Betaine and I-LG may have a predictive value for ATB: A causal study in a large European population.

PURPOSE: To analyze the causal relationship between 486 human serum metabolites and the active tuberculosis (ATB) in European population. METHODS: In this study, the causal relationship between human serum metabolites and the ATB was analyzed by integrating the genome-wide association study (GWAS). The 486 human serum metabolites were used as the exposure variable, three different ATB GWAS databases in the European population were set as outcome variables, and single nucleotide polymorphisms were used as instrumental variables for Mendelian Randomization. The inverse variance weighting was estimated causality, the MR-Egger intercept to estimate horizontal pleiotropy, and the combined effects of metabolites were also considered in the meta-analysis. Furthermore, the web-based MetaboAnalyst 6.0 was engaged for enrichment pathway analysis, while R (version 4.3.2) software and Review Manager 5.3 were employed for statistical analysis. RESULTS: A total of 21, 17, and 19 metabolites strongly associated with ATB were found in the three databases after preliminary screening (P < 0.05). The intersecting metabolites across these databases included tryptophan, betaine, 1-linoleoylglycerol (1-monolinolein) (1-LG), 1-eicosatrienoylglycerophosphocholine, and oleoylcarnitine. Among them, betaine (I2 = 24%, P = 0.27) and 1-LG (I2 = 0%, P = 0.62) showed the lowest heterogeneity among the different ATB databases. In addition, the metabolic pathways of phosphatidylethanolamine biosynthesis (P = 0.0068), methionine metabolism (P = 0.0089), betaine metabolism (P = 0.0205) and oxidation of branched-chain fatty acids (P = 0.0309) were also associated with ATB. CONCLUSION: Betaine and 1-LG may be biomarkers or auxiliary diagnostic tools for ATB. They may provide new guidance for medical practice in the early diagnosis and surveillance of ATB. In addition, by interfering with phosphatidylethanolamine biosynthesis, methionine metabolism, betaine metabolism, oxidation of branched-chain fatty acids, and other pathways, it is helpful to develop new anti-tuberculosis drugs and explore the virulence or pathogenesis of ATB at a deeper level, providing an effective reference for future studies.

The predictive value of TNF family for pulmonary tuberculosis: a pooled causal effect analysis of multiple datasets.

Objective: Despite extensive research on the relationship between pulmonary tuberculosis (PTB) and inflammatory factors, more robust causal evidence has yet to emerge. Therefore, this study aims to screen for inflammatory proteins that may contribute to the susceptibility to PTB in different populations and to explain the diversity of inflammatory and immune mechanisms of PTB in different ethnicity. Methods: The inverse variance weighted (IVW) model of a two-sample Mendelian Randomization (MR) study was employed to conduct causal analysis on data from a genome-wide association study (GWAS). This cohort consisting PTB GWAS datasets from two European and two East Asian populations, as well as 91 human inflammatory proteins collected from 14,824 participants. Colocalization analysis aimed to determine whether the input inflammatory protein and PTB shared the same causal single nucleotide polymorphisms (SNPs) variation within the fixed region, thereby enhancing the robustness of the MR Analysis. Meta-analyses were utilized to evaluate the combined causal effects among different datasets. Results: In this study, we observed a significant negative correlation between tumor necrosis factor-beta levels (The alternative we employ is Lymphotoxin-alpha, commonly referred to as LT) (P < 0.05) and tumor necrosis factor receptor superfamily member 9 levels (TNFRSF9) (P < 0.05). These two inflammatory proteins were crucial protective factors against PTB. Additionally, there was a significant positive correlation found between interleukin-20 receptor subunit alpha levels (IL20Ra) (P < 0.05), which may elevate the risk of PTB. Colocalization analysis revealed that there was no overlap in the causal variation between LT and PTB SNPs. A meta-analysis further confirmed the significant combined effect of LT, TNFRSF9, and IL20Ra in East Asian populations (P < 0.05). Conclusions: Levels of specific inflammatory proteins may play a crucial role in triggering an immune response to PTB. Altered levels of LT and TNFRSF9 have the potential to serve as predictive markers for PTB development, necessitating further clinical validation in real-world settings to ascertain the impact of these inflammatory proteins on PTB.

Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC.

The DRAP1/DR1 Repressor Complex Increases mTOR Activity to Promote Progression and Confer Everolimus Sensitivity in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Transcriptional dysregulation is a hallmark of cancer, and several transcriptional regulators have been demonstrated to contribute to cancer progression. Here, we identified upregulation of the transcriptional corepressor DRAP1 in TNBC, which was closely associated with poor recurrence-free survival in TNBC patients. DRAP1 promoted TNBC proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, the DR1/DRAP1 heterodimer complex inhibited expression of the arginine sensor CASTOR1 and thereby increased activation of mTOR, which sensitized TNBC to treatment with the mTOR inhibitor everolimus. DRAP1 and DR1 also formed a positive feedback loop. DRAP1 enhanced the stability of DR1, recruiting the deubiquitinase USP7 to inhibit its proteasomal degradation; in turn, DR1 directly promoted DRAP1 transcription. Collectively, this study uncovered a DRAP1-DR1 bidirectional regulatory pathway that promotes TNBC progression, suggesting that targeting the DRAP1/DR1 complex might be a potential therapeutic strategy to treat TNBC.

Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells.

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin.

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)2(8HQ)]PF6 (Ru1), [Ru(dpq)2(8HQ)]PF6 (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC50 = 1.98 ± 0.02 µM) and Ru2 (IC50 = 10.02 ± 0.19 µM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 µM and 60 µM were safe and did not have obvious effect on the normal development of zebrafish embryos.

Cyclometalated iridium(III) complexes induce immunogenic cell death in HepG2 cells via paraptosis.

Immunotherapy has been shown to provide superior antitumor efficacy by activating the innate immune system to recognize, attack and eliminate tumor cells without seriously harming normal cells. Herein, we designed and synthesized three new cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3) then evaluated their antitumor activity. When co-incubated with HepG2 cells, the complex Ir1 localized in the lysosome, where it induced paraptosis and endoplasmic reticulum stress (ER stress). Notably, Ir1 also induced immunogenic cell death (ICD), promoted dendritic cell maturation that enhanced effector T cell chemotaxis to tumor tissues, down-regulated proportions of immunosuppressive regulatory T cells within tumor tissues and triggered activation of antitumor immunity throughout the body. To date, Ir1 is the first reported iridium(III) complex-based paraptosis inducer to successfully induce tumor cell ICD. Furthermore, Ir1 induced ICD of HepG2 cells without affecting cell cycle or reactive oxygen species levels.

MYC-driven U2SURP regulates alternative splicing of SAT1 to promote triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC), although highly lethal, lacks validated therapeutic targets. Here, we report that U2 snRNP-associated SURP motif-containing protein (U2SURP), a poorly defined member of the serine/arginine rich protein family, was significantly upregulated in TNBC tissues, and its high expression was associated with poor prognosis of TNBC patients. MYC, a frequently amplified oncogene in TNBC tissues, enhanced U2SURP translation through an eIF3D (eukaryotic translation initiation factor 3 subunit D)-dependent mechanism, resulting in the accumulation of U2SURP in TNBC tissues. Functional assays revealed that U2SURP played an important role in facilitating tumorigenesis and metastasis of TNBC cells both in vitro and in vivo. Intriguingly, U2SURP had no significant effects on proliferative, migratory, and invasive potential of normal mammary epithelial cells. Furthermore, we found that U2SURP promoted alternative splicing of spermidine/spermine N1-acetyltransferase 1 (SAT1) pre-mRNA by removal of intron 3, resulting in an increase in the stability of SAT1 mRNA and subsequent protein expression levels. Importantly, spliced SAT1 promoted the oncogenic properties of TNBC cells, and re-expression of SAT1 in U2SURP-depleted cells partially rescued the impaired malignant phenotypes of TNBC cells caused by U2SURP knockdown both in vitro and in mice. Collectively, these findings reveal previously unknown functional and mechanism roles of the MYC-U2SURP-SAT1 signaling axis in TNBC progression and highlight U2SURP as a potential therapy target for TNBC.

Destabilization of microrchidia family CW-type zinc finger 2 via the cyclin-dependent kinase 1-chaperone-mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule-targeting agents.

BACKGROUND: Microtubule-targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges. METHODS: Immunoblotting and RT-qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein-protein interaction and protein co-localization. RESULTS: Here, we identified microrchidia family CW-type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR. CONCLUSIONS: Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer.

Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer.

Rationale: SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic. Methods: In vivo and in vitro SUMOylation assays were used to determine the SUMOylation levels of MORC2. Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation. The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through in vitro and in vivo functional assays. Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms. Results: Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner. MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1). Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28. MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair. At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair. Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs. Conclusions: Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR. We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway.

Microplastics in soil ecosystems: soil fauna responses to field applications of conventional and biodegradable microplastics.

Although biodegradable plastics are considered an environmentally-friendly alternative to conventional plastics, the effects of biodegradable microplastics (BMPs) on soil faunal communities are poorly understood, especially under field conditions. Here, we investigated the loading impacts of two conventional low-density polyethylene (LDPE) and polypropylene (PP) MPs as well as two biodegradable polylactic acid (PLA) and polybutylene succinate (PBS) MPs at concentrations of 0, 5, 10, and 15 g/m2 on soil fauna communities. After 40 d, all MP types did not affect the soil fauna communities. After 130 d, conventional MPs (LDPE-15 and PP-5) significantly increased the abundance of overall soil fauna-attributed mainly to changes in the abundance of Collembola; however, BMPs did not affect the soil fauna communities. Interestingly, MP-induced changes in the abundance and diversity of soil fauna showed a strong tendency to increase over time. Overall, these results indicate that the short-term effects of all MP types on soil faunal communities are inapparent, while soil fauna responses to conventional MPs and BMPs showed slight differences over time. Given these time-dependent soil fauna responses to MPs, we recommend an evaluation of the long-term effects of MPs on soil organisms to gain a comprehensive understanding of their effects on soil ecosystems.

TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the lack of effective targeted therapies. Transmembrane (TMEM) proteins represent attractive drug targets for cancer therapy, but biological functions of most members of the TMEM family remain unknown. Here, we report for the first time that TMEM63A (transmembrane protein 63A), a poorly characterized TMEM protein with unknown functions in human cancer, functions as a novel oncogene to promote TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung metastasis in vivo. Mechanistic investigations revealed that TMEM63A localizes in endoplasmic reticulum (ER) and lysosome membranes, and interacts with VCP (valosin-containing protein) and its cofactor DERL1 (derlin 1). Furthermore, TMEM63A undergoes autophagy receptor TOLLIP-mediated autophagic degradation and is stabilized by VCP through blocking its lysosomal degradation. Strikingly, TMEM63A in turn stabilizes oncoprotein DERL1 through preventing TOLLIP-mediated autophagic degradation. Notably, pharmacological inhibition of VCP by CB-5083 or knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on TNBC progression both in vitro and in vivo. Collectively, these findings uncover a previously unknown functional and mechanistic role for TMEM63A in TNBC progression and provide a new clue for targeting TMEM63A-driven TNBC tumors by using a VCP inhibitor.Abbreviations: ATG16L1, autophagy related 16 like 1; ATG5, autophagy related 5; ATP5F1B/ATP5B, ATP synthase F1 subunit beta; Baf-A1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CANX, calnexin; DERL1, derlin 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HSPA8, heat shock protein family A (Hsp70) member 8; IP, immunoprecipitation; LAMP2A, lysosomal associated membrane protein 2; NBR1, NBR1 autophagy cargo receptor; OPTN, optineurin; RT-qPCR, reverse transcription-quantitative PCR; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TMEM63A, transmembrane protein 63A; TNBC, triple-negative breast cancer; TOLLIP, toll interacting protein; VCP, valosin containing protein.

Tuberculosis among Ambulatory People Living with HIV in Guangxi Province, China: A Longitudinal Study.

BACKGROUND: This study aims to determine the prevalence of TB among ambulatory people living with HIV in Guangxi Province, which experienced the biggest HIV epidemic in China. METHODS: We undertook a longitudinal study in five HIV/AIDS designated hospitals randomly selected from Guangxi Province; all newly diagnosed HIV/AIDS outpatients from 2019 to 2021 were screened for TB and interviewed with a questionnaire. RESULTS: A total of 4539 HIV/AIDS outpatients were enrolled, with 2886 (63.6%) men and 1653 (26.4%) women. The prevalence of TB/HIV coinfection was 0.8%, with a clear downward trend from 1.3% in 2019 to 0.4% in 2021 (p = 0.0011). The prevalence of LTBI was 24.3%, with no significant differences from 2019 to 2021. The percentages of AIDS, comorbidity, nine symptoms and abnormal chest X-ray of TB were higher than those of the other PLWH. CONCLUSION: The prevalence of TB among ambulatory people with HIV in Guangxi Province was 14 times higher than the general population, and the annual declined TB prevalence indicated the effectiveness of TB and HIV control and prevention over recent years. The findings proved that symptom screening was insufficient for TB diagnosis and highlighted the importance of systematic TB screening at every visit to a health facility.

Space-Time Distribution Characteristics of Tuberculosis and Its Socioeconomic Factors in Southern China from 2015 to 2019.

Purpose: Guangxi is a high prevalence area of tuberculosis (TB) in China, urgent needing of further TB reduction. Our purpose is to analyze the epidemiological characteristics of TB in Guangxi and analyze the relationship between socioeconomic factors and TB from the dimensions of time and space to provide evidence to effectively prevent and control TB. Patients and Methods: We performed a retrospective analysis of the epidemiology of TB. Moran's index (I) was used for spatial autocorrelation analysis, and space-time scanning was used to detect temporal, space, and space-time clusters of TB. A Bayesian space-time model was used to analyze related factors of the TB epidemic at the county level in Guangxi. Results: From 2015 to 2019, a total of 233,623 TB cases were reported in Guangxi. The majority of TB cases were in males; the reported incidence of TB was the highest in people aged ≥65 years. By occupation, farmers were the most frequently affected. The overall reported incidence of TB decreased by 4.95% during this period. Tuberculosis occurs all year round, but the annual reporting peak is usually from March to July. Spatial autocorrelation analysis showed that the reported incidence of TB in 2015-2019 was spatially clustered (Moran's I > 0, P < 0.05); Kulldorff's scan revealed that the space-time cluster (log-likelihood ratio = 2683.76, relative risk = 1.60, P < 0.001) was mainly concentrated in northern Guangxi. Using Bayesian space-time modeling, socioeconomic and healthcare factors are related to the high prevalence of TB. Conclusion: The prevalence of TB is influenced by a space-time interaction effect and is associated with socioeconomic and healthcare status. It is necessary to improve the economic development and health service in areas with a high TB prevalence.

Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated, and cell cycle arrest pathways.

The growing evidence over the past few decades has indicated that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy. This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 > 180 µM in the dark to 1.3 ± 0.7 µM following 10 min of light irradiation (425 nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, and then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the reactive oxygen species level, and decreasing mitochondrial membrane potential and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell cycle arrest and eventually cell death.

Lysosome-targeted ruthenium(II) complexes induce both apoptosis and autophagy in HeLa cells.

Ruthenium complexes with good biological properties have attracted increasing attention in recent decades. In this work, three ruthenium polypyridine complexes containing 5-fluorouracil derivatives as ligands, [Ru(bpy)2(L)]2+ (Ru1), [Ru(phen)2(L)]2+ (Ru2), [Ru(dip)2(L)]2+ (Ru3) (L = 1-((1,10-phenanthroline-5-amino) pentyl)-5-fluorouracil; bpy = 2,2'-bipyridine; phen =1,10-phenanthroline; dip = 4,7-diphenyl-1,10-phenanthroline), were synthesized and characterized. Based on in vitro cytotoxicity tests, Ru3 (IC50 = 7.35 ± 0.39 µM) showed the best anticancer activity among three compounds in the selected cell lines. It is worth noting that Ru3 also exerts less cytotoxicity on LO2 cell lines, with an IC50 value 5 times higher than that on HeLa cells, indicating its selective activity. Mechanism studies revealed that Ru3 can specifically target lysosomes and induce cell apoptosis in a caspase-dependent manner. Specifically, Ru3 can arrest cell cycle at the G0/G1 phase, increase the intracellular reactive oxygen species (ROS) level, and then damage DNA. In short, Ru3 can eventually cause cell death through the synergy of inducing apoptosis and autophagy, which was further proven by western blot assay results.

Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer and antibacterial agents to induce both autophagy and apoptosis.

Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclometalated iridium(III) complexes (Ir1: [Ir(piq)2L]PF6; Ir2: [Ir(bzq)2L]PF6; Ir3: [Ir(dfppy)2L]PF6; Ir4: [Ir(thpy)2L]PF6; piq = 1-phenylisoquinoline; bzq = benzo[h]quinoline; dfppy = 2-(2,4-difluorophenyl)pyridine;thpy = 2-(2-thienyl)pyridine; L = 1,10-phenanthroline-5-amine) were synthesized and characterized. Cytotoxicity tests show that these complexes have excellent cytotoxicity to cancer cells, and mechanism studies indicatethat these complexes can specifically target mitochondria. Complexes Ir1 and Ir2 can damage the function of mitochondria, subsequently increasing intracellular levels of ROS, decreasing MMP (mitochondrial membrane potential), and interfering with ATP energy production, which leads to autophagy and apoptosis. Furthermore, autophagy induced by Ir1 and Ir2 can promote cell death in coordination with apoptosis. Surprisingly, these four complexes also showed moderate antibacterial activity to S. aureusand P. aeruginosa.

Mitochondria-targeted Re(I) complexes bearing guanidinium as ligands and their anticancer activity.

As the "powerhouse" of a cell, mitochondria maintain energy homeostasis, synthesize ATP via oxidative phosphorylation, generate ROS signaling molecules, and modulate cell apoptosis. Herein, three Re(I) complexes bearing guanidinium derivatives have been synthesized and characterized. All of these complexes exhibit moderate anticancer activity in HepG2, HeLa, MCF-7, and A549 cancer cells. Mechanism studies indicate that complex 3, [Re(CO)3(L)(Im)](PF6)2, can selectively localize in the mitochondria and induce cancer cell death through mitochondria-associated pathways. In addition, complex 3 can effectively depress the ability of cell migration, cell invasion, and colony formation.

Sonodynamic Therapy Combined to 2-Deoxyglucose Potentiate Cell Metastasis Inhibition of Breast Cancer.

Metastasis is a major dilemma of cancer therapy. It frequently occurs in breast cancer, which is the leading form of malignant tumor among females worldwide. Although there are therapies that provide a possible method for this challenge, such as chemotherapy, the tumoral metabolic pathway is unconventional and favors metastasis and proliferation. This magnifies the difficulty of treating breast cancer. In this study, we identified 2-deoxyglucose (2 DG) as an important glycolysis suppressor that can potentiate sonodynamic therapy (SDT) to inhibit migration and invasion. In addition, disruptions of the cell membrane microstructure were captured by a scanning electron microscope in cells treated with the co-therapy. Similarly, we detected blockages of the cell cycle process, using flow cytometry. Of note, we observed that hexokinase II (HK2), the rate-limiting enzyme of glycolysis, was notably uncoupled from the mitochondria in SDT + 2 DG co-therapy group. Furthermore, there was altered expression of HK2 and Glut1, which control glycolysis. Simultaneously, the in vivo results revealed that pulmonary metastasis was also seriously suppressed by SDT + 2 DG co-therapy. These results demonstrate this co-therapy is a promising strategy for breast cancer inhibition through metastasis and proliferation.