Sanofi S.A · KCNJ11 · 小分子
glimepiride + metformin SR 是一种小分子，由Sanofi S.A研发。该药已获批，用于治疗相关适应症，给药途径：Oral (PO)。
| 商品名 | Amaryl Mex, Amaryl M SR |
| 公司 | Sanofi S.A |
| 药物类别 | 小分子 |
| 分子靶点 | KCNJ11, ABCC8 |
| 给药途径 | Oral (PO) |
| 状态 | Approved |
glimepiride + metformin SR 作用于 2 个分子靶点：
| KCNJ11 | potassium inwardly rectifying channel subfamily J member 11 (BIR, HHF2) |
| ABCC8 | ATP binding cassette subfamily C member 8 (MRP8, SUR1delta2) |
glimepiride + metformin SR 针对 1 个适应症，涉及 1 个治疗领域。
| 治疗领域 | 疾病/病症 | 分期 |
|---|---|---|
| Metabolism and nutrition disorders | Type 2 diabetes mellitus | ✓ Approved |
Huang Po-Yu PY, Hsieh Yi-Hsien YH, Chen Yong-Syuan YS, Hung Tung-Wei TW et al.
Sunitinib resistance contributes to poor outcomes in advanced renal cell carcinoma (RCC). This study investigated the anti-metastatic effects and underlying mechanisms of melatonin in sunitinib-resistant (SR)-RCC. Melatonin significantly inhibited the migration and invasion of A498-SR and Caki-1-SR cells. SR-RCC cells exhibited elevated CTSD expression, impaired endoplasmic reticulum (ER) stress signaling with reduced GRP78 and IRE1α, and enhanced p38 MAPK activation, all of which were reversed by melatonin. Silencing p38 MAPK further potentiated the inhibitory effects of melatonin on cell migration and invasion. Mechanistically, CTSD expression was regulated through both GRP78/p38 MAPK-mediated ER stress. In vivo, melatonin markedly reduced lung metastasis of Caki-1-SR cells without causing significant toxicity to major organs. Collectively, these findings demonstrate that melatonin inhibited the metastatic potential of SR-RCC by decreasing CTSD expression, restoring ER stress response, and decreasing p38 MAPK expression, supporting its potential as an anti-metastatic therapeutic agent for SR-RCC.
Xin Yuxiang Y, Wang Jianru J, Xiao Xiachu X, Yang Yutao Y et al.
The development of high-performance lanthanide-based fluorescence-intensity-ratio (FIR) thermometers is limited by the lack of a continuously tunable, qualitative guided crystal-field design principle. Most systems still rely on empirical host-dopant screening, and the correlation among lattice geometry, crystal-field strength, energy gap (ΔE), and thermometric sensitivity (Sr) remains unclear. Here, we establish an A-site lattice-site engineering strategy in APb2Cl5 (A = Na, K, Rb, Cs and solid solutions), where the A-site ionic radius acts as a single tunable parameter to regulate local geometry, crystal-field strength, and ΔE. Mapping from Na+ to Cs+ identifies an optimal K-Rb-Cs regime enabling linear tuning of ΔE and Sr, while excessive lattice contraction near the Na boundary suppresses luminescence and disrupts thermal coupling, revealing that ΔE enhances Sr only within a finite, lattice-defined window. Owing to the ultra-low phonon energy of the Pb-Cl lattice, Er3+/Yb3+-doped KPb2Cl5 nanoparticles (NPs) exhibit strong upconversion (UC), including the 490 nm 4F7/2 band, and achieve record Sr values of 33.6% K-1 at 78 K and 2.3% K-1 at 298 K, enabling cross-validated thermometry from 78-418 K. Extending this framework to Nd3+ enables 808 nm excitation and visible/near infrared (NIR) dual-mode thermometry with Sr up to 21.7% K-1. This work establishes a general route for high-performance optical nanothermometers.
Janez Andrej A, Bojic Mirjana M, Bozek Tomislav T, Kamenov Zdravko Z et al.
Real-world evidence on dipeptidyl peptidase-4 (DPP-4) inhibitors is limited by selective populations in randomized trials. The international, prospective DIVERSITY study evaluated the effectiveness, safety, and treatment acceptability of sitagliptin and sitagliptin/metformin single-pill combination (SPC) in routine clinical practice across diverse type 2 diabetes (T2D) populations. This non-interventional, multicenter study enrolled adults with T2D eligible for sitagliptin or sitagliptin/metformin SPC and followed them for 6 months with three data captures (baseline, ~3 months, ~6 months). The analysis set comprised 2,603 patients (mean age 64.6y ± 10.6; 53.1% women) meeting all criteria and with ≥152 days between first and third captures. Primary outcomes were absolute changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and post-prandial glucose (PPG) from baseline to 6 months. Secondary outcomes included the proportion achieving HbA1c <7% at 3 and 6 months, changes in body mass index (BMI), and hypoglycemia incidence. Safety was assessed in all treated patients (safety analysis set [SAS], n=2,697). Glycemic control improved over the 6-month observation period. Among patients with paired data, mean HbA1c fell from 7.98% to 6.99% (Δ -0.99%, 95% CI -1.05 to -0.93). Reductions were observed with both regimens: sitagliptin monotherapy (Δ -0.93%, 95% CI -1.01 to -0.85) and sitagliptin/metformin SPC (Δ -1.03%, 95% CI -1.11 to -0.96). FPG decreased by -1.91 mmol/L (95% CI -2.03 to -1.79) and PPG by -2.39 mmol/L (95% CI -2.56 to -2.21). The share of patients with HbA1c <7% rose from 16.9% at baseline to 53.7% at 6 months. BMI changes were small and consistent with weight neutrality (mean -0.61 ± 1.33 kg/m²). Treatment-related symptoms of hypoglycemia were rare (3 cases [0.1%] of all treated patients) and treatment acceptability was high: ≥90% patients and investigators reported satisfaction at 6 months. In routine practice across heterogeneous T2D populations, sitagliptin and sitagliptin/metformin SPC were associated with clinically meaningful improvements in HbA1c, FPG, and PPG over 6 months, with effects consistent with a weight-neutral profile, a low reported incidence of hypoglycemia, and high treatment satisfaction. These findings are consistent with the use of sitagliptin-based regimens, whether used as monotherapy or as add-on therapy, as treatment options in routine real-world care, including in older and multimorbid patients.
Bautista Geoanna M GM, Manning Declan D, Lieu Emily C EC, Ugochukwu Stephanie I SI et al.
Mechanosensation is fundamentally viewed as a plasma membrane phenomenon. We challenge this paradigm by introducing intracellular mechanosensation in intestinal smooth muscle. We hypothesized that a distinct, organelle-based signalling axis exists to amplify mechanotransduction from the inside out. To test this we investigated whether Piezo1, a canonical plasma membrane (PM) mechanosensor, also operates within the cell. Using tissue-level wire myography, high-resolution confocal microscopy, proximity ligation assays and patch-clamp electrophysiology on freshly dissociated cells, we identified a previously uncharacterized Piezo1-RyR-BKCa signalling axis in small intestinal smooth muscle cells (SMC). This intracellular mechanism relies on a nanoscale signalling complex (<40 nm) comprising an intracellular sensor (intra-Piezo1) and an amplifier (ryanodine receptor, RyR), coupled with a PM effector (large-conductance, Ca2+-activated K+ channels, i.e., BKCa channels). Activating this intracellular complex generated paxilline-sensitive outward currents independent of extracellular Ca2+ and dependent on internal SR Ca2+ stores, consistent with intrinsic organellar mechanotransduction. Within this complex intra-Piezo1 and RyR are positioned to operate as a coupled SR Ca2+ release unit that activates BK channels at SR-PM junctions, driving potent membrane hyperpolarization that reduces smooth muscle contractility, revealing the intra-Piezo1 complex as a molecular brake on excitation. These findings support a model in which mechanotransduction is not confined to the cell surface. Instead a specialized sensor-amplifier-effector complex originating at intracellular organelles amplifies cellular sensitivity to physical force, providing a critical gain-control system that restrains smooth muscle excitability and regulates gastrointestinal (GI) motility. KEY POINTS: This study advances a framework in which intracellular organelles contribute to mechanosensory signalling in gastrointestinal (GI) smooth muscle cells, complementing plasma membrane mechanisms. Piezo1 is predominantly intracellular in intestinal smooth muscle, where this pool, intra-Piezo1, forms a nanoscale signalling complex on the sarcoplasmic reticulum (SR) that positions it within <40 nm of RyR and of sarcolemmal large-conductance, Ca2+-activated K+ (BKCa) channels. Electrophysiological recordings show that this 'sensor-amplifier-effector' mechanism generates potent paxilline-sensitive hyperpolarizing currents that depend on SR Ca2+ release and persist without extracellular Ca2+, amplifying the cell's response to mechanical stress when intra-Piezo1 is activated from the inside out. Activation of this intra-Piezo1-mediated axis significantly dampens smooth muscle contractility, acting as a molecular 'brake' that supports the stretch-induced-relaxation feedback mechanism essential for intestinal function.
Yu Xinyi X, Liu Xiaodan X, Dang Yuanye Y, Liu Ruoxuan R
Macrophage foam-cell formation, triggered by excessive uptake of oxidized low-density lipoprotein (ox-LDL) and subsequent intracellular lipid accumulation, represents a critical pathological event in atherosclerotic plaque initiation that drives localized inflammatory responses. The present study investigated the effects of tafolecimab on ox-LDL-induced foam-cell formation and inflammatory responses in murine macrophages, and further explored the underlying molecular mechanisms. Foam-cell models were established by exposing RAW264.7 cells to 100 µg/ml ox-LDL for 24 h. The study groups included a blank control group, a model group, low-, medium- and high-dose tafolecimab groups (5, 10 and 20 µmol/l, respectively), and a positive control group treated with evolocumab. Intracellular lipid accumulation and cholesterol levels were evaluated using Oil Red O staining and a low-density lipoprotein-cholesterol (LDL-C) assay kit. Western blot analysis was performed to determine the expression of cholesterol metabolism-related proteins [class A scavenger receptor (SR-A) and ATP-binding cassette subfamily G member 1 (ABCG1)] and key components of the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathways (NF-κB p65 and phosphorylated p38). The concentrations of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the cell supernatant were quantified by enzyme-linked immunosorbent assay. Compared with the blank control, ox-LDL treatment markedly increased intracellular lipid-droplet accumulation and LDL-C content, confirming the successful establishment of a foam-cell model. In vitro, compared with the model group, tafolecimab reduced intracellular lipid accumulation and cholesterol content in a dose-dependent manner (P<0.001). In addition, tafolecimab significantly decreased the expression of the cholesterol influx receptor SR-A while increasing that of the cholesterol efflux transporter ABCG1 (P<0.001). Furthermore, it effectively inhibited the phosphorylation of NF-κB p65 and MAPK p38, which was accompanied by reduced secretion of TNF-α and IL-6 (P<0.001). The present results indicate that tafolecimab inhibits ox-LDL-induced macrophage foam-cell formation and inflammatory responses, likely by modulating the balance between SR-A-mediated cholesterol influx and ABCG1-mediated cholesterol efflux in favor of cholesterol efflux, and by inhibiting NF-κB and MAPK pathway activation.
注册免费账户还可查看另外 9996 篇文献
免费注册查看全部文献 →