Iridium(III) complex induces apoptosis in HeLa cells by regulating mitochondrial and PI3K/AKT signaling pathways: In vitro and in vivo experiments.

Cyclometalated iridium complexes with mitochondrial targeting show great potential as substitutes for platinum-based complexes because of their strong anti-cancer properties. Three novel cyclometalated iridium(III) compounds were synthesized and evaluated in five different cell lines as part of the ongoing systematic investigations of these compounds. The complexes were prepared using 4,7-dichloro-1,10-phenanthroline ligands. The cytotoxicity of complexes Ir1-Ir3 towards HeLa cells was shown to be high, with IC50 values of 0.83±0.06, 4.73±0.11, and 4.95±0.62 µM, respectively. Complex Ir1 could be ingested by HeLa cells in 3 h and has shown high selectivity toward mitochondria. Subsequent investigations demonstrated that Ir1 triggered apoptosis in HeLa cells by augmenting the generation of reactive oxygen species (ROS), reducing the mitochondrial membrane potential, and depleting ATP levels. Furthermore, the movement of cells was significantly suppressed and the progression of the cell cycle was arrested in the G0/G1 phase following the administration of Ir1. The Western blot analysis demonstrated that the induction of apoptosis in HeLa cells by Ir1 involves the activation of the mitochondria-dependent channel and the PI3K/AKT signaling pathway. No significant cytotoxicity was observed in zebrafish embryos at concentrations less than or equal to 16 µM, e.g., survival rate and developmental abnormalities. In vivo, antitumor assay demonstrated that Ir1 suppressed tumor growth in mice. Therefore, our work shows that complex Ir1 could be a promising candidate for developing novel antitumor drugs.

Immunohistochemical evaluation and prognostic value of monocarboxylate transporter 1 (MCT1) and 4 (MCT4) in T-cell non-Hodgkin lymphoma.

Tumor cells often exhibit the Warburg effect, wherein, they preferentially undergo glycolysis over oxidative phosphorylation for energy production. Monocarboxylate transporter 1 (MCT1) and 4 (MCT4) are critical symporters mediating lactate efflux and preventing intracellular acidification during tumor growth. Numerous studies have focused on inhibiting MCT1 or MCT4 in various cancers. However, its role in T-cell lymphoma (TCL) is not yet investigated owing to the low incidence of TCL. This study was designed to investigate the expression of MCT1/MCT4 in patients with TCL and determine their prognostic value in this cancer. We performed immunohistochemistry to evaluate the expression level of MCT1/MCT4 in 38 TCL tissue samples and then compared their expression among different TCL subgroups, which were formed based on different clinical characteristics. Survival analysis was performed to evaluate the relationship between MCT1/MCT4 expression and both overall survival (OS) and progression-free survival (PFS). Our results revealed that MCT1 and MCT4 expression was significantly increased in TCL tissues compared to the control group. In addition, increased MCT1 expression associated with the female sex, advanced disease stage, increased serum LDH, Ki-67 at ≥ 50%, and intermediate or high-risk groups as categorized by the International Prognostic Index (IPI) score. We also found that increased MCT1 expression may be associated with reduced OS and PFS. In conclusion, MCT1 and MCT4 are overexpressed in patients with TCL and may predict poor prognosis. MCT1 inhibition might be a novel treatment strategy for TCL, and further preclinical trials are required.

Risk Factors, Incidence, and Prognosis of Thromboembolism in Cancer Patients Treated With Immune Checkpoint Inhibitors.

In recent years, immune checkpoint inhibitors (ICIs) have become the standard treatment option for tumors. With the widespread application of ICIs, immune-related adverse events (irAEs) have gradually attracted the attention of researchers. Owing to the characteristics of ICIs, irAEs can affect each organ of the human body. Thromboembolism is uncommon in cancer patients receiving ICIs, but it may affect their survival. Most thromboembolic events do not cause serious effects after early prediction and treatment, but life-threatening toxic reactions are also observed. This condition should not be ignored because of vague and atypical symptoms, which make early diagnosis more challenging. This article focuses on the high-risk factors, underlying mechanisms, incidence, and prognosis of thromboembolism in patients using ICIs and briefly describes the intervention and treatment measures. This information would allow patients to effectively manage the side effects of thromboembolism during Immune checkpoint inhibitors treatment, ensuring the efficacy of ICIs and reducing mortality.

A simple field method for the determination of sulfite in natural waters: Based on automated dispersive liquid-liquid microextraction coupled with ultraviolet-visible spectrophotometry.

Sulfite is known to be harmful to human health and associated to sulfur related environmental effects and ideally should be analyzed onsite owing to its instability. Here we describe an automated, miniaturized, and highly efficient dispersive liquid-liquid microextraction (DLLME) system that seamlessly coupled to a UV-vis spectrophotometer for the trace analysis of sulfite in natural waters. The automated DLLME system was constructed by a single syringe pump that is coupled with a multiposition valve. Nanomolar levels of sulfite could be extracted from natural water samples and injected into the hyphenated spectrophotometer for quantification. The whole analytical procedures, including chromogenic reactions, DLLME, collecting and transferring of microvolume of extracts, and spectrophotometric quantification, were automatically carried out. Key parameters that affect the performance of the method were investigated. The method allows the determination of trace levels of sulfite in the range of 15-1500 nM with a detection limit of 1.2 nM. Good reproducibility and recoveries were obtained by analyzing a series of natural water samples that were spiked with different concentration levels. The method was successfully applied to real natural water samples with satisfactory results. The proposed analytical system is light (3.9 kg), simple to use, able to be applied in the field, and sensitive enough for fresh and saline waters analysis.

New angle of view on the role of rho/rho kinase pathway in human diseases.

Rho-kinase is an effector molecule of RhoA, a monomeric GTP-binding protein, and causes Ca2+ sensitization through inactivation of myosin phosphatase. The major physiological functions of Rho/Rho-kinase cascade include contraction, proliferation and migration in cells.There are some excellent reviews about Rho/Rho-kinase signal pathway, most of which focus on the specific proteins of the pathway including some upstream regulators and its final effects. But few articles cover signal pathways that can activate the signaling concerned, and/or the pathways that Rho/Rho-kinase can exactly activate. This review hence highlights the two questions after a profound survey of published literatures. Rho/Rho-kinase can exert positive feedback with just another kinase/signal transducers and activator of transcription, receptor tyrosine kinase signal pathways, even reactive oxygen species, which seem to comprise certain signal loops. The authors also presume, accordingly, that the positive feedback suggests a possible reason for exacerbation of some kind of inflammatory diseases including asthma, rheumatoid arthritis, multiple sclerosis, atherosclerosis, etc. This essay, therefore, provides a new angle of view for the therapy of these kinds of diseases.

[Bactericidal permeability increasing protein inhibits lipopolysaccharide-mediated platelet activation in vitro].

This study was purposed to investigate the inhibitory effect of bactericidal permeability-increasing protein (BPI) on lipopolysaccharide (LPS)-mediated activation of platelets. Venous blood samples were obtained from 10 healthy volunteers and were prepared into platelet-rich plasma (PRP, 1 × 10(8)/ml). Experiments were divided into four groups: normal platelet group (untreated group); LPS group, BPI group and BPI+LPS group. PRP were stimulated by LPS (10 µg/ml) in the presence and absence of BPI (100 µg/ml) or BPI alone. Then platelets were harvested and determined for Toll-like receptor-4 (TLR-4) with flow cytometry (FCM), the supernatant was used for detection of cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) with enzyme-linked immunosorbent assay (ELISA). The results showed that as compared with normal platelet group, TLR-4 expression on platelets was significantly increased under LPS stimulation (P < 0.001); the levels of TNF-α and IL-6 in the supernatant were also remarkably elevated (P < 0.001). However, either TLR-4 expression or the cytokine levels significantly decreased in the presence of BPI when platelets underwent LPS-challenge (P < 0.05), but still were higher than that in normal platelet group. Stimulating the platelets with BPI alone could not enhance the TLR-4 expression and cytokine levels. It is concluded that BPI has the ability to inhibit the LPS-induced platelet activation.

[Toll-like receptor 4 expression mediates the activation of platelets induced by LPS].

The study was aimed to investigate the expression of Toll-like receptor 4 (TLR4) on platelets and to determine whether platelet TLR4 involves in its activation induced by lipopolysaccharide (LPS). Human platelet-rich plasma (PRP) and platelet suspension obtained from 15 healthy individuals pretreated with a concentration of 0.2 microg/ml of LPS in the presence or absence of thrombin (1 U/ml) for 1 hour. The expressions of TLR4, CD62P (P-select) and CD40L on platelets were detected by flow cytometry, and platelet TLR4 expression was further determined by Western blot analysis. The results indicated that the percentage of TLR4-positive platelets induced by thrombin was increased by 32.34% compared with the resting platelets (25.44%, p < 0.05). TLR4 expression on platelets treated with LPS was remarkably elevated in the presence or absence of thrombin. However, the expression level of the former was much higher than that of the latter and thrombin stimulation alone (p < 0.05). Moreover, the similar results were found in Western blot analysis. Synchronously, expressions of CD62P and CD40L on resting platelets were 6.39% and 2.45%, they were also markedly increased when treated with thrombin (42.68% and 14.8%) and LPS respectively, and the increases of expression of CD62P and CD40L were more significant when stimulated with both LPS and thrombin (63.03% and 13.94%). Although anti-TLR4 antibody inhibited significantly the increase of TLR4, CD62P and CD40L on platelets induced by LPS, which did not affect their increase induced by thrombin. In conclusion, the evidence has been shown that functional TLR4 can be expressed on human platelets. It may involve in platelet activation as an important mediator of LPS-induced CD62P and CD40L expressions on platelets.

[Effect of age on body composition in healthy Beijing women].

OBJECTIVE: To observe the effect of age and menstrual status on body composition in healthy Beijing women. METHODS: We measured body composition with dual-energy X-ray (GE Lunar Prodigy) in 316 healthy Beijing females aged 20 to 74 years (5-7 cases per age). Parameters provided by the software were as following: total body bone mineral content, lean mass, fat mass and fat percentage (%fat). Local regions measured included arm, leg, trunk, android region and gynoid region. Body mass index (BMI), fat mass index (FMI), free fat mass index (FFMI) and A/G were calculated. Volunteers were assigned to 6 groups according age by every ten years a group. RESULTS: BMC peaked during the 4th decade, LM peaked during the 5th decade, with a decline of 18.1% and 5.2% respectively at age 74 years. Total body fat mass and %fat showed a general increase with aging throughout the studied age range. Total body fat mass increased from 16+/-5 kg at age 20-29 years to 24+/-6 kg at age 70-74 years, while %fat increased from 31.3% to 39.5%. All local region %fat increased with aging at different extents. Android region %fat showed the largest raise extent (32.2%). BMI increased gradually from 21.1 kg/m2 at age 20-29 years to 26.1 kg/m2 at age 70-74 years. FMI changed more obviously than FFMI. A/G increased from 0.85 at age 20-29 years to 1.02 at age 70-74 years. Different menstrual status in women of 40-59 years had obvious effect on A/G and BMC (P<0.05), while it had no significant effect on BMI, body weight and waist circumference (P>0.05). CONCLUSIONS: Aging and menstrual status have evident effect on body composition distribution in healthy Beijing women.