Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the ...chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization.
Doxorubicin is the most frequently used chemotherapeutic agent for the treatment of hepatocellular carcinoma. However, one major obstacle to the effective management of liver cancer is the drug ...resistance derived from the cancer stem cells. Herein, we employed a CD133 aptamer for targeted delivery of doxorubicin into liver cancer stem cells to overcome chemoresistance. Furthermore, we explored the efficacy of autophagy inhibition to sensitize liver cancer stem cells to the treatment of CD133 aptamer-doxorubicin conjugates based on the previous observation that doxorubicin contributes to the survival of liver cancer stem cells by activating autophagy. The kinetics and thermodynamics of aptamer-doxorubicin binding, autophagy induction, cell apoptosis, and self-renewal of liver cancer stem cells were studied using isothermal titration calorimetry, Western blot analysis, annexin V assay, and tumorsphere formation assay. The aptamer-cell binding andintracellular accumulation of doxorubicin were quantified via flow cytometry. CD133 aptamer-guided delivery of doxorubicin resulted in a higher doxorubicin concentration in the liver cancer stem cells. The combinatorial treatment strategy of CD133 aptamer-doxorubicin conjugates and an autophagy inhibitor led to an over 10-fold higher elimination of liver cancer stem cells than that of free doxorubicin in vitro. Future exploration of cancer stem cell-targeted delivery of doxorubicin in conjunction with autophagy inhibition in vivo may well lead to improved outcomes in the treatment of hepatocellular carcinoma.
Graphene-based van der Waals (vdW) heterostructures have attracted much attention because they can enhance the properties of separated materials, possess numerous new phenomena and unusual properties ...and improve the performance of devices. Motivated by the successful fabrication of single-layer transition metal nitrides (TMNs)
Science
, 2020,
369
, 670, we investigate the interfacial properties of heterostructures formed by stacking graphene (GR) on two different TMN monolayers, MoGe
2
N
4
(MGN) and MoSi
2
N
4
(MSN). Both the GR/MGN and GR/MSN heterostructures are characterized by weak vdW interactions, which preserve the intrinsic electronic properties of both the GR and TMN monolayers. The GR/MGN heterostructure forms an n-type Schottky contact, while a p-type Schottky contact is formed at the GR/MSN interface. Both the barrier and contact types in the GR/MGN heterostructure are sensitive to the electric gating and interlayer coupling. The transformation from an n-type Schottky contact to a p-type one or to an n-type ohmic contact can be achieved in the GR/MGN heterostructure by applying electric gating. In addition, adjusting the interlayer spacings between the GR and MGN layers leads to a transition from n-type to p-type Schottky contact. Our findings demonstrate that the GR/TMN heterostructures can be considered as promising high-performance nanodevices.
Graphene-based van der Waals (vdW) heterostructures have attracted much attention because they can enhance the properties of separated materials, possess numerous new phenomena and unusual properties and improve the performance of devices.
Given the limitations and side effects of many synthetic drugs, natural products are an important alternative source for drugs and medications for many diseases. Icariin (ICA), one of the main ...flavonoids from plants of the Epimedium genus, has been shown to ameliorate osteoporosis and improve bone health in preclinical studies. Those studies have used different in vivo models, mostly rodents, but the underlying mechanisms remain unclear. The present study shows, for the first time, that ICA reduces bone damage in a Rankl‐induced medaka fish (Oryzias latipes), a non‐rodent osteoporosis model. Live imaging was previously performed in this model to characterize antiresorptive and bone‐anabolic properties of drugs. Here, a new quantification method (IM) was established based on the length of mineralized neural arches to quantify levels of bone mineralization damage and protection in early post‐embryonic fish. This method was validated by quantification of three levels of bone damage in three independent Rankl fish lines, and by the determination of different degrees of severity of osteoporosis‐like phenotypes in one Rankl line exposed to variable Rankl induction schemes. IM was also used to quantify the efficacy of alendronate and etidronate, two common anti‐osteoporotic bisphosphonates, and revealed comparable bone protective effects for ICA and alendronate in this fish osteoporosis model. This study's data support the value of the medaka fish model for bone research and establish a method to screen for novel osteoprotective compounds.
This study investigated the relationship between molecular arrangement and surface tension of water mixtures with methanol and ethanol. It has been found that the molecular structure of interfacial ...zone was deterministically correlated to alcohol concentration. From the water dipole moment, an interfacial boundary was defined. The boundary then was used to calculate the water and alcohols in the interfacial zone, which was then used to calculate the surface tension. The prediction from simulated data closely followed the experimental data. The analysis revives the relevance of the molecular arrangement, which had been the main focus in the early 20th century, in quantification of surface energy. The results can supplement the current thermodynamic analysis to correctly predict the surface adsorption.
The role of the monoaminergic system in the feeding behavior of neonatal chicks has been reported, but the functional relationship between the metabolism of monoamines and appetite-related ...neuropeptides is still unclear. This study aimed to investigate the changes in catecholamine and indolamine metabolism in response to the central action of neuropeptide Y (NPY) in different feeding statuses and the underlying mechanisms. In Experiment 1, the diencephalic concentrations of amino acids and monoamines following the intracerebroventricular (ICV) injection of NPY (375 pmol/10 μl/chick), saline solution under ad libitum, and fasting conditions for 30 min were determined. Central NPY significantly decreased L-tyrosine concentration, the precursor of catecholamines under feeding condition, but not under fasting condition. Central NPY significantly increased dopamine metabolites, including 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA). The concentration of 3-methoxy-4-hydroxyphenylglycol was significantly reduced under feeding condition, but did not change under fasting condition by NPY. However, no effects of NPY on indolamine metabolism were found in either feeding status. Therefore, the mechanism of action of catecholamines with central NPY under feeding condition was elucidated in Experiment 2. Central NPY significantly attenuated diencephalic gene expression of catecholaminergic synthetic enzymes, such as tyrosine hydroxylase, L-aromatic amino acid decarboxylase, and GTP cyclohydrolase I after 30 min of feeding. In Experiment 3, co-injection of α-methyl-L-tyrosine, an inhibitor of tyrosine hydroxylase with NPY, moderately attenuated the orexigenic effect of NPY, accompanied by a significant positive correlation between food intake and HVA levels. In Experiment 4, there was a significant interaction between NPY and clorgyline, an inhibitor of monoamine oxidase A with ICV co-injection which implies that co-existence of NPY and clorgyline enhances the orexigenic effect of NPY. In conclusion, central NPY modifies a part of catecholamine metabolism, which is illustrated by the involvement of dopamine transmission and metabolism under feeding but not fasting conditions.
Matsumurasca onukii (Matsuda, R. (1952). Oyo‐Kontyu Tokyo, 8(1): 19–21), one of the dominant pests in major tea production areas in Asia, currently is known to occur in Japan, Vietnam, and China, and ...severely threatens tea production, quality, and international trade. To elucidate the population genetic structure of this species, 1633 single nucleotide polymorphisms (SNPs) and 18 microsatellite markers (SSRs) were used to genotype samples from 27 sites representing 18 geographical populations distributed throughout the known range of the species in East Asia. Analyses of both SNPs and SSRs showed that M. onukii populations in Yunnan exhibit high‐genetic differentiation and structure compared with the other populations. The Kagoshima (JJ) and Shizuoka (JS) populations from Japan were separated from populations from China by SNPs, but clustered with populations from Jinhua (JH), Yingde (YD), Guilin (GL), Fuzhou (FZ), Hainan (HQ), Leshan (CT), Chongqing (CY), and Zunyi (ZY) tea plantations in China and the Vietnamese Vinh Phuc (VN) population based on the SSR data. In contrast, CT, CY, ZY, and Shaanxi (SX) populations clustered together based on SNPs, but were separated by SSRs. Both marker datasets identified significant geographic differentiation among the 18 populations. Various environmental and anthropogenic factors, including geographical barriers to migration, human transport of hosts (Camellia sinesis L. O. Kuntze) and adaptation of M. onukii to various local climatic zones possibly account for the rapid spread of this pest in Asia. The results demonstrate that SNPs from high‐throughput genotyping data can be used to reveal subtle genetic substructure at broad scales in r‐strategist insects.
In this study, SNPs and microsatellite markers were used to capture multiscale patterns of genetic structure of Matsumurasca onukii, one of the dominant pests in major tea production areas in Asia. General migration route showed that there are two diffusion sources including Yunnan and the other tea plantations of China, respectively, from where introduced to Japan tea plantations. Our findings indicate that the host plants and geographical distances are significant involved to the genetic variation of M. onukii between different Clusters and that SNPs from high‐throughput genotyping data can be used to reveal subtle genetic substructure at broad scales in r‐strategist insects.
To compare the safety and efficacy of combined laser iridoplasty followed by surgical iridectomy (LI-SI) versus trabeculectomy in the management of medically unresponsive acute primary angle closure ...(APAC) with minimal cataract.
This was a randomized controlled trial conducted among patients with medically unresponsive APAC without significant cataract. Study participants were randomized into: LI-SI or unaugmented trabeculectomy. Primary outcome of the study was the rate of post-operative surgical complications in the first 3 months after surgery. Secondary outcome assessed at 1 year was whether treatment was completely successful (IOP < 21 mmHg without IOP lowering drops), or partially successful (IOP < 21 mmHg with IOP lowering drops). Failure was defined as IOP ≥ 21 mmHg with IOP lowering drops.
The study included 67 eyes of 67 patients (59 females/8 males = 7.4/1) who were randomized into 2 groups: LI-SI (Group 1, 37 eyes), and trabeculectomy (Group 2, 30 eyes). There was no statistical difference between the two groups at baseline. Overall, there were more post-operative complications in Group 1 versus Group 2 (45.9% versus 33.3% - p = 0.23), although all responded well to medical treatment and resolved without sequelae. Complete success was found in 97.1% (34/35 eyes) in Group 1 and 92.6% in group 2 (p = 0.19, Fisher's exact test).
There was a higher rate of post-operative complications after LI-SI compared to trabeculectomy performed for medically unresponsive APAC with minimal cataract. Both procedures had similar surgical outcomes at 1 year.
Water temperature directly affects the body temperature in fish, so increasing water temperatures in oceans and rivers will lead to increases in fish body temperatures. Whilst a range of responses of ...fish to increases in water temperature have been measured, amino acid metabolism in a fish under high water temperature (HT) conditions has not been investigated. The aim of this study was to determine the effects of an acute increase in water temperature on oxygen consumption, plasma cortisol concentrations, and free amino acid concentrations in plasma and several tissues in goldfish (
Carassius auratus
). Oxygen consumption and plasma cortisol concentrations were increased in goldfish exposed to HT (30 ± 1 °C) for 200 min compared with goldfish at a control water temperature (CT 17 ± 1 °C). Oxygen consumption and plasma cortisol concentrations in both groups of fish combined were positively correlated. When goldfish were exposed to HT for 300 min oxygen consumption and plasma concentrations of 15 free amino acids were increased compared with goldish at CT. Concentrations of several free amino acids were increased to varying extents in the brain, liver, and muscle tissues. In conclusion, an acute increase in water temperature affected amino acid metabolism differently in the brain, liver, and muscle tissues. Goldfish will be a useful species for further studies of the possible roles of various amino acids in the brain, muscle, and liver during acute increases in water temperature in fish.
Motivated by the successful synthesis of two-dimensional MoSi2N4 Y.-L. Hong et al., Science, 2020, 369, 670–674 and Janus MoSSe A.-Y. Lu et al., Nat. Nanotechnol., 2017, 12, 744–749, in this work, we ...propose novel 2D Janus XMoGeN2 (X = S, Se and Te) monolayers using first-principles prediction. The controllable electronic features of Janus XMoGeN2 (X = S, Se and Te) monolayers under an external electric field and strain are also examined. Our predictions demonstrated that 2D XMoGeN2 materials are structurally and dynamically stable. All these 2D XMoGeN2 materials are indirect semiconductors with band gaps of 1.60/2.10, 1.54/2.07 and 1.05/1.56 eV obtained by the PBE/HSE functional for SMoGeN2, SeMoGeN2 and TeMoGeN2 monolayers, respectively. Furthermore, the electronic band gap and band structures of these monolayers are controllable under an external electric field and strain, making them promising candidates for flexible optoelectronics and nanoelectronics. The electric field tunes the TeMoGeN2 monolayer from semiconductor to metal and leads to a change in the band gap. While strain modifies the band gap of the TeMoGeN2 monolayer, giving rise to a shift in the CB from the Γ–M path to the M point and a tendency to transform from semiconductor to metal. Our findings suggest that these novel 2D XMoGeN2 materials are potential candidates for use in future high-performance applications.
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