1.Wumeiwan Promotes M1 Polarization of Tumor-associated Macrophages to Treat Metastatic Colorectal Cancer
Nianzhi CHEN ; Shiyun TANG ; Yuanyuan FENG ; Yan WANG ; Ningning LIU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(1):92-100
ObjectiveTo explore the effects of Wumeiwan on liver metastasis and lung metastasis of colorectal cancer and its potential mechanism. MethodsFirstly, mice were randomized into control, low-dose (20 g·kg-1) Wumeiwan, high-dose (40 g·kg-1) Wumeiwan, and paclitaxel (10 mg·kg-1) groups. Secondly, liver metastasis and lung metastasis models of colorectal cancer were established in mice. After 4 weeks of intervention, the body weight of each mouse was recorded, and the lung weight, liver weight, and survival time of mice with metastatic colorectal cancer were determined. Hematoxylin-eosin (HE) staining was employed to detect the effects of Wumeiwan on liver metastasis and lung metastasis. Real-time PCR was employed to determine the mRNA levels of M1 and M2 macrophage markers in the liver tissue. Finally, the content of M1 macrophage markers CD80 and CD86 in the liver tissue was measured by flow cytometry. ResultsCompared with the control group, Wumeiwan and paclitaxel reduced the body weight (P<0.01) and liver weight (P<0.01) and prolonged the survival of the mouse model of liver metastasis of colorectal cancer (P<0.01). In the mouse model of lung metastasis of colorectal cancer, Wumeiwan and paclitaxel also reduced the body weight (P<0.01) and lung weight (P<0.01) and extended the survival time (P<0.01). Histopathological results showed that compared with the control group, Wumeiwan inhibited the liver and lung metastases of colorectal cancer. Real-time PCR results showed that compared with the control group, Wumeiwan upregulated the mRNA levels of M1 macrophage markers IL-1β, IL-6, tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and prostaglandin-endoperoxide synthase 2 (PTGS2) in the liver and lung tissue of mice with liver metastasis and lung metastasis of colorectal cancer (P<0.01). Meanwhile, Wumeiwan downregulated the mRNA levels of M2 macrophage markers Arg1, CD163, and CD206 (P<0.01). Meanwhile, the flow cytometry results showed that compared with the control group, Wumeiwan increased the content of CD86 and CD80 (P<0.01). In addition, immunohistochemical results showed that Wumeiwan promoted the expression of CD86 and inhibited the expression of CD206 in the liver and lung tissue of mice with liver metastasis and lung metastasis. ConclusionWumeiwan can inhibit the liver metastasis and lung metastasis of colorectal cancer by promoting the M1 polarization of macrophages in the liver and lung of the model mice.
2.Mechanism of Wumeiwan on Inhibiting Fatty Acid Metabolism Reprogramming in Prevention and Treatment of Colorectal Cancer Based on Multi-omics Analysis
Gang XIAO ; Shusen YANG ; Mingming SI ; Yanyan YANG ; Hailiang WEI ; Shuguang YAN ; Hui LUO
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(9):21-30
ObjectiveTo investigate the mechanism by which Wumeiwan suppresses the development and progression of colorectal cancer(CRC) through the regulation of fatty acid metabolic reprogramming, thereby providing new experimental evidence for the prevention and treatment of CRC. MethodsA total of 120 C57BL/6 mice were randomly divided into the blank group, model group, Wumeiwan high-, medium-, and low-dose groups(54, 27, 13.5 g·kg-1), and the mesalazine group(0.01 g·kg-1), with 20 mice in each group. Except for the blank group, all mice were subjected to azoxymethane(AOM)/dextran sulfate sodium(DSS) treatment to establish an inflammation-associated CRC model. One week after AOM injection, mice in the treatment groups received intragastric administration of the designated drugs, while the blank and model groups received an equal volume of purified water, continuing until 20 d after the intervention endpoint. Hematoxylin-eosin(HE) staining was used to observe colonic histopathological alterations, and immunohistochemistry for vascular endothelial growth factor(VEGF) was performed to evaluate neovascularization and tumor invasion. Metabolomics combined with Kyoto Encyclopedia of Genes and Genomes(KEGG) and metabolite set enrichment analysis(MSEA) was applied to identify key CRC-related metabolic pathways, which were further validated by transcriptomic Gene Ontology(GO) enrichment and gene heatmap analysis. Subsequently, Western blot was performed to determine the expression levels of core proteins in these pathways, and immunofluorescence was used to analyze their localization and co-expression patterns in tissues, thereby elucidating the mechanism of Wumeiwan from multiple biological dimensions. ResultsCompared with the blank group, mice in the model group exhibited a significant decrease in body weight and a significant increase in the disease activity index(DAI) score(P<0.05), with pronounced colonic mucosal damage accompanied by aggravated tumor invasion. Compared with the model group, Wumeiwan intervention markedly improved body weight loss and reduced DAI score, attenuated mucosal injury, and significantly decreased VEGF expression level(P<0.05). Multi-omics analysis revealed that differential metabolites and genes across groups were commonly enriched in fatty acid metabolism, fatty acid biosynthesis, and other lipid-related pathways. Relative to the blank group, the model group showed significant upregulation levels of fatty acid synthesis-related genes, including sterol regulatory element-binding protein 1(SREBP1), fatty acid synthase(FASN), stearoyl-CoA desaturase 1(SCD1), as well as saturated fatty acids(P<0.05). Compared with the model group, treatment with Wumeiwan significantly reduced the expression of key genes involved in fatty acid metabolic pathways, including SREBP1, FASN, and SCD1(P<0.05). Western blot results further confirmed that proteins in this pathway were significantly elevated in the model group, whereas they were markedly downregulated following Wumeiwan treatment(P<0.05). Immunofluorescence analysis demonstrated enhanced co-localization of SREBP1 with the cancer-associated fibroblast(CAF) marker α-smooth muscle actin(SMA) in the model group, whereas this co-localization signal was attenuated after Wumeiwan intervention(P<0.05). ConclusionWumeiwan can improve survival outcomes and alleviate colonic pathological damage in CRC mice, its therapeutic mechanism may be closely associated with the regulation of fatty acid metabolic reprogramming mediated by the SREBP1/FASN/SCD1 signaling pathway.
3.Clinical Observation of Anshen Buxin Gao in Treating Coronary Heart Disease Complicated with Somatization Disorder After PCI
Yaozhong ZHOU ; Yanzhe WANG ; Wan CAI ; Wenjuan CAI ; Yan SHAO ; Yi SHEN ; Yan WANG ; Qiusheng SHEN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(13):197-204
ObjectiveTo observe the clinical efficacy of Anshen Buxin Gao in patients with coronary artery disease (CAD) complicated with somatization disorder after percutaneous coronary intervention (PCI), as well as its effect on heart rate variability (HRV). MethodsA total of 96 patients with somatization disorder after PCI were selected and randomized into control and treatment groups (48 cases). On the basis of standardized Western medical treatment for CAD, the control group received Dailixin, while the treatment group received Dailixin combined with Anshen Buxin Gao. The somatic symptom scale (SSS), generalized anxiety disorder 7-item scale (GAD-7), patient health questionnaire-9 (PHQ-9), and self-rating scale of sleep (SRSS) scores in both groups were recorded before and after treatment. The traditional Chinese medicine symptom efficacy, HRV, and incidence of adverse drug reactions were observed. ResultsA total of 90 patients completed the trial, encompassing 45 patients in the control group and 45 patients in the treatment group. Baseline characteristics between the two groups showed no statistically significant differences, indicating comparability. After treatment, both groups exhibited reductions in SSS, GAD-7, and PHQ-9 scores (P<0.05), and the treatment group outperformed the control group in alleviating somatic symptoms and anxiety-depression symptoms (P<0.05). The control group did not achieve a significant reduction in SRSS score, whereas the treatment group effectively lowered the SRSS score (P<0.05). Regarding traditional Chinese medicine symptom efficacy, the total response rate in the treatment group was 91.1% (41/45), which was higher than that (71.1%, 32/45) in the control group (Z=-2.663, P<0.05). Both groups improved HRV in patients with somatization disorder, and the treatment group showed greater improvement (P<0.05). There were no serious clinical adverse events during the study period. The incidence of adverse reactions in the treatment group was 6.7% (3/45), which was lower than that (14/45, 31.10%) in the control group (χ2=7.252, P<0.05). ConclusionThe addition of Anshen Buxin Gao to Dailixin therapy significantly alleviates the clinical symptoms and improves the sleep quality, treatment efficacy, and HRV in patients with CAD complicated with somatization disorder after PCI, while reducing the adverse effects associated with Dailixin alone. This approach demonstrates considerable clinical value and warrants further promotion.
4.Effect of Tuina at "Weizhong (BL 40)" on Spinal Microglial Activation-related Proteins and the IL-10/β-EP Pathway in a Rat Model of Chronic Sciatic Nerve Compression Injury
Tianwei ZHANG ; Xiangqian LYU ; Yani XING ; Liuchen ZHU ; Qingguang ZHU ; Lingjun KONG ; Yanbin CHENG ; Zhen YAN ; Wuquan SUN ; Min FANG ; Zhiwei WU
Journal of Traditional Chinese Medicine 2025;66(7):734-740
ObjectiveTo investigate the analgesic effect of Tuina at the "Weizhong (BL 40)" on neuropathic pain in a rat model of chronic constriction injury (CCI) of the sciatic nerve and its potential central spinal mechanisms. MethodsThirty-two Sprague-Dawley rats were randomly divided into four groups (8 rats in each group), sham-operated group, model group, Tuina group, and blockade group. The CCI model was established in the model group, Tuina group, and the blockade group by ligating the sciatic nerve with catgut, while the sham-operated group underwent only sciatic nerve exposure without ligation. From postoperative day 4 to day 14, rats in the Tuina group and the blockade group received Tuina manipulation at the "Weizhong (BL 40)" using a dynamic pressure distribution measurement system (5 N pressure, 2 Hz frequency, 10 min per session, once daily). The blockade group also received intraperitoneal injections of the microglial inhibitor minocycline (10 mg/kg) once daily. The sham-operated and the model group underwent the same handling and fixation as the Tuina group without actual Tuina. Mechanical withdrawal threshold (MWT) and paw withdrawal latency (PWL) were measured before surgery and on day 3, 7, 10, and 14 post-surgery. Transmission electron microscopy was used to evaluate sciatic nerve injury and repair, measuring axon diameter and total myelinated fiber diameter to calculate the g-ratio. Western Blotting was performed to detect the protein levels of ionized calcium-binding adapter molecule 1 (Iba-1), CD206, CD68, interleukin-10 (IL-10), and β-endorphin (β-EP) precursor pro-opiomelanocortin (POMC) in the ipsilateral spinal dorsal horn. ResultsCompared with the sham-operated group, the model group showed significantly reduced MWT and PWL on day 3, 7, 10, and 14 (P<0.01). Compared with the model group, the Tuina group and the blockade group showed increased MWT and PWL on day 10 and 14 (P<0.05). Compared with the Tuina group, the blockade group exhibited higher MWT on day 7, 10, and 14, and higher PWL on day 10 (P<0.05). Sciatic nerve pathological morphology revealed intact and well-structured myelin in the sham-operated group, while the model group exhibited myelin collapse, distortion, and myelin ovoid formation. The Tuina group displayed partially irregular myelin with occasional myelin collapse, whereas the blockade group exhibited partial myelin irregularities and phospholipid shedding. Compared with the sham-operated group, the model group showed a decreased g-ratio and increased levels of Iba-1 and CD68 in the spinal dorsal horn (P<0.05 or P<0.01). Compared with the model group, the Tuina group and the blockade group exhibited an increased g-ratio and reduced Iba-1 and CD68 levels. Additionally, the Tuina group showed elevated levels of CD206, IL-10, and POMC, whereas the blockade group had decreased CD206 levels (P<0.05). ConclusionTuina at "Weizhong (BL 40)" alleviates neuropathic pain in CCI rats, potentially by regulating microglial activation in the spinal cord, inhibiting M1 polarization while promoting M2 polarization, and activating the IL-10/β-EP pathway to exert analgesic effects.
5.Diagnosis and Treatment of Cough Associated with Interstitial Lung Disease from Collaterals Deficiency with Latent Wind
Fang SUN ; Shiqi SUN ; Yan XUE ; Wei ZHANG
Journal of Traditional Chinese Medicine 2025;66(10):1057-1059
It is believed that the basic mechanism of cough associated with interstitial lung disease is collaterals deficiency with latent wind: the deficiency of the lung organs and lung collaterals is the basis of its pathogenesis, and latent wind in lung collaterals is the key mechanism of the cough which is difficult to cure. Treatment is based on the principle of supplementing deficiency and treating wind, dispelling the pathogens and unblocking the collaterals. Supplementing deficiency should supplement lungs, boost kidneys, and strengthen spleens to consolidate the root and banking up the origin, and regulate and tonify the lung collaterals; dispelling the pathogens should treat the internal and external winds at the same time, and taking into account the combined pathogens of phlegm, stasis and dampness to clear the stagnation of the lung collaterals.
6.Influence of Local Tumor Factors and Radiotherapy Dose on Prognosis of Clinical Stage T1-4N0M0 Esophageal Squamous Cell Carcinoma
Yan KONG ; Qian DONG ; Shuguang LI ; Jinrui XU ; Xiaohan ZHAO ; Wenzhao DENG ; Wenbin SHEN
Cancer Research on Prevention and Treatment 2025;52(3):225-232
Objective To investigate the effect of different radiotherapy doses on the prognosis of patients with stage cT1-4N0M0 esophageal squamous cell carcinoma(ESCC)who received radical radio(chemo)therapy categorized into subgroups with different tumor local factors.Methods A retrospective analysis was conducted on 256 patients with clinically nonmetastatic esophageal squamous cell carcinoma.The optimal cutoff for tumor local factors was determined.The relationship between latest treatment efficacy and tumor local factors was analyzed,and independent indicators affecting patient overall survival(OS)were examined using multivariate analysis.The subgroup analysis was performed to determine the correlation between selected factors and radiation therapy doses.Results The shorter the X-ray length of esophageal tumor lesion and the smaller the lesion canal wall thickness and gross tumor volume(GTV),the better the latest treatment efficacy of the patients(χ2=9.066,10.310,15.661,respectively,P=0.011,0.006,P<0.001).Multivariate analysis results showed that GTV(P<0.001),radiation dose(P=0.038),and latest treatment efficacy(P<0.001)were independent predictors of the patients'OS,and the latter two were also independent predictors of the patients'progression-free survival(PFS)(P=0.033,<0.001).Subgroup analysis further showed that high doses of radiotherapy(over 60 Gy)resulted in good OS(χ2=5.040,4.588,5.400,P=0.025,0.032,0.020)and PFS(χ2=6.089,4.353,6.459,P=0.014,0.037,0.011)in the subgroup with maximum wall thickness below 3.7 cm,with esophageal lesions with GTV below 37.34 cm3,or not receiving simultaneous chemotherapy.Conclusion Local tumor factors are important prognostic factors of ESCC patients treated with radical radio(chemo)therapy.Patients with thin lesion walls and small tumor volumes may greatly benefit from high doses of radiation(over 60 Gy).
7.Effect of the treatment sequence of chemoradiotherapy combined with immunotherapy as first-line therapy on the prognosis of patients with stage III non-small cell lung cancer
Shuguang LI ; Jinrui XU ; Luanying WU ; Jingyuan WEN ; Xiaohan ZHAO ; Chunyang SONG ; Ke YAN ; Youmei LI ; Shuchai ZHU ; Wenbin SHEN
Chinese Journal of Radiation Oncology 2025;34(12):1191-1198
Objective:To investigate the impact of different treatment sequences of immunotherapy combined with chemoradiotherapy (CRT) as the first-line therapy on the prognosis of patients with stage III non-small cell lung cancer (NSCLC).Methods:Clinical data of 112 patients with stage III NSCLC treated at the Fourth Hospital of Hebei Medical University from January 2019 to December 2021 were retrospectively collected, with follow-up continued until December 31, 2023. According to the sequence of CRT and immune checkpoint inhibitors (ICIs) therapy, patients were divided into 3 groups: ICIs simultaneous with CRT (sICR, n=20), chemotherapy combined with ICIs followed by CRT (CI-CR, n=53), and CRT followed by consolidative ICIs (CR-I, n=39). Analyses were performed before and after propensity score matching (PSM). Survival outcomes were assessed using the Kaplan-Meier method and compared by log-rank tests, and prognostic factors were identified through multivariate Cox regression analysis. Results:The median overall survival (OS) and progression-free survival (PFS) for the entire cohort were 30.1 months (95% CI: 21.4-38.9) and 12.8 months (95% CI: 9.14-16.1), respectively. Before PSM: No significant differences were observed in OS and PFS among the 3 groups ( χ2=0.18, 1.05; P=0.669, 0.305). However, OS in the sICR and CR-I groups was significantly better than that in the CI-CR group ( χ2=4.43, 6.11; P=0.035, 0.013). After PSM: Each group included 17 patients. There were no significant differences in OS or PFS among the 3 groups ( χ2=2.50, 2.74; P=0.287, 0.254), and pairwise comparisons also showed no significant differences. Multivariate Cox regression analysis revealed that clinical stage ( HR=3.392, 95% CI: 1.215-9.470, P=0.020), number of immunotherapy cycles ( HR=0.312, 95% CI: 0.100-0.972, P=0.044), and treatment response ( HR=6.566, 95% CI: 1.705-25.284, P=0.006) were independent prognostic factors for OS. After PSM, the numbers of patients with grade ≥2 treatment-related adverse events were 13 in the sICR group, 10 in the CI-CR group, and 9 in the CR-I group, with no significant differences among them ( χ2=2.181, P=0.336). Conclusions:First-line immunotherapy combined with chemoradiotherapy showed favorable clinical efficacy in locally advanced NSCLC compared to other studies, but the treatment sequence did not significantly affect prognosis. It is recommended that immunotherapy be administered for at least four cycles.
8.Guideline for Adult Weight Management in China
Weiqing WANG ; Qin WAN ; Jianhua MA ; Guang WANG ; Yufan WANG ; Guixia WANG ; Yongquan SHI ; Tingjun YE ; Xiaoguang SHI ; Jian KUANG ; Bo FENG ; Xiuyan FENG ; Guang NING ; Yiming MU ; Hongyu KUANG ; Xiaoping XING ; Chunli PIAO ; Xingbo CHENG ; Zhifeng CHENG ; Yufang BI ; Yan BI ; Wenshan LYU ; Dalong ZHU ; Cuiyan ZHU ; Wei ZHU ; Fei HUA ; Fei XIANG ; Shuang YAN ; Zilin SUN ; Yadong SUN ; Liqin SUN ; Luying SUN ; Li YAN ; Yanbing LI ; Hong LI ; Shu LI ; Ling LI ; Yiming LI ; Chenzhong LI ; Hua YANG ; Jinkui YANG ; Ling YANG ; Ying YANG ; Tao YANG ; Xiao YANG ; Xinhua XIAO ; Dan WU ; Jinsong KUANG ; Lanjie HE ; Wei GU ; Jie SHEN ; Yongfeng SONG ; Qiao ZHANG ; Hong ZHANG ; Yuwei ZHANG ; Junqing ZHANG ; Xianfeng ZHANG ; Miao ZHANG ; Yifei ZHANG ; Yingli LU ; Hong CHEN ; Li CHEN ; Bing CHEN ; Shihong CHEN ; Guiyan CHEN ; Haibing CHEN ; Lei CHEN ; Yanyan CHEN ; Genben CHEN ; Yikun ZHOU ; Xianghai ZHOU ; Qiang ZHOU ; Jiaqiang ZHOU ; Hongting ZHENG ; Zhongyan SHAN ; Jiajun ZHAO ; Dong ZHAO ; Ji HU ; Jiang HU ; Xinguo HOU ; Bimin SHI ; Tianpei HONG ; Mingxia YUAN ; Weibo XIA ; Xuejiang GU ; Yong XU ; Shuguang PANG ; Tianshu GAO ; Zuhua GAO ; Xiaohui GUO ; Hongyi CAO ; Mingfeng CAO ; Xiaopei CAO ; Jing MA ; Bin LU ; Zhen LIANG ; Jun LIANG ; Min LONG ; Yongde PENG ; Jin LU ; Hongyun LU ; Yan LU ; Chunping ZENG ; Binhong WEN ; Xueyong LOU ; Qingbo GUAN ; Lin LIAO ; Xin LIAO ; Ping XIONG ; Yaoming XUE
Chinese Journal of Endocrinology and Metabolism 2025;41(11):891-907
Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.
9.The role of gut microbiota homeostasis in the occurrence and development of hepatocellular carcinoma and targeted intervention strategies
Yan CUI ; Junzhe JIAO ; Ruijuan YAN ; Shuguang YAN ; Hailiang WEI ; Zhanjie CHANG ; Haibo ZHANG ; Jingtao LI
Journal of Clinical Hepatology 2025;41(9):1913-1919
Hepatocellular carcinoma (HCC), as the sixth most common malignant tumor worldwide, poses a serious threat to human health due to its insidious onset and high mortality rate. This article reviews the molecular mechanisms and intervention strategies of gut microbiota (GM) homeostasis in the development and progression of HCC, in order to provide new ideas for the intervention and treatment of HCC. Studies have shown that GM dysbiosis, intestinal leakage, microbial-associated molecular pattern, bacterial translocation, and metabolic products play key roles in the progression of HCC. GM imbalance may lead to immune escape, thereby promoting tumor cell proliferation and metastasis. This article elaborates on the association between GM and HCC, deeply analyzes the mechanism of action of GM in the development and progression of HCC, investigates the role of bile acid-related metabolites, short-chain fatty acid-related metabolites, and other metabolites in HCC, and explores the strategies for targeting GM in the treatment of HCC, including probiotics, prebiotics, antibiotics, Toll-like receptor 4 antagonists, and fecal microbiota transplantation. This article emphasizes that maintaining the integrity of the intestinal barrier and GM homeostasis is of great significance in the prevention and treatment of HCC, which provides a direction for developing new diagnosis and treatment strategies.
10.Quality control protocol for adult overweight and obesity screening in health management (examination) institutions (2025 edition)
Jianling FAN ; Tiejun WANG ; Pengfei YANG ; Keke DING ; Xiaoning HAO ; Sunfang JIANG ; Ankang LÜ ; Jianping LU ; Sheng RONG ; Weibin SHI ; Shengwei SUN ; Yan TAN ; Qilei TU ; Zhiping WANG ; Bing WANG ; Jianyun WANG ; Weijian WANG ; Yan WANG ; Qun XU ; Chenli ZHANG ; Fan ZHANG ; Ping ZHANG ; Yansong ZHENG ; Jieru ZHOU ; Dan CHEN ; Jiaoyang ZHENG
Chinese Journal of Clinical Medicine 2025;32(6):1097-1111
Obesity, as a chronic recurrent disease, has become a major public health challenge in China. To implement the requirements of the Healthy China Initiative (2019—2030), under domestic guidelines or consensus statements on overweight and obesity, and in alignment with the latest scientific advances globally, the Quality control protocol for adult overweight and obesity screening in health management (examination) institutions (2025 edition) was developed. This protocol was drafted by the Health Management Center of Shanghai Changzheng Hospital and formulated through multiple rounds of deliberation by experts in China’s health examination quality control field. The protocol establishes unified standards for screening facilities, personnel qualifications, and measurement or testing procedures. It defines specific screening items, outlines a standardized screening pathway, and sets requirements for the final medical review, ensuring the scientific validity, effectiveness, and safety of the screening process. The implementation of this protocol will enhance the consistency of weight management practices for adults across health examination institutions and strengthen the quality control of overweight and obesity screening programs.

Result Analysis
Print
Save
E-mail