Eight butyl-phthalides, senkyunolide K(1), senkyunolide N(2), butylphthalide(3), senkyunolide I(4), senkyunolide H(5),(Z)-butylidenephthalide(6),(Z)-ligustilide(7), and 3-butylidene-7-hydroxyphthalide(8) were isolated from the aerial part of Ligusticum sinense by column chromatography on silica gel column, ODS, Sephadex LH-20 and semi-preparative HPLC. Their structures were elucidated on the basis of spectroscopic and chemical data, especially NMR and MS. Compound 1 was a new butyl-phthalide and compounds 2-8 were isolated from the aerial part of L. sinense for the first time. Furthermore, the inhibitory activities of compounds 1-8 against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse RAW264.7 macrophages in vitro were evaluated. The results showed that compounds 1-8 exerted inhibitory activities on NO production with IC_(50) of 19.34-42.16 μmol·L~(-1).
Animals ; Mice ; Nitric Oxide/biosynthesis* ; Ligusticum/chemistry* ; Benzofurans/isolation & purification* ; Drugs, Chinese Herbal/isolation & purification* ; Macrophages/immunology* ; RAW 264.7 Cells ; Molecular Structure

BACKGROUND: Both medication and non-medication therapies are effective approaches to control blood pressure (BP) in hypertension patients. However, the association of joint changes in antihypertensive medication use and healthy lifestyle index (HLI) with BP control among hypertension patients is seldom reported, which needs to provide more evidence by prospective intervention studies. We examined the association of antihypertensive medication use and HLI with BP control among employees with hypertension in China based on a workplace-based multicomponent intervention program. METHODS: Between January 2013 and December 2014, a cluster randomized clinical trial of a workplace-based multicomponent intervention program was conducted in 60 workplaces across 20 urban areas in China. Workplaces were randomly divided into intervention (n = 40) and control (n = 20) groups. Basic information on employees at each workplace was collected by trained professionals, including sociodemographic characteristics, medical history, family history, lifestyle behaviors, medication status and physical measurements. After baseline, the intervention group received a 2-year intervention to achieve BP control, which included: (1) a workplace wellness program for all employees; (2) a guidelines-oriented hypertension management protocol. HLI including nonsmoking, nondrinking, adequate physical activity, weight within reference range and balanced diet, were coded on a 5-point scale (range: 0-5, with higher score indicating a healthier lifestyle). Antihypertensive medication use was defined as taking drug within the last 2 weeks. Changes in HLI, antihypertensive medication use and BP control from baseline to 24 months were measured after the intervention. RESULTS: Overall, 4655 employees were included (age: 46.3 ± 7.6 years, men: 3547 (82.3%)). After 24 months of the intervention, there was a significant improvement in lifestyle [smoking (OR = 0.65, 95% CI: 0.43-0.99; P = 0.045), drinking (OR = 0.52, 95% CI: 0.40-0.68; P < 0.001), regular exercise (OR = 3.10, 95% CI: 2.53-3.78; P < 0.001), excessive intake of fatty food (OR = 0.17, 95% CI: 0.06-0.52; P = 0.002), restrictive use of salt (OR = 0.26, 95% CI: 0.12-0.56; P = 0.001)]. Compare to employees with a deteriorating lifestyle after the intervention, those with an improved lifestyle had a higher BP control. In the intervention group, compared with employees not using antihypertensive medication, those who consistent used (OR = 2.34; 95% CI: 1.16-4.72; P = 0.017) or changed from not using to using antihypertensive medication (OR = 2.24; 95% CI: 1.08-4.62; P = 0.030) had higher BP control. Compared with those having lower HLI, participants with a same (OR = 1.38; 95% CI: 0.99-1.93; P = 0.056) or high (OR = 1.79; 95% CI: 1.27~2.53; P < 0.001) HLI had higher BP control. Those who used antihypertensive medication and had a high HLI had the highest BP control (OR = 1.88; 95% CI: 1.32-2.67, P < 0.001). Subgroup analysis also showed the consistent effect as the above. CONCLUSION These findings suggest that adherence to antihypertensive medication treatment and healthy lifestyle were associated with a significant improvement in BP control among employees with hypertension.

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

Objective To investigate the value of repeat renal biopsy in the treatment and prognosis of nephrotic syndrome(NS)and acute kidney injury(AKI)following immunosuppressive therapy in patients with lupus nephritis(LN). Methods A retrospective analysis was conducted for the clinicopathological data and follow-up records of LN patients undergoing repeat renal biopsy at Peking Union Medical College Hospital from January 1,2009 to December 31,2021. Results A total of 76 patients(55 females,72.4%)were included in this study,with the mean age at the first biopsy being(29.0±10.4)years,the median inter-biopsy interval of 4.0(2.0,7.0) years,and the median total follow-up duration of 7.5(5.0,13.8)years.Pathological transformation occurred in 46(60.5%)patients,and 2 patients had comorbid diabetic nephropathy.At repeat renal biopsy,50(65.8%) patients presented NS.These patients demonstrated lower estimated glomerular filtration rate(eGFR)(P<0.001),higher chronicity index(CI)(P=0.029),and higher complement C3(P<0.001)and C4(P<0.001)levels than those with NS at the first renal biopsy(n=50).Among the 28(36.8%) patients with AKI at repeat renal biopsy,8(28.6%)experienced acute exacerbation of chronic renal insufficiency.These patients exhibited higher serum creatinine level(P=0.002),C4 level(P=0.033),CI(P=0.042),and prevalence of thrombotic microangiopathy(P=0.046)than the patients showing AKI at the first renal biopsy(n=16),while the activity index(AI)showed no significant difference(P=0.051).Over 50% of NS and AKI patients underwent treatment modifications post-repeat renal biopsy,with clinical remission rates comparable to those after the first renal biopsy(both P>0.05).Elevated CI(≥5,P=0.001)and serum creatinine(≥140 μmol/L,P<0.001)at repeat renal biopsy were identified as independent risk factors for poor prognosis.The patients with AKI at repeat renal biopsy had higher incidence of endpoint events than the non-AKI patients(P=0.015).Neither AKI at the first renal biopsy nor NS at both biopsies had significant associations with prognosis. Conclusions Repeat renal biopsy reveals not only sustained high disease activity but also accelerates chronic progression in LN patients,which underscore its critical role in guiding the therapy for severe LN post-immunosuppression.AKI,CI≥5,and serum creatinine ≥140 μmol/L at repeat renal biopsy are strongly associated with poor prognosis.
Humans ; Lupus Nephritis/drug therapy* ; Female ; Retrospective Studies ; Adult ; Male ; Prognosis ; Biopsy ; Kidney/pathology* ; Acute Kidney Injury/pathology* ; Nephrotic Syndrome/pathology* ; Glomerular Filtration Rate ; Young Adult ; Immunosuppressive Agents/therapeutic use* ; Middle Aged

Objectives:To investigate the association between social determinants of health(SDOH)and incident stroke and analyze the main risk factors for stroke among resident with different SDOH levels. Methods:From 2012 to 2015,30 036 residents(≥35 years old)from 30 districts in 14 provincial-level administrative divisions in China were enrolled this study based on stratified multi-stage-random-sampling method.The prevalence of cardiovascular diseases and related risk factors were investigated,and stroke events were followed up in 2018 to 2019.Principal component analysis was performed to establish SDOH scores based on 9 indicators related to socioeconomic and healthcare resources,participants were divided into low SDOH group(n=8 343)when it was≥-2.01 to<-1.14,middle SDOH group(n=7 257)when it was≥-1.14 to<0.10,and high SDOH group(n=8 457)when it was≥0.10 to≤5.79.Multivariate Cox regression was applied to estimate the association of SDOH levels with incident stroke.The random survival forest method was used to analyze the major risk factors in different SDOH levels. Results:A total of 24 057 participants were finally included,669(2.8%)participants developed stroke during a mean of(4.7±0.8)years follow-up.The incidence densities of stroke in the low,medium,and high SDOH groups were 468.39,628.85,and 700.39/100 000 person-years,respectively(Pdifference<0.05,Ptrend=0.01).Compared with individuals with low SDOH level group,fully HR for incident stroke among those with medium and high were 1.91(95%CI:1.54-2.36)and 1.59(95%CI:1.30-1.95),respectively(Ptrend<0.001).Advanced age is the primary risk factor for stroke in the population,especially in districts with high SDOH level.In districts with medium SDOH level,diabetes is an important risk factor for stroke.High blood pressure and alcohol consumption are important modifiable risk factors in low SDOH level districts. Conclusions:Present study shows that higher levels of SDOH are associated with increased risk of stroke.The main risk factors for stroke differ among participants with different SDOH level districts.Targeted interventions should be implemented to improve the prevention and treatment of stroke in populations with different levels of SDOH.

Objective To explore the role of Panax notoginseng saponins(PNS)in regulating the expression of sortilin and ATP-binding cassette transporter A1(ABCA1)in macrophages,and the effect of PNS on inhibiting formation of foam cells and the potential mechanism of PNS adjusting sortilin expression and cholesterol metabolism.Methods The macrophages were divided into five groups as follows:group A(only added with cell culture),group B(transfected with negative control lentivirus),group C(transfected with lentivirus-mediated sortilin overexpression),group D(transfected with lentivirus-mediated sortilin overexpression+60 μg·mL-1PNS),group E(transfected with lentivirus-mediated sortilin overexpression+10 μmol·L-1 mitogen-activated protein kinase kinase(MEK)inhibitor PD98059+60 μg·mL-1 PNS).The protein contents of sortilin,ABCA1,extracellular signal-regulated kinase(ERK)and phosphorylated-ERK(p-ERK)were evaluated with Western blot.All the cells in five groups were cultured with 50 μg·mL-1ox-LDL to form foam cells.The lipid in macrophages was investigated with red O assay.Results The relative expression levels of sortilin protein were 1.00±0.08,0.91±0.15,2.28±0.13,1.62±0.09 and 2.01±0.08;the relative expression levels of ABCA1 protein were 1.00±0.01,0.92±0.07,0.29±0.04,0.66±0.09 and 0.44±0.07;the ratios of p-ERK/ERK protein were 1.00±0.09,0.92±0.05,1.03±0.12,2.00±0.12 and 1.64±0.14;the contents of lipid in macrophages were(4.82±2.19)％,(6.70±0.88)％,(44.56±4.15)％,(27.66±3.25)％and(41.67±5.45)％.Except the ratios of p-ERK/ERK,the other parameters between group C and group A were statistically significant difference(all P＜0.01).Meanwhile,there were also statistically significant difference between group D and group C as well as group D and group E(P＜0.05,P＜0.01).Conclusion PNS inhibits the lipid accumulation in macrophages through upregulating ABCA1 and downregulating sortilin,and ERK signaling pathway may be as one of important mechanisms influencing the expression of sortilin and ABCA1 mediated by PNS.

Objective:To investigate the distribution and primary drainage sites of the venous drainage system in the pedicled nasal septal mucosal flap, as well as to examine protective measures for the venous system of the nasal septal mucosal flap and its application in repairing the nasal skull base through the anatomical study of the nasal septum mucosal venous system in cadavers.Methods:Gross anatomy dissections were performed on 13 sides perfused fresh frozen cadaveric head specimens. The nasal septum mucosal flap was separated along the perichondrium and subperiosteum, then passed across the vomer, anterior wall of sphenoid sinus, clivus, and towards the anterior edge of vertical plate of palatine bone. Detailed documentation, including photographs, was made to record the morphology, distribution and drainage location of veins of the nasal septum mucosal flap and its pedicle, along with number of sphenopalatine veins. Furthermore, venous injuries resulting from obtaining a pedicled nasal septal mucosa flap were observed. From March 2023 to March 2024, a retrospective analysis was conducted on patients with nasopharyngeal lesions who underwent surgical repair using a modified pedicled nasal septum mucosal flap for venous system protection in the ENT institute and Department of Otorhinolaryngology at the Eye & ENT Hospital of Fudan University. The postoperative endoscopy was employed to assess the viability of the mucosal flap.Results:The veins of the nasal septum mucosa were primarily located in the posterior region, including the vomerine region, anterior wall of the sphenoid sinus, clivus region, and posterolateral wall of the nasal cavity, in a reticular pattern. Perforating veins draining into these bony structures could be observed, although their quantity and morphology varied. Notably, no prominent sphenopalatine veins were identified in 10 specimens examined, while 3 specimens exhibited sphenopalatine veins: one with a small single branch and two with venous bundles. Preservation of the nasal septal vein was possible when dissection was limited to the anterior edge of the wing of vomer. A wider range of dissection increased the risk of veinous injury. In cases where only vascular pedicles at the sphenopalatine foramen were preserved, three cadaveric head specimens retained intact sphenopalatine veins, while drainage veins were completely destroyed in ten other specimens. Fifteen patients with unilateral lesions (8 with recurrent nasopharyngeal carcinoma and 7 with nasopharyngeal radionecrosis) were included in this study. The postoperative reconstructions were carried out using contralateral pedicled nasal septal mucosal flaps. The average follow-up time was 7 months (ranging from 3 to 12 months), and all the nasal septal mucosal flaps survived.Conclusions:The primary location of the drainage vein within the nasal septum mucosa is situated in its posterior region, where it penetrates into adjacent bone structures. Very few sphenopalatine veins pass through the sphenopalatine foramen. Extensive dissection of the pedicled nasal septal mucosal flap may potentially impair the venous system and adversely affect flap survival rates, necessitating further clinical exploration.

Objective To investigate the expression of PLCD3 mRNA in the synovium of osteoarthritis(OA)and its relationship with immune cell infiltration.Methods Based on the differentially expressed genes of OA found in the previous study,the expression of phospholipase Cδ3(PLCD3)mRNA was detected by col-lecting synovial samples from OA group and control group.CIBERSORT algorithm was used to analyze the infiltration pattern of immune cells in OA group and control group,and the correlation between PLCD3 and infiltrating immune cells was further analyzed.Results Compared with the control group,the relative expres-sion level of PLCD3 mRNA was significantly increased in synovial samples of OA group(P<0.05).The pro-portions of B cells naive,NK cells activated,M2 macrophages and mast cells activated in synovial tissues of OA group were relatively high(P<0.05).PLCD3 was positively correlated with the proportion of these four immune cells(P<0.05).Conclusion PLCD3 may be a key biomarker for the diagnosis of OA,which may be involved in the pathogenesis of OA by interacting with infiltrating immune cells.

OBJECTIVE: This study aimed to explore the association between humidity exposure and the risk of cardiovascular disease (CVD), utilizing follow-up data and relative humidity (RH) metric assessments. METHODS: We extracted the baseline data from the China Hypertension Survey (CHS) of 24,510 enrolled participants aged ≥ 35 years without a history of CVD between 2012 and 2015 and followed them up from 2018 to 2019. The National Meteorological Information Center (NMIC) of the China Meteorological Administration (CMA) provided the quality-controlled relative humidity (RH) datasets. Cox proportional hazards models were used to estimate hazard ratios ( HRs) for CVD in relation to RH. RESULTS: During the follow-up period (2018-2019), 973 patients with CVD were identified. The HR of CVD risk was 1.17 (95% CI: 1.04-1.31) per 10% increase in summer mean RH. Compared with participants in the 3 ^rd quintile group, those in the 1 ^st and 5 ^th quintiles of RH had a higher risk of CVD. For summer mean RH, the HRs (95% CIs) for the 1 ^st and 5 ^th quintiles were 1.34 (1.04-1.71) and 1.44 (1.14-1.83), respectively. The relationship ("U" shape) between summer mean RH and the risk of CVD was nonlinear. Stratified analyses indicated that the risk of CVD was substantially influenced by the summer mean RH in female, older individuals, and those in southern China. CONCLUSION Unsuitable (too high or low) humidity environments affect the risk of CVD. Our study highlights those future policies for adapting to climate change should consider the humidity-CVD relationship.
Humans ; Humidity/adverse effects* ; Cardiovascular Diseases/etiology* ; Female ; Male ; Middle Aged ; Prospective Studies ; China/epidemiology* ; Adult ; Aged ; Risk Factors ; Proportional Hazards Models ; Seasons

OBJECTIVE: To explore whether casticin (CAS) suppresses stemness in cancer stem-like cells (CSLCs) obtained from human cervical cancer (CCSLCs) and the underlying mechanism. METHODS: Spheres from HeLa and CaSki cells were used as CCSLCs. DNA methyltransferase 1 (DNMT1) activity and mRNA levels, self-renewal capability (Nanog and Sox2), and cancer stem cell markers (CD133 and CD44), were detected by a colorimetric DNMT activity/inhibition assay kit, quantitative real-time reverse transcription-polymerase chain reaction, sphere and colony formation assays, and immunoblot, respectively. Knockdown and overexpression of DNMT1 by transfection with shRNA and cDNA, respectively, were performed to explore the mechanism for action of CAS (0, 10, 30, and 100 nmol/L). RESULTS: DNMT1 activity was increased in CCSLCs compared with HeLa and CaSki cells (P<0.05). In addition, HeLa-derived CCSLCs transfected with DNMT1 shRNA showed reduced sphere and colony formation abilities, and lower CD133, CD44, Nanog and Sox2 protein expressions (P<0.05). Conversely, overexpression of DNMT1 in HeLa cells exhibited the oppositive effects. Furthermore, CAS significantly reduced DNMT1 activity and transcription levels as well as stemness in HeLa-derived CCSLCs (P<0.05). Interestingly, DNMT1 knockdown enhanced the inhibitory effect of CAS on stemness. As expected, DNMT1 overexpression reversed the inhibitory effect of CAS on stemness in HeLa cells. CONCLUSION CAS effectively inhibits stemness in CCSLCs through suppression of DNMT1 activation, suggesting that CAS acts as a promising preventive and therapeutic candidate in cervical cancer.
Female ; Humans ; Cell Line, Tumor ; HeLa Cells ; Neoplastic Stem Cells/metabolism* ; RNA, Small Interfering/metabolism* ; Uterine Cervical Neoplasms/metabolism*