were markedly regulated by BYHWD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these tsRNAs could play therapeutic roles through FoxO signaling pathway, positive regulation of long term synaptic depression, autophagy - animal, IL-17 signaling pathway and regulation of cytoskeleton and transforming growth factor beta. In conclusion, tsRNAs are the potential therapeutic targets of BYHWD on ICH treatment. The present study provides novel insights for future investigations to explore the mechanisms, by which BYHWD promotes neurological function recovery after ICH.

Determinant roles of gender and age on SII, PLR, NLR, LMR and MLR and their reference intervals defining in Henan, China: A posteriori and big-data-based.

OBJECTIVES: By now, there are few data of the reference intervals (RIs) of SII, PLR, NLR, LMR and MLR. We aimed to establish RIs of SII, PLR, NLR, LMR and MLR for healthy persons. METHODS: A retrospective analysis on a cohort of ostensibly healthy, aged no <18 years old physical examinees who took health examination from January to December in 2013 was conducted to explore influences of age and gender on SII, PLR, NLR, LMR and MLR and to establish their RIs. And another cohort of 450 persons in our hospital from January to July in 2016 is included for validations of RIs. RESULTS: NLR, LMR and MLR were significantly different between gender groups (P=.010; P<.001; P<.001, separately), while SII and PLR were not (P=.137; P=.267, separately). While SII was not changed much between age groups (P=.842), PLR, NLR, LMR and MLR were significantly different (all with P<.001). RIs of SII, PLR, NLR, LMR and MLR were: SII: [161,701]; PLR: 18-65 year-old: [61,179]/>65 year-old: [55,179]; NLR: 18-65 year-old male: [0.90,2.94]/18-65 year-old female: [0.85,3.06]/>65 year-old male: [0.95,3.57]/aged >65 year-old female: [0.83,3.30]; LMR: 18-65 year-old male: [2.50,7.50]/18-65 year-old female: [2.75,8.50]/>65 year-old male: [2.16,7.41]/>65 year-old female: [2.40,8.33]; MLR: 18-65 year-old male: [0.12,0.35]/18-65 year-old female: [0.10,0.32]/>65 year-old male: [0.12,0.41]/>65 year-old male: [0.11,0.33]. CONCLUSIONS: RIs of SII, PLR, NLR, LMR and MLR of people in central China were established and validated. It will benefit experimental design of the related studies and lead to better standardizations of SII, PLR, NLR, LMR and MLR for their clinical applications.

Antigen-oriented T cell migration contributes to myelin peptide induced-EAE and immune tolerance.

Treatment with soluble myelin peptide can efficiently and specifically induce tolerance to demyelination autoimmune diseases including multiple sclerosis, however the mechanism underlying this therapeutic effect remains to be elucidated. In actively induced mouse model of experimental autoimmune encephalomyelitis (EAE) we analyzed T cell and innate immune cell responses in the central nervous system (CNS) and spleen after intraperitoneal (i.p.) infusion of myelin oligodendrocyte glycoprotein (MOG). We found that i.p. MOG infusion blocked effector T cell recruitment to the CNS and protected mice from EAE and lymphoid organ atrophy. Innate immune CD11b(+) cells preferentially recruited MOG-specific effector T cells, particularly when activated to become competent antigen presenting cells (APCs). During EAE development, mature APCs were enriched in the CNS rather than in the spleen, attracting effector T cells to the CNS. Increased myelin antigen exposure induced CNS-APC maturation, recruiting additional effector T cells to the CNS, causing symptoms of disease. MOG triggered functional maturation of splenic APCs. MOG presenting APCs interacted with MOG-specific T cells in the spleen, aggregating to cluster around CD11b(+) cells, and were trapped in the periphery. This process was MHC II dependent as an MHC II directed antibody blocked CD4(+) T cell cluster formation. These findings highlight the role of myelin peptide-loaded APCs in myelin peptide-induced EAE and immune tolerance.

The platelet-to-lymphocyte ratio, superior to the neutrophil-to-lymphocyte ratio, correlates with hepatitis C virus infection.

OBJECTIVES: The platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been studied widely in cancer diseases. However, their correlation with hepatitis C virus (HCV) infection is unknown. The aim of this study was to investigate the correlation of PLR and NLR with disease severity in patients with HCV-related liver disease and the virological response in chronic hepatitis C (CHC) patients. METHODS: The clinical data of 120 HCV-infected patients and 40 healthy controls were analyzed. The clinical data of 24 CHC patients who had been followed up regularly were collected for the following time points: before treatment (week 0) and weeks 4, 48, and 72 during treatment. These data were also analyzed. All data were collected from the database of the hospital patient electronic medical record system. RESULTS: The HCV-related cirrhosis group and HCV-related hepatocellular carcinoma group were found to have lower PLRs (61±31 and 51±23) than the healthy controls (115±23). The PLR of the HCV cleared group (154±85) was significantly higher than that of the HCV untreated group and HCV uncleared group (90±28 and 88±40, respectively). Receiver operating characteristics curve analysis for the PLR showed an area under the curve of 0.772 (95% confidence interval 0.674-0.869, p<0.000); for NLR, the area under the curve was 0.612 (95% confidence interval 0.495-0.730, p=0.063). Furthermore, an increasing PLR in CHC patients indicated a good virological response, and a stable PLR or a downward trend in PLR could predict no rapid virological response being achieved by week 4, and even no sustained virological response by week 72. CONCLUSIONS: The PLR is closely related to disease severity in patients with HCV-related liver disease and to the virological response in CHC patients. Dynamic continuous monitoring of the PLR will contribute to disease surveillance, with an increasing tendency predicting a good virological response.