Amlodipine inhibits Synaptotagmin-4's oncogenic activity on gastric cancer proliferation by targeting calcium signaling.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies. PURPOSE: This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC. METHODS: We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity. RESULTS: SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca2+ influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine. CONCLUSION: SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca2+-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.

Visible-light-promoted organic-dye-catalyzed sulfonylation/cyclization to access indolo[2,1-a]isoquinoline derivatives.

An efficient visible-light-promoted organic-dye-catalyzed radical cascade cyclization was developed for the rapid synthesis of sulfonyl-substituted indolo[2,1-a]isoquinolines and benzimidazo[2,1-a]isoquinolin-6(5H)-ones. Using the economical and environmentally benign Eosin B as the photocatalyst, a wide range of indolo[2,1-a]isoquinoline derivatives were obtained in moderate to good yields. Mechanistic studies indicate that a sulfonyl radical pathway is involved in this reaction. Compared with previous works, this protocol has the advantages of being metal- and base-free, using visible light as a traceless energy source, simple operation and mild reaction conditions, all of which make this methodology more attractive.

Metal- and additive-free radical-triggered nitration/cyclization to construct indolo[2,1-α]isoquinoline and benzimidazo[2,1-a]isoquinolin-6(5H)-one derivatives using t-BuONO as nitro reagents.

An efficient metal- and additive-free nitro radical-triggered addition/cyclization of 2-aryl-N-acryloyl indoles/2-arylbenzimidazoles for the synthesis of nitro-substituted indolo[2,1-α]isoquinoline and benzimidazo[2,1-a]isoquinolin-6(5H)-one derivatives has been developed. The commercially available and low-cost t-BuONO was used as a nitro reagent. Due to mild reaction conditions, a variety of functional groups could be tolerated to give the corresponding products in moderate to good yields. Moreover, this nitration process could be scaled-up and the nitro group could be readily converted into the amino group, which may find applications in synthetic and medicinal chemistry.

Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kα inhibitors.

Phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma (ESCC). It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kα inhibitors in an aim to improve the clinical responsive rate in ESCC. Here, ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33, a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC. Elevated level of cyclin D1, p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells. CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase, which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2. Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1, which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21. Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

Performance Testing of Micro-Electromechanical Acceleration Sensors for Pavement Vibration Monitoring.

Pavement vibration monitoring under vehicle loads can be used to acquire traffic information and assess the health of pavement structures, which contributes to smart road construction. However, the effectiveness of monitoring is closely related to sensor performance. In order to select the suitable acceleration sensor for pavement vibration monitoring, a printed circuit board (PCB) with three MEMS (micro-electromechanical) accelerometer chips (VS1002, MS9001, and ADXL355) is developed in this paper, and the circuit design and software development of the PCB are completed. The experimental design and comparative testing of the sensing performance of the three MEMS accelerometer chips, in terms of sensitivity, linearity, noise, resolution, frequency response, and temperature drift, were conducted. The results show that the dynamic and static calibration methods of the sensitivity test had similar results. The influence of gravitational acceleration should be considered when selecting the range of the accelerometer to avoid the phenomenon of over-range. The VS1002 has the highest sensitivity and resolution under 3.3 V standard voltage supply, as well as the best overall performance. The ADXL355 is virtually temperature-independent in the temperature range from -20 °C to 60 °C, while the voltage reference values output by the VS1002 and MS9001 vary linearly with temperature. This research contributes to the development of acceleration sensors with high precision and long life for pavement vibration monitoring.

SN38-based albumin-binding prodrug for efficient targeted cancer chemotherapy.

Developing new therapeutic strategies that damage tumour cells without harming normal tissues is among the primary obstacles in chemotherapy. In this study, a novel ß-glucuronidase-sensitive albumin-binding prodrug was designed and synthesized to selectively deliver the drug SN38 to tumour sites and maximize its efficacy. After intravenous administration, the prodrug Mal-glu-SN38 covalently bound to plasma albumin through the Michael addition, enabling it to accumulate in the tumour and release SN38 when triggered by extracellular ß-glucuronidase. Compared to irinotecan, Mal-glu-SN38 displayed a slower plasma clearance and increased drug exposure over time. Moreover, Mal-glu-SN38 caused an increase in tumour-site accumulation of both the albumin-prodrug conjugate and free SN38 released from albumin conjugate when compared with irinotecan. After administration of multiple doses, Mal-glu-SN38 also significantly delayed the tumour growth, resulting in an impressive reduction or even disappearance of tumours (67% of mice cured) without causing any observable side effects.

[Effects and mechanism of drug serum of prepared radix polygoni multiflori on rat osteoblast in vitro].

OBJECTIVE: To study the effect of drug serum of prepared Radix Polygoni Multiflori on rat osteoblast (Ob) and its mechanism. METHODS: The animal serum was prepared by serum pharmacology means. The cells were getting by separating and inducing the SD neonatal rat skull bone. The proliferation and differentiation of Ob were detected by CCK-8, alkaline phosphatase (ALP) activity analysis. And RT-PCR method was used to determine the osteogenesis-related genes expression. RESULTS: Compared with control group, the groups with drug serum of prepared Radix Polygoni Mutiflori, 10%, 20% and 30% had an effect on promotion the proliferation significantly on Ob (P < 0.01). There was no concentration-related manner among groups. The 5% and 10% drug serum decreased ALP activity at the post-translation phase compared with control group, but higher doses (20% and 30%) did not have the same effect. However, drug serum of PR/MIN increased significantly osteogenesis-related genes (OC, ALP, Cbfalpha1) mRNA expression (P < 0.05). CONCLUSION: The drug serum of prepared Radix Polygoni Multiflori can stimulate osteoblast proliferation in vitro, and its mechanism may be associated with increasing osteogenesis-related genes expression.