Flexible Solid-Electrolyte-Gated-Dielectric Carbon Nanotube Thin Film Transistors and Integrated Circuits with the Recorded Radiation Tolerance and Reparability.

Radiation-tolerance and repairable flexible transistors and integrated circuits (ICs) with low power consumption have become hot topics due to their wide applications in outer space, nuclear power plants, and X-ray imaging. Here, we designed and developed novel flexible semiconducting single-walled carbon nanotube (sc-SWCNT) thin-film transistors (TFTs) and ICs. Sc-SWCNT solid-electrolyte-gate dielectric (SEGD) TFTs showcase symmetric ambipolar characteristics with flat-band voltages (VFB) of ∼0 V, high ION/IOFF ratios (>105), and the recorded irradiation resistance (up to 22 Mrad). Moreover, flexible sc-SWCNT ICs, including CMOS-like inverters and NAND and NOR logic gates, have excellent operating characteristics with low power consumption (≤8.4 pW) and excellent irradiation resistance. Significantly, sc-SWCNT SEGD TFTs and ICs after radiation with a total irradiation dose (TID) ≥ 11 Mrad can be repaired after thermal heating at 100 °C. These outstanding characteristics are attributed to the designed device structures and key core materials including SEGD and sc-SWCNT.

Synthesis, characterization and irradiation enhances anticancer activity of liposome-loaded iridium(III) complexes.

Herein, we synthesized and characterized two novel iridium (III) complexes: [Ir(bzq)2(PPD)](PF6) (4a, with bzq = deprotonated benzo[h]quinoline and PPD = pteridino[6,7-f][1,10]phenanthroline-11,13-diamine) and [Ir(piq)2(PPD)](PF6) (4b, with piq = deprotonated 1-phenylisoquinoline). The anticancer efficacy of these complexes, 4a and 4b, was investigated using 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT). Complex 4a exhibited no cytotoxic activity, while 4b demonstrated moderate efficacy against SGC-7901, A549, and HepG2 cancer cells. To enhance their anticancer potential, we explored two strategies: (I) light irradiation and (II) encapsulation of the complexes in liposomes, resulting in the formation of 4alip and 4blip. Both strategies significantly increased the ability of 4a, 4b to kill cancer cells. The cellular studies indicated that both the free complexes 4a, 4b and their liposomal forms 4alip and 4blip effectively inhibited cell proliferation. The cell cycle arrest analysis uncovered 4alip and 4blip arresting cell growth in the S period. Additionally, we investigated apoptosis and ferroptosis pathways, observing an increase in malondialdehyde (MDA) levels, a reduction of glutathione (GSH), a down-regulation of GPX4 (glutathione peroxidase) expression, and lipid peroxidation. The effects on mitochondrial membrane potential and intracellular Ca2+ concentrations were also examined, revealing that both light-activated and liposomal forms of 4alip and 4blip caused a decline in mitochondrial membrane potential and an enhancement in intracellular Ca2+ levels. In conclusion, these complexes and them encapsulated liposomes induce cell death through apoptosis and ferroptosis.

Mitochondria-targeted iridium(III) complexes encapsulated in liposome induce cell death through ferroptosis and gasdermin-mediated pyroptosis.

This paper unveils a novel perspective on synthesis and characterization of the ligand 5-bromo-2-amino-2'-(phenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (BAPIP), and its iridium(III) complexes [Ir(PPY-)2(BAPIP)](PF6) (1a, with PPY- as deprotonated 2-phenylpyridine), [Ir(PIQ-)2(BAPIP)](PF6) (1b, piq- denoting deprotonated 1-phenylisoquinoline), and [Ir(BZQ-)2(BAPIP)](PF6) (1c, bzq- signifying deprotonated benzo[h]quinoline). Systematic evaluation of the cytotoxicity of 1a, 1b, and 1c across diverse cell lines encompassing B16, HCT116, HepG2, A549, HeLa, and LO2 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, compounds 1b and 1c demonstrated no cytotoxicity against the above cell lines. Motivated by the pursuit of heightened anti-proliferative potential, a strategic encapsulation approach yielded liposomes 1alip, 1blip, and 1clip. As expectation, 1alip, 1blip, and 1clip displayed remarkable anti-proliferative efficacy, particularly noteworthy in A549 cells, exhibiting IC50 values of 4.9 ± 1.0, 5.9 ± 0.1, and 7.6 ± 0.2 µM, respectively. Moreover, our investigation illuminated the mitochondrial accumulation of these liposomal entities, 1alip, 1blip, and 1clip, evoking apoptosis through the mitochondrial dysfunction mediated by reactive oxygen species (ROS). The ferroptosis was confirmed by decrease in glutathione (GSH) concentrations, the downregulation of glutathione peroxidase 4 (GPX4), increase of high mobility group protein 1 (HMGB1), and lipid peroxidation. Simultaneously, pyroptosis as another mode of cell death was undertaken. RNA-sequencing was employed to investigate intricate signalling pathways. In vivo examination provided tangible evidence of 1alip in effectively curbing tumor growth. Collectively, this study provides a multifaceted mode of cellular demise orchestrated by 1a, 1alip, 1blip, and 1clip, involving pathways encompassing apoptosis, ferroptosis, and pyroptosis.

Targeted liposomes encapsulated iridium(III) compound greatly enhance anticancer efficacy and induce cell death via ferroptosis on HepG2 cells.

In this study, ligands 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (PIP), 2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (NPIP), 2-(2-nitronaphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NNIP) and their iridium(III) metal compounds [Ir(ppy)2(PIP)](PF6) (ppy = 2-phenylpyridine, 1a), [Ir(ppy)2(NPIP)](PF6) (1b), [Ir(ppy)2(NNIP)](PF6) (1c) were designed and synthesized. The anti-cancer activities of 1a, 1b and 1c on BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 were detected using MTT method. 1a shows moderate, 1b and 1c display low or no anti-cancer activities. To elevate the anti-cancer effectiveness, encapsulating the compounds 1a, 1b and 1c into the ordinary or targeted liposomes to produce 1alip, 1blip, 1clip, or targeted 1aTlip, 1bTlip and 1cTlip. The IC50 values of 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against HepG2 cells are 7.9 ± 0.1, 8.6 ± 0.2, 16.9 ± 0.5, 5.9 ± 0.2, 7.3 ± 0.1 and 9.7 ± 0.7 µM, respectively. Specifically, the anti-tumor activity assays in vivo found that the inhibitory rates are 23.24 % for 1a, 61.27 % for 1alip, 76.06 % for 1aTlip. It is obvious that the targeted liposomes entrapped iridium(III) compound greatly enhance anti-cancer efficacy. Additionally, 1alip, 1blip and 1clip or targeted 1aTlip, 1bTlip and 1cTlip can effectively restrain the cell colony and proliferation in the G0/G1 period. 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip can increase reactive oxygen species (ROS) concentration, arouse a decline in the mitochondrial membrane potential and promote Ca2+ release. RNA-sequence was applied to examine the signaling pathways. Taken together, the liposomes or targeted liposomes encapsulated compounds trigger cell death by way of apoptosis, autophagy, ferroptosis, disruption of mitochondrial function and PI3K/AKT/mTOR signaling pathways.

Synthesis, characterization, molecular docking, RNA-sequence and anticancer efficacy evaluation in vitro of ruthenium(II) complexes on B16 cells.

In recent years, the studies of the ruthenium(II) complexes on anticancer activity have been paid great attention, many Ru(II) complexes possess high anticancer efficiency. In this paper, three ligands CPIP (2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), DCPIP (2-(3,4-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), TCPIP (2-(2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and their three ruthenium (II) complexes [Ru(dip)2(CPIP)](PF6)2 (1, dip = 4,7-diphenyl-1,10-phenanthroline), [Ru(dip)2(DCPIP)](PF6)2 (2) and [Ru(dip)2(TCPIP)](PF6)2 (3) were synthesized and characterized. 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assay was used to investigate in vitro cytotoxicity of complexes against various cancer cells. The results showed that complexes 1-3 exhibited pronounced cytotoxic effect on B16 cells with low IC50 values of 7.2 ± 0.1, 11.7 ± 0.6 and 1.2 ± 0.2 µM, respectively. The 3D model demonstrated that the complexes can validly prevent the cell proliferation. Apoptosis determined using Annexin V-FITC/PI double staining revealed that complexes 1-3 can effectively induce apoptosis in B16 cells. The intracellular localization of 1-3 in the mitochondria, the levels of intracellular reactive oxygen species (ROS), the opening of mitochondrial permeability transition pore as well as the decline of mitochondrial membrane potential were investigated, which demonstrated that the complexes 1-3 led to apoptosis via a ROS-mediated mitochondrial dysfunction pathway. The RNA-sequence indicated that the complexes upregulate the expression of 74 genes and downregulate the expression of 81 genes. The molecular docking showed that the complexes interact with the proteins through hydrogen bond, π-cation and π-π interaction. The results show that ruthenium(II) complexes 1, 2 and 3 can block tumor cell growth and induce cell death through autophagy and ROS-mediated mitochondrial dysfunction pathways.

Significant increase of anticancer efficacy in vitro and in vivo of liposome entrapped ruthenium(II) polypyridyl complexes.

Two polypyridyl ruthenium(II) complexes [Ru(DIP)2(BIP)](PF6)2 (DIP = 4,7-diphenyl-1,10-phenanthrolie, BIP = 2-(1,1'-biphenyl-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ru1) and [Ru(DIP)2(CBIP)](PF6)2 (CBIP = 2-(4'-chloro-1,1'-biphenyl-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ru2) were synthesized. The cytotoxic activities in vitro of Ru1, Ru2 toward B16, A549, HepG2, SGC-7901, HeLa, BEL-7402, non-cancer LO2 were investigated using MTT method (3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide). Unexpectedly, Ru1, Ru2 can't prevent these cancer cells proliferation. To improve the anti-cancer effect, we used liposomes to entrap the complexes Ru1, Ru2 to form Ru1lipo, Ru2lipo. As expectation, Ru1lipo and Ru2lipo exhibit high anti-cancer efficacy, especially, Ru1lipo (IC50 3.4 ± 0.1 µM), Ru2lipo (IC50 3.5 ± 0.1 µM) display strong ability to block the cell proliferation in SGC-7901. The cell colony, wound healing, and cell cycle distribution show that the complexes can validly inhibit the cell growth at G2/M phase. Apoptotic studied with Annex V/PI doubling method showed that Ru1lipo and Ru2lipo can effectively induce apoptosis. Reactive oxygen species (ROS), malondialdehyde, glutathione and GPX4 demonstrate that Ru1lipo and Ru2lipo improve ROS and malondialdehyde levels, inhibit generation of glutathione, and finally result in a ferroptosis. Ru1lipo and Ru2lipo interact on the lysosomes and mitochondria and damage mitochondrial dysfunction. Additionally, Ru1lipo and Ru2lipo increase intracellular Ca2+ concentration and induce autophagy. The RNA-sequence and molecular docking were performed, the expression of Bcl-2 family was investigated by Western blot analysis. Antitumor in vivo experiments confirm that 1.23 mg/kg, 2.46 mg/kg of Ru1lipo possesses a high inhibitory rate of 53.53% and 72.90% to prevent tumor growth, hematoxylin-eosin (H&E) results show that Ru1lipo doesn't cause chronic organ damage and strongly promotes the necrosis of solid tumor. Taken together, we conclude that Ru1lipo and Ru2lipo cause cell death through the following pathways: autophagy, ferroptosis, ROS-regulated mitochondrial dysfunction, and blocking the PI3K/AKT/mTOR.

Synthesis, characterization, anticancer efficacy evaluation of ruthenium(II) and iridium(III) polypyridyl complexes toward A549 cells.

A new ligand DFIP (2-(dibenzo[b,d]furan-3-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its two complexes iridium(III) [Ir(ppy)2(DFIP)](PF6) (ppy = 2-phenylpyridine, Ir1) and ruthenium(II) [Ru(bpy)2(DFIP)](PF6)2 (bpy = 2,2'-bipyridine, Ru1) were synthesized and characterized. The anticancer effects of the two complexes on A549, BEL-7402, HepG2, SGC-7901, HCT116 and normal LO2 cells were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex Ir1 shows high cytotoxic activity on A549, BEL-7402, SGC-7901 and HepG2, Ru1 exhibits moderate anticancer activity toward A549, BEL-7402 and SGC-7901 cells. The IC50 values of Ir1 and Ru1 toward A549 are 7.2 ± 0.1 and 22.6 ± 1.4 µM, respectively. The localization of complexes Ir1 and Ru1 in the mitochondrial, intracellular accumulation of reactive oxygen species (ROS) levels, and the changes of mitochondrial membrane potential (MMP) and cytochrome c (cyto-c) were investigated. Apoptosis and cell cycle were detected by flow cytometry. Immunogenic cell death (ICD) was used to detect the effects of Ir1 and Ru1 on the A549 using a confocal laser scanning microscope. The expression of apoptosis-related proteins was detected by western blotting. Ir1 and Ru1 can increase the intracellular ROS levels and release cyto-c, reduce the MMP, leading to the apoptosis of A549 cells and blocking the A549 cells at the G0/G1 phase. Additionally, the complexes caused a decrease of the expression of polyADP-ribose polymerase (PARP), caspase 3, Bcl-2 (B-cell lymphoma-2), PI3K (phosphoinositide-3 kinase) and upregulated the expression of Bax. All these findings indicated that the complexes exert anticancer efficacy to induce cell death through immunogenic cell death, apoptosis, and autophagy.

Synthesis, RNA-sequence and evaluation of anticancer efficacy of ruthenium(II) polypyridyl complexes toward HepG2 cells.

In this article, four new Ru(II) complexes [Ru(dmbpy)2(TFBIP)](PF6)2 (dmbpy = 4,4'-dimethyl-2,2'-bipyridine, TFPIP = 2-(4'-trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) (Ru1), [Ru(bpy)2(TFBIP)](PF6)2 (bpy = 2,2'-bipyridine) (Ru2), [Ru(phen)2(TFBIP)](PF6)2 (phen = 1,10-phenanthroline) (Ru3) and [Ru(dmp)2(TFBIP)](PF6)2 (dmp = 2,9-dimethyl-1,10-phenanthroline) (Ru4) were synthesized and characterized by elemental analysis, HRMS, IR, 1H NMR, 13C NMR and 19F NMR. The in vitro anticancer effect of the complexes on HepG2, A549, B16, HeLa, BEL-7402 and non-cancer LO2 cells was screened using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results illustrate that the complexes display moderate anticancer activity. Apoptotic assay with Annexin V/PI double staining method indicated that complexes induce apoptosis in HepG2 cells. Also, the complexes interfere with the mitochondrial functions, accompanied by the production of intracellular ROS as well as a reduction of mitochondrial membrane potential. The results obtained from the western blot demonstrated that the complexes upregulate pro-apoptotic Bax and downregulate anti-apoptotic Bcl-2, which further activates caspase 3 and promotes the cleavage of PARP. RNA-sequence showed that the complexes upregulate the expression of 40 genes and downregulate 66 genes. Antitumour in vivo demonstrated that Ru1 inhibits the tumor growth with a high inhibitory rate of 51.19%. Taken together, these results revealed that complexes Ru1, Ru2, Ru3 and Ru4 induce cell death in HepG2 cells via autophagy and a ROS-mediated mitochondrial apoptotic pathway.

Iridium(III) complexes inhibit the proliferation and migration of BEL-7402 cells through the PI3K/AKT/mTOR signaling pathway.

Iridium(III) complexes are largely studied as anti-cancer complexes due to their excellent anti-cancer activity. In this article, two new iridium(III) complexes [Ir(piq)2(THPIP)]PF6 (THPIP = 2,4-di-tert-butyl-6-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol, piq = deprotonated 1-phenylisoquinoline) (Ir1) and [Ir(bzq)2(THPIP)]PF6 (bzq = deprotonated benzo[h]quinolone) (Ir2) were synthesized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that complex Ir1 exhibits moderate activity (IC50 = 29.9 ± 4.6 µM) and Ir2 shows high cytotoxicity (IC50 = 9.8 ± 1.8 µM) against BEL-7402 cells. Further studies on the mechanism showed that Ir1 and Ir2 induced apoptosis by changing the mitochondrial membrane potential, Ca2+ release, ROS accumulation, and cell cycle arrest at the S phase. The complexes can effectively inhibit cell colony formation and migration. The expression of B-cell lymphoma-2 (Bcl-2) family proteins, PI3K (phosphatidylinositol 3-kinase), AKT (protein kinase B), mTOR (mammalian target of rapamycin), and p-mTOR was studied by immunoblotting. Complexes Ir1 and Ir2 downregulated the expression of anti-apoptotic protein Bcl-2 and increased the expression of autophagy-related proteins of Beclin-1 and LC3-II. Further experiments showed that the complexes inhibited the production of glutathione (GSH) and increased the amounts of malondialdehyde (MDA). Fluorescence of HMGB1 was significantly increased. We also investigated the effect of the complexes on the expression of genes using RNA-sequence analysis, we further calculated the lowest binding energies between the complexes and proteins using molecular docking. Taken together, the above results indicated that complexes Ir1 and Ir2 induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction and inhibition of the PI3K/AKT/mTOR signaling pathway.

Design, synthesis and biological evaluation of liposome entrapped iridium(III) complexes toward SGC-7901 cells.

In this study, two new iridium(III) polypyridyl complexes [Ir(bzq)2(DIPH)](PF6) (bzq = deprotonated benzo[h]quinoline, DIPH = 4-(2,5-dibromo-4-(1H-imidazo[4,5-f][1,10]phenanthrolim-2-yl)-4-hydroxybutan-2-one) (Ir1) and [Ir(piq)2(DIPH)](PF6) (piq = deprotonated 1-phenylisoquinoline) (Ir2) were synthesized and characterized by elemental analysis, HRMS, 1H and 13C NMR. The cytotoxic activity of Ir1, Ir2, Ir1lipo and Ir2lipo against cancer cells SGC-7901, HepG2, A549, HeLa, B16 and normal NIH3T3 cells in vitro was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir1 and Ir2 showed no cytotoxic activity, but their liposome-entrapped Ir1 (Ir1lipo) and Ir2 (Ir2lipo) showed significant cellular activity, especially sensitive to SGC-7901 with IC50 values of 4.7 ± 0.2 and 12.4 ± 0.5 µM, respectively. The cellular uptake, endoplasmic reticulum (ER) localization, autophagy, tubulin polymerization, glutathione (GSH), malondialdehyde (MDA) and release of cytochrome c were investigated to explore the mechanisms of apoptosis. The calreticulin (CRT), heat shock protein 70 (HSP70), high mobility group box 1 (HMGB1) were also explored. Western blotting showed that Ir1lipo and Ir2lipo inhibited PI3K (phosphoinositide-3 kinase), AKT (protein kinase B), p-AKT and activated Bcl-2 (B-cell lymphoma-2) protein and apoptosis-regulated factor caspase 3 (cysteinyl aspartate specific proteinase-3) and cleaving PARP (poly ADP-ribose polymerase). The results demonstrated that Ir1lipo and Ir2lipo induce cell apoptosis through targeting the endoplasmic reticulum (ER), cause oxidative stress damage, inhibiting PI3K/AKT signaling pathway, immunogenic cell death (ICD) and inhibit the cell growth at G2/M phase.

Anticancer effect evaluation of iridium(III) complexes targeting mitochondria and endoplasmic reticulum.

Ligand HMSPIP (2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its iridium(III) complexes [Ir(ppy)2(HMSPIP)]PF6 (ppy = 2-phenylpyridine, Ir1) and [Ir(bzq)2(HMSPIP)]PF6 (bzq = benzo[h]quinoline, Ir2) were synthesized. The complexes were characterized by 1H NMR, 13C NMR, and UV/Vis spectra. The cytotoxicity of the complexes toward cancer cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, the scratch wound healing and colony-forming were also investigated. MTT assay certificated that the complexes show high toxic effect on the HeLa cells. The cell cycle assay illustrated that the complexes blocked cell growth at G0/G1 phase in HeLa cells. A series of subsequent experiments showed that the complexes first enter the endoplasmic reticulum (ER) and then enter the mitochondria, leading to an increase in intracellular Ca2+ and reactive oxygen species (ROS) content, depolarizing mitochondrial membrane potential (MMP), and ultimately resulting in apoptosis. In addition, the experimental results revealed that the complexes not only increase the level of ROS but also inhibit the production of GSH and eventually produce large amounts of MDA and further leading to cell death. Taken together, we consider that the complexes can be used as potential candidate drugs for HeLa cancer treatment.

Synthesis, biological evaluation of novel iridium(III) complexes targeting mitochondria toward melanoma B16 cells.

A new ligand 2-(1E,3E,5E,7E)-2,6-dimethyl-8-(2,6,6-trimethylcyclohex-1-yl)octa-1,2,5,7-tetraen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (DTOIP) was synthesized and combined with [Ir(ppy)2Cl]2·2H2O (ppy = deprotonated Hppy: 2-phenylpyridine), [Ir(piq)2Cl]2·2H2O (piq = deprotonated Hpiq: 1-phenylisoquinoline) and [Ir(bzq)2Cl]2·2H2O (bzq = deprotonated Hbzq: benzo[h]quinolone) to form [Ir(ppy)2(DTOIP)](PF6) (Ir1), [Ir(piq)2(DTOIP)](PF6) (Ir2), and [Ir(bzq)2(DTOIP)](PF6) (Ir3), respectively. The complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRMS), 1H NMR and 13C NMR. The antiproliferative activity of the complexes toward B16, BEL-7402, Eca-109 and normal LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complexes Ir1, Ir2 and Ir3 showed high antiproliferative activity against B16 cells with a low IC50 values of 0.4 ± 0.1, 2.0 ± 0.1 and 1.4 ± 0.09 µM, respectively. Three-dimensional (3D) in vitro cell models also demonstrated that the iridium(III) complexes have a remarkable cytotoxicity to B16 cells. The experiments of cellular uptake, mitochondrial localization, and intracellular distribution of the drugs proved that the three iridium(III) complexes can enter the mitochondria, leading to the loss of mitochondrial membrane potential (MMP), decreased glutathione (GSH) levels, causing an increase of intracellular ROS content, and DNA damage, finally inducing apoptosis. RNA-sequence and bioinformatics analyses were used to analyze the differentially expressed genes and enriched biology processes. Antitumor in vivo demonstrated that complex Ir1 (5 mg/kg) exhibits a high efficacy to inhibit the tumor growth with an inhibitory rate of 71.67%. These results show that the complexes may be potent anticancer candidate drugs.

Severe acute respiratory syndrome coronavirus 2 virus-like particles induce dendritic cell maturation and modulate T cell immunity.

Dendritic cells (DCs) are professional antigen-presenting cells that play an important role in both innate and acquired immune responses against pathogens. However, the role of DCs in coronavirus disease 2019 (COVID-19) is unclear. Virus-like particles (VLPs) that structurally mimic the original virus are one of the candidates COVID-19 vaccines. In the present study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) VLPs were used as an alternative to live virus to evaluate the interaction of the virus with DCs. The results revealed that SARS-CoV-2 VLPs induced DC maturation by augmenting cell surface molecule expression (CD80, CD86, and major histocompatibility complex class II (MHC-II)) and inflammatory cytokine production (tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-12p70) in DCs via the mitogen-activated protein kinase and nuclear factor-κB signaling pathways. In addition, mature DCs induced by SARS-CoV-2 VLPs promoted T cell proliferation, which was dependent on VLPs concentration. Our results suggest that SARS-CoV-2 VLPs regulate the immune response by interacting with DCs. These findings will improve the understanding of SARS-CoV-2 pathogenesis and SARS-CoV-2 vaccine development.

Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-ß1 pathway in mice induced with aldosterone.

Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-ß1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-ß1 pathway may be an effective therapeutic strategy for renal fibrosis.

Iridium (III) complexes induce cervical carcinoma apoptosis via disturbing cellular redox homeostasis disorder and inhibiting PI3K/AKT/mTOR pathway.

Improvement of antineoplastic activity and selectivity is a main goal in the development of antineoplastic agents. Herein, we synthesized three new iridium (III) complexes: [Ir(ppy)2(FTTP)](PF6) (Ir1, ppy = 2-phenylpyridine, FTTP = 2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene), [Ir(bzq)2(FTTP)](PF6) (Ir2, bzq = benzo[h]quinolone), [Ir(piq)2(FTTP)](PF6) (Ir3, piq = 1-phenylisoquinoline). Ir1-3 exhibit excellent cytotoxicity against various cancer cells particularly towards human cervical carcinoma HeLa cells while remaining non-toxic to normal cell lines. Assays on 2D cell colony formation and 3D multicellular tumor spheroid model confirm that Ir1-3 can effectively inhibit the colony-forming and penetrate deeply into HeLa 3D multicellular tumor spheroid model exhibiting a notable cytotoxic effect, which was consistent with the results from the viability assays. Meanwhile, confocal microscopy shows a rapid uptake of Ir1-3 and co-localization experiments with subcellular markers reveal that Ir1-3 locate mainly at the mitochondria. Further investigation of the mechanism indicated the complexes Ir1-3 promote the excessive generation of ROS, inhibit glutathione and thioredoxin reductase that effectively interferes with the intracellular redox balance, induce oxidative stress and result in caspase-dependent apoptosis. Moreover, the ROS-mediated inactivation of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway, DNA damage combing with suppression of the cyclin D1/CDK4/6 activity arrested cell cycle in the G0/G1 phase are involved in complexes-induced cell apoptosis. Finally, assays on xenografted cervical carcinoma mouse model confirm the excellent biocompatibility and antineoplastic efficiency of Ir3 in vivo. Collectively, this work offers building blocks for developing iridium (III) complexes as clinical application potential.

Synthesis and characterization of polypyridine ruthenium(II) complexes and anticancer efficacy studies in vivo and in vitro.

In this article, ligand IPP (IPP = 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N,N-diphenylaniline) and its three Ru(II) complexes: [Ru(bpy)2(IPP)](ClO4)2 (1) (bpy = 2,2'-bipyridine), [Ru(dmbpy)2(IPP)](ClO4)2 (2) (dmbpy = 4,4'-dimethyl-2,2'-bipyridine), and [Ru(phen)2(IPP)](ClO4)2 (3) (phen = 1,10-phenanthroline) were synthesized and characterized. The anticancer activity in vitro of the complexes was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The scratching and colony-forming experiments confirmed the complexes 1, 2, 3 interfered with the proliferation and migration ability of cells. The accumulation of the complexes in cells was researched and we found that these complexes directly accumulated in mitochondria, then the complexes cause a decline of the mitochondrial membrane potential and induce an increase of intracellular reactive oxygen species (ROS) levels. The growth of B16 cells were inhibited by 1, 2 and 3 at G0/G1 phase. Apoptosis was induced through mitochondrial pathway and the expression of apoptosis-related factors was regulated. In addition, the complexes promoted the transition of poly(ADP-ribose)polymerase (PARP) into the cleaved form (Cleaved PARP), downregulated the anti-apoptotic proteins, and upregulated the pro-apoptotic proteins. Consequently, complexes 1, 2 and 3 exerted their anticancer activity by regulating B-cell lymphoma-2 (Bcl-2) family proteins. Complex 2 showed excellent antitumor effects with a high inhibitory rate of 65.95% in vivo. Taken together, the complexes cause apoptosis in B16 cells through a ROS-mediated mitochondrial dysfunction pathway.

Light activation of iridium(III) complexes driving ROS production and DNA damage enhances anticancer activity in A549 cells.

The work aimed to synthesize and characterize two iridium(III) complexes [Ir(ppy)2(IPPH)](PF6) (Ir1, IPPH = (2S,3R,5S,6R)-2-(2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, ppy = 2-phenylpyridine), [Ir(piq)2(IPPH)](PF6) (Ir2, piq = 1-phenylisoquinoline). The cytotoxicity of the complexes against BEL-7402, A549, HCT-116, B16 cancer cells and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The complexes show no cytotoxic activity (IC50 > 100 µM) against these cancer cells, while their cytotoxicity can significantly be elevated upon illumination. The IC50 values range from 0.2 ± 0.05 to 35.5 ± 3.5 µM. The cellular uptake, endoplasmic reticulum and mitochondria localization, reactive oxygen species, the change of mitochondrial membrane potential, γ-H2AX levels, cycle arrest, apoptosis and the expression of B-cell lymphoma-2 were investigated. The calreticulin (CRT), heat shock protein 70 (HSP70), high mobility group box 1 (HMGB1) were explored. This study demonstrates that photoactivatable complexes induce cell death in A549 through ROS-mediated endoplasmic reticulum stress-mitochondrial pathway, DNA damage pathways, immunogenic cell death (ICD), activation of PI3K/AKT signaling pathway and inhibit the cell growth at S phase.

Wet-Etched Microchamber Array Digital PCR Chip for SARS-CoV-2 Virus and Ultra-Early Stage Lung Cancer Quantitative Detection.

We report a novel design of chamber-based digital polymerase chain reaction (cdPCR) chip structure. Using a wet etching process and silicon-glass bonding, the chamber size can be adjusted independently of the process and more feasibly in a normal lab. In addition, the structure of the chip is optimized through hydrodynamic computer simulations to eliminate dead space when the sample is injected into the chip. The samples will be distributed to each separated microchambers for an isolated reaction based on Poisson distribution. Due to the difference in expansion coefficients, isolation of the sample in the microchambers by the oil phase on top ensures homogeneity and independence of the sample in the microchambers. The prepared microarray cdPCR chip enables high-throughput and high-sensitivity quantitative measurement of the SARS-CoV-2 virus gene and the mutant lung cancer gene. We applied the chip for the detection of different concentrations of the mix containing the open reading frame 1ab (ORF1ab) gene, the most specific and conservative gene region of the SARS-CoV-2 virus. In addition to this, we also successfully detected the fluorescence of the epidermal growth factor receptor (EGFR) mutant gene in independent microchambers. At a throughput of 46 200 microchambers, solution mixtures containing both genes were successfully tested quantitatively, with a detection limit of 10 copies/µL. Importantly, the chips are individually inexpensive and easy to industrialize. In addition, the microarray can provide a unified solution for other viral sequences, cancer marker assay development, and point-of-care testing (POCT).

Clinical analysis of the "small plateau" sign on the flow-volume curve followed by deep learning automated recognition.

BACKGROUND: Small plateau (SP) on the flow-volume curve was found in parts of patients with suspected asthma or upper airway abnormalities, but it lacks clear scientific proof. Therefore, we aimed to characterize its clinical features. METHODS: We involved patients by reviewing the bronchoprovocation test (BPT) and bronchodilator test (BDT) completed between October 2017 and October 2020 to assess the characteristics of the sign. Patients who underwent laryngoscopy were assigned to perform spirometry to analyze the relationship of the sign and upper airway abnormalities. SP-Network was developed to recognition of the sign using flow-volume curves. RESULTS: Of 13,661 BPTs and 8,168 BDTs completed, we labeled 2,123 (15.5%) and 219 (2.7%) patients with the sign, respectively. Among them, there were 1,782 (83.9%) with the negative-BPT and 194 (88.6%) with the negative-BDT. Patients with SP sign had higher median FVC and FEV1% predicted (both P < .0001). Of 48 patients (16 with and 32 without the sign) who performed laryngoscopy and spirometry, the rate of laryngoscopy-diagnosis upper airway abnormalities in patients with the sign (63%) was higher than those without the sign (31%) (P = 0.038). SP-Network achieved an accuracy of 95.2% in the task of automatic recognition of the sign. CONCLUSIONS: SP sign is featured on the flow-volume curve and recognized by the SP-Network model. Patients with the sign are less likely to have airway hyperresponsiveness, automatic visualizing of this sign is helpful for primary care centers where BPT cannot available.

A TAT peptide-based ratiometric two-photon fluorescent probe for detecting biothiols and sequentially distinguishing GSH in mitochondria.

Although biothiols, including cysteine (Cys), glutathione (GSH), and homocysteine (Hcy) can be used to diagnose many diseases and research physiological metabolism in many physiological processes, in situ real-time detection and differentiation of biothiols is still challenging because their similar chemical properties and molecular structures. Herein, we utilized the native chemical ligation (NCL) reaction mechanism to develop a Förster resonance energy transfer (FRET) strategy for designing a cell penetration peptide TAT-modified ratiometric two-photon biothiols probe (TAT-probe). The TAT-probe can not only rapidly enter into mitochondria assisted by TAT peptide, but also simultaneously detect biothiols and sequentially distinguish GSH. When the TAT-probe was excited with 404/820 nm wavelength light, it showed a change in the ratio of fluorescence after adding biothiols, including a quenched red fluorescence intensity (λem = 585 nm) and an enhanced signal in green fluorescence intensity (λem = 520 nm). Excitingly, the TAT-probe excited at 545 nm could display a red fluorescence (λem = 585 nm) towards GSH and a quenched signal towards Hcy or Cys. This specific fluorescence response indicated the TAT-probe could effectively detect biothiols and differentiate GSH from Cys/Hcy in mitochondria. This work pioneered a new approach to design and synthesize biothiol-probes based on peptides and NCL reaction mechanism.