This insight review introduces the new concepts, theories, technology, instruments, frontier issues, and key strategies of ADMET (absorption, distribution, metabolism, elimination, and toxicity) biosensors, from the fermi to the quantum levels. Information about ADMET, originating from one author's invention, a patented pharmacotherapy for rescuing cardio-cerebral vascular stunning and regulating vascular endothelial growth-factor signaling at the post-genomic level, can be detected by a new generation of ADMET biosensor. This is a single-cell/single-molecule fi eld-effect transistor (FET) hybrid system, where single molecules or single cells are assembled at the FET surface in a high density array manner via complementary metal-oxide-semiconductor (CMOS)-compatible technologies. Within a given nanometer distance, ADMET-mediated oxidation-reduction (redox) potentials, electrochemistry responses, and electron transfer processes can be simultaneously and directly probed by the gates of fi eld-effect transistor arrays. The nanometer details of the functional coupling principles and characterization technologies of DNA single-molecule/singlecell FETs, as well as the design of lab-on-a-chip instruments, are indicated. Four frontier issues and key strategies are elucidated in detail. This can lead to innovative technology for high-throughout screening of labs-on-chips to resolve the pharmaceutical industry's current bottleneck via novel, FET-based drug discovery and single-molecule/single-cell screening methods, which can bring about a pharmaceutical industry revolution in the 21st century.

1. The present study aimed to demonstrate that interactions of cations hydrogen peroxied (H2O2) and the Na+-Ca2+ exchanger stimulate Ca2+ release and oscillations of cytosolic Ca2+[Ca2+]I in non-transfected Chinese Hamster Ovary (CHO) C1 cells and in transfected CHO (CK1.4) cells that contained an expression vector coding the Na+-Can2+ exchanger sequence. 2. The [45Ca2+] uptake assay, fura-2 fluorescence imaging and 2 2and 2 3 factorial orthogonal statistics provide compara-tive, direct, efficient, quantitative and transient methods to delineate the effects of such interactons on Ca2+ influx, Ca2+ release and [Ca2+]i in C1 and CK1.4 cells. 3. In contrast to the control of either Na2+-, Ca2+- or H2O2-free or C1 cells, ana elevated [45Ca2+] uptake was induced by Ca2+, Na+ and H2O2 individually and in combination, intra-cellular Ca2+ release was activated by H2O2 and by combinations of either H2O2 and Na+, H2O2 and the Na+-Ca2+ exchanger, Na+ and the Na+-Ca2+ exchanger or by H2O2, Na+ and the Na+-Ca2+ exchanger and a rise in [Ca2+]i was triggered by H2O2 Na+ and a combination of Na+ and the Na+-Ca2+ exchanger. 4. These results indicated that interactions between H2O2, Na+ and the Na+-Ca2+ exchanger stimulate intracellular Ca2+Na+ and the Na+-Ca2+ exchanger stimulate intracellular Ca2+ mobilization via Ca2+-induced Ca2+ release mechanisms, ATP-activated G-protein coupled P2y-purinoceptor-sensitive path-ways, Na+-Ca2+ exchanger-mediated Ca2+ influx and cation-π interaction (a strong non-covalent force between the cation and theπ face of an aromatic structure in the transmembrane protein). 5. The present findings, provide important clues for under-standing Ca2+ signal transduction mechanisms from the plasma membrane to the endoplasmic reticulum.

Summary-Mode-actions of the Na+-Ca2+ exchanger from genes to mechanisms to a new strategy for brain disorders were comparatively s*udlea in oxidative stress, Io tran~femed Chinese hamster ovary (CHO) cells steadily expressing the Na+-Ca2+ exchanger's gone. Ca+-efflux via an active mode of the Na+-Ca2+ exchanger was elicited by hydrogen peroxide (H2O2) after preincubation of the cell with a Ca2+-free medium, whereas Ca2+-influx via a reverse mode of the Na+-Ca2+ exchanger was dramatically evoked by H2O2 after preincuhatlon of the cell with a Ca2+ medium, as a prelude to neuronal death. Accnrding to (45Ca2+) uptake of transfected CHO cells at given time inlervals or extracelluiar Na+[Na+]. gradients, hyperbola, logarithmic and sigmoid curve equations of the Na+-Ca2+ exchanger's mode-actions were respeetively defined in the absence and the presence of H2O2. The Na+-Ca2+ exchanger's eonfornational transition in oxidative stress was dominated by adenosine triphosphate (ATP)-dependent cytoskeletal redox modification, eation-π interactions and secondary Ca2+ activation These echanisms were used to generate an intracellularly distributed tetra-cluster (named VISA931) for rescuing G-protein agonist-sensitive signal transduetion and cortico-cerebral somatosensury evoke potential (SEP) from oxidation via activating forward o0eration of the Na+-Ca2+ exchanger, the β-adrenergic and the P2-purinergic receptors, bilking Ca2+ influx and catalyzing the dismutation ol superoxide anions (O2) to H2O2, In conclusion, knowledge-bascd drug design is a new strategy for developing promising candidates of neuroprotective agents

Summary-Interactions of the Na+-Ca2+ exchanger with small molecules on celt Ca2+ signaling were elucidated in Chinese hamster ovary (CHO) CI cells, which transfected a control vector without any expression of the Na*-Ca2+ exchanger's gene while CHO CK 1.4 cells transfected an expression vector encoding the bovine cardiac Na+-Caz+ exchanger's eDNA, treated with lithium or sodlum-buffer medRIm respectively, by using L16(2)15 muhifaetnrial orthogonal stallstics and fura-2 fluorescence real-time intaging In contrast to controls of Li*-treated Cl cells, [he store dependent CaZ+-influx (SDCI) was enhanced by either the Na*-Ca2+ exchanger, Na+, 1-β-3-(4-methoxyphenvl)propnxy1-4-methoxyphcnethyl}-IH-im daze e HC (SK&F96365 of nuahain. and by interactions of the Na*-Ca2+ exchanger with either Na" SK&F96365 or both SK&F96365 and ouabain; and ATP induced Ca2+. release (AICR) was activated by SK&F96365 or Na+ alone, interactions of the Na+-Ca2+ exchanger with SK&F96365 or Na+, and an interaetion between SK&F96365 and ouabain The dramatic interaction of the Na+-Ca2+ exchanger with small molecules indieates that cell Ca2+ signaling is generated by nositol triphnsphale (InsP3)-dependent pathways, allnsterie effects el the G protein coupled P2y&2u. purinoceptor and mnlti-sile recognition Our findings provide meaningful clues for designing new strategies of cardiocerebral vascular oxidative diseases

Summary-Ras-VEGF concerned angiogenesis is correlated with oncogene maintenance, tumori-gagesis, metastasis and resistance to anti cancer therapies; however, this association is not clearly elucidated by serum VEGF, due to VEGF signalling in blood cells themselves The present study aimed to elucidate tumorigenic VEGF eignalling in eight human HCC cell types and reveal the kinetics of tumorigenic VEG F signalling in three time intervals, thereby discovering the relationships Of VEGF concemed argiogenesis signalling with the extent of the human HCC cell growth, metastasis and resistance to anti-cancer drugs, by using the poorly metastatic SMMC7721, 7402/D+ (doxorubicin- resistance) and 7402/b (dOxoruhicin withdrawal), the highly metastatic MHCC1 non-transfected human HCC cell lines, and the highly melaetatic A3-1, FS, Ftf and E3 human HCC cell lines trans teated with exgressing green fluorescence protein into the phenotype of MHCC1 ceils, and quantita- tive 'sandwtch" ELISA analyses. The unique results indicated attdbetes and objective taws as follows Human HCC cell growth requites time dependent tumorigenic VEGF signalling; levets ot VEGF sig nailing are positively correlated with each cell phenotyge itself; and levels at VEGF signalling are inversely correlated with the possibility of rnetaslaSis and drug resistance. The contrast data first feveal important elues for exploring dual metastatic mechanisms via tumor celt-generated non- endothelium vasculogenesis and VEGF-endetheliurn-attached anglogeneeis that may be essential for developing novel strategies aimed at VEGF-concerned signal networks in iSchemic/metastatic dis- eases arid transgenic models.