OBJECTIVE To evaluate the therapeutic effects and safety of everolimus combined with letrozole and conventional chemotherapy for metastatic or recurrent endometrial carcinoma （EC）. METHODS The clinical and follow-up data of 156 patients with metastatic or recurrent EC admitted to Nanyang Central Hospital from January 2020 to January 2024 were analyzed retrospectively. They were divided into a control group （77 cases） and an observation group （79 cases） according to different therapeutic regimens. The control group received paclitaxel+carboplatin/cisplatin regimen， and concurrently took Letrozole tablets at a dose of 2.5 mg orally once daily； the observation group took Everolimus tablets 10 mg orally， once a day， in addition to the treatment regimen given to the control group. Each treatment cycle lasted 21 days， and both groups of patients underwent continuous treatment for 6 to 8 cycles. The short-term efficacy indicators （objective response rate and disease control rate）， the levels of serum tumor markers [carbohydrate antigen 125， human epididymis protein 4， vascular endothelial growth factor and matrix metalloproteinase-9] and medium- to long-term efficacy indicators [progression-free survival （PFS） and overall survival （OS）] were compared between the two groups. Additionally， the occurrence of toxic and side effects in both groups of patients was recorded. RESULTS The objective response rate （53.16%）， disease control rate （89.87%）， median PFS （6.47 months） and median OS （10.79 months） of the observation group were significantly higher or longer than those （22.08%， 68.83%， 4.63 months， 8.84 months） of the control group （P＜0.05）. Compared with before treatment， the levels of serum tumor markers in both groups decreased significantly after 6 cycles of treatment； the above indexes of the observation group were significantly lower than those of the control group （P＜0.05）. The proportion of patients with stomatitis in the observation group was significantly higher than that of the control group （P＜0.05）， and there was no statistically significant difference in the proportions of patients experiencing other toxic and side effects， such as leukopenia， between the two groups （P＞0.05）. CONCLUSIONS The everolimus combined with letrozole and conventional chemotherapy can effectively improve the short-term efficacy and prolong the survival period in patients with metastatic or recurrent EC， but attention should be paid to the occurrence of toxic and side effects， especially stomatitis.

This article reports a case of a male patient with anti-N-methyl-D-aspartate receptor （NMDAR） encephalitis comorbid with early-onset Alzheimer's disease （AD）. The patient presented with depression， hallucinations and delusions syndrome， and cognitive impairment， and was admitted to a psychiatric hospital. Through multidisciplinary consultation， the diagnosis was confirmed based on positive biological and pathological biomarkers. The patient's symptoms improved after receiving a therapeutic regimen comprising high-dose glucocorticoid therapy and psychiatric-related treatments. Based on relevant current research findings domestically and internationally， this article reviews the pathogenesis and clinical manifestations of early-onset AD and anti-NMDAR encephalitis， in order to enhance the discrimination ability of psychiatric specialists for such patients and improve the diagnosis and treatment level. ［Funded by Medical Research Project of Chengdu City （number， 2024403）］

AIM To evaluate the quality of Rubi Fructus.METHODS UPLC-Q-TOF-MS/MS was adopted in the component identification,after which the HPLC fingerprints were established,cluster analysis,principal component analysis and orthogonal partial least squares discriminant analysis were used for chemical pattern recognition.and the contents of chlorogenic acid,ferulic acid,ellagic acid,isoquercitrin,kaempferol-3-O-rutinoside,astragalin,tiliroside quercetin,kaempferol were determined.RESULTS Total 34 constituents were identified.There were 19 common peaks in the fingerprints for 31 batches of medicinal materials with the similarities of more than 0.8.Wild varieties and cultivated varieties,and medicinal materials from different producing areas could be distinguished;4 principal components demonstrated the accumulative variance contribution rate of 84.142％;8 differential components were screened,2 of which were ellagic acid and astragalin.Ellagic acid and astragalin displayed higher contents in the wild varieties than those in the cultivated varieties(P＜0.05,P＜0.01).CONCLUSION UPLC-Q-TOF-MS/MS,HPLC fingerprints combined with content determination can be used for the quality control of Rubi Fructus.

Objective:To explore the association between cumulative blood pressure (BP) and the risk of cerebrovascular disease (CVD) in older adults.Methods:This retrospective cohort study consecutively selected 4 480 older adults who participated in the Chinese Longitudinal Healthy Longevity Survey from 2008 to 2009 as the study subjects. The cumulative BP was calculated using the area under the curve from measurements taken at baseline (2008-2009), the first follow-up (2011), and the second follow-up (2014). The subjects were grouped with the quartiles (Q1-Q4) of cumulative systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). The Cox proportional hazards regression models were used to analyze the hazard ratios (HR) and 95% CI for the association between cumulative BP and the risk of CVD among older adults. The restricted cubic spline function was employed to examine the potential dose-response pattern between cumulative BP and the risk of CVD. Results:During a total of 40 230 person-years of follow-up, with a mean follow-up duration of (8.98±2.16) years, 768 new cases of CVD were identified. The older adults in the highest quartile (Q4) of cumulative SBP, DBP, and PP had a significantly higher risk of CVD compared to those in the lowest quartile (Q1), with a HR of 1.68 (95% CI: 1.36-2.06), 1.67 (95% CI: 1.36-2.06), and 1.52 (95% CI: 1.24-1.84), respectively (all P<0.001). For every 10 mmHg (1 mmHg=0.133 kPa)×year increase in cumulative SBP, DBP, and PP, the risk of CVD increased by 2% ( HR=1.02, 95% CI: 1.01-1.03), 3% ( HR=1.03, 95% CI: 1.01-1.05), and 2% ( HR=1.02, 95% CI: 1.01-1.03), respectively (all P<0.05). The restricted cubic spline model revealed a linear positive correlation between cumulative SBP, DBP, and PP with the risk of CVD among older adults (all P for nonlinearity>0.05). When cumulative SBP, DBP, and PP exceeded 791.9 mmHg×years, 462.9 mmHg×years, and 323.6 mmHg×years, corresponding to an average BP level of 132.0 mmHg, 77.2 mmHg, and 53.9 mmHg, respectively, the risk of CVD began to increase. Conclusions:Elevated long-term cumulative BP may increase the risk of CVD in older adults. Caution is warranted when SBP, DBP, and PP exceed 132.0 mmHg, 77.2 mmHg, and 53.9 mmHg, respectively.

Acute ischemic stroke (AIS) is a comprehensive syndrome characterized by neurological dysfunction, resulting from cerebral tissue ischemia and hypoxia due to impaired blood supply, which further leads to tissue softening or even necrosis. Restoring blood flow through recanalization of the occluded vessel is crucial for AIS treatment. Although more and more patients benefit from intravenous thrombolysis or endovascular therapy, some still have poor prognosis after vessel recanalization. Most studies indicate that ineffective recanalization, early neurological deterioration, and hemorrhagic transformation are the three main causes of adverse prognosis after recanalization therapy for AIS. This article systematically reviews the epidemiological characteristics, pathogenesis, and risk factors of the above three aspects based on previous studies, aiming to provide guidance for the diagnosis and treatment of adverse prognosis in AIS patients after recanalization therapy.

OBJECTIVE: To explore the role of the natural compound hesperidin in glycolysis, the key ratelimiting enzyme, in colorectal cancer (CRC) cell lines. METHODS: In vitro, HCT116 and SW620 were treated with different doses of hesperidin (0-500 µmol/L), cell counting kit-8 and colone formation assays were utilized to detected inhibition effect of hesperidin on CRC cell lines. Transwell and wound healing assays were performed to detect the ability of hesperidin (0, 25, 50 and 75 µmol/L) to migrate CRC cells. To confirm the apoptotic-inducing effect of hesperidin, apoptosis and cycle assays were employed. Western blot, glucose uptake, and lactate production determination measurements were applied to determine inhibitory effects of hesperidin (0, 25 and 50 µmol/L) on glycolysis. In vivo, according to the random number table method, nude mice with successful tumor loading were randomly divided into vehicle, low-dose hesperidin (20 mg/kg) and high-dose hesperidin (60 mg/kg) groups, with 6 mice in each group. The body weights and tumor volumes of mice were recorded during 4-week treatment. The expression of key glycolysis rate-limiting enzymes was determined using Western blot, and glucose uptake and lactate production were assessed. Finally, protein interactions were probed with DirectDIA Quantitative Proteomics, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. RESULTS: Hesperidin could inhibit CRC cell line growth (P<0.05 or P<0.01). Moreover, hesperidin presented an inhibitory effect on the migrating abilities of CRC cells. Hesperidin also promoted apoptosis and cell cycle alterations (P<0.05). The immunoblotting results manifested that hesperidin decreased the levels of hexokinase 2, glucose transporter protein 1 (GLUT1), GLUT3, L-lactate dehydrogenase A, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), PFKFB3, and pyruvate kinase isozymes M2 (P<0.01). It remarkably suppressed tumor xenograft growth in nude mice. GO and KEGG analyses showed that hesperidin treatment altered metabolic function. CONCLUSION Hesperidin inhibits glycolysis and is a potential therapeutic choice for CRC treatment.
Hesperidin/therapeutic use* ; Colorectal Neoplasms/metabolism* ; Glycolysis/drug effects* ; Animals ; Humans ; Apoptosis/drug effects* ; Mice, Nude ; Cell Movement/drug effects* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Glucose/metabolism* ; Cell Cycle/drug effects* ; Mice, Inbred BALB C ; Mice ; HCT116 Cells ; Lactic Acid

The prevalence of rheumatoid arthritis (RA) has sharply increased in recent years, posing a serious threat to human health. RA is characterized as a chronic, multisystem disease with morning stiffness and symmetric small joint pain. However, its fundamental processes are poorly understood. With the advancements in molecular biology techniques, a growing body of research indicates that numerous non-coding RNAs (ncRNAs) are essential for the pathogenesis of RA. These ncRNAs not only contribute to the onset of RA but also play a role in the pathological processes of RA development, including synovial immune inflammation and bone destruction. Chinese medicine (single compounds, single herbs, and compound formulae, as well as non-drug therapies such as acupuncture and moxibustion), offer significant benefits for treating RA. This study examined the role of 3 different ncRNA types (circular RNA, long ncRNA, and microRNA) as biomarkers in RA diagnosis, as well as their regulatory roles in rheumatoid arthritis fibroblast-like synoviocytes functions such as inflammatory response, proliferation, cell cycle, apoptosis, and invasion. Additionally, the study explored the mechanisms by which Chinese medicine regulates these ncRNAs, with the goal of offering innovative strategies for RA treatment.
Arthritis, Rheumatoid/pathology* ; Humans ; RNA, Untranslated/metabolism* ; Medicine, Chinese Traditional ; Synoviocytes/metabolism* ; RNA, Circular ; Biomarkers/metabolism* ; Apoptosis/genetics*

OBJECTIVES: To investigate the antioxidative mechanism of snake venom-derived protein C activator (PCA) in mitigating vascular endothelial cell injury. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in DMEM containing 1.0 g/L D-glucose and exposed to hypoxia (1% O₂) for 6 h followed by reoxygenation for 2 h to establish a cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The cell model was treated with 2 μg/mL PCA alone or in combination with 2-ME2 (a HIF-1α inhibitor) or DMOG (a HIF-1α stabilizer), and intracellular production of reactive oxygen species (ROS) and protein expression levels of HIF-1α, BNIP3, and Beclin-1 were detected using DCFH-DA fluorescence probe, flow cytometry, and Western blotting. The OGD/R cell model was transfected with a BNIP3-specific siRNA or a scrambled control sequence prior to PCA treatment, and the changes in protein expressions of HIF-1α, BNIP3 and Beclin-1 and intracellular ROS production were examined. RESULTS: In the OGD/R cell model, PCA treatment significantly upregulated HIF-1α, BNIP3 and Beclin-1 expressions and reduced ROS production. The effects of PCA were obviously attenuated by co-treatment with 2-ME2 but augmented by treatment with DMOG (a HIF-1α stabilizer). In the cell model with BNIP3 knockdown, PCA treatment increased BNIP3 expression and decreased ROS production without causing significant changes in HIF-1α expression. Compared with HUVECs with PCA treatment only, the cells with BNIP3 knockdown prior to PCA treatment showed significantly lower Beclin-1 expression and higher ROS levels. CONCLUSIONS Snake venom PCA alleviates OGD/R-induced endothelial cell injury by upregulating HIF-1α/BNIP3 signaling to suppress ROS generation, suggesting its potential as a therapeutic agent against oxidative stress in vascular pathologies.
Humans ; Reactive Oxygen Species/metabolism* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Human Umbilical Vein Endothelial Cells/drug effects* ; Membrane Proteins/metabolism* ; Proto-Oncogene Proteins/metabolism* ; Up-Regulation ; Cell Hypoxia ; Cells, Cultured ; Snake Venoms/chemistry* ; Beclin-1

OBJECTIVE: Observational studies have shown inconsistent associations of loneliness or social isolation (SI) with ischemic heart disease (IHD), with unknown mediators. METHODS: Using data from genome-wide association studies of predominantly European ancestry, we performed a bidirectional two-sample Mendelian Randomization (MR) study to estimate causal effects of loneliness ( N = 487,647) and SI traits on IHD ( N = 184,305). SI traits included whether individuals lived alone, participated in various types of social activities, and how often they had contact with friends or family ( N = 459,830 to 461,369). A network MR study was conducted to evaluate the mediating roles of 20 candidate mediators, including metabolic, behavioral and psychological factors. RESULTS: Loneliness increased IHD risk ( OR= 2.129; 95% confidence interval [ CI]: 1.380 to 3.285), mediated by body fat percentage, waist-hip ratio, total cholesterol, and low-density lipoprotein cholesterol. For SI traits, only fewer social activities increased IHD risk ( OR= 1.815; 95% CI: 1.189 to 2.772), mediated by hypertension, high-density lipoprotein cholesterol, triglycerides, fasting insulin, and smoking cessation. No reverse causality of IHD with loneliness and SI was found. CONCLUSION These findings suggested more attention should be paid to individuals who feel lonely and have fewer social activities to prevent IHD, with several mediators as prioritized targets for intervention.
Loneliness/psychology* ; Humans ; Mendelian Randomization Analysis ; Social Isolation ; Myocardial Ischemia/etiology* ; Male ; Female ; Middle Aged ; Genome-Wide Association Study ; Risk Factors ; Aged

The aim of this study was to investigate the contribution of lung zinc ions to pathogenesis of lung ischemia/reperfusion (I/R) injury in rats. Male Sprague Dawley (SD) rats were randomly divided into control group, lung I/R group (I/R group), lung I/R + low-dose zinc chloride group (LZnCl₂+I/R group), lung I/R + high-dose ZnCl₂ group (HZnCl₂+I/R group), lung I/R + medium-dose ZnCl₂ group (MZnCl₂+I/R group) and TPEN+MZnCl₂+I/R group (n = 8 in each group). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of zinc ions in lung tissue. The degree of lung tissue injury was analyzed by observing HE staining, alveolar damage index, lung wet/dry weight ratio and lung tissue gross changes. TUNEL staining was used to detect cellular apoptosis in lung tissue. Western blot and RT-qPCR were used to determine the protein expression levels of caspase-3 and ZIP8, as well as the mRNA expression levels of zinc transporters (ZIP, ZNT) in lung tissue. The mitochondrial membrane potential (MMP) of lung tissue was detected by JC-1 MMP detection kit. The results showed that, compared with the control group, the lung tissue damage, lung wet/dry weight ratio and alveolar damage index were significantly increased in the I/R group. And in the lung tissue, the concentration of Zn²⁺ was markedly decreased, while the cleaved caspase-3/caspase-3 ratio and apoptotic levels were significantly increased. The expression levels of ZIP8 mRNA and protein were down-regulated significantly, while the mRNA expression of other zinc transporters remained unchanged. There was also a significant decrease in MMP. Compared with the I/R group, both MZnCl₂+I/R group and HZnCl₂+I/R group exhibited significantly reduced lung tissue injury, lung wet/dry weight ratio and alveolar damage index, increased Zn²⁺ concentration, decreased ratio of cleaved caspase-3/caspase-3 and apoptosis, and up-regulated expression levels of ZIP8 mRNA and protein. In addition, the MMP was significantly increased in the lung tissue. Zn²⁺ chelating agent TPEN reversed the above-mentioned protective effects of medium-dose ZnCl₂ on the lung tissue in the I/R group. The aforementioned results suggest that exogenous administration of ZnCl₂ can improve lung I/R injury in rats.
Animals ; Reperfusion Injury/pathology* ; Male ; Rats, Sprague-Dawley ; Rats ; Chlorides/administration & dosage* ; Lung/pathology* ; Zinc Compounds/administration & dosage* ; Apoptosis/drug effects* ; Caspase 3/metabolism* ; Cation Transport Proteins/metabolism*