Dose-Response最新文献

Objectives: We aimed to investigate the concentration of adenosine (ADO) in the tumor microenvironment (TME), focusing on its potential to modulate tumor cells and natural killer (NK) cells, thereby facilitating tumor immune escape.

Methods: In this study, an in vitro simulation system was developed to systematically evaluate the effects of ADO (0-500 μM) on the colony formation and migration capability of A549 (lung carcinoma) and A375 (melanoma) cell lines, as well as its action on NK92 cell activity, cytokine secretion, and cytotoxicity against tumor cells.

Results: The results showed that 50 μM ADO significantly promoted tumor cell proliferation (increasing the colony formation rate by 60%-80%) and migration (increasing the migration rate by 30%-40%), whereas high concentrations (>200 μM) exhibited an inhibitory effect. ADO suppressed NK92 cell activity in a dose-dependent manner, reducing the relative proliferation rate by 14.5% at 50 μM, significantly decreasing IFN-γ secretion (by 24% at 50 μM), and impairing the killing efficiency of A549, A375, and HepG2 cells (reducing their respective cytotoxicity by 20.3%, 22.4%, and 31.5%).

Conclusion: This study provides biological evidence that 50 μM represents a critical threshold concentration for TME simulation, elucidates the concentration-dependent bidirectional regulation of ADO.

Objectives: The current study investigated angiogenesis-arresting attributes of Mesua ferrea oleo-gum resin extract and its underlying molecular mechanisms.

Methods: Series of in vitro, ex vivo and in vivo models were used to assess anti-angiogenic properties.

Results: MTT cell viability experiments showed that oleo-gum resin extract induced moderate cytotoxicity towards EA.hy926 cells (IC₅₀ = 42 µg/mL). Extract-treated cells showed significant reduction in invasion, migration, and tube formation potential. At the protein level, down-regulation in expression of angiopoietin-1 and -2, Tie-2, MMP-1 and -9, VEGF-A, and VEGFR2 pro-angiogenic proteins was observed in extract-treated EA.hy926 cells. Signalling array data indicated a marked down-regulation of transcription factors, i.e., HIF-1α and WNT (-3.68 ± 5.74 and -6.24 ± 6.50 fold-change). Furthermore, extract treatment diminished vessel-sprouting in in vitro 3D spheroids, ex vivo rat aorta ring, and in vivo chick embryo chorioallantoic membrane models. Treatment with extract significantly reduced intracellular ROS and caspases-8 and -9 levels. GC-MS and HPLC analyses of extract indicated the presence of (+)-α-longipinene, isoledene, cedrene and α-elemene. ADMET prediction of detected compounds revealed good intestinal absorption (> 90%) and skin permeability (log Kp < -2.5), making the extract a suitable candidate for the treatment of angiogenesis-associated intestinal and skin disorders.

Conclusion: Overall, these findings suggest that Mesua ferrea extract exhibits anti-angiogenic properties by down-regulating the VEGF/angiopoietin axis, warranting further investigations in treating angiogenesis-associated diseases.

Objectives: MiR-107 upregulation represents a key target among the multiple pathways associated with T2DM. Given that drug combinations offer significant therapeutic potential, this study investigated the antidiabetic, antioxidant, and anti-inflammatory effects of γ-irradiation, the quercetin (common flavonol), and the metformin (biguanide) on HFD/STZ-induced diabetic rats' brains. Methods: Diabetic rats were treated with metformin (200 mg/kg b.w./day) alone or in combination with quercetin (30 mg/kg b.w./day) and/or γ-radiation (fractionated 4 Gy) for 4 weeks. Results: The diabetic group exhibited increased body weight, blood glucose, HOMA-IR, AChE, MMP-2, and lipid peroxidation, while serum insulin and brain GPx antioxidant enzyme activity were significantly decreased. Similarly, BDNF and SIRTI transcript levels and IRS1 protein expression were reduced, whereas NF-κB and MiR-107 transcript levels were elevated in diabetic rats compared to controls. Histopathological examination of diabetic brain tissue corroborated the biochemical findings. Treatment with metformin alone or in combination with γ-irradiation and/or quercetin effectively mitigated these effects by downregulating miR-107 and improving brain function, with optimal results achieved through combined therapy. Conclusion: The synergistic combination of Metformin, fractionated gamma-irradiation, and quercetin effectively attenuates brain injury in diabetic rats by enhancing IRS1/SIRT1/BDNF signaling while suppressing MiR-107/NF-κB pathways.

Objectives: Ginseng and its extracts have shown promising therapeutic effects on gastric cancer (GC). We aimed to investigate the functions and potential mechanisms of Ginsenoside Rk1 (Rk1) on GC.

Methods: GC cell lines were treated with different doses of Rk1. The CCK-8 assay and BrdU assay were used to measure cell viability and proliferation. A Transwell assay was used to evaluate cell invasion and migration. A TUNEL assay was used to assess cell apoptosis. RT-PCR was conducted to detect apoptosis-associated genes. Western blotting was used to determine the activation of the AMPK/mTOR pathway. An in vivo tumor-bearing nude mouse model was generated to investigate the impact of Rk1 on tumor growth.

Results: Rk1 inhibited the proliferation, migration, invasion, and EMT of GC cells and promoted cell apoptosis. It also enhances the sensitivity of GC cells to chemotherapy drugs (including 5-fluorouracil, vincristine, cisplatin, and oxaliplatin). Mechanistically, Rk1 increased AMPK phosphorylation and repressed mTOR phosphorylation. AMPK inhibition strongly decreased the inhibitory effect of Rk1 on GC cells. In-vivo assays suggested that Rk1 considerably hindered GC growth and had synergistic effects when combined with cisplatin or oxaliplatin.

Conclusion: Ginsenoside Rk1 exerts an antitumor effect on GC by activating the AMPK/mTOR pathway.

Objectives: Radiation Adaptive Response (AR) is a biological phenomenon in which exposure to low-dose radiation (LDR) enhances an organism's ability to withstand subsequent higher doses. This scoping review explores AR across multiple disciplines, summarizing evidence, identifying research gaps, and evaluating potential applications in cancer therapy, neurodegenerative disease management, space medicine, and pandemic response.

Methods: A comprehensive review of experimental/clinical studies on AR was conducted, focusing on molecular mechanisms, biological implications, biophysical modeling, and translational applications.

Results: In oncology, AR has shown promise in selectively protecting normal tissues during radiotherapy while sensitizing tumor cells, yet its effects remain cell-type dependent. LDR may manage neurodegenerative diseases by modulating oxidative stress and inflammation. In space medicine, AR-based astronaut selection has been proposed as a novel strategy to mitigate radiation risks during long-term space missions, although empirical validation is lacking. LDR therapy for managing COVID-19 pneumonia has been explored, but ethical concerns and long-term safety risks require further investigation.

Conclusion: Despite AR's potential, its clinical and spaceflight implementation requires mechanistic elucidation, standardized protocols, and rigorous studies. The risks of tumorigenesis, individual variability in AR, and potential immunomodulatory effects must be evaluated before widespread application. Moreover, inconsistent AR appearance complicates its study and clinical use.

In this study we used biosynthesis methods to create bimetallic nickel cobalt nanoparticles (Ni-Co NPs) utilizing seaweed. Before exposure to target cells, the characterization of Ni-Co NPs is done by UV-Vis spectrophotometry, EDX, SEM, TEM, the shape of g Ni-Co NPs are polygonal form and its size is measured 38.27 ± 3 nm. The cytotoxic effect of g Ni-Co NPs on HuH7 and HCT cells were determined by MTT and NRU assays. The cytotoxicity of NPs increased in a concentration dependent manner and it showed high cytotoxic effect on HCT-116 cells than HuH-7 cells. We determined IC₅₀ 24 h for HuH-7 and HCT -116 cells at 24 h, it was 65.84 and 24.73 μg/mL, respectively. ROS was elevated at higher concentration of Ni-Co NPs. LPO was increased at 16 μg/mL in HuH-7 cells and 19 μg/mL in HCT-116 cells. CAT was reduced in HCT-116 cells than HuH-7 cells high concentration of NPs. JC-1 staining, the loss of MMP in control, Ni-Co NPs exposed cell were evaluated. In HuH-7 and HCT-116 cells, maximum apoptotic cells were observed at high concentration. Apoptotic genes were expressed in both type cells. The above findings highlight the significance of Ni-Co NPs and useful in a number of cancer treatments.

Background: Previously the author was unable to develop a formal mathematical characterization of his probability-based hormetic relative risk (HRR) model for cancer prevention/elimination by absorbed doses (D) of ionizing radiation in the hormetic zone where D < D _t (population absorbed dose threshold for cancer induction).

Objective: To develop a formal mathematical characterization of the HRR model's disease prevention function DPF(D), which is the cancer prevention/elimination probability.

Approach: Use distributed (over a population) individual-specific, natural-defenses-enhancing (E) and suppressing (S) dose thresholds.

Results: DPF(D) is now mathematically characterized based on Weibull-type E and S thresholds distributions. The E thresholds predominate at very low radiation doses and the S thresholds predominate at higher doses just below D _t. This leads to a hormetic dose-response relationship for cancer relative risk RR(D) (= 1 - DPF(D)) for doses from zero (representing natural background radiation exposure) to dose D _t. The greatly improved HRR model is quite flexible and was applied to lung cancer and reticulum cell sarcoma prevention/elimination data from a study involving more than 15 000 gamma-ray exposed mice.

Conclusion: The System of Radiological Protection needs to be updated to account for health benefits rather than invalid LNT-hypothesis-based phantom radiation-caused cancers from radiation doses < D _t.

In comparing magnetic resonance imaging (MRI) and computed tomography (CT), it is often stated thata significant advantage of MRI is its lack of ionizing radiation, which may contribute to carcinogenesis. This article questions whether this concern is justified. First, the basis for the linear no-threshold (LNT) hypothesis, which suggests a carcinogenic potential of CT, is now considered weak. Historically, the foundation of the LNT model was not grounded in robust scientific data, and the epidemiological evidence indicating an increased cancer incidence in children undergoing CTscans is not scientifically reliable. Both MRI and CT examinations elevate reactive oxygen species, leading to DNA damage, chromosomal aberrations, and micronucleus formation. Following a single scan with either MRI or CT, the γH2AX index in human lymphocytes increased to a similar degree; however, the small amounts of DNA damage produced are efficiently repaired, thus not resulting in carcinogenesis. While it may be argued that ionizing radiation induces more complex DNA damage than electromagnetic fields, no studies have compared the quality of DNA damage between MRI and CT at clinically relevant exposure levels. Considering the effective defense mechanisms of living organisms, infrequent MRI and CT examinations do not appear to pose an increased risk of carcinogenesis.

Objective: To elucidate the role of NEDD4 in ionizing radiation (IR)-induced endothelial-mesenchymal transition (EndMT) and its molecular mechanism in radiation-induced lung injury (RILI), given the unclear regulatory pathways of EndMT in RILI pathogenesis.

Methods: IR-induced EndMT was observed during RILI in vivo and in vitro by immunohistochemical staining and Western blot analysis. Proteomics identified NEDD4 as a candidate, validated by RNA sequencing (RNA-seq) and quantitative real-time polymerase chain reaction (qRT‒PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis linked NEDD4 to PI3K-AKT signaling. Co-immunoprecipitation (Co-IP) confirmed NEDD4-ATM interaction.

Results: IR upregulated NEDD4 in endothelial cells, correlating with EndMT progression. NEDD4 overexpression enhanced ATM pathway activation, modulating genes upstream/downstream of ATM. Co-IP verified physical NEDD4-ATM binding, suggesting NEDD4 stabilizes ATM to promote EndMT.

Conclusion: Overall, our study shows that NEDD4 mediates EndMT to participate in RILI through the ATM signaling pathway, which may break new ground for understanding the occurrence and development of RILI.

Objectives: The primary objective of this experimental study was to evaluate the severity of the anxiolytic effect of Prospekta, a novel drug for treating cognitive, behavioral, and mental disorders, under different administration regimens. Methods: The pharmacological activity of Prospekta was studied in adult male Wistar rats using the open field test. The drug was administered once, twice, or three times daily over a period of five days. Results: The most pronounced anxiolytic effect was observed with twice-daily administration of Prospekta. This regimen led to an increase in the total distance travelled and enhanced exploratory behaviour, as indicated by a greater number of entries into the center and more time spent in the central zones of the open field arena. Conclusion: Given the nature of Prospekta's composition, the conventional concept of "dose" is not fully applicable. Therefore, the observed effects may result from the cumulative impact of each administration. Furthermore, as with several other drugs used in neurology and psychiatry, a non-linear relationship between the frequency of administration and the anxiolytic effect was established for Prospekta.