Persistent Endoplasmic Reticulum Stress Stimulated by Peptide Assemblies for Sensitizing Cancer Chemotherapy.

Pharmacological targeting of endoplasmic reticulum (ER) stress represents one of important methods for disease therapy, which, however, is significantly suppressed by the ER homeostatic processe. Herein, a proof-of-concept strategy is reported for persistent stimulation of ER stress via preventing ER stress adaptation by utilizing multifunctional peptide assemblies. The strategy is established via creation of peptide assemblies with ER-targeting and chaperone glucose-regulated protein 78 (GRP78)-inhibiting functions. The peptides assemblies form well-defined nanofibers that are retrieved by ER organelles in human cervical cancer cell. The underlying mechanism studies unravel that the ER-accumulated peptide assemblies simultaneously stimulate ER stress and inhibit GRP78 refolding activity and thereby promoting endogenous protein aggregation. Combining the internalized peptide assemblies with the induced protein aggregates leads to the persistent stimulation of ER stress. The persistent ER stress induced by the peptide assemblies bestows their application in sensitizing cancer chemotherapy. Both in vitro and in vivo results confirm the enhanced cytotoxicity of drug toyocamycin against HeLa cells by peptide assemblies, thus efficiently inhibiting in vivo tumor growth. The strategy reported here discloses the fundamental keys for efficient promotion of ER stress, thus providing the guidance for development of ER-targeting-assisted cancer chemotherapy in the future.

Early diagnosis, treatment, and outcomes of five patients with acute thallium poisoning.

BACKGROUND: Thallium poisoning is rare and difficult to recognize. Early diagnosis and treatment of thallium-poisoned patients are essential to prevent morbidity and mortality. AIM: To evaluate the efficacy of treatments and outcomes of five patients with early diagnosis of acute thallium poisoning. METHODS: Five patients who consumed a thallium-contaminated meal were hospitalized in succession, and underwent clinical examinations such as blood tests and electromyography tests. Urine and blood tests confirmed the diagnosis of thallotoxicosis, revealing the occurrence of food poisoning. All patients underwent detoxification treatment, including hemoperfusion (HP) and treatment with Prussian blue (PB). A 24-mo follow-up was performed to evaluate the long-term outcomes on the patients after discharge. RESULTS: Initially, the patients presented with symptoms of acute thallium poisoning including hyperalgesia of the limbs and abdominalgia, which may differ from common peripheral neuropathy. Accompanying symptoms such as hepatic damage and alopecia were observed in all the patients, which further confirmed the diagnosis of poisoning. Treatment with chelating agents was ineffective, while HP and treatment with PB drastically decreased the thallium concentration in the urine and blood. With early diagnosis and intervention, four patients had a good prognosis and no permanent sequelae. One patient developed blindness and disability during the 24-mo follow-up period. CONCLUSION: Identification of incident cluster and characteristic symptoms is extremely important for early diagnosis of acute thallium poisoning. HP plus PB is essential to improve the prognosis of thallium-poisoned patients.

microRNA-1906 protects cerebral ischemic injury through activating Janus kinase 2/signal transducer and activator of transcription 3 pathway in rats.

This study aimed to investigate the effects of miR-1906 on cerebral ischemic injury and its underlying mechanisms. After 24 h of reperfusion, neurological deficit scores, brain water content and infarct volume were measured. Neuronal apoptosis was detected by using terminal dexynucleotidyl transferase-mediated dUTP nick end labeling assay. Hematoxylin-eosin staining was used to evaluate the histopathological damage of neurons. The expression of miR-1906 was detected by qRT-PCR. And the expressions of Bax, Bcl-2, caspase-3, Janus kinase 2 (JAK2), p-JAK2, signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured by western blot. Furthermore, the levels of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 were measured by ELISA. We found that miR-1906 expression was significantly decreased in the cerebral ischemia injury rats. miR-1906 decreased neurological score, infarct volume, brain water content, neuronal apoptosis and inflammatory factors (TNF-α, IL-6 and IL-1ß) expression. In addition, miR-1906 promoted the phosphorylation of JAK2 and STAT3. After treating with JAK2/STAT3 pathway inhibitor AG490, the phosphorylation of JAK2 and STAT3 was inhibited and the effects of miR-1906 on neurological score, infarct volume, brain water content, neuronal apoptosis and inflammatory factors were reversed. miR-1906 could protect cerebral ischemic injury through activating the JAK2/STAT3 pathway in rats.

Humidity-Driven Soft Actuator Built up Layer-by-Layer and Theoretical Insight into Its Mechanism of Energy Conversion.

An improved protocol is proposed for preparation of a humidity-sensitive soft actuator through the layer-by-layer assembling of weight-ratio-variable composites of sodium alginate (SA) and poly(vinyl alcohol) (PVA) into laminated structures. The design induces nonuniform hygroscopicity in the thickness direction and gives rise to strong interfacial interaction between layers, making the actuator have directional motility. A mathematical model reveals that the directional motion is driven by the chemical potential of humidity, and its energy conversion efficiency from humidity to mechanical work reaches 81.2% at 25 °C. By coating with CoCl2, the composite film of SA@PVA/CoCl2 can act as a warning sign that provides reminder information to prevent people from slipping or falling by a conspicuous red sign during a high-humidity environment. When the film is involved in a bidirectional switch, it is capable of turning on/off light-emitting diodes by humidity, showing promising potential in control over humidity-dependent devices.

Influence of mesophilic and thermophilic conditions on the anaerobic digestion of food waste: Focus on the microbial activity and removal of long chain fatty acids.

The mesophilic reactor (MR) exhibited advantages in biogas production and performance stability over thermophilic reactor (TR) during the long-term anaerobic digestion (AD) of food waste (FW) with stepwise organic loading rate elevating. It was interesting to explore the mechanism causing the divergences in performances between these two reactors. The microbial activity was compared on day 110 when TR began to deteriorate. The results show that MR had significantly higher specific acetoclastic methanogenic activities (SAMA) and specific propionate and butyrate oxidative activities (SPOA and SBOA) than TR. The SAMA, SPOA and SBOA in TR were only 50.3%, 18.6% and 46.4% of those values in MR, respectively. Remarkably, the specific hydrogenotrophic methanogenic activity of 15.5±2.1, 15.7±4.6 mmol CH4·L-1 original slurry·d-1 in MR and TR was comparative with insignificant difference, which indicates that the microbial activity in TR had been inhibited widely apart from the hydrogenotrophic methanogenesis. Additionally, many particles with the diameters of 1-2 mm were observed to form in MR and identified as complexes of calcium and long chain fatty acids (LCFAs). The formation of calcium crystallization might alleviate the inhibition of LCFAs during AD of FW, which further supports the better performance in MR than TR.

Adenovirus type 3 induces platelet activation in vitro.

In the present study, we aimed to investigate platelet activation induced by adenovirus type 3 (HAdV3) in vitro. Platelet-rich plasma (PRP) or whole blood was incubated with or without HAdV at various concentrations. Platelet aggregation, platelet counting, fibrinogen and expression of platelet membrane antigens (CD41a and CD62P) were determined following incubation with HAdV for different periods of time. The results demonstrated that HAdV at the concentrations of 109-1011 vp/ml enhanced adenosine diphosphate (ADP) or ristocetin-induced platelet aggregation, however did not alter the platelet count. Infection with HAdVs also reduced fibrinogen level. P-selectin and CD41a appeared rapidly on the surface after platelets were incubated with HAdVs in vitro for 30 min. In conclusion, HAdVs may induce activation of platelets and lead to a pre-thrombotic state of peripheral blood. This finding may aid in the development of measures to prevent severe HAdV infection.