ObjectiveTo investigate the anti‑pancreatic fibrosis mechanism of Klotho‑derived peptide 7 （KL7） by observing its effect on a mouse model of chronic pancreatitis （CP） induced by cerulean， and to provide a basis for clinical medication. MethodsA total of 40 male BALB/c mice were randomly divided into control group， model group， low-dose KL7 group （2 mg/kg）， and high-dose KL7 group （4 mg/kg）， with 10 mice in each group. All mice except those in the control group were given intraperitoneal injection of cerulean （50 μg/kg） 6 times a day at an interval of 1 hour， twice a week for 4 consecutive weeks to establish a model of CP. The mice in the low-dose KL7 group and the high-dose KL7 group were treated with different doses of KL7 once a day for 4 consecutive weeks. In vivo imaging was used to observe the accumulation of KL7 in the pancreas； molecular docking was used to detect the binding of KL7 to transforming growth factor-β type Ⅱ receptor （TβRⅡ）； the mice were measured in terms of body weight and pancreatic weight； HE staining was used to observe the pathological changes of pancreatic tissue； Masson staining was used to observe the degree of pancreatic fibrosis； immunohistochemical staining was used to measure the expression of α-smooth muscle actin （α-SMA） and type Ⅰ collagen （COL1A1）； Western blotting was used to measure the protein expression levels of α-SMA， TβRII， and phosphorylated small mothers against decapentaplegic homolog 2/3 （p-Smad2/3） in pancreatic tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test and the Dunnett’s-T3 test were used for further comparison between two groups. ResultsKL7 was significantly enriched in the pancreatic tissue of CP mice， and there was a strong binding activity between KL7 and TβRⅡ. Compared with the control group， the model group had significant reductions in pancreatic mass and relative pancreatic mass （P<0.000 1）， with disordered structure of pancreatic tissue， an increase in inflammatory cell infiltration， and significant increases in fibrosis degree， the positive areas of α-SMA and COL1A1 （P<0.000 1）， and the protein expression levels of α-SMA， TβRⅡ， and p-Smad2/3 （P<0.05）. Compared with the model group， the high-dose KL7 group had significant increases in pancreatic mass and relative pancreatic mass （P<0.01）， with alleviation of structural damage of pancreatic tissue and inflammatory cell infiltration， a significant reduction in fibrosis degree， and significant reductions in the positive areas of α-SMA and COL1A1 （P<0.001） and the protein expression levels of α-SMA， TβRⅡ， and p-Smad2/3 （P<0.01）. ConclusionKL7 has a significant targeted therapeutic effect on pancreatic fibrosis in CP mice through specific binding of KL7 to TβRⅡ， thereby inhibiting the activation of the TGF-β/Smad signaling pathway.

Objective To analyze the factors affecting the prognosis of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) undergoing immunotherapy and construct an individualized prognostic nomogram prediction model. Methods A retrospective analysis was conducted on the clinical data of 385 patients with driver gene-negative, locally advanced or metastatic NSCLC who received first-line immune checkpoint inhibitors. Univariate and multivariate Cox regression analyses were used to identify prognostic risk factors, and a prognostic nomogram model was established. The predictive performance of the model was evaluated using the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves and area under the curve (AUC), and calibration curves. The cutoff value of the nomogram was calculated to stratify patients by risk. Survival curves were calculated by Kaplan-Meier analysis. Results Age (HR=1.775, 95%CI: 1.265-2.490), degree of differentiation (HR=0.365, 95%CI: 0.257-0.519), low PD-L1 expression (HR=0.661, 95%CI: 0.455-0.960), high PD-L1 expression (HR=0.423, 95%CI: 0.297-0.603), SCC-Ag (HR=1.549, 95%CI: 1.109-2.163), and CONUT score (HR=2.527, 95%CI: 1.797-3.554) were independent risk factors affecting overall survival (OS) of patients with NSCLC undergoing immunotherapy. The nomogram prediction model constructed on the basis of these factors had a C-index of 0.767. Time-dependent ROC curves for survival showed that the AUCs for 1-, 2-, and 3-year OS were 0.830, 0.853, and 0.886, respectively. Calibration curves indicated that the nomogram-predicted survival rates were in good agreement with the actual outcomes. The cutoff value for the study’s nomogram prediction model was 136.60 points, and survival curves showed statistically significant differences between different risk groups (P<0.05). Conclusion The nomogram model established in this study can effectively predict the prognosis of patients with driver gene-negative locally advanced or metastatic NSCLC treated with first-line immunosuppressive therapy. It provides a new tool for assessing prognosis and aids clinicians in formulating individualized treatment plans.

OBJECTIVE To evaluate the influence of pharmaceutical quality control on the efficiency and outcomes of standardized medication therapy management （MTM） services for patients with coronary heart disease by using Economic， Clinical and Humanistic Outcomes （ECHO） model. METHODS This study collected case data of coronary heart disease patients who received MTM services during January-March 2023 （pre-quality control implementation group， n＝96） and June-August 2023 （post-quality control implementation group， n＝164）. Using propensity score matching analysis， 80 patients were selected from each group. The study subsequently compared the economic， clinical， and humanistic outcome indicators of pharmaceutical services between the two matched groups. RESULTS There were no statistically significant differences in baseline data between the two groups after matching （P＞0.05）. Compared with pre-quality control implementation group， the daily treatment cost （16.26 yuan vs. 24.40 yuan， P＜0.001）， cost-effectiveness ratio [23.12 yuan/quality-adjusted life year （QALY） vs. 32.32 yuan/QALY， P＜0.001]， and the incidence of general adverse drug reactions （2.50% vs. 10.00%， P＝0.049） of post-quality control implementation group were decreased significantly； the utility value of the EuroQol Five-Dimensional Questionnaire （0.74± 0.06 vs. 0.71±0.07， P＝0.003）， the reduction in the number of medication related problems （1.0 vs. 0.5， P＜0.001）， the medication adherence score （[ 6.32±0.48） points vs. （6.10±0.37） points， P＝0.001]， and the satisfaction score （[ 92.56±1.52） points vs. （91.95±1.56） points， P＝0.013] all showed significant improvements. Neither group experienced serious adverse drug reactions. There was no statistically significant difference in the incidence of new adverse reactions between the two groups （1.25% vs. 3.75%， P＝0.310）. CONCLUSIONS Pharmaceutical quality control can improve the quality of pharmaceutical care， and the ECHO model can quantitatively evaluate the effect of MTM services， making pharmaceutical care better priced and more adaptable to social needs， thus being worthy of promotion.

Objective:To investigate the distribution of CGG repeat numbers in the FMR1 gene among reproductive-age women in China, providing data reference for carrier screening and genetic counseling of Fragile X syndrome. Methods:This cross-sectional study recruited 16 610 reproductive-age women from 12 medical institutions between July 2022 and October 2023. Peripheral venous blood samples (3 mL) were collected, and genomic DNA was extracted. The number of CGG repeats in the FMR1 gene was determined using the triplet-primed polymerase chain reaction (TP-PCR) combined with capillary electrophoresis technology. Statistical analyses were performed to assess the prevalence and distribution of CGG repeat expansions. Results:Among 16 610 women of childbearing age, 5 684 (34.220%) women had the same number of CGG repeats in the two alleles of FMR1 gene, and 10 926 (65.780%) women had different numbers of repeats in the two alleles. Among the 33 220 FMR1 alleles in 16 610 women of reproductive age, the most common CGG repeat numbers were 29 [48.645% (16 160/33 220)] and 30 [26.276% (8 729/33 220)], while the most frequent CGG genotype was CGG 29/29 [24.726% (4 107/16 610)]. The CGG repeat numbers of FMR1 gene were normal in 16 498 women (99.326%). Among the 112 women (0.674%) with CGG repeat abnormities, 96 (0.578%) women were classified as intermediate carriers, 15 (0.090%) as premutation carriers, and 1 (0.006%) as a full mutation carrier, whose CGG genotype was (36, >200). Conclusion:In the general reproductive-age female population in China, the normal CGG repeat numbers of the FMR1 gene account for 99.326%, while the intermediate carrier rate is 0.578%, and the combined carrier rate of the premutation and full mutation types is 0.096%.

Objective To compare the effects of different doses of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet in the treatment of cough variant asthma(CVA)and the improvement of airway function and inflammatory factors.Methods Elderly patients with cough variant asthma were randomly divided into group A and group B.Both groups of patients received budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet.Group A was given budesonide and formoterol fumarate powder for inhalation(Ⅱ),2 inhalation per time,twice a day;Group B was given budesonide and formoterol fumarate powder for inhalation,4 inhalation per time,twice a day;budesonide fumatrol inhalation powder mist for continuous treatment for 6 months,and montelukast sodium tablet 10 mg once a day for at least 3 months.The nighttime cough scores of the two groups were compared before treatment and after treatment.The percentage of forced expiratory volume in one second(FEV1)in the predicted value,the maximum mid expiratory flow(MMEF),the fractional exhaled nitric oxide(FeNO),interleukin-5(IL-5)and eosinophils were compared between the two groups.The incidence of adverse drug reactions and the recurrence rate within 1 year were compared between the two groups.Results A total of 45 cases were enrolled in both the group A and the group B.At 9 months after treatment,the nocturnal cough scores of the group A and the group B were(0.93±0.42)and(0.65±0.29)points,respectively;the percentage of FEV1 in the predicted value were(97.75±9.67)％and(100.93±11.06)％,respectively;the MMEF values were(2.81±1.04)and(3.08±1.09)L·s-1,respectively;the FeNO values were(18.94±9.75)and(15.94±7.96)ppb,respectively;the IL-5 levels were(10.88±7.06)and(8.11±5.56)pg·mL-1,respectively.The above indicators in group B showed statistically significant differences compared to group A(all P＜0.05).The total incidence of adverse drug reactions in group A and group B were 8.89％(5 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.The recurrence rates was 15.56％(7 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.There was no statistically significant difference in the above indicators between group B and group A(all P＞0.05).Conclusion For elderly patients with CVA,higher dose of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet can better improve cough symptoms,reduce the level of airway hyperresponsiveness and inflammatory factors,reduce the recurrence rate,and the patients are well tolerated.

Objective:To investigate the association between social support and subjective and objective cognitive functions among the middle-aged and elderly population in Pingyin County, Jinan City, Shandong Province.Methods:Employing a multi-stage cluster random sampling method, a cross-sectional study was conducted in 2023 by selecting people aged 45-70 years from seven villages in three towns within Pingyin County, Jinan City, as survey respondents. Social Support Rating Scale (SSRS), Subjective Cognitive Decline-Questionnaire 9 (SCD-Q9) and Montreal Cognitive Assessment-Basic (MoCA-B) were used to assess the social support and cognitive status of interviewees, and a self-developed questionnaire was used to collect other basic information. Pearson correlation analysis, multiple linear regression and multifactorial logistic regression were used to explore the relationship between social support and subjective and objective cognitive functions.Results:A total of 1 891 subjects were finally included in the study, with 45.52±6.99 for the SSRS total score, an abnormal rate of 43.68% (826/1 891) for the SCD-Q9 score and an abnormal rate of 60.02% (1 135/1 891) for the MoCA-B score. The SSRS total score, subjective support score, objective support score and support utilization score were negatively correlated with SCD-Q9 scores and positively correlated with MoCA-B scores (all P<0.05). An increase in SSRS total score ( β=-0.034, 95% CI: -0.051--0.017, P<0.001) and objective support score ( β=-0.074, 95% CI: -0.121--0.027, P=0.002) can lower SCD-Q9 scores. Compared to those who had only 1 source of financial support or help with practical problems when experiencing an acute situation, those with 2-4 ( OR=0.53, 95% CI: 0.34-0.82), 5 ( OR=0.46, 95% CI: 0.27-0.79), or 6-7 ( OR=0.42, 95% CI: 0.22-0.81) sources of help were more likely to have normal SCD-Q9 scores. Compared to individuals with ≤2 close friends who provided support and help, those with 3-5 ( OR=0.67, 95% CI: 0.50-0.91) or ≥6 friends ( OR=0.72, 95% CI: 0.54-0.97) were more likely to have normal MoCA-B scores. Moreover, compared to individuals who never participated in group activities, those who actively participated ( OR=0.59, 95% CI: 0.42-0.81) were more likely to have normal MoCA-B scores. Conclusions:Social support has protective effects on subjective and objective cognitive functions, and various social support conditions have different protective effects on subjective and objective cognitive functions among middle-aged and older people. Improving social support conditions for middle-aged and elderly individuals may delay the process of cognitive decline.

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Hypertension/pathology* ; Renin-Angiotensin System/drug effects* ; Rats, Inbred SHR ; Oxidative Stress/drug effects* ; Male ; Rats, Inbred WKY ; Blood Pressure/drug effects* ; Myocardium/pathology* ; Rats ; Inflammation/pathology*

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Acute respiratory distress syndrome (ARDS) is the leading cause of respiratory failure with high morbidity and mortality. Pulmonary surfactant (PS)-based complementary therapies have exhibited potential for ARDS healing and applied as an adjunctive therapy strategy. Coacervate (Coac) has the characteristics of softness, deformability and excellent molecular enrichment properties, and has attracted extensive attention in the biomedical field. Here PS and coacervate were combined for the potential ARDS treatment. The Coac, fabricated from polyallylamine hydrochloride (PAH) and adenosine triphosphate (ATP) by simple mixing, exhibited soft droplet property and high enrichment for dexamethasone sodium phosphate (DSP). To avoid the fusion effect of membraneless coacervate and endow it with biological functions of PS, liposomes with PS-biomimetic lipid components (PS-lipo) were further introduced to construct PS-biomimetic membranized coacervate (DSP@PS-Coac). The DSP@PS-Coac demonstrated high lung targeting effect and significant penetration efficiency after intravenous injection. Furthermore, PS-lipo replenished the endogenous PS pool and facilitated the distribution of DSP in inflammatory cells in the lung. In the ARDS mouse model, PS-Coac and DSP exerted synergetic anti-inflammatory functions, via reducing the recruitment of inflammatory neutrophils and modulating macrophages into anti-inflammatory phenotype. The overall results confirmed that DSP@PS-Coac may provide a promising delivery option for the treatment of ARDS.