Acute liver injury (ALI) is one of the common severe diseases in clinic, which is characterized by redox imbalance and inflammatory storm. Untimely treatment can easily lead to liver failure and even death. Rosmarinic acid (RA) has been proved to have anti-inflammatory and antioxidant activity, but it is not clear how to protect ALI through antioxidation and inhibition of inflammation. Therefore, this study explored the therapeutic effect and molecular mechanism of RA on ALI through in vitro and in vivo experiments. In the mouse ALI model, the effects of RA on liver function and inflammatory indexes were studied, the pathological changes of liver were observed by HE, the effect of RA on reactive oxygen species in liver was detected by fluorescence method, and the level of F4/80 in liver tissue was detected by immunohistochemical method. The levels of thioredoxin interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3) and cysteinyl aspartate specific proteinase-1 (CASPASE-1) in liver tissue were measured by Western blot. All animal welfare and experimental procedures follow the rules of the Animal Ethics Committee of Southwest Minzu University. In vitro, human hepatoma cell line HepG2 was used to establish the model of oxidative damage induced by H₂O₂. The cell viability was detected by CCK-8 method. The level of interleukin-1β (IL-1β) in the supernatant was detected by enzyme linked immunosorbent assay (ELISA), the activity of lactatede hydrogenase (LDH) was detected by LDH kit, and the level of ROS was detected by fluorescence probe DCFH-DA labeling. The mRNA expression of Txnip, Nlrp3, Caspase 1, Il1β was detected by real-time fluorescence quantitative PCR (qPCR), and the protein levels of nuclear factor erythroid-2 related factor 2 (NRF2), TXNIP, NLRP3 and CASPASE-1 were measured by Western blot. The results showed that compared with the model group, the degree of liver swelling, tissue injury, liver function index in RA group were significantly lower than those in model group. And RA significantly attenuated the increases of ROS in liver tissue. The expression levels of TXNIP, NLRP3 and CASPASE-1 in liver tissue were significantly lower than those in model group. Additionally, RA inhibited the expressions of F4/80 and IL-1β. In vitro experiment, compared with model group, RA effectively inhibited the secretion of IL-1β and LDH. The level of ROS also decreased significantly. RA inhibited the mRNA expressions of Txnip, Caspase 1, Il1β. Furthermore, RA significantly increased the expression level of NRF2 protein in nucleus, and decreased the expression level of TXNIP and NLRP3 protein. Specifically, with the addition of ML385, the effect of RA on NRF2, TXNIP, NLRP3, CASPASE-1 protein expression was reversed. Collectively, these findings suggested that RA may inhibit the production of ROS by promoting NRF2 nuclear transfer, and then reduce the activation of NLRP3 inflammatory bodies by TXNIP, reduce cell death and inflammatory response to prevent the liver injury.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Male infertility (MI) and male sexual dysfunction (MSD) can often coexist together due to various interplay factors such as psychosexual, sociocultural and relationship dynamics. The presence of each form of MSD can adversely impact male reproduction and treatment strategies will need to be individualized based on patients’ factors, local expertise, and geographical socioeconomic status. The Asia Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men’s Health and Aging (ASMHA) aim to provide a consensus statement and practical set of clinical recommendations based on current evidence to guide clinicians in the management of MI and MSD within the Asia-Pacific (AP) region. A comprehensive, narrative review of the literature was performed to identify the various forms of MSD and their association with MI. MEDLINE and EMBASE databases were searched for the following English language articles under the following terms: “low libido”, “erectile dysfunction”, “ejaculatory dysfunction”, “premature ejaculation”, “retrograde ejaculation”, “delayed ejaculation”, “anejaculation”, and “orgasmic dysfunction” between January 2001 to June 2022 with emphasis on published guidelines endorsed by various organizations. This APSSM consensus committee panel evaluated and provided evidence-based recommendations on MI and clinically relevant MSD areas using a modified Delphi method by the panel and specific emphasis on locoregional socioeconomic-cultural issues relevant to the AP region. While variations exist in treatment strategies for managing MI and MSD due to geographical expertise, locoregional resources, and sociocultural factors, the panel agreed that comprehensive fertility evaluation with a multidisciplinary management approach to each MSD domain is recommended. It is important to address individual MI issues with an emphasis on improving spermatogenesis and facilitating reproductive avenues while at the same time, managing various MSD conditions with evidence-based treatments. All therapeutic options should be discussed and implemented based on the patient’s individual needs, beliefs and preferences while incorporating locoregional expertise and available resources.

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Ursodeoxycholic Acid/adverse effects* ; Berberine/pharmacology* ; Interleukin-6 ; Tumor Necrosis Factor-alpha/pharmacology* ; Drugs, Chinese Herbal/pharmacology* ; Colon ; Nanoparticles ; Dextran Sulfate/adverse effects* ; Disease Models, Animal ; Colitis/chemically induced*

Patients with congenital unilateral absence of the vas deferens (CUAVD) manifest diverse symptoms from normospermia to azoospermia. Treatment for CUAVD patients with obstructive azoospermia (OA) is complicated, and there is a lack of relevant reports. In this study, we describe the clinical features and evaluate the treatments and outcomes of CUAVD patients with OA. From December 2015 to December 2020, 33 patients were diagnosed as CUAVD with OA in Shanghai General Hospital (Shanghai, China). Patient information, ultrasound findings, semen analysis, hormone profiles, and treatment information were collected, and the clinical outcomes were evaluated. Of 33 patients, 29 patients were retrospectively analyzed. Vasoepididymostomy (VE) or cross VE was performed in 12 patients, the patency rate was 41.7% (5/12), and natural pregnancy was achieved in one of the patients. The other 17 patients underwent testicular sperm extraction as the distal vas deferens (contralateral side) was obstructed. These findings showed that VE or cross VE remains an alternative treatment for CUAVD patients with OA, even with a relatively low rate of patency and natural pregnancy.
Pregnancy ; Female ; Humans ; Male ; Vas Deferens/abnormalities* ; Azoospermia/surgery* ; Epididymis/surgery* ; Retrospective Studies ; Tertiary Care Centers ; China ; Semen

MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.
Humans ; Tumor Necrosis Factor-alpha ; DNA-Binding Proteins/metabolism* ; Ubiquitin-Specific Peptidase 7 ; Cisplatin ; Temozolomide ; Transcription Factors ; Glioma ; Cell Proliferation ; Melanoma ; Cell Line, Tumor ; Apoptosis ; Nuclear Proteins/genetics*

Objective: To verify the feasibility and accuracy of the transanal multipoint full-layer puncture biopsy (TMFP) technique in determining the residual status of cancer foci after neoadjuvant therapy (nCRT) in rectal cancer. Methods: Between April 2020 and November 2022, a total of 78 patients from the Beijing Chaoyang Hospital of Capital Medical University, the Beijing Friendship Hospital of Capital Medical University, the Qilu Hospital of Shandong University, the Zhongnan Hospital of Wuhan University with advanced rectal cancer received TMFP after nCRT participated in this prospective multicenter trial. There were 53 males and 25 females, aged (M(IQR)) 61 (13) years (range: 35 to 77 years). The tumor distance from the anal verge was 5 (3) cm (range: 2 to 10 cm). The waiting time between nCRT and TMFP was 73 (26) days (range: 33 to 330 days). 13-point transanal puncture was performed with a 16 G tissue biopsy needle with the residual lesion as the center. The specimens were submitted for independent examination and the complications of the puncture were recorded. The consistency of TMFP and radical operation specimen was compared. The consistency of TMPF with clinical remission rates for the diagnosis of complete pathological remission was compared by sensitivity, specificity, negative predictive value, positive predictive value and accuracy. Statistical analysis between groups was performed using the χ² analysis, and a paired χ² test was used to compare diagnostic validity. Results: Before TMFP, clinical complete response (cCR) was evaluated in 27 cases. Thirty-six cases received in vivo puncture, the number of punctures in each patient was 13 (8) (range: 4 to 20), 24 cases of tumor residue were found in the puncture specimens. The sensitivity to judgment (100% vs. 60%, χ²=17.500, P<0.01) and accuracy (88.5% vs. 74.4%, χ²=5.125, P=0.024) of TMFP for the pathologic complete response (pCR) were significantly higher than those of cCR. Implement TMFP based on cCR judgment, the accuracy increased from 74.4% to 92.6% (χ²=4.026, P=0.045). The accuracy of the in vivo puncture was 94.4%, which was 83.3% of the in vitro puncture (χ²=1.382, P=0.240). Overall, the accuracy of TMFP improved gradually with an increasing number of cases (χ²=7.112, P=0.029). Conclusion: TMFP is safe and feasible, which improves the sensitivity and accuracy of rectal cancer pCR determination after nCRT, provides a pathological basis for cCR determination, and contributes to the safe development of the watch and wait policy.

OBJECTIVE: To investigate the inflammatory effects of Cinobufotalin on monocytes in resting state and macrophages in activated state and its molecular mechanism. METHODS: THP-1 cells were stimulated with Phorbol 12-myristate 13-acetate to induce differentiation into macrophages. Lipopolysaccharides was added to activate macrophages in order to establish macrophage activation model. Cinobufotalin was added to the inflammatory cell model for 24 h as a treatment. CCK-8 was used to detect cell proliferation, Annexin V /PI double staining flow cytometry was used to detect cell apoptosis, flow cytometry was used to detect macrophage activation, and cytometric bead array was used to detect cytokines. Transcriptome sequencing was used to explore the gene expression profile regulated by Cinobufotalin. Changes in the significantly regulated molecules were verified by real-time quantitative polymerase chain reaction and Western blot. RESULTS: 1∶25 concentration of Cinobufotalin significantly inhibited the proliferation of resting monocytes(P<0.01), and induced apoptosis(P<0.01), especially the activated macrophages(P<0.001, P<0.001). Cinobufotalin significantly inhibited the activation of macrophages, and significantly down-regulated the inflammatory cytokines(IL-6, TNF-α, IL-1β, IL-8) released by activated macrophages(P＜0.001). Its mechanism was achieved by inhibiting TLR4/MYD88/P-IκBa signaling pathway. CONCLUSION Cinobufotalin can inhibit the inflammatory factors produced by the over-activation of macrophages through TLR4/MYD88/P-IκBa pathway, which is expected to be applied to the treatment and research of diseases related to the over-release of inflammatory factors.
Humans ; Toll-Like Receptor 4/metabolism* ; Myeloid Differentiation Factor 88/genetics* ; Macrophages/metabolism* ; Cytokines/metabolism* ; Lipopolysaccharides/pharmacology* ; NF-kappa B

Objective:To evaluate the safety and efficacy of trimodality treatment (TMT) which is complete transurethral resection of bladder tumor with concurrent radiotherapy and chemotherapy for invasive bladder cancer.Methods:From Mar. 2016 to Oct.2021, patients who were indicated of radical cystectomy (RC) but refused were enrolled to TMT treatment prospectively. Inclusive criteria were: ① the patients refused radical surgery; ② male or female, no older than 80 years; ③ no matter the tumor size, the bladder tumor be completely resected by transurethral surgery, and the hydronephrosis be improved after resecting the tumor; ④ the postoperative pathology of urothelial carcinoma; ⑤ recurrent T 1 and high-grade non-muscle invasive bladder cancer (NMIBC) or T 2-4a muscle invasive bladder cancer (MIBC); ⑥ no definitive metastasis in preoperative chest, abdominal CT or MRI; ⑦ hemoglobin ≥100 g/L, white blood cell count ≥4×10 9/L, platelet count ≥100×10 9/L, and normal liver and renal function. The exclusion criteria were: ① tumor invading bladder neck or anterior or posterior urethra; ② bladder contracture or severe urethral stricture; ③ regional lymph node metastasis or distant metastasis by imaging examination; ④ no improvement of hydronephrosis after resection; ⑤ definitive contraindications of radiotherapy or chemotherapy; ⑥ uncontrolled hypertension, diabetes, coronary heart disease or other severe diseases. After cTURBT, paclitaxel (50 mg/m 2 on Day 1 of each week) combined with cisplatin(20 mg/m 2 on day 1-2 of each week)was administered with concurrent radiotherapy (2 Gy/fraction/day) for 4 weeks. If cystoscopy and/or radiographic detected no recurrence or metastasis, the patients were treated with concurrent chemoradiotherapy for 2 and a half weeks (total dose of 64 Gy). The side effects of radiotherapy and chemotherapy during TMT were observed, the quality of life(QOL)was evaluated by FACT-P scale, and the bladder recurrence, distant metastasis and survival were assessed with imaging and cystoscopy. From March 2016 to October 2021, 79 patients with RC were enrolled, including 67 males and 12 females, aged 44-86 years. The pathology of RC was urothelial carcinoma of the bladder. There was no definitive lymph node or distant metastasis in preoperative imaging. The progress and survival after TMT and RC treatment were followed up and the survival rates were calculated by Kaplan-Meier method. Results:Of the 30 patients who underwent TMT, including 25 males and 5 females, aged 32-76 years, there were 7 cases of cT 1 (23.3%), 19 cases (63.3%) of cT 2, 2 cases of cT 3 (6.7%)and 2 cases of cT 4(6.7%), respectively. A total of 132 adverse events of all grades of chemoradiotherapy occurred, of which only 4 were grade Ⅳ, with no bowel leakage or death due to complications. The mean scores of negative questions in FACT-P were 3.22±0.67, 1.30±0.63 and 0.87±0.69 before TMT treatment, 6 and 12 months after TMT treatment, respectively. The quality of life was significantly improved( F=129.081, P<0.001), and the rate of bladder preservation was 86.7%(26/30). Two cases underwent salvage RC(6.7%)and 2 cases died of bladder recurrence(6.7%). There were 8, 4 and 2 patients survived 4, 5 and 6 years, respectively. Seven cases (23.3%) had bladder recurrence, 3 cases (10.0%) underwent distant metastasis and 6 patients (20.0%)died after TMT because of the progression. The 1, 2 and 5 year overall survival rates by TMT treatment were 88.89%, 82.96% and 62.77%, respectively. Median follow-up was 19.5(6.8-44.5) months in the TMT group and 35.5(18.8-53.3) months in the RC group ( z=-1.998, P=0.046). Progression-free survival in the TMT and RC group were 66.7% and 80.0%( χ2=1.047, P=0.306), and the overall survival rates were 80.0% and 80.0% ( χ2=0.482, P=0.488) respectively. The difference was not statistically significant. Conclusions:The TMT is a safe and effective alternative for RC, which can improve the quality of life and control the tumor sufficiently.

Objective:To analyze the efficacy and safety of radium-223 in the treatment of metastatic castration resistant prostate cancer (mCRPC).Methods:The clinical data of 22 patients with mCRPC treated with radium-223 in the Chongqing University Cancer Hospital from January 2021 to January 2022 were analyzed retrospectively. The average age was (70.7±1.3)years old. There were 7 cases with ECOG score of 1 and 15 cases with ECOG score of 2. There were 7 cases with grade 2 and 15 cases with grade 3 bone metastasis. For mCRPC, 1 case (4.6%) received first-line treatment, 4 cases (18.2%) received second-line treatment, 10 cases (45.5%) received third-line treatment, 4 cases (18.2%) received fourth-line treatment, and 3 cases (13.6%) received fifth-line treatment. The median time from the diagnosis of mCRPC to the start of radium-223 treatment was 29 (20, 34) months. Radium-223 (55kbq/kg) was injected intravenously every 4 weeks for up to 6 cycles. Before treatment, the median alkaline phosphatase (ALP) was 147.0 (101.8, 212.5)U/L, the median prostate specific antigen (PSA) was 44.7(20.2, 99.1)ng/ml, and 6 patients (27.3%) were complicated with grade 1-2 anemia. The median hemoglobin was 115.0 (103.8, 122.5) g/L, the average neutrophil was (3.0 ± 0.3)×10 9/L, and the average platelet was (169.8 ± 17.0)×10 9/L. The overall survival (OS), radiographic progression-free survival time (rPFS), time to PSA progression, PSA response rate, pain response rate, and time to pain progression were analyzed. Stratified analysis was carried out according to the number of treatment lines experienced before radium-223 treatment. At the same time, the main adverse reactions during radium-223 treatment were analyzed. Results:The mean number of treatment courses with radium-223 was 2.7(ranging 1 to 6), with 4 patients completing 6 courses, 12 (54.6%) completing ≥ 3 courses, and 10 (45.5%) completing < 3 courses. Thirteen patients (59.1%) were treated with radium-223 alone and 9 (40.9%) in combination with other treatments (1 of docetaxel chemotherapy, 2 of enzalutamide, 3 of olaparib, and 3 of estramustine phosphate). None of the patients in this group were treated with bisphosphonates. Ten patients (45.5%) in this group died, all due to disease progression. The median overall survival time of the 22 cases was 11.0 (2.2, 19.8) months. Three patients (13.6%), 7 patients (31.8%), 3 patients (13.6%), and 1 patient (4.5%) showed radiographic progression at 2, 3, 4, and 10 months after treatment, respectively, while the remaining 8 patients (36.4%) did not show radiographic progression during the follow-up period, and the median radiographic progression free time for the 22 patients was 4.0 (3.1, 4.9) months. There were four cases (18.2%) showed PSA response, of which three cases (13.6%) showed PSA rising again later, and one case (4.5%) showed continuous PSA decline. The median time to PSA progression for the 22 patients was 3.6 (2.2, 5.1) months. Fifteen patients (68.2%) experienced pain response at 1 month of treatment, of whom 5 (22.7%) experienced increased pain later and 10 (45.5%) experienced sustained pain relief. The median time to pain progression was 5.5 (3.5, 7.6) months in 22 patients. No patients received radiotherapy or surgery for pain, and no patients experienced fracture. In this group, 7 patients (31.8%) had a post-treatment ALP decrease ≥30% from baseline. Major adverse events during radium-223 treatment were all grade 1 to 2 events, no grade ≥3 adverse events, and no treatment discontinuers due to adverse events.Conclusions:Radium-223 resulted in high pain response rates and prolonged OS, rPFS and time to PSA progression in patients with mCRPC. Adverse effects were low during treatment. The conclusions need to be validated by further expansion of the sample size and extended follow-up.