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The study was intended to determine the antineoplastic effects of two new iridium(III) complexes [Ir(ppy)₂(PTTP)](PF₆) (1) (ppy = 2-phenylpyridine) and [Ir(piq)₂(PTTP)](PF₆) (2) (piq = 1-phenylisoquinoline, PTTP = 2-phenoxy-1,4,8,9-tetraazatriphenylene). In MTT assay, the ligand PTTP displayed ineffective inhibition on cell growth in SGC-7901, BEL-7402, HepG2 as well as NIH3T3 cell lines, while complexes 1 and 2 showed high cytotoxic activity on SGC-7901 cells with an IC₅₀ value of 0.5 ± 0.1 µM and 4.4 ± 0.6 µM, respectively. Cellular uptake, cell cloning experiments, wound healing assay and cell cycle arrest indicated that the two complexes can inhibit the cell proliferation in SGC-7901 and induce cell cycle arrest at G0/G1 phase. Additionally, reactive oxygen species (ROS) and mitochondrial membrane potential suggested that the two complexes induced cell apoptosis through disrupting mitochondrial functions. Further, western blot analysis illustrated that the two complexes caused apoptosis via regulating expression levels of Bcl-2 family proteins. Moreover, complex 1 could suppress tumor growth in vivo with an inhibitory rate of 49.41%. Altogether, these results demonstrated that complexes 1 and 2 exert a potent anticancer effect against SGC-7901 cells via mitochondrial apoptotic pathway and have a potential to be developed as antineoplastic drug candidates for human gastric cancer. Show less

Being polymorphic, deoxyribonucleic acid is worthy of raise a variety of structure like right-handed B to left-handed Z conformation. In left-handed contour of DNA consecutive nucleotides substitute between syn-arrangement and anti-arrangement, through the chain. 2D gel electrophoresis comprising d(PCpG)n of topo isomers of a plasmid inserts d(pCpG)n, in this 'n' ranges among 8 to 21, indicate the change of B-Z DNA. The high denseness of salt is required for conversion of B configuration d(CG)n toward Z configuration. The rate of B to Z transition is measured by "Cytosine Analogues" and "Fluorescence Spectroscopy". h-ZαADAR1 that a Z-DNA's binding domain, binds and stabilizes one part in Z configuration and therefore the remaining half in B deoxyribonucleic acid configuration. At halfway point, it creates B-Z junction. "Stacking" is the main reason for the B-Z DNA junction construction. Upregulation of ADAM-12, related with Z-DNA is said to a cause for cancer, arthritis, and hypertrophy. Z-DNA forming sequence (ZFS) conjointly generates massive - scale deletion in cells from mammals. Show less

Herein, we report a neutral iridium complex, [Ir(4-(2-pyridinyl)benzaldehyde)2(acetylacetone)] (Ir-ER), with viscosity-responsive phosphorescent emission intensity and lifetime. Quantitative measurement by two-photon phosphorescent lifetime imaging shows that the viscosity of ER increases significantly in the process of erastin-induced ferroptosis. Our work provides an effective strategy for quantitative measurement of the micro-environmental alternations of subcellular organelles during a specific cell death process. Show less

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy. Show less

Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation. Show less

New dithiocarbamate cycloaurated complexes have been synthesized and their physicochemical and in vitro antitumor properties have been evaluated. All the performed studies highlighted good transport through the blood and biodistribution, according to the balance between the properties of hydrophilicity/lipophilicity and the binding of moderate strength to the BSA protein. Furthermore, none of the complexes exhibited reduction or decomposition reactions, presenting excellent physiological stability. The in vitro cytotoxic effect was evaluated on human colon cancer cell line Caco-2/TC7, and the complexes showed great antiproliferative activity and excellent selectivity, as much less effect was detected on normal Caco-2/TC7 cells. Most of the complexes exhibit antiproliferative activity that was better than or similar to auranofin, and at least nine times better than that of cisplatin. Its action mechanism is still under discussion since no evidence of cell cycle arrest was found, but an antioxidant role was shown for some of the selective complexes. All complexes were also tested as antimicrobial drugs, exhibiting good activity towards S. aureus and E. coli. bacteria and C. albicans and C. neoformans fungi. Show less

SUMMARY The role of intracellular pH (pHi) of lymphocytes in the control of the magnitude of immune response is unknown. We found that low pHi induces apoptosis of proliferating lymphocytes, whereas high pHi promotes their survival. In the ovalbumin sensitization and challenge model, energy metabolism is a major mechanism for regulating pHi. TCA cycle using carbohydrates lowers whereas glutaminolysis or aerobic glycolysis increases pHi. Proliferation powered by high mitochondrial membrane potentials (MMPs) in lymphocytes of low but not high pHi causes apoptosis. After antigenic challenge, lymphocytes of high pHi gradually increase and assume a positive relation between pHi and MMPs while lymphocytes of low pHi and an inverse relation between pHi and MMPs diminish. This change is at least partly dependent on glutaminolysis and aerobic glycolysis. One Sentence Summary TCA cycle fueled with carbohydrates but not glutaminolysis or aerobic glycolysis lowers intracellular pH to induce apoptosis. Show less

Photodynamic therapy (PDT) is a clinically approved therapeutic modality that has shown great potential for the treatment of cancers owing to its excellent spatiotemporal selectivity and inherently noninvasive nature. However, PDT has not reached its full potential, partly due to the lack of ideal photosensitizers. A common molecular design strategy for effective photosensitizers is to incorporate heavy atoms into photosensitizer structures, causing concerns about elevated dark toxicity, short triplet-state lifetimes, poor photostability, and the potentially high cost of heavy metals. To address these drawbacks, a significant advance has been devoted to developing advanced smart photosensitizers without the use of heavy atoms to better fit the clinical requirements of PDT. Over the past few years, heavy-atom-free nonporphyrinoid photosensitizers have emerged as an innovative alternative class of PSs due to their superior photophysical and photochemical properties and lower expense. Heavy-atom-free nonporphyrinoid photosensitizers have been widely explored for PDT purposes and have shown great potential for clinical oncologic applications. Although many review articles about heavy-atom-free photosensitizers based on porphyrinoid structure have been published, no specific review articles have yet focused on the heavy-atom-free nonporphyrinoid photosensitizers.In this account, the specific concept related to heavy-atom-free photosensitizers and the advantageous properties of heavy-atom-free photosensitizers for cancer theranostics will be briefly introduced. In addition, recent progress in the development of heavy-atom-free photosensitizers, ranging from molecular design approaches to recent innovative types of heavy-atom-free nonporphyrinoid photosensitizers, emphasizing our own research, will be presented. The main molecular design approaches to efficient heavy-atom-free PSs can be divided into six groups: (1) the approach based on traditional tetrapyrrole structures, (2) spin-orbit charge-transfer intersystem crossing (SOCT-ISC), (3) reducing the singlet-triplet energy gap (ΔE_ST), (4) the thionation of carbonyl groups of conventional fluorophores, (5) twisted π-conjugation system-induced intersystem crossing, and (6) radical-enhanced intersystem crossing. The innovative types of heavy-atom-free nonporphyrinoid photosensitizers and their applications in cancer diagnostics and therapeutics will be discussed in detail in the third section. Finally, the challenges that need to be addressed to develop optimal heavy-atom-free photosensitizers for oncologic photodynamic therapy and a perspective in this research field will be provided. We believe that this review will provide general guidance for the future design of innovative photosensitizers and spur preclinical and clinical studies for PDT-mediated cancer treatments. Show less

The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers. Show less

A new series of half-sandwich ruthenium(II) compounds [(η⁶-arene)Ru(L)Cl][CF₃SO₃] bearing 1,2,3-triazole ligands (arene = p-cymene, L = L1 (1); arene = p-cymene, L = L2 (2); arene = benzene, L = L1 (3); arene = benzene, L2 (4); L1 = 2-[1-(p-tolyl)-1H-1,2,3-triazol-4-yl]pyridine and L2 = 1,1'-di-p-tolyl-1H,1'H-4,4'-bi(1,2,3-triazole) have been synthesized and fully characterized by ¹H and ¹³C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of 1, 2, and 4 have been determined by single-crystal X-ray diffraction. The cytotoxic activity of 1-4 was evaluated using the MTS assay against human tumor cells, namely ovarian carcinoma (A2780), colorectal carcinoma (HCT116), and colorectal carcinoma resistant to doxorubicin (HCT116dox), and against normal primary fibroblasts. Whereas compounds 2 and 4 showed no cytotoxic activity toward tumor cell lines, compounds 1 and 3 were active in A2780, while showing no antiproliferative effect in human normal dermal fibroblasts at the IC₅₀ concentrations of the A2780 cell line. Exposure of ovarian carcinoma cells to IC₅₀ concentrations of compound 1 or 3 led to an accumulation of reactive oxygen species and an increase of apoptotic and autophagic cells. While compound 3 displayed low levels of angiogenesis induction, compound 1 showed an ability to induce cell cycle delay and to interfere with cell migration. When the in vivo toxicity studies using zebrafish and chicken embryos are considered, compounds 1 and 3, which were not lethal, are promising candidates as anticancer agents against ovarian cancer due to their good cytotoxic activity in tumor cells and their low toxicity both in vitro and in vivo. Show less

Background

Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases.

Scope of review

In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis (NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic.

Major conclusions

Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns. Show less

Metabolic plasticity enables cancer cells to switch between glycolysis and oxidative phosphorylation to adapt to changing conditions during cancer progression, whereas metabolic dependencies limit plasticity. To understand a role for the architectural environment in these processes we examined metabolic dependencies of cancer cells cultured in flat (2D) and organotypic (3D) environments. Here we show that cancer cells in flat cultures exist in a high energy state (oxidative phosphorylation), are glycolytic, and depend on glucose and glutamine for growth. In contrast, cells in organotypic culture exhibit lower energy and glycolysis, with extensive metabolic plasticity to maintain growth during glucose or amino acid deprivation. Expression of KRAS^G12V in organotypic cells drives glucose dependence, however cells retain metabolic plasticity to glutamine deprivation. Finally, our data reveal that mechanical properties control metabolic plasticity, which correlates with canonical Wnt signaling. In summary, our work highlights that the architectural and mechanical properties influence cells to permit or restrict metabolic plasticity. Show less