1.Exploration of relationship between IL-17/IL-23 immunoinflammatory axis and chronic heart failure and clinical prognosis
Mingyan CHENG ; Jinghua WANG ; Wenyue WANG ; Na TIAN ; Yanfei GAO ; Yanchun WANG ; Tao YANG
Chinese Journal of Immunology 2025;41(1):153-156,162
Objective:To investigate relationship between IL-17/IL-23 immunoinflammatory axis and chronic heart failure(CHF)and clinical prognosis.Methods:A total of 112 patients with CHF in Chengde Central Hospital from January 2020 to Septem-ber 2021 were selected as observation group,and another 112 patients admitted to same period for healthy physical examination were selected as control group.Serum IL-17 and IL-23 levels of two groups were compared,relationship between serum IL-17 and IL-23 levels and degree of disease were analyzed;clinical data,serum IL-17 and IL-23 levels of patients with different prognosis were compared,relationship between serum IL-17 and IL-23 levels and clinical prognosis of CHF patients were analyzed.Predictive value of serum IL-17 and IL-23 levels on clinical prognosis of CHF patients was evaluated,and predictive value of each prediction scheme was compared.Results:Serum IL-17 and IL-23 levels were higher in observation group than control group(P<0.05);serum IL-17 and IL-23 levels of CHF patients were positively correlated with NYHA classification(P<0.05).Serum IL-17 and IL-23 levels were higher in patients with poor prognosis than in those with good prognosis(P<0.05).Serum IL-17 and IL-23 were independently associated with clinical prognosis of CHF patients,and the higher the serum IL-17 and IL-23 levels,the greater risk of poor clinical prognosis of CHF patients.AUC of serum IL-17 and IL-23 levels for predicting clinical prognosis of CHF patients were 0.787 and 0.726,respectively,and combined predicted AUC was 0.918(P<0.001);combined predicted AUC of serum IL-17 and IL-23 was significantly higher than single index(P<0.05).Conclusion:IL-17 and IL-23 levels in IL-17/IL-23 immunoinflammatory axis of CHF patients are significantly elevated and involve in disease occurence and development,whose clinical detection can help predict clinical prognosis of CHF.
2.Chlorogenic acid mitigates glucocorticoid-induced osteoporosis via modulation of HER2/AKT/mTOR signaling pathway.
An-Na XIE ; Sun-Zheng-Yuan ZHANG ; Yu ZHANG ; Jin-Long CAO ; Cheng-Long WANG ; Li-Bo WANG ; Hong-Jin WU ; Jie ZHANG ; Wei-Wei DAI
Journal of Integrative Medicine 2025;23(6):670-682
OBJECTIVE:
Glucocorticoid-induced osteoporosis (GIOP) is a common complication of prolonged glucocorticoid therapy. Chlorogenic acid (CGA), a polyphenol with antioxidant properties that is extracted from traditional Chinese medicines such as Eucommiae Cortex, has potential anti-osteoporotic activity. This study aimed to investigate the possible effects of CGA on GIOP in mice and murine long bone osteocyte Y4 (MLO-Y4) cells and explore the underlying molecular mechanisms.
METHODS:
The protective effects of CGA were initially evaluated in the GIOP mouse model induced by dexamethasone (Dex). The micro-computed tomography, hematoxylin-eosin staining, silver nitrate staining, and serum detection were used to assess the efficacy of CGA for improving bone formation in vivo. Then, network pharmacology analysis was used to predict the potential targets and molecular mechanisms underlying the therapeutic efficacy of CGA against GIOP. After that, 2',7'-dichlorofluorescein diacetate staining, flow cytometry, real-time quantitative reverse transcription polymerase chain reaction, and Western blotting were used to verify the mechanisms of CGA against GIOP in vitro.
RESULTS:
Animal experiments showed that CGA treatment effectively attenuated Dex-induced decreases in bone mass and strength and improved disrupted osteocyte morphology in mice. The protein-protein interaction analysis highlighted erb-b2 receptor tyrosine kinase (ERBB2), which is also known as human epidermal growth factor receptor 2 (HER2), caspase-3, kinase insert domain receptor, matrix metallopeptidase 9, matrix metallopeptidase 2, proto-oncogene tyrosine-protein kinase Src, and epidermal growth factor receptor as core targets. The Kyoto Encyclopedia of Genes and Genomes analysis revealed several significantly enriched pathways (P < 0.05), including the ERBB, phosphoinositide 3 kinase-AKT serine/threonine kinase 1 (AKT), and mechanistic target of rapamycin kinase (mTOR) pathways. Cellular experiments verified that CGA enhanced bone formation and promoted autophagy while inhibiting apoptosis in MLO-Y4 cells exposed to Dex, which was associated with the upregulated expression of HER2 and activation of the HER2/AKT/mTOR signaling pathway.
CONCLUSION
CGA exerted anti-osteoporotic effects against GIOP, partially through targeting osteocytes and modulating the HER2/AKT/mTOR signaling pathway. Please cite this article as: Xie AN, Zhang SZY, Zhang Y, Cao JL, Wang CL, Wang LB, Wu HJ, Zhang J, Dai WW. Chlorogenic acid mitigates glucocorticoid-induced osteoporosis via modulation of HER2/AKT/mTOR signaling pathway. J Integr Med. 2025; 23(6):670-682.
Animals
;
Chlorogenic Acid/therapeutic use*
;
Osteoporosis/metabolism*
;
Signal Transduction/drug effects*
;
Proto-Oncogene Proteins c-akt/metabolism*
;
TOR Serine-Threonine Kinases/metabolism*
;
Mice
;
Glucocorticoids/adverse effects*
;
Receptor, ErbB-2/metabolism*
;
Proto-Oncogene Mas
;
Dexamethasone/adverse effects*
;
Osteocytes/drug effects*
;
Osteogenesis/drug effects*
;
Male
;
Cell Line
;
Mice, Inbred C57BL
;
Humans
3.Shenlian Extract Protects against Ultrafine Particulate Matter-Aggravated Myocardial Ischemic Injury by Inhibiting Inflammation and Cell Apoptosis.
Shui Qing QU ; Yan LIANG ; Shuo Qiu DENG ; Yu LI ; Yue DAI ; Cheng Cheng LIU ; Tuo LIU ; Lu Qi WANG ; Li Na CHEN ; Yu Jie LI
Biomedical and Environmental Sciences 2025;38(2):206-218
OBJECTIVE:
Emerging evidence suggests that exposure to ultrafine particulate matter (UPM, aerodynamic diameter < 0.1 µm) is associated with adverse cardiovascular events. Previous studies have found that Shenlian (SL) extract possesses anti-inflammatory and antiapoptotic properties and has a promising protective effect at all stages of the atherosclerotic disease process. In this study, we aimed to investigated whether SL improves UPM-aggravated myocardial ischemic injury by inhibiting inflammation and cell apoptosis.
METHODS:
We established a mouse model of MI+UPM. Echocardiographic measurement, measurement of myocardialinfarct size, biochemical analysis, enzyme-linked immunosorbent assay (ELISA), histopathological analysis, Transferase dUTP Nick End Labeling (TUNEL), Western blotting (WB), Polymerase Chain Reaction (PCR) and so on were used to explore the anti-inflammatory and anti-apoptotic effects of SL in vivo and in vitro.
RESULTS:
SL treatment can attenuate UPM-induced cardiac dysfunction by improving left ventricular ejection fraction, fractional shortening, and decreasing cardiac infarction area. SL significantly reduced the levels of myocardial enzymes and attenuated UPM-induced morphological alterations. Moreover, SL significantly reduced expression levels of the inflammatory cytokines IL-6, TNF-α, and MCP-1. UPM further increased the infiltration of macrophages in myocardial tissue, whereas SL intervention reversed this phenomenon. UPM also triggered myocardial apoptosis, which was markedly attenuated by SL treatment. The results of in vitro experiments revealed that SL prevented cell damage caused by exposure to UPM combined with hypoxia by reducing the expression of the inflammatory factor NF-κB and inhibiting apoptosis in H9c2 cells.
CONCLUSION
Overall, both in vivo and in vitro experiments demonstrated that SL attenuated UPM-aggravated myocardial ischemic injury by inhibiting inflammation and cell apoptosis. The mechanisms were related to the downregulation of macrophages infiltrating heart tissues.
Animals
;
Apoptosis/drug effects*
;
Particulate Matter/adverse effects*
;
Mice
;
Male
;
Inflammation/drug therapy*
;
Drugs, Chinese Herbal/therapeutic use*
;
Mice, Inbred C57BL
;
Myocardial Ischemia/drug therapy*
;
Cell Line
4.Exploring the clinical efficacy of Yangyin Shugan Formula in treating 307 patients with ovarian dysfunction at different stages based on the"preventive treatment of disease"theory:a real world study
Xuchun HUANG ; Feifei WANG ; Na LIANG ; Shuang HUANG ; Piaoying CHEN ; Jiarui HOU ; Fangping CHENG ; Xiaojing CAO ; Xiaoyun WANG
Journal of Beijing University of Traditional Chinese Medicine 2025;48(7):943-953
Objective Based on the"preventive treatment of disease"theory and real-world data,this study aimed to evaluate the clinical efficacy of Yangyin Shugan Formula in patients with ovarian dysfunction characterized by the syndrome of kidney deficiency and liver depression at different stages and to provide evidence for optimizing the timing of traditional Chinese medicine(TCM)in premature ovarian insufficiency(POI)management.Methods Ovarian dysfunction patients under 40 years old characterized by syndrome of kidney deficiency and liver depression,registered in the outpatient electronic medical records of the Second Affiliated Hospital of Guangzhou University of Chinese Medicine from January 2020 to December 2023,were stratified into three groups:subclinical POI,POI,and premature ovarian failure(POF)groups.The therapeutic outcomes of the three groups of patients were compared,including TCM syndrome total response rates,menstrual total response rates/normalization(cured)rates,base follicle-stimulating hormone(FSH)total response rate/normalization rates and anti-Müllerian hormone(AMH)levels.Results A total of 307 patients meeting the research criteria were included(97 cases in subclinical POI group,112 cases in POI group,and 98 cases in POF group).The TCM syndrome total response rates ranked as subclinical POI group(98.97%,96/97)>POI group(95.54%,107/112)>POF group(83.67%,82/98),with the POF group was lower than that of the subclinical POI and POI groups(P<0.017);while the difference of the subclinical POI group with the POI group was not significant.Menstrual total response rates ranked as subclinical POI group(97.22%,70/72)>POI group(72.32%,81/112)>POF group(51.02%,50/98),the differences among the three groups and in the post-hoc comparisons were significant(P<0.01,P<0.017);normalization rates ranked as subclinical POI group(90.28%,65/72)>POI group(54.46%,61/112)>POF group(26.53%,26/98),the differences among the three groups and in the post-hoc comparisons were significant(P<0.01,P<0.017).FSH total response rates ranked as subclinical POI group(89.69%,87/97)>POI group(81.25%,91/112)>POF group(60.20%,59/98),while POF group was lower than that of the other two groups(P<0.017),and the difference of the subclinical POI group with the POI group was not significant.Normalization FSH rates ranked as subclinical POI group(71.13%,69/97)>POI group(53.57%,60/112)>POF group(16.33%,16/98),the differences among the three groups and in the post-hoc comparisons were significant(P<0.01,P<0.017).Compared with before treatment,the FSH levels in all three groups decreased after treatment(P<0.01).The reduction of FSH in the POF and POI groups were better than that in the subclinical P OI group(P<0.017).No significant difference was observed in the reduction of FSH between the POI and POF groups.Post-treatment AMH elevation observed in the subclinical POI and POI groups(P<0.01).Conclusion Yangyin Shugan Formula improves the menstrual conditions and TCM syndromes across all the stages.It also improves elevated FSH levels across all the stages and has a specific effect on normalizing FSH and menstruation.Yangyin Shugan Formula increases the AMH levels of patients with subclinical POI and POI,highlighting the applicability of TCM in staged preventive management.
5.Research Progress on Antiviral Herbalism,Material Basis and Mechanism of Dendrobium Genus
Na LUO ; Tingting WANG ; Yang HU ; Baode YE ; Wenshuai BAO ; Yangqing LIU ; Dong LIU ; Jianming CHENG
Journal of Nanjing University of Traditional Chinese Medicine 2025;41(11):1560-1572
Dendrobium is the largest genus of the Orchidaceae family.The fresh and dried stems of many species of this genus have been used as Shihu(Dendrobii Caulis)in traditional Chinese medicine,it is known as the foremost of the"Nine Great Herbs of China".Ancient texts highlight its uses for"strengthening yin,enhancing essence,nourishing the five viscera,alleviating fatigue,and dispelling skin heat and prickly heat".Modern research confirms that the polysaccharides and alkaloids it contains have antiviral ef-fects,it can apply in treating immunodeficiency caused by viral infections clinically.While studies are gradually uncovering the antivi-ral mechanisms and material basis of Dendrobium,the lack of systematic analysis and organization has hindered its resource develop-ment.The paper employed CiteSpace software for bibliometric analysis of Chinese and English literature on Dendrobium.It reviewed the herbalism,material basis,and mechanisms of its antiviral properties building upon the systematic review of ancient materia medica and modern literature.Results indicate that Dendrobium can boost vital energy and resist pathogens,showing great potential in antiviral drug development.
6.Resource Allocation Status and Equity Analysis of Elderly Care Institutions in Northeast Region Based on Time Series
Yining SHE ; Na WANG ; Lian CHENG ; Siyu WANG ; Zhong ZHANG
Chinese Health Economics 2025;44(4):39-45
Objective:To analyze the equity of elderly care institution resource allocation in Northeast China and its influencing factors,and provide certain reference for the further development of elderly care care in Northeast China.Methods:The total amount of nursing institution resource allocation and the per capita old and above per 1 000 km2 were summarized by using general descriptive analysis.The Lorenz curve,Gini coefficient,and Theil index were calculated to evaluate the equity of nursing institution resource allocation.Results:Jilin Province did not have an advantage in the total allocation of elderly care insitution resources in Northeast China.In terms of resource allocation per 1 000 km2,Heilongjiang Province still has considerable room for improvement.The overall arc of the Lorenz curve for allocating resources by geographical area has become smaller year by year,while the overall arc of the Lorenz curve for allocating resources by population has become larger year by year.Conclusion:The equity of allocating institution home resources by population has generally weakened over the years,while the equity of allocating elderly care institution resources by geographical area has generally strengthened over the years.The development pressure of nursing care in Liaoning Province is relatively large,and efforts should be made to enhance the fairness of nursing home resource allocation.
7.The effects of intermittent oro-esophageal tube feeding on post-stroke dysphagia
Fang ZHOU ; Yan MA ; Rui SUN ; Xue CHENG ; Na QIAO ; Qing BAO ; Xiaoyun WANG
Chinese Journal of Physical Medicine and Rehabilitation 2025;47(10):901-905
Objective:To compare the effects of intermittent oro-esophageal tube feeding (IOE) and nasogastric tube feeding (NGT) on nutritional status, complications, swallowing function and airway protection in persons with post-stroke dysphagia (PSD).Methods:Sixty PSD patients were randomized into an observation group ( n=30) and a control group ( n=30). In addition to conventional medication and swallowing rehabilitation, the observation group received supplemental IOE nutrition, while the control group was given NGT. Before and after one month, both groups were evaluated using the Functional Oral Intake Scale (FOIS), and such nutritional indicators as body mass index (BMI), hemoglobin (Hb) levels, albumin (ALB), prealbumin (PAB), skinfold at the triceps (TSF) and arm muscle circumference (AMC) were measured. The morphology of each subject′s epiglottis, any edema of the arytenoid mucosa and vocal cord mobility were assessed using fiberoptic endoscopic evaluation of swallowing (FEES). Murray Secretion Scale ratings were documented, along with laryngeal sensation during swallowing, swallowing reflex, the Yale Pharyngeal Residue Severity Rating Scale, and the Rosenbek Penetration-aspiration Scale. Results:Both groups showed significant improvement in their average FOIS scores and all of the nutritional descriptors, but with significantly greater improvement in the observation group. Abnormalities in the shape of the epiglottis, arytenoid edema and vocal cord mobility had decreased significantly in both groups. This was also true of larynx sensation, swallowing reflex, pharyngeal secretions, residue and penetration/aspiration. On average the improvements were significantly greater in the observation group.Conclusion:Compared with NGT, IOE more effectively improves swallowing, enhances airway functioning and reduces NGT syndrome among PSD patients. These observations support its clinical adoption.
8.A Cross-sectional Survey on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Elderly Patients with Non-Valvular Atrial Fibrillation
Yifan NA ; Junpeng LIU ; Yatong ZHANG ; Zinan ZHAO ; Tianqi ZHANG ; Yuhao WAN ; Min ZENG ; Ning SUN ; Cheng WU ; Jun WANG ; Fang WANG ; Jiefu YANG
Chinese Journal of Geriatrics 2025;44(4):458-464
Objective:To investigate the use of non-vitamin K antagonist oral anticoagulants(NOACs)and their associated comorbidities in patients aged 80 years and older with non-valvular atrial fibrillation(NVAF), as well as to understand the challenges faced by elderly patients receiving NOAC therapy.Methods:We retrospectively enrolled elderly patients(≥80 years old)with NVAF who were treated with NOACs at a hospital in Beijing from January 2018 to August 2023.Patients were categorized into two age groups: 80-89 years and ≥90 years.We collected baseline data, including demographic characteristics, details of atrial fibrillation, comorbidities, laboratory test results, and medication combinations, for descriptive statistical analysis and intergroup comparisons.Results:A total of 695 elderly patients with NVAF receiving NOACs were included in the study, with a median age of 84 years.Among these patients, there were 328 males(47.19%, 328/695)and 422 cases of paroxysmal atrial fibrillation(60.72%, 422/695).The age group of 80-89 years comprised 640 cases(92.09%, 640/695), while the group aged 90 years and above included 55 cases(7.91%, 55/695).The use of NOACs in patients aged 90 and older exhibited an increasing trend over the years.Inter-group comparisons indicated that the ≥90 years group had lower body mass index, longer hospital stays, increased bedridden time, poorer renal function, lower levels of albumin and hemoglobin, and higher D-dimer levels.Inappropriate dosing of DOACs occurred in 49.64%(345/695)of cases, with 90.72%(313/345)receiving doses lower than recommended.Lower-than-recommended doses were more prevalent in the ≥90 years group, while higher-than-recommended doses were more common in the 80-89 years group.Polypharmacy was noted in 61.29%(426/695)of patients.The concurrent use of antiplatelet drugs, rhythm control medications, and ventricular rate control drugs was observed in 12.52%(87/695), 19.57%(136/695), and 54.53%(379/695)of patients, respectively, with no significant differences between groups.Conclusions:Inappropriate dosing and polypharmacy are prevalent issues among elderly NVAF patients.Therefore, it is essential to enhance multidisciplinary collaboration to optimize anticoagulation treatment strategies.
9.Feasibility study on shortening the detection time of long exercise test in the diagnosis of periodic paralysis
Shuo YANG ; Na CHEN ; Lin CHEN ; Feng CHENG ; Jingfen LI ; Lei ZHANG ; Ying WANG ; Fan JIAN ; Zaiqiang ZHANG ; Hua PAN
Chinese Journal of Neurology 2025;58(4):359-365
Objective:To explore the feasibility of shortening the time of long exercise test (LET) from 120 to 60 minutes by analyzing the positive rate within 60 minutes among periodic paralysis (PP) patients who were positive in 120-minute test.Methods:The data of patients undergoing 120-minute LET from January 2015 to October 2021 in Beijing Tiantan Hospital, Capital Medical University were retrospectively analyzed, with 30%, 33%, and 40% as diagnostic cut-off values, respectively. PP patients with positive results within 120 minutes after exercise were enrolled in the study. The positive rate within 30 minutes and 60 minutes after exercise was calculated. The change rates of compound muscle action potential (CMAP) amplitude and the sensitivity and specificity of LET at 30 minutes, 60 minutes, and 120 minutes after exercise were analyzed. The change rate of CMAP amplitude in PP patients who did not show positive results within 60 minutes was further calculated.Results:A total of 254 patients were examined, including 114 PP patients. With 30%, 33%, and 40% as diagnostic cut-off values, the results showed that there were 88, 88, and 82 positive PP patients, respectively. Under each diagnostic cut-off values, the age of positive PP patients was (32±10) years, with a male proportion of 98% (86/88), 98% (86/88), and 99% (81/82), respectively; the positive rate of PP patients within 30 minutes after exercise was 60% (53/88), 58% (51/88), and 41% (34/82), respectively; the positive rate of PP patients within 60 minutes after exercise was 91% (80/88), 86% (76/88), and 83% (68/82), respectively. At the cut-off values of 30%, 33% and 40%, the change rate of CMAP amplitude at 30 minutes [-36% (-49%, -23%), -36% (-49%, -23%), -37% (-51%, -24%)], 60 minutes [-51% (-66%, -40%), -51% (-66%, -40%), -53% (-66%, -42%)] and 120 minutes [-57% (-67%, -45%), -57% (-67%, -45%), -58% (-67%, -46%)] after exercise showed statistically significant difference among 3 time points ( H=57.764, 57.764, 59.616, respectively, all P<0.001); the further comparison between time points showed that there was statistically significant difference in the change rate of CMAP amplitude between 60 minutes ( Z=5.419, 5.419, 5.531, respectively, all P<0.001), 120 minutes ( Z=7.325, 7.325, 7.431, respectively, all P<0.001) and 30 minutes after exercise, but there was no statistically significant difference in the change rate of CMAP amplitude between 120 minutes and 60 minutes after exercise ( Z=1.906, 1.906, 1.899, respectively, all P>0.05); the sensitivity of LET for the diagnosis of PP at 60 minutes after exercise was 70.2% (80/114), 66.7% (76/114) and 59.6% (68/114), and the specificity of LET for the diagnosis of PP was 77.9% (109/140), 84.3% (118/140) and 91.4%(128/140), respectively. When 30%, 33% and 40% were used as the diagnostic cut-off values, and the change rate of CMAP amplitude at 60 minutes after exercise fell below these cut-off values but showed a decline of ≥20%, ≥22% and ≥24%, respectively, the detection time should be extended to 120 minutes. Conclusions:Whether using 30%, 33%, or 40% as diagnostic cut-off values, it is feasible to shorten the LET time from 120 minutes to 60 minutes. The 60-minute LET has good sensitivity and specificity for the diagnosis of PP. It is recommended to extend the detection time to 120 minutes for patients with a ≥20%, ≥22%, or ≥24% decline in CMAP amplitude at 60 minutes after exercise while falling short of corresponding diagnostic cut-off values when 30%, 33%, and 40% are used as diagnostic cut-off values. This method can not only improve the examination efficiency of LET, but also minimize the missed diagnosis as much as possible.
10.Effects of cytomegalovirus infection on gene expression and signaling pathways in preauricular somatic cells
Na CHENG ; Lingzhang TIAN ; Chengmin WANG ; Danhua ZHANG
Journal of Chinese Physician 2025;27(9):1366-1371
Objective:To analyze the effects of cytomegalovirus (CMV) infection on gene expression and signaling pathways in preauricular somatic cells, and to explore potential intervention approaches for neonatal hearing loss caused by CMV infection.Methods:CMV infection data (GSE234062) were retrieved and downloaded from the GEO database. R studio software was used to analyze the differentially expressed genes (DEGs) between the CMV-infected group and the control group. ExpressAnalyst and String tools were employed to analyze the enrichment of DEGs in signaling pathways, biological processes, molecular functions, and protein-protein interactions.Results:After CMV infection of preauricular somatic cells, the expression levels of viral RNA and green fluorescent protein (GFP) RNA increased significantly. Meanwhile, 233 genes were upregulated and 123 genes were downregulated post-infection. Signaling pathway analysis showed that the upregulated genes were mainly enriched in pathways such as calcium ion channels, GABA synapses, morphine addiction, and cGMP-PKG, while the downregulated genes were primarily enriched in pathways including focal adhesion, extracellular matrix (ECM)-receptor interaction, amebiasis, and proteoglycans in cancer. Biological process analysis revealed that the upregulated genes were closely associated with neuron development and cell maturation, whereas the downregulated genes were mainly involved in actin filament-dependent processes, tissue development, and vascular development. Molecular function enrichment analysis indicated that the upregulated genes were mainly clustered in sequence-specific DNA binding, RNA polymerase Ⅱ distal enhancer binding, and G protein-coupled amine receptor activity, while the downregulated genes were closely related to molecular functions such as actin binding, structural molecule activity, and extracellular matrix structure.Conclusions:CMV infection can activate calcium ion channel and GABA synaptic pathways, and impair focal adhesion and ECM-receptor interaction pathways in preauricular somatic cells. This suggests that targeting these related pathways may help alleviate neonatal hearing impairment caused by CMV infection.

Result Analysis
Print
Save
E-mail