Ulcerative colitis (UC) is a chronic inflammatory disorder with a complex etiology, characterized by intestinal inflammation and barrier dysfunction. Platycodon grandiflorus polysaccharides (PGP), the primary component of Platycodon grandiflorus, and hesperidin (Hesp), a prominent active component in Citrus aurantium L. (CAL), have both demonstrated anti-inflammatory properties. This study aims to elucidate the underlying mechanism of the synergistic effect of PGP combined with Hesp on UC, focusing on the coordinated interaction between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. A mouse model of UC induced by dextran sulfate sodium (DSS) and a cell model using lipopolysaccharide (LPS)-induced RAW264.7/IEC6 cells were employed to investigate the in vitro and in vivo anti-inflammatory effects of PGP combined with Hesp on UC and its potential mechanism of action. The results indicated that compared to the effects of either drug alone, the combination of PGP and Hesp significantly modulated inflammatory factor levels, inhibited oxidative stress, regulated colonic mucosal immunity, suppressed apoptosis, and restored intestinal barrier function in vitro and in vivo. Further in vitro studies revealed that PGP significantly inhibited the PI3K/AKT signaling pathway, while Hesp significantly inhibited the JAK2/STAT3 signaling pathway. The use of inhibitors and activators targeting both pathways validated the synergistic effects of PGP combined with Hesp on the PI3K/AKT and JAK2/STAT3 signaling pathways. These findings suggest that PGP combined with Hesp exhibits a synergistic effect on DSS-induced colitis, potentially mediated through the phosphatase and tensin homolog (PTEN)/PI3K/AKT and interleukin-6 (IL-6)/JAK2/STAT3 signaling pathways.
Animals ; STAT3 Transcription Factor/genetics* ; Janus Kinase 2/genetics* ; Polysaccharides/administration & dosage* ; Colitis, Ulcerative/chemically induced* ; Mice ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Drug Synergism ; Male ; Hesperidin/administration & dosage* ; Platycodon/chemistry* ; Phosphatidylinositol 3-Kinases/genetics* ; Disease Models, Animal ; RAW 264.7 Cells ; Mice, Inbred C57BL

AIM:To investigate the mechanism through which esculetin induces ferroptosis of mouse breast cancer 4T1 cells.METHODS:Molecular docking of esculetin with p53,solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4)proteins was performed,and Kaplan-Meier curves and time-dependent receiver oper-ating characteristic curves were drawn.The 4T1 cells were divided into 6 groups,namely the control(CON),1/2 IC50,IC50,2 IC50,erastin,and capecitabine groups.The appropriate drug concentration for treating 4T1 cells was screened by CCK-8 assay.The invasion and migration abilities of 4T1 cells following esculetin treatment at the selected drug concentra-tion were analyzed by scratch test and Transwell assay.Mitochondrial morphological change were examined by electron mi-croscopy.The levels of ferroptotic cell death were then quantified by Fe2+,reactive oxygen species(ROS),malondialde-hyde(MDA),glutathione(GSH),and GPX4 assays.Western blot was performed to evaluate the protein levels of p53,SLC7A11,GPX4 and acyl-CoA synthetase long-chain family member 4(ACSL4).RESULTS:Compared with CON group,the esculetin 1/2 IC50,IC50 and 2 IC50 groups showed smaller size,increased membrane density,and decreased ridge of mitochodria,as well as decreased levels of GSH and GPX4,reduced cell invasion and migration abilities,and de-creased levels of SLC7A11 and GPX4 proteins(P＜0.05).Furthermore,these groups exhibited increased levels of Fe2+,ROS,and MDA,as well as elevated p53 and ACSL4 protein abundance(P＜0.05).CONCLUSION:Esculetin pro-motes ferroptosis of 4T1 cells through a mechanism involving the p53/SLC7A11/GPX4 regulatory axis.

Objective:To investigate the risk factors for lymph node metastasis in patients with early gastric cancer and establish a model for prediction of risk.Methods:The cohort of this retrospective observational study comprised 1096 patients who had undergone radical gastric cancer surgery combined with standard D1 lymphadenectomy and been diagnosed with early gastric cancer by postoperative pathology in Zhongshan Hospital affiliated with Fudan University from January 2016 to July 2022. The patients were allocated to groups with and without lymph node metastases. Clinicopathological characteristics were compared between the two groups and multi-factor logistic regression analysis used to identify independent risk factors for lymph node metastasis in patients with early gastric cancer. Indications for endoscopic resection in the Japanese Gastric Cancer Association (JGCA) guideline were also incorporated into construction of the model. The patient cohort was divided into training and validation sets in a 6:4 ratio. The identified independent risk factors were used to construct a predictive nomogram. Receiver operating characteristic curves were plotted separately and the difference between them in predictive efficacy was compared using the area under the curve (AUC).Results:A total of 1,096 patients with early gastric cancer were included, with 750 males and 346 females. Their average age was (61.4±10.9) years old, and the mean tumor diameter was (23.8±11.4) mm. Among them, 188 patients (17.2%) had positive lymph node metastasis, with 109 cases in N1 stage, 42 cases in N2 stage, and 37 cases in N3 stage. Additionally, 462 patients were in T1a stage, while 634 patients were in T1b stage. Univariate analysis showed that tumor diameter, location, Lauren classification, gross morphology, histological type, intravascular invasion, ulceration, differentiation type and tumor T stage were associated with lymph node metastasis after radical gastrectomy for early gastric cancer (all P<0.05). Multifactorial analysis showed that the presence of intravascular invasion (OR=14.822, 95%CI: 9.323–23.572, P<0.001), undifferentiated type (OR=3.095, 95%CI: 1.649–5.811, P<0.001), tumor T1b (OR=1.798, 95%CI: 1.053–3.079, P=0.032), and tumor diameter ≥2 cm (OR=1.229, 95%CI: 1.031–1.469, P=0.022) were independent risk factors for lymph node metastasis. The baseline data of the training set and validation set were consistent in terms of balance (all P>0.05). We used the above variables to establish a predictive nomogram for lymph node metastasis in patients with early gastric cancer. The AUC values obtained from the validation of the model in the training and validation sets were 0.880 (95%CI: 0.849–0.911) and 0.881 (95%CI: 0.841–0.921), respectively, and were significantly better than the predictive efficacy based on the JGCA guideline (AUC=0.777, 95%CI: 0.746–0.809, P<0.001). Conclusions:Patients with early gastric cancer and intravascular invasion, undifferentiated tumors, tumor T1b, and diameter ≥2 cm are at higher risk of postoperative lymph node metastasis than other patients. The predictive model developed in this study more accurately predicts lymph node metastasis in patients with early gastric cancer than previously proposed methods.

Objective:To investigate the risk factors for lymph node metastasis in patients with early gastric cancer and establish a model for prediction of risk.Methods:The cohort of this retrospective observational study comprised 1096 patients who had undergone radical gastric cancer surgery combined with standard D1 lymphadenectomy and been diagnosed with early gastric cancer by postoperative pathology in Zhongshan Hospital affiliated with Fudan University from January 2016 to July 2022. The patients were allocated to groups with and without lymph node metastases. Clinicopathological characteristics were compared between the two groups and multi-factor logistic regression analysis used to identify independent risk factors for lymph node metastasis in patients with early gastric cancer. Indications for endoscopic resection in the Japanese Gastric Cancer Association (JGCA) guideline were also incorporated into construction of the model. The patient cohort was divided into training and validation sets in a 6:4 ratio. The identified independent risk factors were used to construct a predictive nomogram. Receiver operating characteristic curves were plotted separately and the difference between them in predictive efficacy was compared using the area under the curve (AUC).Results:A total of 1,096 patients with early gastric cancer were included, with 750 males and 346 females. Their average age was (61.4±10.9) years old, and the mean tumor diameter was (23.8±11.4) mm. Among them, 188 patients (17.2%) had positive lymph node metastasis, with 109 cases in N1 stage, 42 cases in N2 stage, and 37 cases in N3 stage. Additionally, 462 patients were in T1a stage, while 634 patients were in T1b stage. Univariate analysis showed that tumor diameter, location, Lauren classification, gross morphology, histological type, intravascular invasion, ulceration, differentiation type and tumor T stage were associated with lymph node metastasis after radical gastrectomy for early gastric cancer (all P<0.05). Multifactorial analysis showed that the presence of intravascular invasion (OR=14.822, 95%CI: 9.323–23.572, P<0.001), undifferentiated type (OR=3.095, 95%CI: 1.649–5.811, P<0.001), tumor T1b (OR=1.798, 95%CI: 1.053–3.079, P=0.032), and tumor diameter ≥2 cm (OR=1.229, 95%CI: 1.031–1.469, P=0.022) were independent risk factors for lymph node metastasis. The baseline data of the training set and validation set were consistent in terms of balance (all P>0.05). We used the above variables to establish a predictive nomogram for lymph node metastasis in patients with early gastric cancer. The AUC values obtained from the validation of the model in the training and validation sets were 0.880 (95%CI: 0.849–0.911) and 0.881 (95%CI: 0.841–0.921), respectively, and were significantly better than the predictive efficacy based on the JGCA guideline (AUC=0.777, 95%CI: 0.746–0.809, P<0.001). Conclusions:Patients with early gastric cancer and intravascular invasion, undifferentiated tumors, tumor T1b, and diameter ≥2 cm are at higher risk of postoperative lymph node metastasis than other patients. The predictive model developed in this study more accurately predicts lymph node metastasis in patients with early gastric cancer than previously proposed methods.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Previous studies have found that As2 O3 can interfere with serum thyroid hormone TH levels in rats and cause chronic liver damage,but the mechanism remains unclear.In order to ex-plore the role of TH signaling pathway in As2 O3-induced chronic liver injury,qRT-PCR and West-ern blot techniques were used to detect the expression changes of genes and protein of TRβ1(a key regulator of TH signaling pathway in rat liver)and cyclin D1(the downstream factor of TRβ1 in nuclear pathway).Meanwhile,the changes in the protein of key factors(Bax,Bcl-2)of the TH sig-nal nuclear outside pathway were detected.The results indicated that:after As2 O3 treatment for 110 days,compared with the control group,the expression of TRβ1 protein in the liver of female mice significantly decreased(P＜0.01),the expression of cyclin D1 significantly increased in the 0.1 and 0.2 mg/L groups(P＜0.01).Meanwhile,the expression of TRβ1 protein in male mice sig-nificantly decreased in 0.4 mg/L group(P＜0.01),and the expression of cyclin D1 in each group significantly increased(P＜0.01).The mRNA expression results were basically the same as those of protein expression.After As2 O3 treatment for 194 days,compared with the control group,the expression of TRβ1 protein in each group significantly decreased(P＜0.01),and the expression of cyclin D1 significantly increased(P＜0.01).The mRNA expression results were basically consist-ent with the protein.As2 O3 interfered with the expression of Bcl-2 and Bax proteins in rats and in-duced the increase in the ratio of Bcl-2/Bax protein as the action time increased.Among them,the Bcl-2/Bax ratio of female rats in each group and male rats in the 0.4 mg/L group significantly in-creased(P＜0.01),and male rats in the 0.1 mg/L group significantly increased(P＜0.05).It shows that As2O3 can cause abnormal levels of TRβ1,cyclin D1 and the Bcl-2/Bax ratio in rat liv-er.

Objective:To investigate the effects of external application of Sanying Plaster on the size of thyroid nodules and the states of depression and anxiety in patients with benign thyroid nodules.Methods:A randomized controlled trial was conducted. A total of 120 patients with benign thyroid nodules from the outpatient clinic of the Department of Thyroid Diseases at Shanghai Traditional Chinese Medicine Hospital from June to December 2022 were selected as the subjects of the study. They were divided into two groups using the random number table method, with 60 patients in each group. The control group received lifestyle intervention treatment, while the treatment group received Sanying Ointment in addition to the treatment of the control group. Both groups were treated for 3 months. TCM syndrome scores were measured before and after treatment; the maximum diameter of thyroid nodules was measured using a color Doppler ultrasound transverse section; the quality of life was assessed using the short form 36 (SF-36); the degree of anxiety and depression was evaluated using the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS); adverse reactions during the treatment period were recorded, and the clinical efficacy was evaluated.Results:During the treatment period, 4 cases in the treatment group and 3 cases in the control group did not complete the treatment. Finally, 56 cases in the treatment group and 57 cases in the control group entered the efficacy evaluation. The total effective rate of the treatment group was 71.4% (40/56), and that of the control group was 14.0% (8/57), with a statistically significant difference between the two groups ( χ2=26.82, P<0.001). After treatment, the TCM syndrome score of the treatment group (10.02±3.65 vs. 16.65±3.44, t=-10.24) was lower than that of the control group ( P<0.001); the maximum diameter of thyroid nodules [11.00 (4.65, 19.93) mm vs. 15.00 (7.15, 28.50) mm, Z=-2.43] was lower than that of the control group ( P<0.05); the SF-36 score [121.83 (117.00, 130.00) vs. 114.42 (104.25, 127.50), Z=-2.62] was higher than that of the control group ( P<0.01); the SDS (46.72±4.59 vs. 57.02±5.99, t=14.80) and SAS (42.25±5.72 vs. 50.60±7.12, t=10.04) scores were lower than those in the control group ( P<0.001). The incidence of adverse reactions during the treatment period in the treatment group was 3.5% (2/57), and no adverse reactions occurred in the control group. Conclusion:The external application of Sanying Ointment helps to reduce the size of thyroid nodules in patients with benign thyroid nodules, improve the quality of life and anxiety and depression, and increase clinical efficacy with good safety.

Objective:To investigate the incidence of abnormal bone mineral density (BMD) in male patients with alcoholic cirrhosis.Methods:Clinical data of 72 patients with alcoholic cirrhosis admitted in Beijing Ditan Hospital, Capital Medical University from March 2017 to July 2023 were enrolled as study group, and 40 age-and BMI-matched non-hepatopathy subjects were selected as control group.The incidence of abnormal BMD were compared between two groups. The serum levels of osteocalcin (OC), total procollagen type 1 amino-terminal propeptide (TP1NP), β-C-terminal telopeptide of typeⅠcollagen (CTX) and 25-hydroxy vitamin D [25-(OH)VD] were measured and compared among patients with different Child-Pugh grades.Results:Among 72 alcoholic cirrhosis patients, there were 54 cases (75.0%) complicated with abnormal BMD, including 21 cases (29.2%) of bone loss and 33 cases (45.8%) of osteoporosis. In control group there were 15 subjects with abnormal bone mineral density, including 9 cases (22.5%) of bone loss and 6 cases (15.0%) of osteoporosis( χ2=5.623 and 15.900,both P<0.05). The average BMDs of L1-L4, femoral neck, intertrochanteric region and trochanter of the femur in patients with alcoholic cirrhosis were significantly lower than those in control group ( t=3.574, 8.640, 7.282, 7.958, 3.755, 5.573, 5.026,all P<0.05); the average BWDs of L1-L3 and hip joint in patients with Child-Pugh C were significantly lower than those in patients with Child-Pugh A and B ( t=1.414, 1.699, 3.786, 2.590, 8.763, 2.581, 1.392, 6.232,all P<0.05). The serum levels of 25-(OH)VD in alcoholic cirrhosis patients with Child-Pugh C grade were significantly lower than those with Child-Pugh A and B ( t=3.969 and 2.911, P<0.05); the serum calcium levels in patients with Child-Pugh C grade were lower than those with Child-Pugh A( t=3.627, P<0.05); while the TP1NP levels in patients with Child-Pugh C were higher than those with Child-Pugh A and B grades( t=6.722 and 5.034, P<0.05).The Child-Pugh grade was negatively correlated with 25-(OH)VD level( β=-0.767, P<0.05)and positively correlated with TP1NP level ( β=2.186, P<0.05). Conclusion:The incidence of bone loss and osteoporosis in patients with alcoholic cirrhosis is increased significantly, and the deterioration of their liver function is closely associated with an increased TP1NP level and decreased 25-(OH)VD levels.

Objective:To observe whether Cyclosporin A(CSA)treatment may protect acute pancreatitis(AP)mice and related cardiac injury by consequent attenuation of systemic inflammation via regulating macrophage polarization.Methods:RAW264.7 cells were used for in vitro experiments,stimulated with 0,5,10 and 20 nmol/L CSA for 24 hours,and M2 markers were detected by flow cytometry.C57BL/6J mice were used for experiments in vivo.The mice were randomly divided into 3 groups(n=15):control group,AP model group(intraperitoneal injection of L-arginine)and AP+CSA(20 mg/kg)group,CSA was administered in a pre-treated manner.ELISA kit was used to detect the indexes of pancreatic and myocardial injury in mice;HE staining was used to detect the pathological changes of pancreas and heart tissue;TUNEL method was used to detect apoptosis in tissue sections;CETSA was used to determine the relationship between CSA and PKM;The expressions of PKM2,HIF1α,p-STAT1 and p-STAT6 were detected by Western blot.Results:CSA increased the number of M2 macrophages and decreased the number of M1 macrophages in a dose-dependent manner in vitro.CSA pretreatment significantly improved pancreatic structure and myocardial injury in AP mice,decreased pancreatic histopathological score and serum amylase,lipase,TNF-α,CK-MB,LDH and cTnT levels.CSA pretreatment significantly reduced the number of TUNEL positive cells in myocardium of AP mice.Flow cytometry analysis showed that CSA pretreatment significantly inhibited the proportion of CD11c+F4/80+ and promoted the ratio of CD206+F4/80+ in AP induced myocardial macrophages.CETSA analysis showed that PKM2 was the target of CSA.Conclusion:CSA can significantly improve the severity of L-arginine-induced cardiac damage in AP model mice,and its mechanism of action is related to increasing the number of M2 macro-phages and inhibiting the production of proinflammatory cytokines.

We reported a case of a patient dignosed as tuberculosis and severe malnutrition with coronavirus disease 2019 （critical type） treated with a combination of Chinese medicine and Western medicine. Through the retrospective analysis of the diagnosis and treatment process of this patient， on the basis of Chinese medicine's understanding of the etiology and pathogenesis of “old state” and “deficient state”， the critical coronavirus pneumonia combined with pulmonary tuberculosis and severe malnutrition was mostly due to the physical condition and the invasion of epidemic toxin， resulting in dysfunctions of the internal organs such as the lungs， spleens， kidneys and other organs. Based on the understanding of the cause and mechanism of the coronavirus disease， the treatment combined Chinese and Western medical therapies was given. The western medicine was used with the main treatments of oxygen therapy， anti-viral， intestinal nutritional support， and anti-coagulation， while the Chinese medicine was used by tonifying qi， blood， yin， and yang， warming yang and dissipating cold， and clearing heat and dampness， then tonifying qi， nourishing yin and eliminating heat， in which tonifying middle and replenishing qi ran through the whole process. The integrated treatment eventually improved the patient's symptoms and accelerated the negative conversion of nucleic acid of the coronavirus.