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关键词： Cost per patient treated to target   glycemic control   hypoglycemia   semaglutide   tirzepatide   type 2 diabetes   weight loss  

摘要： Introduction Tirzepatide is a treatment for type 2 diabetes associated with improvements in glycemic control and weight loss, and a low risk of hypoglycemia when not used in combination with insulin or insulin secretagogues. A cost to target analysis of tirzepatide 5, 10 and 15 mg versus subcutaneous semaglutide 1 mg in the UK setting was performed, calculating the annual pharmacy cost per patient treated to six composite endpoints combining glycemic control (glycated hemoglobin [HbA1c] <= 6.5% [48 mmol/mol] and <7.0% [53 mmol/mol]) with weight loss (>= 5%, >= 10%, >= 15%) and avoidance of hypoglycemia. The costing analysis was based on the tirzepatide costs appraised by NICE as part of TA924. Methods The proportions of patients achieving composite treatment targets with tirzepatide and semaglutide (both in combination with metformin) were taken from a post-hoc analysis of the SURPASS-2 clinical trial (N = 1,845). Costs per patient treated to target were calculated by dividing the annual treatment costs associated with each intervention by the proportion of patients achieving the treatment target with each intervention. Results Tirzepatide 5, 10 and 15 mg were associated with a lower pharmacy cost per patient achieving treatment target than semaglutide 1 mg for the majority of endpoints evaluated. Differences became greater at more strict treatment targets. For example, the cost per patient achieving HbA1c <= 6.5%, weight loss >= 15%, and no hypoglycemia was GBP 5,650, GBP 8,665 and GBP 9,462 lower with tirzepatide 5, 10 and 15 mg, respectively, compared with semaglutide 1 mg over a 1-year time horizon. The only endpoint where semaglutide 1 mg was associated with a lower cost per patient achieving target was HbA1c <7.0%, weight loss >= 5%, and no hypoglycemia. Conclusions Compared to semaglutide, tirzepatide was associated with a lower annual pharmacy cost per patient with diabetes achieving treatment target in the UK for the majority of endpoints, with greater diff

关键词： Acute kidney injury   cisplatin   ischemia reperfusion injury   salvianolic acid C   gluconeogenesis   fructose-1, 6-bisphosphatase 1  

摘要： This research was targeted to investigate the pharmacological effects and mechanisms of Salvianolic acid C (SAC), a natural compound extracted from the Chinese traditional herbal Danshen (Salviae Miltiorrhizae Radix et Rhizoma), in acute kidney injury (AKI). Male C57BL/6J mice were used to create animal models and SAC (10 mg/kg, i.p.) or saline was administered 24 h before modeling. In both ischemia reperfusion injury (IRI) induced AKI and cisplatin (Cis) induced AKI models, SAC significantly alleviated the decline of renal function and destruction of renal pathological structure, which were correlated with reduced expression of renal injury markers and inhibited renal cell apoptosis. Non-targeted metabolomics sequencing revealed that the gluconeogenesis pathway was downstream of the renal protective effect of SAC in AKI. Further experiments revealed that the expression of key gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) was significantly decreased in AKI kidneys. AKI induced the reduction in glucose levels from serum and increase in lactate levels from serum and renal tissue. All of these metabolic changes were improved after the SAC treatment. The protective effects of SAC were reversed by an FBP1 inhibitor. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha) and forkhead box O1 (FOXO1), identified as gluconeogenesis promoting factor, were decreased after injection of cisplatin, which were reversed by SAC. Finally, molecular docking and SPR experiments revealed the direction interaction between FBP1 and SAC. Collectively, SAC possibly exerts its effect through a dual regulatory mechanism: by modulating the FOXO1/PGC1 alpha/FBP1 signaling axis and via direct interaction with FBP1.

关键词： NSCLC   IL-1 beta   chemotherapy   immunotherapy  

摘要： Interleukin (IL)-1 beta is known to promote lung cancer growth in both humans and mice. However, in the context of the current standard of care, which includes chemotherapy and immune checkpoint inhibitors, IL-1 beta can overcome resistance.

关键词： HIF-1 alpha   VEGF   lung   liver   roiler ascites syndrome  

摘要： Broiler ascites syndrome (BAS), a hypoxia-driven metabolic disorder, causes significant economic losses in poultry production. This study aimed to evaluate the pathological changes in the lungs and liver of broiler chickens and the expression of HIF-1 alpha and VEGF. HE, Masson and Van Gieson staining were used to observe histopathological changes in the lungs and liver, and molecular biology methods such as qPCR, Western blotting and immunohistochemistry were used to detect the expression of HIF-1 alpha and VEGF in the lungs and liver. The histopathological results revealed significant thickening and remodelling of the pulmonary artery wall in BAS broiler chickens;the boundaries of the vascular intima, media and adventitia were unclear;and there was a significant increase in the collagen fibre content around the arteries. Additionally, the hepatic cords were loosely arranged liver cords. The molecular biology results revealed that both the mRNA and protein expression levels of HIF-1 alpha and VEGF were significantly increased (p < 0.05) in the lungs and liver of AS broiler chickens. These findings establish an association between HIF-1 alpha/VEGF dysregulation and BAS pathogenesis, providing a foundation for mechanistic investigation.

关键词： Salvianolic acid B   benzoylpaeoniflorin   ischemic stroke   angiogenesis   Nrf2/HO-1/VEGFA signaling axis  

摘要： ContextAngiogenesis is one of the essential protective mechanisms that promote neural repair and regeneration after ischemic stroke (IS). Salvianolic Acid B (SAB) and Benzoyl paeoniflorin (BP) are compounds extracted from the Chinese medicines Salvia miltiorrhiza Bunge and Paeonia suffruticosa Andrews, *** investigated whether SAB combined with BP alleviated IS by promoting micrangium angiogenesis and determined the potential molecular *** and methodsThe impact of SAB-BP on angiogenesis after IS was investigated in middle cerebral artery occlusion (MCAO) rat model, ponatinib-induced ischemic stroke in zebrafish, and human umbilical vein endothelial cells (HUVECs). The neuroprotective effect of SAB-BP in rats was assessed using behavior tests and histopathological staining. The cerebral thrombosis assessment and angiogenesis assay were performed in the zebrafish model. Cell proliferation and angiogenesis in oxygen-glucose deprivation and reperfusion (OGD/R) HUVECs were assessed through cell viability, tube formation, migration, and invasion assays. Western blot analysis and immunofluorescence staining were used to determine the protein expression levels of Nrf2, HO-1, and *** findings indicated that SAB-BP significantly reduced neurological impairment following IS and promoted the formation of functional vessels in the cerebral ischemic penumbra. Furthermore, SAB-BP up-regulated the protein expression of Nrf2, HO-1, HIF-1 alpha, and VEGFA. Intriguingly, the pro-angiogenic effect of SAB-BP markedly restrained by adding the inhibitor of Nrf2 (ML385).Discussion and conclusionOur study demonstrates that SAB-BP enhances angiogenesis following IS by modulating the Nrf2/HO-1/VEGFA signaling axis both in vivo and in vitro. SAB-BP could serve as a promising therapeutic agent for IS recovery.

关键词： Xijiaqi Formula   chronic heart failure   myocardial fibrosis   extracellular matrix remodeling   TGF-beta 1  

摘要： ContextChronic heart failure (CHF) is the common concern following myocardial infarction. Xijiaqi Formula (XJQ) effectively treats CHF clinically while the underlying mechanism remains *** study was designed to investigate the effect and mechanism of XJQ on CHF in rats following *** and methodsUHPLC-Q-TOF-MS/MS was utilized to analyze the constituents of XJQ. Post-MI CHF was induced in rats by permanent ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiogram and hemodynamic. Myocardial morphology, fibrosis, and ultrastructure were evaluated through HE staining, Masson staining, and transmission electron microscopy, respectively. Myocardial transcriptomics were employed to identify genes that may be altered in response to XJQ treatment. Consistently, XJQ inhibited TGF-beta 1-induced myofibroblast activation in *** significantly improved cardiac function and structure, mitigating fibrosis, edema, and mitochondrial damage, while reducing key biomarkers (BNP, NT-proBNP, cTnT, Ang II). Transcriptomic analysis indicated that the differentially expressed genes influenced by XJQ were predominantly associated with extracellular matrix (ECM) remodeling. Notably, XJQ inhibited the upregulation of ECM proteins, including Adamts2, Fbln1, Itgbl1, and Ltbp3 mRNAs, as well as the proteins TGF-beta 1, P-Smad2/3, and MMP2. Additionally, in vitro experiments revealed that XJQ significantly suppressed the activation of myofibroblasts induced by TGF-beta *** significantly attenuated the progression from MI to CHF by inhibiting fibroblast activation mediated by TGF-beta 1/Smads signaling. The molecular mechanisms underlying this effect appear to be intricately linked to its regulation of ECM remodeling proteins, specifically Adamts2, Itgbl1, Fbln1, and Ltbp3.

关键词： Semaglutide   liraglutide   GLP-1 receptor agonists   CKD outcomes   meta-analysis  

摘要： Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in patients with chronic kidney disease (CKD), but existing evidence regarding their efficacy and safety remains inconsistent. To evaluate the cardiorenal outcomes and adverse effects of GLP-1 RAs in this population, we conducted a systematic review and meta-analysis of randomized controlled trials from PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science up to December 2024. Nine trials involving 21,717 patients, the vast majority of whom had T2DM, were included. GLP-1RAs treatment for CKD was associated with decreasing the incidence of major adverse kidney events (MAKE;RR, 0.84;95% CI, 0.76-0.94) and major adverse cardiac and cerebrovascular events (MACE;RR, 0.84;95% CI, 0.72-0.97), reducing all-cause mortality (RR, 0.83;95% CI, 0.76-0.90) and albuminuria level (SMD, -1.22;95% CI, -1.53 - 0.90). Gastrointestinal events associated with GLP-1 RA treatments including nausea (RR, 4.14;95% CI, 2.70-6.33), vomiting (RR, 3.05;95% CI, 1.88-4.97), diarrhea (RR, 2.65;95% CI, 1.76-3.98), and dyspepsia (RR, 3.79;95% CI, 1.02-14.12) have garnered significant attention. In conclusion, administration of GLP-1RAs treatment demonstrates excellent cardiorenal protective effects in CKD, primarily in patients with co-existing T2DM, though with notable gastrointestinal concerns.

关键词： Bifurcations   Khater method   strange attractors   return maps   phaseportraits  

摘要： Soliton solutions and chaotic analysis in integrable equations have become a hot topic in recent years. This work presents the qualitative dynamics and analytical solutions of (4+1)-D Boiti-Leon-Manna-Pempinelli (BLMP) model. Utlizing dynamical system approach, the mathematical analysis is performed. The given model is transformed into system of nonlinear ordinary differential equations (ODEs) via the Galilean transform. We study the bifurcations, quasi-periodic and chaotic dynamics, return maps, power spectrum, and strange attractors of the proposed model. Moreover, the soliton solutions are obtained with applications of the Khater method and the modified extended Tanh-function method (METM). The obtained results are illustrated in detail through 2D and 3D graphical representations.