Dose-Response最新文献

Objective: Pinus roxburghii Sarg. (Pinaceae) has shown useful effects in the treatment of urinary problems. This research aimed to explore P.roxburghii scientifically via in-vitro, in-vivo and in-silico techniques to find out its therapeutic benefits on kidney and bladder.

Method: Pharmacologically active components of aqueous ethanolic extract of P.roxburghii were analyzed by HPLC-DAD screening. These components were predicted for multfi-mechanisms and spasmolytic effects in network pharmacology. In-vitro experiments were conducted on isolated bladder of rat to analyze the spasmolytic effects of plant extract. Spasmolytic effects were also compared with the standard drugs verapamil and oxybutynin In-vivo experiments were also performed to observe diuretic and nephroprotective potential of the plant.

Result: Phytochemical analysis indicated the presence of chlorogenic acid, gallic acid, P-coumaric acid, kaempferol, salicylic acid, sinapic acid and benzoic acid. Aqueous ethanolic extract of plant relaxed the contractions induced by high K⁺ (80 mm) and carbachol (1 µM) in isolated urinary bladder strips of rat. In-vivo experiments revealed the nephroprotective and diuretic potential.

Conclusion: So it has been proved via scientific evidence that the concerned plant possesses spasmolytic, nephroprotective and diuretic potential and may be an important therapeutic agent against urinary problems in the near future.

Living organisms have been exposed to ionizing radiation throughout Earth's 4-billion-year history, with humans presently receiving about 2 mSv of ionizing radiation every year. While radiation generates reactive oxygen and nitrogen species (ROS and RNS), organisms have evolved mechanisms to neutralize these toxic molecules and utilize them as signal transducers. High doses of radiation are harmful, but low doses are seemingly essential, and moderate doses can provide benefits-a phenomenon known as hormesis. Radiation exposure is currently regulated by the linear no-threshold model (LNT), which assumes all radiation is harmful, even at the smallest doses. However, substantial evidence, including insights into biological defense mechanisms like DNA repair, apoptosis, and immune system, supports hormesis. Although the Life Span Study (LSS) data historically backed the LNT, closer analysis reveals that low-dose radiation is linked to increased life expectancy and reduced cancer risk, invalidating LNT. During the 2011 Fukushima nuclear disaster, the Japanese government, adhering to the LNT-based precautionary principle, evacuated residents despite low contamination levels. This decision caused over 2000 deaths, though no fatalities were directly attributed to radiation. These findings challenge the LNT model and highlight the need for regulatory standards that incorporate thresholds and/or hormesis principles, better reflecting biological evidence.

Objectives: This study investigated the cardioprotective effects of stachydrine (STA) in lipopolysaccharide (LPS)-induced septic mice and H9c2 cardiomyocytes, focusing on its anti-apoptotic, anti-inflammatory, and anti-ferroptotic actions.

Methods: We established an LPS-induced sepsis model in mice and an LPS-stimulated H9c2 cardiomyocyte model in vitro.

Results: STA markedly reduced LPS-induced myocardial apoptosis, as demonstrated by decreased TUNEL-positive cells, and attenuated the elevation of serum cardiac injury markers, including creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), brain natriuretic peptide (BNP), cardiac troponin I (cTnI), and cardiac troponin T (cTnT) levels. STA also suppressed systemic inflammation, significantly reducing interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) levels at both mRNA and protein levels. Additionally, STA significantly inhibited LPS-induced production of pro-inflammatory cytokines in H9c2 cardiomyocytes. Mechanistically, STA activated the SIRT1/Nrf2 signaling axis and enhanced the expression of ferroptosis-related proteins, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Additionally, STA reduced oxidative stress and iron accumulation by decreasing malondialdehyde (MDA), Total Fe, and Fe²⁺ levels, while increasing glutathione (GSH) content in cardiomyocytes.

Conclusion: Our results suggest that STA confers robust cardioprotective effects in LPS-induced models by mitigating apoptosis, inflammation, and ferroptosis, partly via SIRT1/GPX4 pathway activation.

The natural radiation background contributes to the dose of ionizing radiation received by the whole population. However, the telluric component of the natural background radiation is not homogenous on Earth: while the average effective dose has been estimated to be 2.4 mSv/year worldwide, certain regions are considered as high natural background radiation areas (HBRA). To investigate the specificities of a continuous exposure to low-dose-rate irradiation, we reviewed data of the major HBRA from 98 studies published between 1973 and 2023. Three conclusions were drawn: 1) the dose received by the HBRA inhabitants is much lower than values assessed on hot spots : at Ramsar (Iran), 260 mSv/year were assessed at the highest hotspots but the maximal estimated dose-rate received by inhabitants is 80 mSv/year; 2) when DNA or chromosome breaks, cancer or accelerated aging are used as endpoints, no significant difference was observed between cells from HBRA and non-HBRA inhabitants; 3) conversely, adaptive response effect was systematically observed on ex vivo lymphocytes from HBRA inhabitants when they are exposed to a high dose ranging for 0.25 to 4 Gy. A mechanistic model based on the radiation-induced nucleoshuttling of the ATM protein provides an explanation to these last two conclusions.

Postural alignment is a critical determinant of health status. Its degradation is associated with deformity-caused and compensation-related back pain, neurologic involvement, osteoarthritic development, as well as disability and reduced quality of life. Radiography remains the most efficient method of evaluating standard sagittal and coronal spine and pelvic metrics that are used to plan surgical and nonsurgical treatment strategies. Many current spine guidelines dissuade the use of initial screening X-rays and some chiropractic guidelines condemn repeat imaging to assess progress from treatment regimens; these are anti-scientific viewpoints that ignore alternate viewpoints and evidence. Current understanding of the relationship between different spinopelvic parameters are essential to plan biomechanically appropriate interventions that are patient-specific. There are radiographically measured parameter thresholds critically related to several spinal disorders and positive patient outcomes. Current guidelines must include a caveat for contemporary biomechanical evaluation and its consequent specific treatments and should recommend routine radiographic imaging for spine patients undergoing corrective rehabilitative interventions. The failure to radiographically diagnose spinal deformity is argued to be negligence in many cases. The prime obstacle to routine X-ray imaging lies with the presumed threat of cancer, however, this is dogma; we summarize the main evidence from recent publications why this is so.

Background: The elevated mortality rate associated with sepsis is a primary global health concern. The correlation between bicarbonate levels and mortality risk in sepsis remains unclear.

Method: A retrospective cohort study was conducted using data from the MIMIC-IV database, including 12 744 adult sepsis patients. The primary exposure was serum bicarbonate levels, categorized into quintiles. The primary outcome was 28-day mortality, and secondary outcomes included 90-day mortality. Multivariable Cox regression models adjusted for demographic, clinical, and laboratory variables were used to examine the relationship between bicarbonate levels and mortality. Curve fitting and sensitivity analyses were performed to validate the findings.

Results: A U-shaped relationship between serum bicarbonate levels and 28-day mortality was identified. Both low (≤19.0 mEq/L) and high (>26.0 mEq/L) bicarbonate levels were associated with increased mortality risk. Patients with bicarbonate levels between 24.0-26.0 mEq/L had the lowest 28-day mortality. The relationship remained consistent across subgroups, and an inflection point was observed at 25.0 mEq/L. Sensitivity analyses confirmed the robustness of the findings across different data imputations.

Conclusion: This study demonstrates that both low and high serum bicarbonate levels are associated with increased mortality in sepsis patients. The optimal bicarbonate range for minimizing mortality risk appears to be between 24.0-26.0 mEq/L. These findings highlight the importance of monitoring bicarbonate levels in clinical practice, suggesting that maintaining bicarbonate within this range may improve patient outcomes. Further prospective studies are needed to confirm these findings and explore potential therapeutic strategies.

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.