Biofeedback electrostimulation for bionic and long-lasting neural modulation.

Invasive electrical stimulation (iES) is prone to cause neural stimulus-inertia owing to its excessive accumulation of exogenous charges, thereby resulting in many side effects and even failure of nerve regeneration and functional recovery. Here, a wearable neural iES system is well designed and built for bionic and long-lasting neural modulation. It can automatically yield biomimetic pulsed electrical signals under the driven of respiratory motion. These electrical signals are full of unique physiological synchronization can give biofeedback to respiratory behaviors, self-adjusting with different physiological states of the living body, and thus realizing a dynamic and biological self-matched modulation of voltage-gated calcium channels on the cell membrane. Abundant cellular and animal experimental evidence confirm an effective elimination of neural stimulus-inertia by these bioelectrical signals. An unprecedented nerve regeneration and motor functional reconstruction are achieved in long-segmental peripheral nerve defects, which is equal to the gold standard of nerve repair -- autograft. The wearable neural iES system provides an advanced platform to overcome the common neural stimulus-inertia and gives a broad avenue for personalized iES therapy of nerve injury and neurodegenerative diseases.

Astragaloside IV promotes pharmacological effect of Descurainia sophia seeds on isoproterenol-induced cardiomyopathy in rats by synergistically modulating the myosin motor.

Descurainia sophia seeds (DS), Astragalus mongholicus (AM), and their formulas are widely used to treat heart failure caused by various cardiac diseases in traditional Chinese medicine practice. However, the molecular mechanism of action of DS and AM has not been completely understood. Herein, we first used mass spectrometry coupled to UPLC to characterize the chemical components of DS and AM decoctions, then applied MS-based quantitative proteomic analysis to profile protein expression in the heart of rats with isoproterenol-induced cardiomyopathy (ISO-iCM) before and after treated with DS alone or combined with AM, astragaloside IV (AS4), calycosin-7-glucoside (C7G), and Astragalus polysaccharides (APS) from AM. We demonstrated for the first time that DS decoction alone could reverse the most of differentially expressed proteins in the heart of the rats with ISO-iCM, including the commonly recognized biomarkers natriuretic peptides (NPPA) of cardiomyopathy and sarcomeric myosin light chain 4 (MYL4), relieving ISO-iCM in rats, but AM did not pronouncedly improve the pharmacological efficiency of DS. Significantly, we revealed that AS4 remarkably promoted the pharmacological potency of DS by complementarily reversing myosin motor MYH6/7, and further downregulating NPPA and MYL4. In contrast, APS reduced the efficiency of DS due to upregulating NPPA and MYL4. These findings not only provide novel insights to better understanding in the combination principle of traditional Chinese medicine but also highlight the power of mass spectrometric proteomics strategy combined with conventional pathological approaches for the traditional medicine research.

Baicalin Targets HSP70/90 to Regulate PKR/PI3K/AKT/eNOS Signaling Pathways.

Baicalin is a major active ingredient of traditional Chinese medicine Scutellaria baicalensis, and has been shown to have antiviral, anti-inflammatory, and antitumor activities. However, the protein targets of baicalin have remained unclear. Herein, a chemical proteomics strategy was developed by combining baicalin-functionalized magnetic nanoparticles (BCL-N3@MNPs) and quantitative mass spectrometry to identify the target proteins of baicalin. Bioinformatics analysis with the use of Gene Ontology, STRING and Ingenuity Pathway Analysis, was performed to annotate the biological functions and the associated signaling pathways of the baicalin targeting proteins. Fourteen proteins in human embryonic kidney cells were identified to interact with baicalin with various binding affinities. Bioinformatics analysis revealed these proteins are mainly ATP-binding and/or ATPase activity proteins, such as CKB, HSP86, HSP70-1, HSP90, ATPSF1ß and ACTG1, and highly associated with the regulation of the role of PKR in interferon induction and the antiviral response signaling pathway (P = 10-6), PI3K/AKT signaling pathway (P = 10-5) and eNOS signaling pathway (P = 10-4). The results show that baicalin exerts multiply pharmacological functions, such as antiviral, anti-inflammatory, antitumor, and antioxidant functions, through regulating the PKR and PI3K/AKT/eNOS signaling pathways by targeting ATP-binding and ATPase activity proteins. These findings provide a fundamental insight into further studies on the mechanism of action of baicalin.

Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy.

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.

In Vitro Evaluation of Probiotic Potential of Lactic Acid Bacteria Isolated from Yunnan De'ang Pickled Tea.

This study aimed to investigate the probiotic potential of lactic acid bacteria (LAB) strains isolated from De'ang pickled tea, a traditional food consumed by the De'ang nationality of Yunnan, China. Twenty-six LAB strains isolated from De'ang pickled tea were subjected to identification based on 16S rRNA gene sequence analysis. Twenty-four belonged to Lactobacillus plantarum, one belonged to Enterococcus casseliflavus, and one belonged to Lactobacillus acidophilus. Eighteen out of 26 LAB strains which showed a higher capability to tolerate simulated gastrointestinal juices were chosen to further evaluate their probiotic properties. Varied adhesive abilities and auto-aggregative capacities of selected LAB strains were dependent on species and even strains. All tested LAB strains were resistant to kanamycin, streptomycin, gentamycin, and vancomycin and sensitive to tetracycline and chloramphenicol. Ten out of the 18 strains are resistant to ampicillin, and the remaining strains are sensitive to ampicillin; 4 out of the 18 strains showed resistance to erythromycin. Compared to reference strain Lactobacillus rhamnosus strain GG, these LAB strains had a greater or comparative antimicrobial activity against Salmonella typhimurium or Escherichia coli. In contrast, eight out of the 18 strains suppressed growth of Shigella flexneri. Two L. plantarum strains, ST and STDA10, not only exhibited good probiotic properties but also showed a good ability of scavenging DPPH and ABTS+. This study suggests that L. plantarum ST and STDA10 could be used as potential probiotics applied in functional foods.

Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors.

We report here the design and synthesis of a series of 4-anilinoquinazoline derivatives, of which 7 compounds were crystallographically characterized, as epidermal growth factor receptor (EGFR) inhibitors by modifications on the aniline ring or at the 6-alkoxy site of the 6,7-dimethoxy-4-anilinoquinazoline pharmacophore. The relative inhibition efficiency on EGFR of all as-prepared compounds were measured and ordered, and the IC50 values of nine highly active compounds were determined by ELISA. Docking studies indicated that all 4-anilinoquinazoline derivatives could be inserted into the ATP-binding pocket of the EGFR via indirect docking, and that the modifications at the 3'-position of the anilino group and 6-alkoxy site of the quinazoline ring have little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring and Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769. The displacing of the phenyl at 4-position with pyridinyl dramatically reduces the activity of the quinazoline pharmacophore, the resulting derivative (10) being the least active compound. The docking results also showed that the formation of new H-bonds between the N-H of the ethylenediamine group linked to the 6-alkoxy site and Asp776/Cys773 in the binding pocket of EGFR makes compounds 19 (IC50=12.1±1.6 nM) and 20 (IC50=13.6±0.8 nM) the most potent EGFR inhibitors in this class and worthy of further modification to obtain more potent anticancer compounds.