ObjectiveTo explore therapeutic mechanisms and clinical application prospects of novel weight-loss medications in patients with obesity complicated by cardiovascular-kidney-metabolic (CKM) syndrome, aiming to provide theoretical support and therapeutic strategies for personalized precision management of CKM syndrome. MethodsRecent domestic and international studies were retrospectively reviewed, focusing on the mechanisms of action, clinical research outcomes, and application progress of novel weight-loss medications, including glucagon-like peptide 1 (GLP-1) receptor agonists, dual glucose-dependent insulinotropic peptide (GIP)/GLP-1 receptor agonists, triple GIP/GLP-1/glucagon receptor agonists, and amylin analogues. Special emphasis was placed on their comprehensive effects on cardiovascular, renal, and metabolic parameters. ResultsNovel weight-loss medications have demonstrated significant weight reduction and multisystem benefits through precise regulation of central appetite pathways, insulin sensitivity, and lipid metabolism. Among these medications, GLP-1 receptor agonists (e.g., semaglutide) and dual receptor agonists (e.g., tirzepatide) have been confirmed in phase Ⅲ clinical trials to effectively reduce cardiovascular event risks, slow renal function deterioration, and markedly improve glycemic control in obese patients with CKM syndrome. Triple receptor agonists (e.g., retatrutide) and combination medication regimen (e.g., CagriSema regimen) have further enhanced weight-loss efficacy, providing novel therapeutic avenues for obesity-related diseases. Additionally, these medications usually require combined application with traditional chronic disease medications, such as sodium-glucose linked transporter 2 inhibitors and renin-angiotensin-aldosterone system blockers, to achieve comprehensive therapeutic outcomes in CKM syndrome patients. However, further studies are needed to address long-term safety in real-world settings, optimization of drug formulations, and application in precision medicine. ConclusionsNovel weight-loss medications offer promising strategies for personalized precision treatment of obesity with CKM syndrome due to their significant weight-loss efficacy and multisystem synergistic effects. Although current clinical trials demonstrate substantial therapeutic potential, the complexity of CKM syndrome and individual patient variability necessitate additional in-depth research to facilitate broader clinical adoption and optimization of these medications.
Objective To explore effects of zinc on the contents of cycl in D2, cycl in-dependent kinase 4 (CDK4), and their DNA and total cellular protein in human umbil ical cord blood-drived mesenchymal stem cells (hUCBMSCs). Methods hUCBMSCs were isolated and cultured by density gradient centrifugation adherence method in vitro. At the serial subcultivation, the hUCBMSCs were randomly divided into 7 groups. In control group, hUCBMSCs were cultured with DMEM medium (containing 15%FBS). In treatment groups, hUCBMSCs were cultured with DMEM medium (containing 15%FBS plusZnSO4•7H2O). The final concentrations of zinc were 0.5, 1.5, 2.5, 3.5, 4.5, and 5.5 mg/L, respectively. The cellular surface antigens of CD29, CD34, CD44, and CD45 at the 3rd generation of hUCBMSCs were detected by flow cytometry. MTT assay was used to detect cell activity of the 3rd generation of hUCBMSCs. The optimum concentration of zinc was selected by the results of MTT as experimental group. The cell growth curves of experimental group and control group were drown by counting cell. The cell surface antigen, reproductive cycle, and DNA content were detected by flow cytometry motheds. The contents of cycl in D2 and CDK4 were detected by Western blot method. Results The positive expression rates of CD29 and CD44 were more than 70% in hUCBMSCs. The cell activity of 2.5 mg/L treatment group was superior to other treatment groups, as experimental group. At 7, 14, and 28 days, the contents of DNA, total cellular protein, cycl in D2, and CDK4 of hUCBMSCs were significantly higher in experimental group than those in control group (P lt; 0.01). The percentage of hUCBMSCs at S stage and prol iferation index in experimental group were also significantly higher than those in control group (P lt; 0.01). Conclusion Zinc (0.5-4.5 mg/L) has the promoting effect on the hUCBMSCs activity, and 2.5 mg/L is the optimal concentration. Zinc (2.5 mg/L) can accelerate the prol iferation and DNA reproduction of hUCBMSCs and increase the contents of cycl in D2 , CDK4, and cellular total protein.
Objective To observe the influence of the transforming growth factor β1(TGF-β1) on the denervated mouse musclederived stem cells（MDSCs） producing the connective tissue growth factor（CTGF）at different time points in vitro. Methods MDSCs from the primarycultureof the denervated mouse skeletal muscle were isolated and purified by the preplate technique, and they were identified before the culture and after the culturein vitro with TGF-β1 (10 ng/ml) for 24 hours. Then, MDSCs were randomlydivided into 6 groups (Groups A, B, C, D, E and F) according to the different time points, and were cultured in vitro with TGF-β1 (10 ng/ml) for 0, 3, 6, 12, 24 and 48 hours, respectively. The levels of CTGF mRNA in MDSCs were measured by the real time RT-PCR and the expression of CTGF protein was detected by the CTGF Western blot. Results The immunohistochemistry revealed that before the adding of TGF-β1, MDSCs highly expressed Sca-1, with a positivityrate of 96%; however, after the adding of TGF-β1, the positive expression of Sca-1 decreased greatly, with a negativity rate gt;99%. The Western blot test showed that the ratios of CTGF to the average absorbance of βactin in Groups A-F were 0.788±0.123, 1.063±0.143, 2.154±0.153, 2.997±0.136, 3.796±0.153 and 3.802±0.175, respectively. In Groups AD，the absorbance increased gradually, with a significant difference between the abovementioned groups (Plt;0.05). However, in Groups D-F, there was no significant difference between the groups as the promotive tendency became less significant (P＞0.05). The RT-PCR test showed that the △Ct values in GroupsA-F were 1.659±0.215, 1.897±0.134, 2.188±0.259, 2.814±0.263,2.903±0.125 and 3.101±0.186, respectively. In Groups A-D, the increase in the △Ct value was gradual, but the differences were significant between the groups (Plt;0.05). But in Groups E and F, the promotive tendency became less significant（Pgt;0.05）. Conclusion TGF-β1 can promote the production of CTGF inthe mouse MDSCs cultured in vitro and the time-dependent relation exists for 3-12 hours.
Objective To investigate the role and mechanism of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in the activation of aortic valve interstitial cells (AVICs) in aortic stenosis. Methods Isolating primary AVICs and stimulating their activation with transforming growth factor β1 (TGF-β1, 30 ng/mL), the expression of PGC-1α was detected. The activation of AVICs induced by TGF-β1 was observed after overexpression of PGC-1α by adenovirus or inhibition of PGC-1α function by GW9662. The possible downstream molecular mechanism of PGC-1α in AVICs activation was screened. Finally, the phenotype was further verified in primary human AVICs. Results The expression of PGC-1α decreased after the activation of AVICs induced by TGF-β1 (control group: 1.00±0.18; 24 h: 0.31±0.10; 48 h: 0.32±0.06; 72 h: 0.20±0.07; P<0.05). Specific overexpression of PGC-1α by adenovirus inhibited the activation of AVICs induced by TGF-β1 stimulation (periostin: 3.17±0.64 vs. 1.45±0.54, P<0.05; α-smooth muscle actin: 0.77±0.11 vs. 0.28±0.06, P<0.05). On the contrary, inhibition of PGC-1α function by GW9662 promoted the activation of AVICs (periostin: 2.20±0.68 vs. 7.99±2.50, P<0.05). Subsequently, it was found that PGC-1α might inhibit the activation of AVICs through downregulating the expression of calcium/calmodulin-dependent protein kinase (CAMK1δ) (0.97±0.04 vs. 0.74±0.11, P<0.05), and downregulating the expression of CAMK1δ alleviated the activation of AVICs (periostin: 1.76±0.11 vs. 0.99±0.20, P<0.05). The possible mechanism was that the activation of mammalian target of rapamycin (mTOR) signaling pathway was inhibited by reducing the accumulation of reactive oxygen species (ROS) (778.3±139.4 vs. 159.3±43.2, P<0.05). Finally, the protective effect of PGC-1α overexpression was verified in the activated phenotype of human AVICs (periostin: 2.73±0.53 vs. 1.63±0.14, P<0.05; connective tissue growth factor: 1.27±0.04 vs. 0.48±0.09, P<0.05). Conclusions The expression of PGC-1α significantly decreases during the activation of AVICs induced by TGF-β1. The overexpression of PGC-1α significantly inhibites the activation of AVICs, suggesting that PGC-1α plays a protective role in the activation of AVICs. The possible mechanism is that PGC-1α can inhibit the activation of CAMK1δ-ROS-mTOR pathway. In conclusion, interventions based on PGC-1α expression levels are new potential therapeutic targets for aortic stenosis.
ObjectiveTo review the recent progress in the role of thrombospondins (TSPs) in synapse formation in the central nervous system (CNS).MethodsA wide range of domestic and foreign literature on the role of TSPs in the synapse formation of the CNS was reviewed. The role of TSPs in structural features, molecules, and related diseases was reviewed.ResultsAs an oligosaccharide protein, TSPs play important roles in angiogenesis, inflammation, osteogenesis, cell proliferation, and apoptosis. In the nervous system, they bind to voltage-dependent calcium channels, neuronectin, and other extracellular matrix proteins and cell surface receptors, and participate in and regulate multiple processes such as synapse formation, maturation, and function in the CNS.ConclusionTSPs as an oligomeric extracellular matrix protein play an important role in the formation of synapses and the repair of synapses after CNS injury.
The temperature dependence of relative permittivity and conductivity of ex-vivo pig liver, lung and heart at 2 450 MHz was studied. The relative permittivity and conductivity of three kinds of biological tissues were measured by the open-end coaxial line method. The dielectric model was fitted according to the principle of least square method. The results showed that the relative permittivity and conductivity of pig liver, pig lung and pig heart decreased with the increase of tissue temperature from 20 to 80 ℃. The relative permittivity and conductivity models of pig liver, pig lung and pig heart were established to reflect the law of dielectric properties of biological tissue changing with temperature and provide a reference for the parameters setting of thermal ablation temperature field.
ObjectiveThe re-hospitalization and death events of patients heart failure caused by coronary heart disease are characterized by non-independence, heterogeneity, and censored data. A joint frailty model is established to jointly model the events, explore the risk factors affecting the prognosis of patients, and reduce the re-hospitalization rate and mortality of patients. MethodsThe sample included 4 682 patients with heart failure caused by coronary heart disease in two tertiary hospitals from January 2014 and June 2019. The electronic medical record information of patients during hospitalization and their follow-up information were collected. The Cox model, conditional frailty model and joint frailty model were used to analyze patient re-hospitalization and death. ResultsThe joint frailty model identified patients with a higher risk of both relapse and death (θ=0.209, P<0.001). Risk factors for re-hospitalization were advanced age, grade 3 hypertension, mental work, no medical insurance, high cystatin C, low ejection fraction, and low free thyroxine-3 and thyroxine-4. Antiplatelet drugs and statins significantly reduced the risk of re-hospitalization. Risk factors for death were advanced age, New York Heart Association classification Ⅲ to Ⅳ, no medical insurance, mental work, high cystatin C level, high troponin-I level, low free thyroxine-3, and low ejection fraction. Percutaneous coronary intervention, and taking antiplatelet drugs and statins significantly reduced the risk of death. ConclusionThe joint frailty model can simultaneously model recurring and terminal events, and accurately predict them. Our results suggest that thyroid hormone levels and cystatin C levels of patients should be considered more carefully. People with mental jobs should change bad working habits to reduce adverse outcomes.
目的 观察电压依赖性钙通道是否作用于大鼠脊髓背角胶状质层（SG）神经元大振幅微小兴奋性突触后电流的形成。 方法 选用成年雄性Sprague-Dawley（SD）大鼠，2%～3%异氟烷麻醉后，分离其腰骶部的脊髓，然后切片。采用全细胞电压钳技术，玻璃微电极的电阻为4~6 MΩ，钳制电压为?70 mV，记录胶状质层神经元微小兴奋性突触后电流（mEPSC）电流。将电流信号用Axopatch 200来放大并储存于电脑。对照组和用药结束后，持续采样mEPSC电流30 s。mEPSC电流的频率和振幅用Clampfit 8.1进行分析。 结果 钳制电压为?70 mV时，所有SG神经元均有自发性的EPSC。辣椒素增加mEPSC发生的频率和波幅。钴离子抑制辣椒素诱导的大振幅mEPSC。钴离子抑制辣椒素诱导的mEPSC的平均振幅，而不抑制其发生频率。 结论 电压依赖性钙离子通道参与了辣椒素引起的痛觉形成。
ObjectiveTo improve the knowledge of a rare disease named pyridoxine-dependent epilepsy.MethodsHigh-throughput sequencing and Sanger sequencing were used to validate the genes of epilepsy. Mutation gene validation was performed on two probands and their parents. Analyze clinical manifestations, electroencephalogram (EEG), imaging and prognostic features of the two probands.ResultsProbands 1, seizure onset at 4 months, progress as drug-refractory epilepsy, manifested as seizures types origin of multi-focal lesions. Head MRI and fluorodeoxyglucose-positron-based tomography (FDG-PET) were both normal. Gene detection showed that Aldehydedehydrogenase (ALDH7A1) gene has a complex heterozygous mutation contain c.1442G> and c.1046C> T.Proband 2, seizure onset at 5 months, manifested as a tonic-clonic seizure. Intermittent EEG and head MRI were both normal. Genotyping revealed ALDH7A1 gene contain a complex heterozygous mutation c.1547A> G and c.965C> T. Two cases were both seizure free by vitamin B6 therapy and gradually reduce the antiepileptic drugs.ConclusionsPyridoxine-dependent epilepsy may be late onset, some patient can be atypical and early experimental treatment can help to identify and the diagnosis should be confirmed by gene test.