Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis.

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3ß signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.

Characteristic of immune function decline in the process of “Declined of Vital Qi” caused by aging in mice / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：基于小鼠渐进衰老模型探讨衰老所致“正虚”的免疫功能衰退表征的特点。方法：使用不同月龄（2、6、15月龄）C57BL/6小鼠，通过流式细胞术检测并比较小鼠外周血和脾组织中T细胞、髓源性抑制细胞（MDSC）及其亚群的丰度变化。结果：外周血中T细胞亚群表型为CD3+CD4+CD44-CD62L+的幼稚CD4+ T细胞（2 vs 6月龄，P=0.137；2 vs 15月龄，P=0.004；6 vs 15月龄，P=0.105）和表型为CD3+CD8+CD44-CD62L+的幼稚CD8+ T细胞（2 vs 6月龄，P=0.179；2 vs 15月龄，P=0.001；6 vs 15月龄，P=0.015）出现与衰老有关的细胞比例降低，差异具有统计学意义。表型为CD3+CD4+CD44+CD62L+的中央记忆CD8+ T细胞出现与衰老有关的比例升高，差异具有统计学意义（2 vs 6月龄，P=0.01；2 vs 15月龄，P=0.007；6 vs 15月龄，P=0.164）。对脾组织的检测结果具有与外周血相同特点。同时，CD8+ T细胞比例随衰老逐渐升高（2 vs 6月龄，P=0.027；2 vs 15月龄，P<0.001；6 vs 15月龄，P<0.001）；表型为CD8+CD28+的活化CD8+ T细胞亚群比例也出现随月龄增长的上升（2 vs 6月龄，P=0.863； 2 vs 15月龄，P=0.016；6 vs 15月龄，P=0.024），差异均具有统计学意义。结论：衰老所致“正虚”过程中，不同免疫细胞亚群变化并不都反映免疫抑制特点，虽然总体免疫功能下降，但单一表型难以反应整体免疫功能变化。

Corrected Serum Ionized Calcium as a Risk Factor Related to Adult Dyslipidemia.

Background: Dyslipidemia is a significant threat to global public health due to its pivotal role as a cardiovascular disease (CVD) risk factor. Calcium is a critical nutritional element required for electrical signal transduction and muscle and heart function, and calcium supplementation is widespread in the general population. However, associations between serum calcium and serum lipid profiles remain conflicting. Considering ionized calcium [Ca(2+)] is the best measure of active serum calcium and the lack of Ca(2+) analyzers, we aimed to examine the independent and joint associations between serum ionized calcium corrected by albumin ([Ca2+]corr) and the known modifiable risk factors and dyslipidemia. Methods: We collected physical examination records, including demographic, anthropometric, laboratory tests, and clinical characteristics from individuals who had health checkups in 2019 at the health examination center of the First Affiliated Hospital of China Medical University. Subjects were categorized into Q1-Q4 groups using [Ca2+]corr quartiles, and odds ratios (ORs) with 95% confidence intervals (CIs) for dyslipidemia and associated components were calculated using logistic regression. We also performed non-linear and threshold effect analyses of [Ca2+]corr and triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (Non-HDL-C) levels. Findings: Of 5,416 individuals aged 18-92 years, multivariable-adjusted models showed that ORs for dyslipidemia increased gradually with elevated [Ca2+]corr levels. Logistic regression analyses demonstrated that [Ca2+]corr levels were associated with the increased odds of dyslipidemia (per 1 mmol/L increase: OR = 3.53, 95% CI: 1.56-8.00, P < 0.001). When compared with individuals in the Q1 group, those in groups Q3 and Q4 had significantly higher dyslipidemia odds (OR Q3 vs. Q1 = 1.20, 95% CI: 1.01-1.42; OR Q4 vs. Q1 = 1.31, 95% CI: 1.10-1.56, all P < 0.05). Furthermore, a linear, positive relationship between [Ca2+]corr levels and dyslipidemia odds was observed (P for non-linear trend = 0.506), and the optimal cut-off point of [Ca2+]corr for dyslipidemia management was 2.26 mmol/L. A modifiable effect of albumin on the relationship between [Ca2+]corr and dyslipidemia odds was also found (P for interaction = 0.014). High [Ca2+]corr levels were positively associated with elevated TC, LDL-C, and Non-HDL-C but inversely associated with decreased HDL-C odds. Moreover, Locally weighted regression (Loess) analyses showed a non-linear, positive relationship between [Ca2+]corr and TG, TC, HDL-C, LDL-C, and Non-HDL-C levels. Interpretation: Corrected serum ionized calcium was positively associated with increased odds of dyslipidemia and elevated TC, LDL-C, and Non-HDL-C, but inversely associated with the odds of decreased HDL-C.

Improved Utilization of Nitrate Nitrogen Through Within-Leaf Nitrogen Allocation Trade-Offs in Leymus chinensis.

The Sharply increasing atmospheric nitrogen (N) deposition may substantially impact the N availability and photosynthetic capacity of terrestrial plants. Determining the trade-off relationship between within-leaf N sources and allocation is therefore critical for understanding the photosynthetic response to nitrogen deposition in grassland ecosystems. We conducted field experiments to examine the effects of inorganic nitrogen addition (sole NH4 +, sole NO3 - and mixed NH4 +/NO3 -: 50%/50%) on N assimilation and allocation by Leymus chinensis. The leaf N allocated to the photosynthetic apparatus (NPSN) and chlorophyll content per unit area (Chlarea) were significantly positively correlated with the photosynthetic N-use efficiency (PNUE). The sole NO3 - treatment significantly increased the plant leaf PNUE and biomass by increasing the photosynthetic N allocation and Chlarea. Under the NO3 treatment, L. chinensis plants devoted more N to their bioenergetics and light-harvesting systems to increase electron transfer. Plants reduced the cell wall N allocation or increased their soluble protein concentrations to balance growth and defense under the NO3 treatment. In the sole NH4 + treatment, however, plants decreased their N allocation to photosynthetic components, but increased their N allocation to the cell wall and elsewhere. Our findings demonstrated that within-leaf N allocation optimization is a key adaptive mechanism by which plants maximize their PNUE and biomass under predicted future global changes.

Paclitaxel-loaded and folic acid-modified PLGA nanomedicine with glutathione response for the treatment of lung cancer.

Targeted delivery and smart response of nanomedicine hold great promise for improving the therapeutic efficacy and alleviating the side effects of chemotherapy agents in cancer treatment. However, availability of only a few studies that discuss organic nanomedicines with these properties limits the development prospects of nanomedicines. In the present study, folic acid (FA)-targeted delivery and glutathione (GSH) smart responsive nanomedicine were rationally designed for paclitaxel (PTX) delivery for the treatment of lung cancer. Compared with other stimuli-responsive nanomedicines, this nanocarrier was not only sensitive to biologically relevant GSH for on-demand drug release but also biodegradable into biocompatible products after fulfilling its delivery task. The nanomedicine first entered tumor cells via FA and its receptor-mediated endocytosis. After the lysosomal escape, poly(lactic-co-glycolic acid) (PLGA) nanomedicine was triggered by a higher level of GSH and released its cargo into the tumor microenvironment. In vitro and in vivo results revealed that the PLGA nanomedicine not only inhibited the proliferation and promoted the apoptosis of lung cancer cells significantly but also possessed less toxic side effects when compared with free PTX. Therefore, the proposed drug delivery system demonstrates the potential of a multifunctional nano-platform to enhance bioavailability and reduce the side effects of chemotherapy agents.

Hydrogen production in single-chamber microbial electrolysis cell under high applied voltages.

The aim of this study was to investigate the performance of single-chamber MEC under applied voltages higher than that for water electrolysis. With different acetate concentrations (1.0-2.0 g/L), the MEC was tested under applied voltages from 0.8 to 2.2 V within 2600 h (54 cycles). Results showed that the MEC was stably operated for the first time within 20 cycles under 2.0 and 2.2 V, compared with the control MEC with significant water electrolysis. The maximum current density reached 27.8 ± 1.4 A/m2 under 2.0 V, which was about three times as that under 0.8 V. The anode potential in the MEC could be kept at 0.832 ± 0.110 V (vs. Ag/AgCl) under 2.2 V, thus without water electrolysis in the MEC. High applied voltage of 1.6 V combined with alkaline solution (pH = 11.2) could result in high hydrogen production and high current density. The maximum current density of MEC at 1.6 V and pH = 11.2 reached 42.0 ± 10.0 A/m2, which was 1.85 times as that at 1.6 V and pH = 7.0. The average hydrogen content reached 97.2% of the total biogas throughout all the cycles, indicating that the methanogenesis was successfully inhibited in the MEC at 1.6 V and pH = 11.2. With high hydrogen production rate and current density, the size and investment of MEC could be significantly reduced under high applied voltages. Our results should be useful for extending the range of applied voltages in the MEC.

Jinfukang inhibits lung cancer metastasis by upregulating CX3CL1 to recruit NK cells to kill CTCs.

ETHNOPHARMACOLOGICAL RELEVANCE: Circulating tumor cells (CTCs) play an important role in tumor metastasis and may be a target for metastasis prevention. The traditional Chinese medicine Jinfukang functions to improve immunity, prevent metastasis, and prolong lung cancer patient survival periods. Yet, whether Jinfukang prevents metastasis by regulating immune cells to clearance CTCs is still unknown. AIM OF THE STUDY: To explore the anti-metastasis mechanism of Jinfukang from the perspective of regulating NK cells to clear CTCs. MATERIALS AND METHODS: CTC-TJH-01 cell was treated with Jinfukang. Cytokine chip was used to detect cytokines in cell culture supernatant. Lymphocyte recruitment assay was detected by Transwell and flow cytometry. Protein expression was analysis by Western blot. LDH kit was used to detect cytotoxicity. NOD-SCID mice used for tail vein injection to study lung metastasis. RESULTS: Jinfukang could promote the expression and secretion of the chemokine CX3CL1 by CTCs. In addition, Jinfukang could promote the recruitment of natural killer (NK) cells by CTCs and significantly increase the cytotoxic effect of NK cells on CTCs. Moreover, Jinfukang could upregulate the expression of FasL and promote the secretion of TNF-α by NK cells and that NK cells could induce the apoptosis of CTCs through the Fas/FasL signaling pathway. Finally, we confirmed that Jinfukang could promote NK cells to kill CTCs and then inhibit lung cancer metastasis in vivo. The above effects of Jinfukang could be partially reversed by an anti-CX3CL1 mAb. CONCLUSIONS: These results suggest that Jinfukang may prevent lung cancer metastasis by enhancing the clearance of CTCs in the peripheral blood by NK cells, providing evidence for the anti-metastasis effect of Jinfukang.

Controlled Synthesis of BaYF5:Er3+, Yb3+ with Different Morphology for the Enhancement of Upconversion Luminescence.

In this work, Er3+/Yb3+-codoped BaYF5 with different sizes and shapes have been synthesized by a simple solvothermal method. By changing the fluoride source, pH value, solvent, surfactants, Yb3+ concentration, temperature, and reaction time, the optimum synthetic conditions of BaYF5:Er3+, Yb3+ were found to improve the upconversion luminescent properties. It is found that the emission intensity of green and red light is enhanced for several times by the way of using NaBF4 as a fluoride source with the comparison of NH4F and NaF. Moreover, the effects of different surfactants are not the same. Adding 5% polyetherimide (PEI) as surfactant can also improve the upconversion emission. On the contrary, when sodium citrate (CIT) as another surfactant was used to add, the sizes of the nanocrystals were gradually increased and the luminous properties also declined.

[Optimization of the parameters of microcirculatory structural adaptation model based on improved quantum-behaved particle swarm optimization algorithm].

The vessels in the microcirculation keep adjusting their structure to meet the functional requirements of the different tissues. A previously developed theoretical model can reproduce the process of vascular structural adaptation to help the study of the microcirculatory physiology. However, until now, such model lacks the appropriate methods for its parameter settings with subsequent limitation of further applications. This study proposed an improved quantum-behaved particle swarm optimization (QPSO) algorithm for setting the parameter values in this model. The optimization was performed on a real mesenteric microvascular network of rat. The results showed that the improved QPSO was superior to the standard particle swarm optimization, the standard QPSO and the previously reported Downhill algorithm. We conclude that the improved QPSO leads to a better agreement between mathematical simulation and animal experiment, rendering the model more reliable in future physiological studies.