1.Mechanism of Huanglian Wendantang on Damp-heat Type Diabetes Enteropathy Rats Based on TGR5/GLP-1 Signaling Pathway and Intestinal Flora
Yujin WANG ; Yulong QIE ; Hua JIANG ; Chen YUAN ; Xirui DENG ; Xuelian MENG ; Wenli WANG ; Yanjin SU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(15):10-18
ObjectiveTo explore the mechanism of Huanglian Wendantang on damp-heat type diabetes enteropathy rats based on the G protein coupled bile acid receptor 5/glucagon like peptide-1 (TGR5/GLP-1) signaling pathway and intestinal flora. MethodsA total of 72 male Sprague Dawley (SD) rats were adaptively fed for one week. Twelve SD rats were randomly selected as a blank group and fed with an ordinary diet. The rest of the SD rats were fasted for 12 hours without water. A rat model with damp-heat type diabetes enteropathy was made by left intraperitoneal injection of streptozotocin (55 mg·kg-1) and high sugar and high fat diet (20% sucrose solution + high fat diet) in a humid and hot environment (artificial climate box: temperature 30-34 ℃, relative humidity: 85%-95%). After successful modeling, the rats were randomly divided into a model group, a metformin group (200 mg·kg-1), low-dose, medium-dose, and high-dose Huanglian Wendantang groups (7.10, 14.20, 28.39 g·kg-1), with 12 rats in each group. The normal group and the model group were orally administered with physiological saline once a day for 6 consecutive weeks. During the observation period, the weight and blood glucose levels of rats were measured and recorded weekly. After the administration, fresh feces were collected from rats, and 16S rRNA sequencing technology was used to study the differences and changes in intestinal flora among different groups. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the serum of rats were detected by enzyme-linked immunosorbent assay (ELISA), and the pathological morphological changes of colon tissue were examined. The expression of TGR5 and GLP-1 in colon tissue was detected by immunohistochemistry, and the expression of TGR5 and GLP-1 proteins in colon tissue was measured by Western blot. ResultsCompared with the blank group, the model group showed a decrease in body weight, an increase in blood glucose, and significant damp-heat symptoms. The levels of IL-6 and TNF-α in serum were significantly increased (P<0.01). The expression of TGR5 and GLP-1 was decreased (P<0.01), and the pathogenic bacteria were increased. Compared with the model group, the treatment groups exhibited improvements in body weight, blood glucose levels, and damp-heat syndrome in rats. Among them, the high-dose group of Huanglian Wendantang displayed the most significant improvement effect, with significantly reduced inflammation levels (P<0.01) and elevated expression of TGR5 and GLP-1 (P<0.01). Colonic pathological sections showed that Huanglian Wendantang could effectively ameliorate colonic pathological changes. The 16S rRNA sequencing result indicated a significant increase in beneficial bacteria in the treatment groups. ConclusionHuanglian Wendantang can effectively ameliorate the damp-heat symptoms and blood glucose levels in rats with damp-heat type diabetes enteropathy, and it may exert an effect by regulating the TGR5/GLP-1 signaling pathway and intestinal flora disorder.
2.Baihe Wuyaotang Ameliorates NAFLD by Enhancing mTOR-mediated Liver Autophagy
Rui WANG ; Tiantian BAN ; Lihui XUE ; Xinyi FENG ; Jiyuan GUO ; Jiaqi LI ; Shenghe JIANG ; Xiaolei HAN ; Baofeng HU ; Wenli ZHANG ; Naijun WU ; Shuang LI ; Yajuan QI
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(7):66-77
ObjectiveTo investigate the therapeutic effect of Baihe Wuyaotang (BWT) on non-alcoholic fatty liver disease (NAFLD) and elucidate its underlying mechanism. MethodC57BL/6J mice were randomly assigned to six groups: normal control, model, positive drug (pioglitazone hydrochloride 1.95×10-3 g·kg-1), and low-, medium-, and high-dose BWT (1.3,2.5 and 5.1 g·kg-1). Following a 12-week high-fat diet (HFD) inducement, the mice underwent six weeks of therapeutic intervention with twice-daily drug administration. Body weight was monitored weekly throughout the treatment period. At the fifth week, glucose tolerance (GTT) and insulin tolerance (ITT) tests were conducted. Subsequently, the mice were euthanized for the collection of liver tissue and serum, and the subcutaneous adipose tissue (iWAT) and epididymal adipose tissue (eWAT) were weighed. Serum levels of total triglycerides (TG) and liver function indicators,such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were determined. Histological examinations, including oil red O staining, hematoxylin-eosin (HE) staining, Masson staining, and transmission electron microscopy, were performed to evaluate hepatic lipid deposition, pathological morphology, and ultrastructural changes, respectively. Meanwhile, Western blot and real-time quantitative polymerase chain reaction (Real-time PCR) were employed to analyze alterations, at both gene and protein levels, the insulin signaling pathway molecules, including insulin receptor substrate 1/2/protein kinase B/forkhead box gene O1 (IRS1/2/Akt/FoxO1), glycogen synthesis enzymes phosphoenolpyruvate carboxy kinase (Pepck) and glucose-6-phosphatase (G6Pase), lipid metabolism-related genes stearoyl-coA desaturase-1 (SCD-1) and carnitine palmitoyltransferase-1 (CPT-1), fibrosis-associated molecules α-smooth muscle actin (α-SMA), type Ⅰ collagen (CollagenⅠ), and the fibrosis canonical signaling pathway transforming growth factor-β1/drosophila mothers against decapentaplegic protein2/3(TGF-β1/p-Smad/Smad2/3), inflammatory factors such as interleukin(IL)-6, IL-8, IL-11, and IL-1β, autophagy markers LC3B Ⅱ/Ⅰ and p62/SQSTM1, and the expression of mammalian target of rapamycin (mTOR). ResultCompared with the model group, BWT reduced the body weight and liver weight of NAFLD mice(P<0.05, P<0.01), inhibited liver lipid accumulation, and reduced the weight of white fat: it reduced the weight of eWAT and iWAT(P<0.05, P<0.01) as well as the serum TG content(P<0.05, P<0.01). BWT improved the liver function as reflected by the reduced ALT and AST content(P<0.05, P<0.01). It improved liver insulin resistance by upregulating IRS2, p-Akt/Akt, p-FoxO1/FoxO1 expressions(P<0.05). Besides, it improved glucose and lipid metabolism disorders: it reduced fasting blood glucose and postprandial blood glucose(P<0.05, P<0.01), improved GTT and ITT(P<0.05, P<0.01), reduced the expression of Pepck, G6Pase, and SCD-1(P<0.01), and increased the expression of CPT-1(P<0.01). The expressions of α-SMA, Collagen1, and TGF-β1 proteins were down-regulated(P<0.05, P<0.01), while the expression of p-Smad/Smad2/3 was downregulated(P<0.05), suggesting BWT reduced liver fibrosis. BWT inhibited inflammation-related factors as it reduced the gene expression of IL-6, IL-8, IL-11 and IL-1β(P<0.01) and it enhanced autophagy by upregulating LC3B Ⅱ/Ⅰ expression(P<0.05)while downregulating the expression of p62/SQSTM1 and mTOR(P<0.05). ConclusionBWT ameliorates NAFLD by multifaceted improvements, including improving IR and glucose and lipid metabolism, anti-inflammation, anti-fibrosis, and enhancing autophagy. In particular, BWT may enhance liver autophagy by inhibiting the mTOR-mediated signaling pathway.
3.Rehabilitation effects of psychomotor therapy on young and middle-aged schizophrenic inpatients
Haiyun LI ; Liang MING ; Daojin WANG ; Wenli ZHU ; Xiumei WU ; Yuan PAN ; Tingting JIANG
Sichuan Mental Health 2024;37(2):114-119
BackgroundRehabilitation for schizophrenia typically relies on pharmacological interventions, yet their efficacy in improving social function and quality of life remains limited. In recent years, non-pharmacological approaches have shown promise in enhancing rehabilitation outcomes. However, research on the effectiveness of psychomotor therapy specifically for young and middle-aged schizophrenic inpatients is limited. ObjectiveTo explore the effects of psychomotor therapy on the rehabilitation of young and middle-aged schizophrenic inpatients, and to provide a reference for treatment strategies. MethodsA total of 104 young and middle-aged schizophrenic inpatients who met the International Classification of Diseases,tenth edition (ICD-10) diagnostic criteria and hospitalized in the Fourth People's Hospital of Wuhu from June 2021 to June 2022 were selected. Patients were randomly divided into two groups of 52 each using random number table method. Both groups received treatment with risperidone tablets (2~4 mg/d) , along with routine nursing care. Additionally, the research group received an extra 45~55 minutes of psychomotor therapy 2~3 times per week for 12 weeks. The control group received the same psychomotor therapy after the study. Positive and Negative Symptom Scale (PANSS), Scales of Social-skills for Psychiatric Inpatient (SSPI) and Insight and Treatment Attitude Questionnaire (ITAQ) were used to assess the patients before the intervention and at 4th, 8th and 12th week after the intervention. ResultsThe main effects of intervention at different time points for PANSS positive symptoms, negative symptoms and general psychopathology subscale scores, PANSS total score, SSPI score and ITAQ score were all statistically significant (F=33.989, 204.245, 82.817, 279.596, 26.144, 7.463, P<0.01). Furthermore, statistically significant between-group differences were observed in PANSS negative symptoms and general psychopathology subscale scores, PANSS total score, SSPI score and ITAQ score (F=30.053, 5.306, 33.417, 33.013, 18.608, P<0.05 or 0.01). Moreover, the interaction effect of time and group were statistically significant for PANSS positive symptoms, negative symptoms and general psychopathology subscale score, PANSS total score and SSPI score (F=3.472, 9.798, 3.843, 14.390, 20.661, P<0.05 or 0.01). After 12 weeks of intervention, the research group exhibited statistically significantly lower PANSS total score and subscale scores compared with baseline (P<0.01), while their SSPI total score was significantly higher than that of control group(P<0.01). Additionally, compared with the control group, the research group had statistically significantly lower PANSS total score and subscale scores , while their SSPI score was statistically significantly higher than those of control group(P<0.01). ConclusionPsychomotor therapy may contribute to the improvement of the psychiatric symptoms and social function in young and middle-aged inpatients with schizophrenia, enhancing their rehabilitation outcomes. [Funded by Health Commission Scientific Research Project of Wuhu (number, WHWJ2021y073)]
4.Trends in prevalence and disability-adjusted life years of cataract in China from 1990 to 2019
Wenli CHEN ; Yi XU ; Congcong JIANG ; Ziya LIU ; Jing ZHAO
International Eye Science 2024;24(2):182-188
AIM:To assess the evolving burden of cataracts in China from 1990 to 2019.METHODS: Data on disease burden related to cataracts in China were retrieved from the Global Burden of Disease(GBD)2019 study based on large public databases. Utilizing data from the GBD 2019 study, we extracted information on cataract-related disease burden in China from extensive public databases. Analysis of prevalence and disability-adjusted life years(DALYs)associated with cataracts in China was conducted based on GBD 2019 findings. The variable characteristics of age-standardized prevalence rates(ASPR)and age-standardized DALYs rates(ASDR)in China and its neighboring countries were also explored.RESULTS: Between 1990 and 2019, the number of prevalent cases of blindness and vision loss caused by cataracts in China increased by 223.54%, and the corresponding DALYs raised by 142.14%. Over the past 30 years, females exhibited higher age-standardized prevalence and DALYs rates compared to males. Meanwhile, individuals aged 65 to 84 years were found to be more susceptible to cataracts than other age groups. Compared with neighboring countries, China ranked from the 9th position in 1990(867.09, 95%UI: 761.36 to 975.42, per 100 000 population)to the 11th in 2019(991.56, 95%UI: 861.52 to 1131.04, per 100 000 population)in ASPR, while from the 9th in 1990(65.85, 95%UI: 46.39 to 89.41, per 100 000 population)to the 10th position in 2019(59.16, 95%UI: 41.70 to 80.15, per 100 000 population)in ASDR. However, on a global scale, China maintained relatively low ASDR and ASPR for cataracts in 2019.CONCLUSION: The study highlights a substantial rise in the prevalence and DALYs associated with blindness and vision loss due to cataracts from 1990 to 2019 in China, and underscores the urgent need for increased early screening of cataracts, particularly among the elderly and females.
5.Effect of Tibetan Medicine Zuomaoxing with Different Origins and Characteristics on Rats with Pattern of Toxic Heat-induced Blood Stasis
Maohua YUAN ; Jing TAO ; Bixing GAO ; Jieyu SUN ; Diandian KANG ; Wenli CHEN ; Rui GU ; Guihua JIANG
Chinese Journal of Modern Applied Pharmacy 2024;41(5):599-605
OBJECTIVE
To investigate the effects of 3 different primitives or the same primitives with different characters of Tibetan medicine Zuomoxing[Caragana changduenais Liou f. with red heartwood, Caragana jubata(Pall.) Poir. with brown and white heartwood] on rats with pattern of toxic heat-induced blood stasis. METHODS Ninety SD rats were randomly divided into the blank group, model group, aspirin-positive group, Changdu low-dose group(CDD), Changdu high-dose group(CDG), whitewood of Guijian low-dose group(GJBD), whitewood of Guijian high-dose group(GJBG), brown wood of Guijian low-dose group(GJZD), Brown wood of Guijian high-dose group(GJZG). Models with heat toxicity and blood stasis pattern were established by intraabdominal injection of carrageenan combined with tail vein injection of lipopolysaccharide. The effects of each group on blood rheology, coagulation four indices and blood routine were determined, and the content of arachidonic acid(AA), IL-1β, IL-6, TNF-α and thromboxane B2(TXB2) were measured with ELISA.
RESULTS
①Blood rheology: Compared with model group, CDD and CDG significantly decreased whole blood viscosity(WBV), reduction viscosity of whole blood(WBRV), erythrocyte rigidity index(HGX), erythrocyte deformability index(EDI), whole blood relative index(WBRI) (P<0.01), and increased plasma viscosity(P<0.01). GJZG and GJZD significantly decreased HGX(P<0.01 or P<0.05), and increased plasma viscosity(P<0.01). GJBG and GJBG significantly decreased WBHSV, WBHSRV, HGX, EDI, and whole blood high shear relative index(WBHSRI)(P<0.01). ②Coagulation four indices: Compared with model group, CDD significantly reduced the thrombin time(TT)(P<0.01). GJZG significantly reduced activated partial thromboplastin time(APTT) and TT(P<0.01 or P<0.05). GJBD significantly reduced prothrombin time(PT) and APTT (P<0.01 or P<0.05). ③Blood routine: Compared with model group, GJZD and GJBD significantly decreased the percentage of monocytes(P<0.01 or P<0.05). The number of large platelets in CDD significantly increased(P<0.05). CDG significantly increased the platelet number, platelet hematocrit, and large platelet number(P<0.01 or P<0.05), and tended which to be normal. ④Inflammatory factors: Compared with model group, the levels of TNF-α, IL-6, TXB2 were significantly increased in CDD and CDG(P<0.01 or P<0.05). The levels of IL-6 and TXB2 were significantly increased in GJZD and GJZG(P<0.01). GJBD was significantly increased TXB2(P<0.01), and GJBG was significantly increased IL-1β, IL-6, and TXB2(P<0.01), while decreased AA(P<0.05).
CONCLUSION
Zuomoxing with separate sources have different degrees of effects on rats with pattern of toxic heat-induced blood stasis, and have different degrees of effects on hemorheology, coagulation factors, blood routine and inflammatory mediators, and the degree and trend of effects are different with different doses. The effect of promoting blood circulation and removing blood stasis was generally manifested as Changdu > whitewood of Guijian > Brown wood of Guijian. The effect of promoting blood circulation and removing blood stasis may be the result of multiple pathways and mechanisms.
6.Retrospective analysis of 62 cases who received clinical application of artificial temporomandibular joint
Peng WANG ; Yao LIU ; Nan JIANG ; Ruiye BI ; Pinyin CAO ; Wenli ZHAO ; Mingjun REN ; Songsong ZHU
Chinese Journal of Stomatology 2024;59(10):1014-1018
Objective:To conduct a retrospective study on the treatment outcomes of patients who underwent artificial temporomandibular joint (TMJ) replacement surgery and to evaluate the effectiveness of artificial TMJ treatment.Methods:This study selected 62 patients who received standard Biomet artificial TMJ treatment at Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University from May 2010 to September 2023 as the study subjects. Among them, there were 15 male patients and 47 female patients. The average age was 33.5 years old(ranging from 18 to 67 years). This study statistically analyzed postoperative indicators, including maximum mouth opening, forward jaw movement, lateral movement, postoperative pain scores, and patient satisfaction.Results:This study included a total of 62 patients with 99 TMJ joints. No infections occurred postoperatively. The average follow-up period was 33.7 months (ranging from 7 to 170 months). At 6 months postoperatively, the mean mouth opening was (36.1±6.2) mm, lateral movement was (2.1±0.9) mm, and forward jaw movement was (1.0±0.9) mm. The pain visual analog scale score at 6 months postoperatively was (2.8±0.6), and patient satisfaction with the surgery was (8.8±1.1). Spiral CT scans conducted after surgery showed no joint dislocation or migration, and the artificial joint remained stable during the follow-up period.Conclusions:Artificial TMJ replacement is a valuable method for effectively restoring TMJ structure and essential functions related to mouth opening and chewing. It is worthy of promotion as a reconstructive approach for the temporomandibular joint
7.Research progress on quality control methods of traditional Chinese medicine based on artificial intelligence sense technology
Rulan JIANG ; Jieyu LEI ; Wenli CHEN ; Xinjun XU
China Pharmacist 2024;28(11):550-556
In order to further promote and achieve the modernization of traditional Chinese medicine,it is particularly important to establish a quality control system of traditional Chinese medicine which not only respects the theory of traditional Chinese medicine but also conforms to the development of the times.Since ancient times,the appearance character of traditional Chinese medicine,such as color,gas and taste,is one of the important criteria to distinguish its authenticity and quality.At present,the research on the appearance of traditional Chinese medicine has gradually shifted from subjective"evaluation of quality from appearance traits"to artificial intelligence sensory technology which can provide objective data support.According to the different simulated senses,intelligent sensory technology can be divided into electronic eyes,electronic nose,electronic tongue,electronic ear and electronic skin.This paper combs the principles of five kinds of artificial intelligence sensory technology and their application in the quality evaluation of traditional Chinese medicine,introduces the research status and future development trend of the quality control system of traditional Chinese medicine based on intelligent sense,in order to provide a reference for the upgrade and modern development of the quality control system of traditional Chinese medicine.
8.Quality evaluation of total flavonoids of Lamiophlomis rotata from different producing areas
Ruixin CHEN ; Yunbin JIANG ; Wenli CHEN ; Diandian KANG ; Rui LI ; Guihua JIANG
China Pharmacy 2023;34(4):419-422
OBJECTIVE To evaluate the quality of total flavonoids of Lamiophlomis rotata from different producing areas. METHODS Total flavonoids of S1-S15 batches of L. rotata from different producing areas were extracted by percolation and purified by polyamide column. The content of total flavonoids was determined by UV spectrophotometry, and its purity was calculated. HPLC fingerprint chromatograms and control fingerprint of total flavonoids from 15 batches of L. rotata were established with Similarity Evaluation System of Chromatographic Fingerprint of TCM (2012 version). Their similarities were analyzed. Cluster analysis, principal component analysis and orthogonal partial least squares-discriminant analysis were used to evaluate the quality of total flavonoids from 15 batches of L. rotata, and the main components which affected the quality of total flavonoids were analyzed. RESULTS The purities of total flavonoids from 15 batches of L. rotata were 55.82%-94.12%, with an average value of 77.72%; a total of five common peaks were identified in the fingerprint, and No. 3 peak was luteolin; the similarities between the fingerprint of each batch of samples and the control fingerprint were 0.925-1.000. By cluster analysis, S1 and S3-S9 were clustered into the first class, which were samples from Qinghai Province and Tibet Autonomous Region. S14 and S15 were clustered into the second class, which were samples from Yunnan Province. S10-S13 were clustered into the third class, which were all samples from Sichuan Province. S2 was clustered into the fourth class. The principal component analysis showed that the qualities of samples from the first and fourth classes were better; peaks 2, 3 and 5 were identified as the main components that caused the differences among different batches of samples by orthogonal partial least squares-discriminant analysis. CONCLUSIONS The qualities of total flavonoids of L. rotata from Qinghai Province and Tibet Autonomous Region are better.
9.Study on the Influence of Yunnan Rice Products on Blood Sugar
Murong JIANG ; Yuanqin LEI ; Ke ZHANG ; Qiumei LIU ; Wenli YANG ; Hongyi LIU ; Jie YAN ; Qingwen ZHANG
Journal of Kunming Medical University 2023;44(12):41-45
Objective To explore the effect of Yunnan specialty rice products on blood sugar by measuring the glycemic index of 5 Yunnan special rice foods:rice noodles,rice cakes,rice rolls,sour rice noodles and dry rice noodles.Methods Following the national standard method to determine the carbohydrate content of 5 Yunnan specialty rice products,and the target amount of the test substance was calculated.Food Glycemic Index Determination Method was used to determine the glycemic index of 5 Yunnan specialty rice products and observe their impact on blood sugar.Results The GI value of Yunnan specialty food rice noodle is 63,rice cake is 64,rice roll is 46,sour rice noodles is 38,and dry rice noodles is 33.Conclusion Yunnan specialty foods rice noodle and rice cake belong to medium GI foods,and diabetes patients should reduce consumption;rice roll,sour rice noodles,and dry rice noodles belong to low GI foods and can be a better staple food source for diabetes patients.
10.Establishment of a prognostic nomogram model for predicting acute renal injury in patients with moderate and severe burns.
Xin YANG ; Xinli TIAN ; Jiang LIU ; Ying LI ; Wenli GUO ; Santao OU ; Weihua WU
Chinese Critical Care Medicine 2023;35(7):736-740
OBJECTIVE:
To establish a prediction model of acute kidney injury (AKI) in moderate and severe burn patients, so as to provide basic research evidence for early identification of burn-related AKI.
METHODS:
Patients who were admitted to the department of plastic burn surgery of the Affiliated Hospital of Southwest Medical University from November 2018 to January 2021 were selected, and their clinical characteristics, laboratory examinations and other indicators were recorded. Multivariate Logistic regression analysis was used to screen out the risk factors of AKI related to moderate and severe burns, and R software was used to establish the nomogram of moderate and severe burn patients complicated with AKI. The Bootstrap method model was used for internal verification by repeating sample for 1 000 times. Consistency index and calibration curve were used to evaluate the accuracy of the model, and the receiver operator characteristic curve (ROC curve) and the area under the curve (AUC) were used to evaluate the prediction efficiency, decision curve analysis (DCA) was used to evaluate the clinical utility of the model.
RESULTS:
A total of 186 patients with moderate and severe burn were included, among which 54 patients suffered from AKI, and the incidence rate was 29.03%. Multivariate Logistic regression analysis showed that the total burn surface area [TBSA; odds ratio (OR) = 1.072, 95% confidence interval (95%CI) was 1.031-1.115, P = 0.001], estimated glomerular filtration rate (eGFR; OR = 0.960, 95%CI was 0.931-0.990, P = 0.010), neutrophil (NEU; OR = 1.190, 95%CI was 1.021-1.386, P = 0.026), neutrophil/lymphocyte ratio (NLR; OR = 0.867, 95%CI was 0.770-0.977, P = 0.019), D-dimer (OR = 4.603, 95%CI was 1.792-11.822, P = 0.002) were the risk factors for patients with moderate and severe burn complicated with AKI. Taking the above indexes as predictive factors, a nomogram prediction model was established, the ROC curve was plotted with AUC of 0.998 (95%CI was 0.988-1.000). Optimum threshold of ROC curve was -0.862, the sensitivity was 98.0% and the specificity was 98.2%, and the consistency index was 0.998 (95%CI was 0.988-1.000). The calibration curve showed that the prognostic nomogram model was accurate, DCA showed that most patients can benefit from this model.
CONCLUSIONS
The burned patients with higher TBSA, NEU, NLR, D-dimer and lower eGFR tend to suffer from AKI. The nomogram based on the above five risk factors has high accuracy and clinical value, which can be used as a predictive tool to evaluate the risk of AKI in moderate and severe burn patients.
Humans
;
Prognosis
;
Nomograms
;
Retrospective Studies
;
Burns/complications*
;
Acute Kidney Injury/etiology*
;
ROC Curve


Result Analysis
Print
Save
E-mail