Freelance Investigator in Translational Science and Medicine, Charleston, West Virginia, United States of America.
PLoS One. 2020 Oct 6;15(10):e0236446. doi: 10.1371/journal.pone.0236446. eCollection 2020.
Molecular diameter, lipophilicity and hydrophilicity exclusion affinity limits exist for small molecule carrier-mediated diffusion or transport through channel pores or interaction with the cell surface glycocalyx. The molecular structure lipophilicity limit for non-specific carrier-mediated transmembrane diffusion through polarity-selective transport channels of the cell membrane is Lexternal structure ∙ Hpolar group-1 of ≥ 1.07. The cell membrane channel pore size is > 0.752 and < 0.758 nm based on a 3-D ellipsoid model (biphenyl), and within the molecular diameter size range 0.744 and 0.762 nm based on a 2-D elliptical model (alkanol). The adjusted van der Waals diameter (vdWD, adj; nm) for the subset of halogenated vapors is predictive of the required MAC for anesthetic potency at an initial (-) Δ Cmicro effect. The molecular structure L ∙ Hpolar group-1 for Neu5Ac is 0.080, and the L ∙ Hpolar group-1 interval range for the cell surface glycocalyx hydrophilicity barrier interaction is 0.101 (Saxitoxin, Stx; Linternal structure ∙ Hpolar group-1) - 0.092 (m-xylenediamine, Lexternal structure · Hpolar group). Differential predictive effective pressure mapping of gene activation or repression reveals that p-dioxin exposure results in activation of AhR-Erβ (Arnt)/Nrf-2, Pparδ, Errγ (LxRα), Dio3 (Dio2) and Trα limbs, and due to high affinity Dio2 and Dio3 (OH-TriCDD, Lext · H-1: 1.91-4.31) exothermy-antagonism (Δ contraction) with high affinity T4/rT3-TRα-mediated agonism (Δ expansion). co-planar PCB metabolite exposure (Lext · H-1: 1.95-3.91) results in activation of AhR (Erα/β)/Nrf2, Rev-Erbβ, Errα, Dio3 (Dio2) and Trα limbs with a Δ Cmicro contraction of 0.89 and Δ Cmicro expansion of 1.05 as compared to p-dioxin. co-, ortho-planar PCB metabolite exposure results in activation of Car/PxR, Pparα (Srebf1,-Lxrβ), Arnt (AhR-Erβ), AR, Dio1 (Dio2) and Trβ limbs with a Δ Cmicro contraction of 0.73 and Δ Cmicro expansion of 1.18 (as compared to p-dioxin). Bisphenol A exposure (Lext struct ∙ H-1: 1.08-1.12, BPA-BPE, Errγ; BPAF, Lext struct ∙ H-1: 1.23, CM Erα, β) results in increased duration at Peff for Timm8b (Peff 0.247) transcription and in indirect activation of the AhR/Nrf-2 hybrid pathway with decreased duration at Peff 0.200 (Nrf1) and increased duration at Peff 0.257 (Dffa). The Bpa/Bpaf convergent pathway Cmicro contraction-expansion response increase in the lower Peff interval is 0.040; in comparison, small molecule hormone Δ Cmicro contraction-expansion response increases in the lower Peff intervals for gene expression ≤ 0.168 (Dex· GR) ≥ 0.156 (Dht · AR), with grade of duration at Peff (min·count) of 1.33x105 (Dex/Cort) and 1.8-2.53x105 (Dht/R1881) as compared to the (-) coupled (+) Δ Cmicro Peff to 0.136 (Wnt5a, Esr2) with applied DES (1.86x106). The subtype of trans-differentiated cell as a result of an applied toxin or toxicant is predictable by delta-Cmicro determined by Peff mapping. Study findings offer additional perspective on the basis for pressure regulated gene transcription by alterations in cell micro-compliance (Δ contraction-expansion, Cmicro), and are applicable for the further predictive modeling of gene to gene transcription interactions, and small molecule modulation of cell effective pressure (Peff) and its potential.
分子直径、亲脂性和疏水性排除亲和力限制存在于小分子载体介导的扩散或通过通道孔或与细胞表面糖萼的相互作用的运输中。非特异性载体介导的通过细胞膜极性选择性转运通道的跨膜扩散的分子结构亲脂性限制是 Lexternal structure ∙ Hpolar group-1 大于 1.07。细胞膜通道孔径基于 3-D 双苯模型（联苯）为 >0.752 且 <0.758nm，基于 2-D 椭圆模型（烷醇）为 0.744 至 0.762nm。调整的范德华直径（vdWD，adj；nm）对于卤代蒸气子集可预测初始（-）ΔCmicro 效应的麻醉效力所需的 MAC。Neu5Ac 的 L ∙ Hpolar group-1 为 0.080，细胞表面糖萼亲水性屏障相互作用的 L ∙ Hpolar group-1 间隔范围为 0.101（石房蛤毒素，Stx；Linternal structure ∙ Hpolar group-1）-0.092（间-二甲苯二胺，Lexternal structure · Hpolar group）。基因激活或抑制的差异预测有效压力图揭示了 p-二恶英暴露导致 AhR-Erβ（Arnt）/Nrf-2、Pparδ、Errγ（LxRα）、Dio3（Dio2）和 Trα 分支的激活，并且由于高亲和力的 Dio2 和 Dio3（OH-TriCDD，Lext · H-1：1.91-4.31）放热拮抗（Δ收缩）与高亲和力的 T4/rT3-TRα 介导的激动剂（Δ扩张）。共平面 PCB 代谢物暴露（Lext · H-1：1.95-3.91）导致 AhR（Erα/β）/Nrf2、Rev-Erbβ、Errα、Dio3（Dio2）和 Trα 分支的激活，与 p-二恶英相比，ΔCmicro 收缩为 0.89，ΔCmicro 扩张为 1.05。共-，邻-平面 PCB 代谢物暴露导致 Car/PxR、Pparα（Srebf1，-Lxrβ）、Arnt（AhR-Erβ）、AR、Dio1（Dio2）和 Trβ 分支的激活，与 p-二恶英相比，ΔCmicro 收缩为 0.73，ΔCmicro 扩张为 1.18。双酚 A 暴露（Lext struct ∙ H-1：1.08-1.12，BPA-BPE，Errγ；BPAF，Lext struct ∙ H-1：1.23，CM Erα，β）导致 Timm8b（Peff 0.247）转录的 Peff 持续时间增加，并通过降低 Peff 0.200（Nrf1）和增加 Peff 0.257（Dffa）的持续时间间接激活 AhR/Nrf-2 杂合途径。Bpa/Bpaf 收敛途径的ΔCmicro 收缩-扩张响应增加在较低的 Peff 间隔为 0.040；相比之下，小分子激素ΔCmicro 收缩-扩张响应在基因表达的较低 Peff 间隔中增加≤0.168（Dex·GR）≥0.156（Dht·AR），与 Peff（min·count）的持续时间（1.33x105（Dex/Cort）和 1.8-2.53x105（Dht/R1881）相比，与（-）偶联（+）ΔCmicro Peff 至 0.136（Wnt5a，Esr2）与应用 DES（1.86x106）相比。应用毒素或毒物后转分化细胞的亚型可通过 Peff 映射确定的ΔCmicro 预测。研究结果为基于细胞微顺应性（Δ收缩-扩张，Cmicro）变化的压力调节基因转录提供了额外的视角，并可用于进一步预测基因间转录相互作用以及小分子对细胞有效压力（Peff）及其潜力的调节。
