Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition.

Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.

Functional Upgrading of an Organo-Ir(III) Complex to an Organo-Ir(III) Prodrug as a DNA Damage-Responsive Autophagic Inducer for Hypoxic Lung Cancer Therapy.

The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.

Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition.

Breast cancer is the most commonly diagnosed cancer and second­leading cause of cancer deaths in women. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting breast cancer cell proliferation, invasion, angiogenesis, and metastasis, and the high expression of STAT3 is related to the occurrence and poor chemotherapy sensitivity of breast cancer. Iridium(III) complexes Ir-PTS-1- 4 containing a pterostilbene-derived ligand were synthesized to inhibit the STAT3 pathway in breast cancer. Ir-PTS-4 inhibited the proliferation of breast cancer cells by suppressing the expression of phosphorylated STAT3 and STAT3-related cyclin D1, arresting cell cycle in the S-phase, inducing DNA damage and reactive oxygen species (ROS) generation, eventually leading to autophagic cell death. The cell metastasis and invasion were also inhibited after Ir-PTS-4 treatment. Besides, Ir-PTS-4 exhibited excellent anti-proliferation activity in 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work presents the rational design of metal-based anticancer agents to block the STAT3 pathway for simultaneously inhibiting breast cancer proliferation and metastasis.

Eukaryotic Translation Initiation Factor 2 Subunit ß as a Prognostic Biomarker Associates With Immune Cell Infiltration in Breast Cancer.

INTRODUCTION: The present study aims to explore the expression level of eukaryotic translation initiation factor 2 subunit ß (EIF2S2) in breast cancer tissue, and its role both in breast cancer prognosis and in the immune microenvironment. METHODS: To assess the association between the expression levels of EIF2S2 and prognosis, the Gene Expression Profiling Interactive Analysis database was initially applied to determine differences in the gene expression of EIF2S2 in various malignant and normal tissues. Furthermore, the expression levels of EIF2S2 were determined in the clinical breast cancer tissues and corresponding para-neoplastic tissues using immunohistochemical analysis. In addition, Kaplan-Meier survival and Cox regression analyses were employed to explore the association between EIF2S2 expression levels and patient prognosis. Finally, the correlation between the expression levels of EIF2S2 and immune cell infiltration in breast cancer was analyzed using the TIMER2.0 database, and subsequently validated by immunohistochemical experiments. RESULTS: The Gene Expression Profiling Interactive Analysis database revealed the presence of higher expression levels of EIF2S2 in various different types of cancer compared with normal cells, also correlating its expression with both the age and the tumor stage of patients with breast cancer. The survival analysis results revealed that high expression levels of EIF2S2 could be a risk factor for poor prognosis in patients with breast cancer. Moreover, the EIF2S2 expression level was found to be closely associated with the infiltration levels of various immune cells, including regulatory T cells, CD4+, CD8+, and natural killer cells, in breast cancer. CONCLUSIONS: In conclusion, the present study has demonstrated that an upregulated expression level of EIF2S2 in breast cancer may be associated with poor patient prognosis, affecting immune cell infiltration in breast cancer. Taken together, the findings of the present study have shown that EIF2S2 expression may be a novel therapeutic target for breast cancer.

Coupling of Dissolved Organic Matter Molecular Fractionation with Iron and Sulfur Transformations during Sulfidation-Reoxidation Cycling.

Iron (oxyhydr)oxides and organic matter (OM) are intimately associated in natural environments, and their fate might be linked to sulfur during sulfidation-reoxidation cycling. However, the coupling of DOM molecular fractionation with Fe and S transformations following a full sulfidation-reoxidation cycle remains poorly understood. Here, we reacted Fh and Fh-OM associations with S(-II) anaerobically and then exposed the sulfidic systems to air. S(-II) preferentially reacted with Fh to form inorganic S (e.g., mackinawite, S0, and S22-) over being incorporated into OM as organic S and therefore indirectly affected OM fate by altering Fe speciation. Fh sulfidation was inhibited by associated OM, and the main secondary Fe species were mackinawite, Fe(II)-OM compounds, and lepidocrocite. Concomitantly, organic molecules high in unsaturation, aromaticity, and molecular weight were detached from solid-phase Fe species due to their lower affinities for secondary Fe species than for Fh. During the reoxidation stage, the previously formed Fe(II) species were reoxidized to Fh with a stronger aggregation, which recaptured formerly released OM with higher selectivity. Additionally, •OH was generated from Fe(II) oxygenation and degraded a portion of the DOM molecules. Overall, these results have significant implications for Fe, C, and S cycling in S-rich environments characterized by oscillating redox conditions.

Effectiveness of oncology nurse navigator on the incidence of postoperative pulmonary complications in gastric cancer patients undergoing radical gastrectomy.

BACKGROUND: Management of postoperative pulmonary complications (PPCs) can be challenging in gastric cancer patients undergoing radical gastrectomy and is always associated with poor prognosis. Even though oncology nurse navigator (ONN) provide effective and critical individualized care to patients, little is known about their impact on the occurrence of PPCs in gastric cancer patients. This study aimed to determine whether ONN decreases the incidence of PPCs in gastric cancer patients. METHODS: This was a retrospective review in which data for gastric cancer patients at one centre was evaluated before and after an ONN hired. An ONN was introduced to patients at their initial visit to manage pulmonary complications throughout treatment. The research was conducted from 1 August 2020 to 31 January 2022. The study participants were divided into the non-ONN group (from 1 August 2020 to 31 January 2021) and the ONN group (from 1 August 2021 to 31 January 2022). The incidence and severity of PPCs between the groups were then compared. RESULTS: ONN significantly decreased the incidence of PPCs (15.0% vs. 9.8%) (OR = 2.532(95% CI: 1.087-3.378, P = 0.045)), but there was no significant difference in the components of PPCs including pleural effusion, atelectasis, respiratory infection, and pneumothorax. The severity of PPCs was also significantly higher in the non-ONN group (p = 0.020). No significant statistical difference was observed for the major pulmonary complications ([Formula: see text] 3) between the two groups (p = 0.286). CONCLUSIONS: Role of ONN significantly decrease the incidence of PPCs in gastric cancer patients undergoing radical gastrectomy.

Self-Assembly Mitochondria-Targeting Donor-Acceptor Type Theranostic Nanosphere Activates ROS Storm for Multimodal Cancer Therapy.

The rational design of cancer theranostics with natural diagnostic information and therapeutic behavior has been considered to be a big challenge, since common theranostics from photothermal and photodynamic therapy need to be activated with external stimuli of photoirradiation to enable the chemotherapeutic effects. In this contribution, we have designed and synthesized a series of simple theranostic agents, TPA-N-n (n = 4, 8, 12), which could accumulate at the tumor site over 48 h and indicate superior antiproliferative performance in vivo. TPA-N-n was constructed with electron donor triphenylamine-acceptor benzothiadiazole-mitochondria-targeting moiety pyridinium. Complex TPA-N-8 indicated the best cytotoxicity to cancerous HeLa cells, with an IC50 value of 4.3 µM, and could self-assemble to a nanosphere with a size of 161.2 nm in the DMSO/PBS solution. It is worth noting that TPA-N-8 could accumulate in the mitochondria and produce major ROS species O2•- and OH• as well as small amounts of 1O2 without photoirradiation. Oxidative DNA damage is initiated due to the imbalance of intracellular redox homeostasis from the significant ROS storm. Multimodal synergistic therapy for HeLa cells was activated, as the PINK1-mediated mitophagy from the damaged mitochondria and DNA damage responsive (DDR) induced necroptosis and autophagy. This work not only provided a successful D-A type theranostic agent with superior anticancer performance from multimodal synergistic therapy but also further demonstrated the high efficacy of a mitochondria-targeting strategy for cancer treatment.

Switching the Mode of Cell Death between Apoptosis and Autophagy by Histone Deacetylase 6 Inhibition Levels.

Inhibition of histone deacetylase (HDAC) has been demonstrated to be an effective strategy for cancer treatment. In this work, we have developed a new agent Ir-VPA, which exhibits the cell death mode switching between apoptosis and autophagy due to the distinct level of HDAC6 inhibition. Ir-VPA indicates the best anticancer activity to HeLa cells, and could be hydrolyzed due to the high expression of the esterase in HeLa cells. Ir-VPA could accumulate in nuclei, induce severe DNA damages and cell cycle arrest at G2/M phase. The anticancer mechanism of Ir-VPA to HeLa cells was dependent on the HDAC6 inhibitory performance, as the caspase dependent apoptosis at low concentration (IC50 ) and autophagy with the autophagy flux blockage at high concentration (2×IC50 ). This is resulted from the distinct inhibitory levels of HDAC6, as moderate/complete inhibition at the concentration of IC50 /2×IC50 .In the presence of autophagic inhibitor chloroquine, the apoptotic population elevated from 32.7 % to 61.7 %, indicating that Ir-VPA could activate apoptotic process through the autophagolysosome fusion inhibition. Ir-VPA also exhibits excellent antiproliferative behavior to 3D HeLa multicellular tumor spheroids (MCTSs). This work not only provided a new HDAC6 inhibitor and novel anticancer mechanism for the effective treatment of cervical cancer, but also demonstrated the strategy to conjugate the metal fragment with active organic drug to enhance the anticancer performance.

Combination of Peglated-H1/HGFK1 Nanoparticles and TAE in the Treatment of Hepatocellular Carcinoma.

Transarterial embolization (TAE) constitutes the gold standard for the treatment of hepatocellular carcinoma. The effect of combination of TAE and peglated-H1/HGFK1 nanoparticles was explored on hepatocellular carcinoma. MTT and Annexin V-FITC were used to determine the cell viability and apoptosis of HepG2, ml-1, LO2, and VX2 cells after the treatment of HGFK1. Next, the orthotopic rabbit was selected to establish the in situ models of VX2 hepatocellular carcinoma. Nanoparticles were synthesized with peglated-PH1 and used to deliver HGFK1 overexpressing plasmids. MRI was performed to monitor tumor volume after being treated with TAE. The protein expression levels of CD31, CD90, and Ki67 were determined by immunohistochemistry. H&E and TUNEL staining were used to determine the necrosis and apoptosis in vivo. HGFK1 significantly inhibited the proliferation and increased the apoptosis of HepG2 and ml-1 cells (P < 0.05). MRI on 14 days after modeling suggested that the tumor showed ring enhancement. MRI on 7 days and 14 days after interventional therapy showed that tumor volume was significantly inhibited after the treatment with TAE and HGFK1 (P < 0.05). The immunohistochemical results 7 days after interventional therapy indicated that the expressions of CD31, CD90, and Ki67 were significantly lower after treatment with TAE and HGFK1 (P < 0.05). TAE and HGFK1 all extended the survival period of rabbits (P < 0.05). PH1/HGFK1 nanoparticle is an innovative and effective embolic agent, which could limit angiogenesis post-TAE treatment. The combination of TAE with PH1/HGFK1 is a promising strategy and might alter the way that surgeons manage hepatocellular carcinoma (HCC).

Identification of the CD16low CD56low CD38pos Natural Killer Cell as a Key Subset in Patients with Multiple Myeloma.

BACKGROUND: Natural killer (NK) cells are classified as innate immune cells which can directly recognize and kill tumor cells without antigen sensitization. NK cell-based adoptive immunotherapy for blood malignancies has attracted more attention in recent years. OBJECTIVE: To analyze different NK cell subsets in the peripheral blood and bone marrow (BM) of patients with multiple myeloma (MM). METHODS: Using flow cytometry we analyzed: (i) the distribution of distinct NK cell subpopulations (i.e. CD16low CD56low, CD16pos CD56high, CD16neg CD56high, CD16high CD56low, CD16neg CD56low, CD16low CD56low CD38pos) in the BM from MM patients at distinct disease stages. (ii) the expression of NKG2D, DNAM-1 and NKp30, and (iii) the expression of CD107a in CD16low CD56low CD38pos and CD16low CD56low CD38neg NK cells subsets. RESULTS: CD16low CD56low CD38pos was the dominant subset in BM from patients with MM at the CR stage with a decreased expression of NKp30. CD16low CD56low CD38pos subset showed a higher proportion of CD107a expression compared to CD16low CD56low CD38neg cells. In vitro experiments indicated that the CD16low CD56low CD38pos NK cell subset possesses more cytotoxicity than CD16low CD56low CD38neg NK cells. CONCLUSION: Our data suggest that CD16low CD56low CD38pos NK cells may reflect as an effector population with the potential therapeutic target in patients with MM. This group of cells may be useful for adoptive immunotherapy in MM in the future.

C-reactive protein as a non-linear predictor of prolonged length of intensive care unit stay after gastrointestinal cancer surgery.

BACKGROUND: The relationship between C-reactive protein (CRP) levels and prolonged intensive care unit (ICU) length of stay (LoS) has not been well defined. AIM: To explore the association between CRP levels at ICU admission and prolonged ICU LoS in gastrointestinal cancer (GC) patients after major surgery. METHODS: A retrospective study was performed to quantify serum CRP levels and to establish their association with prolonged ICU LoS (≥ 72 h) in GC patients admitted to the ICU. Univariate and multivariate regression analyses were conducted, and restricted cubic spline curves with four knots (5%, 35%, 65%, 95%) were used to explore non-linearity assumptions. RESULTS: A total of 408 patients were enrolled. Among them, 83 (20.3%) patients had an ICU LoS longer than 72 h. CRP levels were independently associated with the risk of prolonged ICU LoS [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.00-2.17]. Restricted cubic spline analysis revealed a non-linear relationship between CRP levels and OR for the prolonged ICU LoS (P = 0.035 for non-linearity). After the cut-off of 2.6 (log transformed mg/L), the OR for prolonged ICU LoS significantly increased with CRP levels. The adjusted regression coefficient was 0.70 (95%CI 0.31-1.57, P = 0.384) for CRP levels less than 2.6, whereas it was 2.43 (95%CI 1.39-4.24, P = 0.002) for CRP levels higher than 2.6. CONCLUSION: Among the GC patients, CRP levels at ICU admission were non-linearly associated with prolonged ICU LoS in survivors. An admission CRP level > 2.6 (log transformed mg/L) was associated with increased risk of prolonged ICU LoS.

Adsorption behavior and mechanism of CO2 in the Longmaxi shale gas reservoir.

CO2 is the main greenhouse gas in Earth's atmosphere, and has been causing global warming since the industrial revolution. Therefore, technologies to mitigate carbon emissions have attracted extensive research. Shale gas reservoirs could serve as potential sequestration space for CO2. This paper aims to gain insight in the CO2 adsorption behavior and mechanism in Longmaxi shale. The micropore filling theory is the best model for CO2 adsorption in the shale samples with the smallest MSR (Mean Square of Residual). This model fits better than that of the monolayer adsorption and multi-layer adsorption theories. Specifically, micropore filling adsorption mainly occurs in micropores, including the closed end of slit pores, capillary pores, and ink-shaped pores. Molecular layer adsorption mainly occurs in mesopores and macropores, including the open end of slit pores, plate pores, capillary pores, and ink-shaped pores. Moreover, the prediction model of CO2 storage quantity in deep shale gas reservoirs of China is established. This model shows that 91.5-388.89 × 1012 m3 of CO2 could in theory be stored in an adsorbed state. CO2 is mostly stored by an adsorbed state (higher than 95%) and a free state with good security and low leakage risk. The results from this work are of specific interest for global research on CO2 adsorption characteristics and adsorption mechanisms in different pore structures. Furthermore, it provides certain guidance for geological storage of CO2 in shale.

A model for superimposed coalbed methane, shale gas and tight sandstone reservoirs, Taiyuan Formation, Yushe-Wuxiang Block, eastern Qinshui Basin.

Superimposed accumulation mechanism and model of vertical source rock-reservoir system of coal-measure gas is crucial to evaluate the exploration potential, and also the basis of co-exploration and co-production of coal measure gas. This work investigates the formation mechanism of various types of reservoirs (coalbed methane, shale gas, tight sandstone) in the Taiyuan Formation (Yushe-Wuxiang Block, eastern Qinshui Basin). Source rocks (coal seams and coal-measure mudstones) in the study area are characterized by type III kerogen, organic rich and over-mature, and reach a gas generation peak during the Early to Late Cretaceous. Coalbed methane mainly adsorbs on the surface of micropores, shale gas mainly occurs in micropores, macropores and micro-factures in adsorbed and free states, and tight sandstone gas mainly occurs in macropores in a free state. The combinations of successions are identified, coalbed methane, shale gas, and tight sandstone gas horizons are divided into a mudstone-sandstone reservoir (combination I), a coal-mudstone-sandstone reservoir (combination II), and a coal-mudstone reservoir (combination III). This division occurs from top to bottom in the succession and is identified on the basis of lithology, total organic carbon content (TOC) of mudstones, gas logging, superimposition relationships, and the source rock-reservoir-caprock assemblage. The strata thickness, continuity, and gas logging results of combination III comprise the most favorable conditions for fairly good development potential, followed by combination I. The development potential of combination II is poor due to the small strata thickness and poor continuity. The identification of superimposed reservoirs can provide an engineering reference for the exploration of coal-measure gas.