ObjectiveThis paper aims to study the potential active compound components and action mechanism of Shenqi Dihuangtang in the treatment of diabetic kidney disease （DKD） through network pharmacology and in vivo experimental verification. MethodsUltra-high-performance liquid chromatography-Q-exactive orbitrap mass spectrometry （UPLC-Q-Exactive Orbitrap MS） technology was used to clarify the main active chemical components of Shenqi Dihuangtang， and it was combined with network pharmacology methods such as gene ontology （GO） functional annotations and Kyoto encyclopedia of genes and genome （KEGG） to predict the potential action mechanism of Shenqi Dihuangtang in treating DKD. Subsequently， the DKD model of db/db male mice was established， and the mice were randomly divided into model group， low-dose Shenqi Dihuangtang group （6.10 g·kg^-1）， medium-dose Shenqi Dihuangtang group （12.19 g·kg^-1）， high-dose Shenqi Dihuangtang group （24.38 g·kg^-1）， and daplizin group （1.25 mg·kg^-1）. During the same period， C57BL/6J male mice were selected into normal group and received drug intervention for 8 weeks， respectively. During this period， the body weight and fasting blood glucose （FBG） of the mice were dynamically monitored， and oral glucose tolerance test （OGTT） and insulin tolerance test （ITT） were performed at the end of dosing. The levels of serum creatinine （SCr）， blood urea nitrogen （BUN）， uric acid （UA）， albumin （ALB）， and total protein （TP） were measured by an automatic biochemical analyzer， and 24-hour urine protein was measured by a urine protein quantitative kit. Hematoxylin-eosin （HE）， periodic-acid Schiff （PAS）， and Masson staining were employed to observe the renal histopathology. The expression of nephrotic protein Nephrin was observed by immunohistochemistry. Western blot was used to detect the expression of epithelial-mesenchymal transition （EMT）-related proteins such as TGF-β₁， Smad2/3， α-smooth muscle actin （α-SMA）， neural-cadherin （N-Cadherin）， and snail protein. ResultsUPLC-Q-Exactive Orbitrap MS identified 384 active compounds in the aqueous extract of Shenqi Dihuangtang. According to oral bioavailability≥30% and the five drug-like principles， 44 key active ingredients were screened out， and 169 intersection targets highly correlated with DKD were matched. Among them， there was a significant interaction relationship between tumor necrosis factor（TNF）， interleukin（IL）-6， protein kinase B（Akt）1， Caspase-3， Jun proto-oncogene （JUN）， hypoxia inducible factor-1α（HIF-1α）， B cell lymphoma-2（Bcl-2）， matrix metallopeptidase-9（MMP-9）， IL-1β， and TGF-β₁. GO functional annotations were significantly enriched in cellular components such as membrane rafts， membrane microdomains， and collagen-containing extracellular matrix， molecular functions such as DNA-binding transcription factor binding， R-Smad binding， and Smad protein binding， as well as biological processes such as reactions to lipopolysaccharides（LPS）， reactions to bacteria-derived molecules， and wound healing. The KEGG pathway was significantly enriched in lipids and atherosclerosis， TGF-β signaling pathway， phosphatidylinositol 3 kinase （PI3K）/Akt signaling pathway， etc. In vivo experimental results showed that the high-dose Shenqi Dihuangtang group could significantly reduce FBG levels in db/db mice （P<0.01）， improve OGTT （P<0.01） and ITT （P<0.01） levels， reduce SCr （P<0.01）， BUN （P<0.01）， UA （P<0.01） and 24-hour BUN （P<0.01）， and increase ALB （P<0.01） and TP （P<0.01） levels. Pathological staining confirmed that the high-dose Shenqi Dihuangtang group could significantly reduce the glomerular mesangial matrix area and collagen deposition （P<0.01） and upregulate the positive expression rate of Nephrin （P<0.01）. Western blot results showed that the high-dose Shenqi Dihuangtang group significantly downregulated the expression of TGF-β₁ （P<0.01） and Smad2/3 （P<0.01） signal molecules and inhibited the protein levels of α-SMA （P<0.01）， N-Cadherin （P<0.01）， and Snail （P<0.01）. ConclusionShenqi Dihuangtang can inhibit the TGF-β₁/Smad signaling axis and block the renal EMT process， thereby improving DKD renal fibrosis damage. Further analysis of its key active components and clinical transformation pathways is needed in the future.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Image 1.

ObjectiveTo observe the clinical effectiveness of horticultural therapy involving the planting of Chinese medicinal herbs （mint and lily potted plants） combined with intradermal needling therapy for generalized anxiety disorder （GAD） of liver depression transforming into fire syndrome under transcranial magnetic stimulation and basic psychological therapy， and to explore the possible mechanisms of action. MethodsA total of 180 patients with GAD of liver depression transforming into fire syndrome were randomly divided into three groups， horticultural therapy group， intradermal needling group， and horticultural therapy+intradermal needling group， with 60 patients in each. All groups received basic treatment including basic psychological therapy and transcranial magnetic stimulation. The horticultural therapy group received horticultural therapy in addition to the basic treatment； the intradermal needling group received intradermal needling therapy once a week for 8 weeks in addition to the basic treatment； the horticultural therapy+intradermal needling group received both horticultural therapy and intradermal needling therapy， following the same procedures and duration. Hamilton Anxiety Rating Scale （HAMA）， Self-Rating Anxiety Scale （SAS）， and Pittsburgh Sleep Quality Index （PSQI） scores were assessed at baseline and after 2， 4， 6， and 8 weeks of treatment. Serum levels of adrenocorticotropic hormone （ACTH） and corticosterone （CORT） were measured before treatment and after 8 weeks of treatment. Motor-evoked potential （MEP） baseline levels were recorded before treatment， and MEP amplitude ratios were compared after 1 week and 8 weeks of treatment. Clinical effectiveness and safety were evaluated after 8 weeks of treatment. Pearson correlation analysis was used to examine the relationships between serum ACTH and CORT levels， MEP amplitude， and anxiety. ResultsIn the horticultural therapy group and intradermal needling group， HAMA， SAS and PSQI scores after 4， 6， and 8 weeks treatment were lower than baseline scores （P＜0.05）. In the horticultural therapy+intradermal needling group， these scores showed a significant decline starting after 2 weeks treatment and continuing through 8 weeks after treatment （P＜0.05）. The HAMA， SAS， and PSQI scores in the horticultural therapy+intradermal needling group were significantly lower than those in the other two groups after 2， 4， 6， and 8 weeks treatment （P＜0.05）. After 8 weeks of treatment， serum CORT and ACTH levels in the horticultural therapy+intradermal needling group were significantly lower than baseline levels （P＜0.05） and were also lower than those in the horticultural therapy group and intradermal needling group at the same time point （P＜0.01）. When comparing the level after 8 weeks treatment to that after 1 week treatment， under PAS10 stimulation， the MEP amplitude ratio in the intradermal needling group decreased at 30 minutes， while in the horticultural therapy+intradermal needling group， the MEP amplitude ratio decreased at all time points （P＜0.05 or P＜0.001）； under PAS25 stimulation， the MEP amplitude ratio in the horticultural therapy group increased at 20 minutes， and in the intradermal needle group at 10 minutes （P＜0.05）. In the horticultural therapy+intradermal needling group， the MEP amplitude ratio increased significantly at all time points after treatment （P＜0.001）. The cure rate in the horticultural therapy+intradermal needling group （74.14%， 43/58） was significantly higher than that in the horticultural therapy group （30.00%， 18/60） and the intradermal needling group （48.28%， 28/58， P＜0.05）. Correlation analysis revealed that serum ACTH and CORT levels were positively correlated with HAMA scores （r = 0.488， P＜0.01； r = 0.428， P＜0.01）. Following PAS10 intervention， the MEP amplitude ratio was positively correlated with HAMA scores （r = 0.458， P＜0.01）， whereas after PAS25 intervention， the MEP amplitude ratio was negatively correlated with HAMA scores （r = -0.562， P＜0.01）. ConclusionHorticultural therapy combined with intradermal needling treatment， under transcranial magnetic stimulation and basic psychological therapy， demonstrates significant clinical effectiveness in patients with GAD of liver depression transforming into fire syndrome. Its mechanism of action may be related to the regulation of hyperactivation of the hypothalamic-pituitary-adrenal （HPA） axis and the reduction of cortical excitability.

BACKGROUND: Congenital heart disease (CHD) is a leading cause of birth defect-related mortality. However, more recent CHD mortality data for China are lacking. Additionally, limited studies have evaluated sex, rural-urban, and region-specific disparities of CHD mortality in China. METHODS: We designed a population-based study using data from the Dataset of National Mortality Surveillance in China between 2008 and 2021. We calculated age-adjusted CHD mortality using the sixth census data of China in 2010 as the standard population. We assessed the temporal trends in CHD mortality by age, sex, area, and region from 2008 to 2021 using the joinpoint regression model. RESULTS: From 2008 to 2021, 33,534 deaths were attributed to CHD. The period witnessed a two-fold decrease in the age-adjusted CHD mortality from 1.61 to 0.76 per 100,000 persons (average annual percent change [AAPC] = -5.90%). Females tended to have lower age-adjusted CHD mortality than males, but with a similar decline rate from 2008 to 2021 (females: AAPC = -6.15%; males: AAPC = -5.84%). Similar AAPC values were observed among people living in urban (AAPC = -6.64%) and rural (AAPC = -6.12%) areas. Eastern regions experienced a more pronounced decrease in the age-adjusted CHD mortality (AAPC = -7.86%) than central (AAPC = -5.83%) and western regions (AAPC = -3.71%) between 2008 and 2021. Approximately half of the deaths (46.19%) due to CHD occurred during infancy. The CHD mortality rates in 2021 were lower than those in 2008 for people aged 0-39 years, with the largest decrease observed among children aged 1-4 years (AAPC = -8.26%), followed by infants (AAPC = -7.01%). CONCLUSIONS CHD mortality in China has dramatically decreased from 2008 to 2021. The slower decrease in CHD mortality in the central and western regions than in the eastern regions suggested that public health policymakers should pay more attention to health resources and health education for central and western regions.
Humans ; Heart Defects, Congenital/mortality* ; Male ; Female ; China/epidemiology* ; Infant ; Child, Preschool ; Adult ; Child ; Adolescent ; Infant, Newborn ; Middle Aged ; Young Adult ; Aged ; Rural Population

BACKGROUND: Generalized pustular psoriasis (GPP), a rare and recurrent autoinflammatory disease, imposes a substantial burden on patients and society. Awareness of GPP in China remains limited. METHODS: This cross-sectional survey, conducted between September 2021 and May 2023 across 14 hospitals in China, included GPP patients of all ages and disease phases. Data collected encompassed demographics, clinical characteristics, economic impact, disease severity, quality of life, and treatment-related complications. Risk factors for GPP recurrence were analyzed. RESULTS: Among 127 patients (female/male ratio = 1.35:1), the mean age of disease onset was 25 years (1st quartile [Q1]-3rd quartile [Q3]: 11-44 years); 29.2% had experienced GPP for more than 10 years. Recurrence occurred in 75.6% of patients, and nearly half reported no identifiable triggers. Younger age at disease onset ( P  = 0.021) and transitioning to plaque psoriasis ( P  = 0.022) were associated with higher recurrence rates. The median diagnostic delay was 8 months (Q1-Q3: 2-41 months), and 32.3% of patients reported misdiagnoses. Comorbidities were present in 53.5% of patients, whereas 51.1% experienced systemic complications during treatment. Depression and anxiety affected 84.5% and 95.6% of patients, respectively. During GPP flares, the median Dermatology Life Quality Index score was 19.0 (Q1-Q3: 13.0-23.5). This score showed significant differences between patients with and without systemic symptoms; it demonstrated correlations with both depression and anxiety scores. Treatment costs caused financial hardship in 55.9% of patients, underscoring the burden associated with GPP. CONCLUSIONS The substantial disease and economic burdens among Chinese GPP patients warrant increased attention. Patients with early onset disease and those transitioning to plaque psoriasis require targeted interventions to mitigate the high recurrence risk.
Humans ; Male ; Female ; Psoriasis/pathology* ; Adult ; Cross-Sectional Studies ; Adolescent ; Child ; Young Adult ; Quality of Life ; Middle Aged ; China/epidemiology* ; Recurrence ; Risk Factors ; Surveys and Questionnaires ; East Asian People

OBJECTIVES: Cardiovascular disease (CVD) poses a major threat to global health. Evaluating atherosclerosis in asymptomatic individuals can help identify those at high risk of CVD. This study aims to establish an individualized nomogram prediction model to estimate the risk of vascular plaque formation in asymptomatic individuals. METHODS: A total of 5 655 participants who underwent CVD screening at the Health Management Center of The Third Xiangya Hospital, Central South University, between January 2022 and June 2024 we retrospectively enrolled. Using simple random sampling, participants were divided into a training set (n=4 524) and a validation set (n=1 131) in an 8꞉2 ratio. Demographic and clinical data were collected and compared between groups. Multivariate logistic regression analysis was used to identify independent factors associated with vascular plaques and to construct a nomogram prediction model. The predictive performance and clinical utility of the model were evaluated using receiver operating characteristic (ROC) curves, the Hosmer-Lemeshow goodness-of-fit test, calibration plots, and decision curve analysis (DCA). RESULTS: The mean age of participants was 52 years old. There were 3 400 males (60.12%). The overall detection rate of vascular plaque in the screening population was 49.87% (2 820/5 655). No statistically significant differences were observed in clinical indicators between the training and validation sets (all P>0.05). Multivariate Logistic regression analysis identified age, systolic blood pressure, high-density lipoprotein (HDL), low-density lipoprotein (LDL), lipoprotein(a), male sex, smoking history, hypertension history, and diabetes history as independent risk factors for vascular plaque in asymptomatic individuals (all P<0.05). The area under the curve (AUC) of the nomogram model for predicting vascular plaque risk were 0.778 (95% CI 0.765 to 0.791, P<0.001) in the training set and 0.760 (95% CI 0.732 to 0.787, P<0.001) in the validation set. The Hosmer-Lemeshow goodness-of-fit test indicated good model calibration (training set: P=0.628; validation set: P=0.561). The calibration curve plotted using the Bootstrap method demonstrated good agreement between predicted probabilities and actual probabilities. DCA showed that the nomogram provided a clinical net benefit for predicting vascular plaque risk when the threshold probability ranged from 0.02 to 0.99. CONCLUSIONS The nomogram prediction model for vascular plaque risk, constructed using readily available and cost-effective physical examination indicators, exhibited good predictive performance. This model can assist in the early identification and intervention of asymptomatic individuals at high risk for cardiovascular disease.
Humans ; Male ; Middle Aged ; Female ; Nomograms ; Retrospective Studies ; Risk Factors ; Plaque, Atherosclerotic/diagnosis* ; Aged ; Adult ; Physical Examination ; Logistic Models ; Cardiovascular Diseases/epidemiology* ; ROC Curve

OBJECTIVES: Stress urinary incontinence (SUI) is a common condition among women that severely impairs quality of life. Pelvic floor proprioceptive training (PFPT) has attracted increasing attention for its potential to enhance pelvic floor muscle function and alleviate SUI symptoms. This study aims to observe and compare the clinical efficacy of PFPT combined with electroacupuncture, electrical stimulation, and biofeedback therapy versus conventional therapy consisting of electroacupuncture, electrical stimulation, and biofeedback alone in women with SUI, and to explore the role of PFPT in improving symptom and functional outcomes. METHODS: In this randomized controlled trial, 72 women with mild to moderate SUI were recruited from the Department of Rehabilitation Medicine at Third Xiangya Hospital, Central South University, between December 2021 and October 2023. Participants were randomly assigned to an experimental group (n=36) or a control group (n=36). Both groups received health education. The control group underwent electroacupuncture combined with electrical stimulation and biofeedback therapy, while the experimental group additionally received PFPT 3 times per week for 4 weeks. The primary outcome was assessed using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). Secondary outcomes included pelvic floor muscle strength, bladder neck mobility, and balance ability. The ICIQ-SF was reassessed at 1, 3, 6, and 12 months post-treatment. RESULTS: Both groups showed statistically significant improvements in all parameters after treatment (all P<0.05). However, there were no statistically significant differences between groups in most measures (all P>0.05). The experimental group demonstrated longer single-leg stance duration with eyes closed than the control group (left leg: P=0.026; right leg: P=0.006), with a significant increase from baseline (P<0.001). At 6 months post-treatment, the cure rate in the experimental group was significantly higher than that in the control group (P=0.037). CONCLUSIONS Conventional therapy effectively improves SUI symptoms, but adding PFPT provides notable additional benefits, including enhanced balance ability and sustained mid-term cure rates. These findings suggest that PFPT is a valuable adjunct to standard SUI management strategies.
Humans ; Female ; Urinary Incontinence, Stress/physiopathology* ; Pelvic Floor/physiopathology* ; Middle Aged ; Biofeedback, Psychology ; Adult ; Exercise Therapy/methods* ; Proprioception ; Electroacupuncture/methods* ; Quality of Life ; Electric Stimulation Therapy/methods* ; Treatment Outcome ; Combined Modality Therapy

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

AIM:To investigate the effect of spermidine(SPD)on pressure overload-induced cardiac hyper-trophy and heart failure model in mice and its underlying mechanisms.METHODS:(1)Eight-week-old male C57BL/6J mice were randomly divided into 4 groups:sham group,sham+SPD group,transverse aortic constriction(TAC)group,and TAC+SPD group.After TAC,the mice in sham+SPD group and TAC+SPD group were fed with 3 mmol/L SPD via drinking water,and the mice in other groups were fed with normal water.Western blot was used to detect the protein ex-pression levels of silent information regulator 6(SIRT6),peroxisome proliferator-activated receptor γ coactivator-1(PGC-1)and mitofusin 2(MFN2).Adult mouse cardiomyocytes were isolated to detect cell length and width.Wheat germ agglu-tinin staining was used to detect the cardiac cell size.Masson staining was used to detect the extent of fibrosis.Echocar-diography was used to detect cardiac function and myocardial hypertrophy.Transmission electron microscopy was used to analyze mitochondrial morphology.Oxygraph-2k high-resolution respirometer was used to detect cardiac mitochondrial oxy-gen consumption.(2)In vitro,primary rat ventricular cardiomyocytes were cultured and treated with angiotensin II(Ang II;1 μmol/L)to construct a hypertrophy model of cardiomyocytes.These cardiomyocytes were divided into control(Con)group,Con+SPD(1 mmol/L)group,Ang II group,Ang II+SPD group and Ang II+SPD+SIRT6 siRNA(siSIRT6)group.Confocal microscopy was used to detect cardiomyocytes area and mitochondrial.RESULTS:(1)Compared with sham group,cardiac function of the mice in TAC group was significantly decreased(P＜0.05),the degree of myocardial hyper-trophy was significantly increased(P＜0.05),and the expression levels of SIRT6,PGC-1 and MFN2 in the myocardial tis-sue were significantly decreased(P＜0.05).Compared with TAC group,the expression levels of SIRT6,PGC-1 and MFN2 in mouse myocardial tissues of TAC+SPD group were significantly increased(P＜0.05),pathological myocardial hy-pertrophy was reduced(P＜0.05),the numbers of mitochondria and mitochondrial cristae were increased(P＜0.05),mito-chondrial function was restored(P＜0.05),myocardial fibrosis was alleviated(P＜0.05),and cardiac function was im-proved(P＜0.05).(2)In vitro,compared with Con group,the expression levels of SIRT6,PGC-1 and MFN2 in cardio-myocytes of Ang II group were decreased(P＜0.05),and the degree of cardiomyocyte hypertrophy was significantly in-creased(P＜0.05).Treatment with SPD increased the expression levels of SIRT6,PGC-1 and MFN2 in cardiomyocytes of Ang II group(P＜0.05),reversed myocardial hypertrophy and improved mitochondrial dynamics(P＜0.05).Compared with Ang II group,the expression levels of SIRT6,PGC-1 and MFN2 in Ang II+SPD+siSIRT6 group showed no significant changes,and the degree of cardiomyocyte hypertrophy and mitochondrial dynamics also had no statistically significant changes.CONCLUSION:Spermidine promotes the expression of SIRT6,PGC-1 and MFN2,thus improving mitochon-drial function,reducing myocardial hypertrophy and alleviating heart failure in mice with pressure overload.