Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Aim To study the apoptosis of human hep-atoma cell line ( HepG2 ) induced by different polar parts of Arnebia euchroma ( Royle ) Johnst ( AE ) and to verify its anti-hepatoma effect by a mouse orthotopic liver cancer model so as to explore the anti-cancer effect of AE extract. Methods Firstly, MTT method and Annexin V-FITC/PI double staining method were used to detect the anti-proliferative and pro-apoptotic effects of each polar part of AE on HepG2 cells, and Western blot was used to detect the expression of Bcl-2 apoptosis family proteins incells. Based on the above experimental results, the effective parts with significant pro-apoptotic effect were screened out for anti-in situ liver cancer experiments in mice, and the organ indexes, liver function indexes and tissue sections of mice with orthotopic liver cancer before and after administration were evaluated. Results With the decrease of the polarity of AE extract,the anti-proliferation and pro-apoptotic effects on HepG2 cells were enhanced, and the anti-proliferation and apoptosis-inducing effects of AE petroleum ether fraction ( AEP) were the most significant. When AEP dose was 1.56 (μg • L

OBJECTIVE: Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism. It is not clear whether phenolic acids or their metabolites play a major role in vivo. In this study, caffeic acid (CA) and ferulic acid (FA), the two most ingested phenolic acids, and their glucuronic acid metabolites, caffeic-4'-O-glucuronide (CA4G) and ferulic-4'-O-glucuronide (FA4G), were investigated. METHODS: Three insulin resistance models in vitro were established by using TNF-α, insulin and palmitic acid (PA) in HepG2 cells, respectively. We compared the effects of FA, FA4G, CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels. The potential targets and related pathways were predicted by network pharmacology. Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target. To investigate the binding mode, molecular docking was performed. Then, we performed membrane recruitment assays of the AKT pleckstrin homology (PH) domain with the help of the PH-GFP plasmid. AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds. Finally, the downstream signaling pathway of AKT was investigated by Western blot analysis. RESULTS: The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption. AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis. The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds. The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site. CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane, while increasing the activity of AKT. Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3β in the AKT signaling pathway to increase glucose consumption. CONCLUSION In conclusion, our results suggested that the metabolites of phenolic acids, which contain glucuronic acid, are the key active substances and that they activate AKT by targeting the PH domain, thus improving glucose metabolism.

Objective: To explore the safety and efficacy of excimer laser coronary angioplasty (ELCA) for the treatment of degenerated great saphenous vein graft (SVG). Methods: This is a single-center, prospective, single-arm study. Patients, who were admitted to the Geriatric Cardiovascular Center of Beijing Anzhen Hospital from January 2022 to June 2022, were consecutively enrolled. Inclusion criteria were recurrent chest pain after coronary artery bypass surgery (CABG), and coronary angiography confirmed that the SVG stenosis was more than 70% but not completely occluded, and interventional treatment for SVG lesions was planned. Before balloon dilation and stent placement, ELCA was used to pretreat the lesions. Optical coherence tomography (OCT) examination was performed and postoperative index of microcirculation resistance (IMR) were assessed after stent implantation. The technique success rate and operation success rate were calculated. The technique success was defined as the successful passage of the ELCA system through the lesion. Operation success was defined as the successful placement of a stent at the lesion. The primary evaluation index of the study was IMR immediately after PCI. Secondary evaluation indexes included thrombolysis in myocardial infarction (TIMI) flow grade, corrected TIMI frame count (cTFC), minimal stent area and stent expansion measured by OCT after PCI, and procedural complications (Ⅳa myocardial infarction, no reflow, perforation). Results: A total of 19 patients aged (66.0±5.6) years were enrolled, including 18 males (94.7%). The age of SVG was 8 (6, 11) years. The length of the lesions was greater than 20 mm, and they were all SVG body lesions. The median stenosis degree was 95% (80%, 99%), and the length of the implanted stent was (41.7±16.3)mm. The operation time was 119 (101, 166) minutes, and the cumulative dose was 2 089 (1 378, 3 011)mGy. The diameter of the laser catheter was 1.4 mm, the maximum energy was 60 mJ, and the maximum frequency was 40 Hz. The technique success and the operation success rate were both 100% (19/19). The IMR after stent implantation was 29.22±5.95. The TIMI flow grade of patients after ELCA and stent implantation was significantly improved (all P>0.05), and the TIMI flow grade of all patients after stent implantation was Grade Ⅲ. The cTFC decreased significantly after ELCA (33.2±7.8) and after stent placement (22.8±7.1) than preoperative level (49.7±13.0) (both P<0.001). The minimum stent area was (5.53±1.36)mm², and the stent expansion rate was (90.0±4.3)%. Perforation, no reflow, type Ⅳa myocardial infarction and other complications were not observed. However, postoperative high-sensitivity troponin level was significantly increased ((67.937±33.839)ng/L vs. (5.316±3.105)ng/L, P<0.001). Conclusion: ELCA is safe and effective in the treatment of SVG lesions and could improve microcirculation and ensure full expansion of stent.
Male ; Humans ; Aged ; Prospective Studies ; Percutaneous Coronary Intervention ; Lasers, Excimer/therapeutic use* ; Saphenous Vein/transplantation* ; Constriction, Pathologic ; Atherectomy, Coronary/methods* ; Myocardial Infarction ; Coronary Angiography ; Stents ; Treatment Outcome

Humans ; Herpesvirus 4, Human ; Insect Bites and Stings ; Killer Cells, Natural ; Epstein-Barr Virus Infections ; Neoplasms ; Lymphoproliferative Disorders

Blood loss and blood transfusion requirement are important quality control indicators of cardiovascular surgery and cardiovascular anesthesia. Patient blood management (PBM) is an evidence-based, multidisciplinary approach to optimizing the care of patients who may need transfusion, which encompasses anemia management, hemodilution, cell salvage, hemostatic treatment, and other approaches to reducing bleeding and minimizing blood transfusion. PBM in cardiovascular surgery is a "team sport" that involves cardiac and vascular surgeons, anesthesiologists, perfusionist, intensivists, and other health care providers. The current work provides an overview of evidence and practice of PBM at Fuwai Hospital. Implementation of PBM should also take local resource availability and cost-effectiveness of different devices, drugs, technologies, and techniques into consideration.
Humans ; Blood Transfusion/methods* ; Anemia/therapy* ; Hemorrhage ; Hospitals ; Blood Loss, Surgical

OBJECTIVE: To investigate the effect of atovaquone on the cell cycle and apoptosis of non-Hodgkin's lymphoma Raji cells, and clarify the related mechanisms. METHODS: MTT assay and trypan blue dye exclusion method were used to evaluate the effect of atovaquone on the proliferation of Raji cells. After the cells were stained by PI staining, the cell cycle distribution was detected by flow cytometry. Cell apoptosis was analyzed by Annexin V/PI double binding assay. The intracellular alterations of reactive oxygen species were detected by 2', 7'-dichlorofluorescein diacetate (DCFH-DA). The protein expression of cell cycle and apoptosis related molecules were detected by Western blot. RESULTS: Various concentrations of atovaquone (5-40 μmol/L) inhibited the growth of Raji cells in a concentration-dependent manner (r=0.951). The proliferation of Raji cells was significantly inhibited after treated by atovaquone (20 and 30 μmol/L) for 24, 48 and 72 h, which showed statistically different with that in the control group (P<0.01, P<0.001, P<0.001). G₁ phase arrest (P<0.01, P<0.001) and apoptosis (P<0.01) of Raji cells was induced by atovaquone (20 and 30 μmol/L) significantly for 24 h and 48 h, respectively. The expression of p-JAK2 and p-STAT3(Y705) protein were down-regulated significantly induced by atovaquone (P<0.001, P<0.05). Furthermore, atovaquone treatment could induce the decreasing of antiapoptotic protein Mcl-1, Bcl-2, and Bcl-xl expression level (P<0.05) and increasing of cleaved caspase-3 protein expression level. In addition, atovaquone could also induce the down-regulation of c-Myc (P<0.001, P<0.01) and cell cycle related molecules Cyclin D1, CDK4, and CDK6 (P<0.01, P<0.05) protein expression. CONCLUSION Atovaquone effectively inhibits cell proliferation and induces cell cycle arrest and apoptosis by suppression of STAT3 signaling pathway in Raji cells. It can be a potential therapeutic agent against non-Hodgkin's lymphoma.
Humans ; Atovaquone/pharmacology* ; Cell Cycle Checkpoints ; Apoptosis ; Lymphoma, Non-Hodgkin

Objective:To investigate the clinical efficacy of different doses of atorvastatin in the treatment of chronic heart failure.Methods:A total of 100 patients with chronic heart failure who received treatment in the Third People's Hospital of Bengbu Medical College from June 2019 to June 2020 were included in this study. They were randomly divided into a control group (conventional treatment + atorvastatin calcium tablet 10 mg, n = 49) and an observation group (conventional treatment + atorvastatin calcium tablet 20 mg, n = 51). Before and after 12 weeks of treatment, serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and inflammatory cytokines such as high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-10 (IL-10) as well as ventricular remodeling (echocardiographic index) were compared between the two groups. Results:After treatment, serum level of NT-proBNP was (506.56 ± 62.37) pg/mL and (660.85 ± 74.55) pg/mL, serum level of hs-CRP was (14.74 ± 2.69) mg/L and (23.31 ± 3.45) mg/L, serum level of IL-6 was (36.77 ± 4.78) ng/L and (43.12 ± 5.22) ng/L, serum level of IL-10 was (12.36 ± 2.63) ng /L and (15.39 ± 3.56) ng/L, left ventricular end diastolic diameter was (37.74 ± 6.83) mm and (42.36 ± 7.73) mm, left ventricular ejection fraction was (45.78 ± 3.31)% and (42.63 ± 2.56)%, and the ratio of early (E wave) to late (A wave) diastolic velocities (E/A) was (1.44 ± 0.06) and (1.21 ± 0.03), respectively in the observation and control groups. There were significant differences in serum levels of NT-proBNP, hs-CRP, IL-6 and IL-10 as well as LVEDD and LVEF between the observation and control groups ( t = 3.73, 3.07, 3.58, 3.68, 2.99, 3.12 and 2.98, all P < 0.05). Conclusion:Atorvastatin is beneficial to the prognosis of patients with chronic heart failure. The therapeutic efficacy of 20 mg atorvastatin per day is better than that of 10 mg atorvastatin per day.

OBJECTIVE: To compare clinical effect of movable external fixation and fusion fixation for the treatment of elbow tuberculosis. METHODS: From October 2013 to June 2019, 52 patients with elbow tuberculosis treated with standard antituberculosis therapy were divided into movable external fixation group and fusion fixation group according to treatment methods. In group A, there were 25 patients, including 11 males and 14 females, aged from 24 to 75 years old with an average of (42.81± 9.01) years old; the courses of diseases ranged from 2 to 9 months with an average of (3.96±1.45) months. In group B, there were 27 patients, including 15 males and 12 females, aged from 23 to 77 years old with an averageof (44.08±7.44) years old; the courses of diseases ranged from 2 to 7 months with an average of (3.88±1.67) months. All patients were performed focus debridement. Intraoperative blood loss, operative time were compared between two groups. VAS score before operation, 2 weeks and 12 months after operation were applied to evaluate pain relieve;Mayo elbow performance score (MEPS) before operation, 1 and 12 months after operation were used to evaluate clinical effect;changes of erythrocyte sedimentation rate (ESR) and Creactive protein, CRP) before operation, 3 weeks after antituberculosis therapy, 1 week and 6 months after operation were compared between two groups. RESULTS: All patients were followed up from 12 to 20 months with an average of (13.50±4.85) months. No mixed infection and recurrence of tuberculosis occurred. There were no statistical differences in intraoperative blood loss and operative time( CONCLUSION For elbow tuberculosis, movable external fixation and fusion fixation have equal effect in operative time, amount of bleeding and control of tuberculosis infection indicator. Movable external fixation need earlier functional exercise, not conducive to pain relief at early stage, which may be better than fusion fixation, it is worth clinical promoting.
Elbow ; Elbow Joint/surgery* ; External Fixators ; Female ; Fracture Fixation ; Humans ; Infant ; Male ; Treatment Outcome ; Tuberculosis/surgery*

Diabetic foot ulcers (DFUs) is a severe complication of the diabetes mellitus, which is the first leading cause of non-traumatic lower limbs amputations. The pathogenesis of diabetic foot involves a variety of mechanisms, treatment involves the department of foot and ankle surgery, department of vascular surgery, endocrinology, and infection control. Treatment need multidisciplinary diagnosis and treatment. Debridement is the basis of treating diabetic foot ulcers, and the normal anatomical structure should be maintained during the process. Vacuum sealing drainage (VSD) and antibiotic-laden bone cement (ALBC) have more advantages of controlling infection and ulceration wound healing, which could receive good clinical effect. Tendon lengthening could alleviate the problem of ulcer occurrence and progression caused by stress concentration on the bottom of foot, which has widely application and has advantages of preventing formation of foot ulcers. Flap transplantation could solve the problem of wound healing, but it is necessary to consider whether the transplanted flap could bear the same function as plantar tissue. Tibial bone transverse distraction is a relatively new technique, and the mechanism is not clear, but it has certain application prospects from the perspective of clinical efficacy.
Debridement ; Diabetes Mellitus ; Diabetic Foot/surgery* ; Foot Ulcer ; Humans ; Salvage Therapy ; Wound Healing