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Myocarditis is characterized as local or diffuse inflammatory lesions in the myocardium, primarily caused by viruses and other infections. It is a common cause of sudden cardiac death and dilated cardiomyopathy. In recent years, the global prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the widespread vaccination have coincided with a notable increase in the number of reported cases of myocarditis. In light of the potential threat that myocarditis poses to global public health, numerous studies have sought to elucidate the pathogenesis of this condition. However, despite these efforts, effective treatment strategies remain elusive. To collate the current research advances in myocarditis, and thereby provide possible directions for further research, this review summarizes the mechanisms involved in viral invasion of the organism and primarily focuses on how viruses trigger excessive inflammatory responses and in result in different types of cell death. Furthermore, this article outlines existing therapeutic approaches and potential therapeutic targets for the acute phase of myocarditis. In particular, immunomodulatory treatments are emphasized and suggested as the most extensively studied and clinically promising therapeutic options.
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Angiogenesis, whether physiological or pathological, plays a pivotal role in various physiological and disease conditions. This intricate process relies on a complex and meticulously orchestrated signal transduction network that connects endothelial cells, their associated parietal cells (VSMCs and pericytes), and various other cell types, including immune cells. Given the significance of m6A and its connection to angiogenesis and vascular disease, researchers must adopt a comprehensive and ongoing approach to their investigations. This study aims to ascertain whether a common key mechanism of m6A exists in angiogenesis and vascular diseases and to elucidate the potential application of m6A in treating vascular diseases.
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In this study, the copper-nickel (Cu-Ni) bimetallic electrocatalysts for electrochemical CO2 reduction reaction(CO2RR) are fabricated by taking the finely designed poly(ionic liquids) (PIL) containing abundant Salen and imidazolium chelating sites as the surficial layer, wherein Cu-Ni, PIL-Cu and PIL-Ni interaction can be readily regulated by different synthetic scheme. As a proof of concept, Cu@Salen-PIL@Ni(NO3)2 and Cu@Salen-PIL(Ni) hybrids differ significantly in the types and distribution of Ni species and Cu species at the surface, thereby delivering distinct Cu-Ni cooperation fashion for the CO2RR. Remarkably, Cu@Salen-PIL@Ni(NO3)2 provides a C2+ faradaic efficiency (FEC2+) of 80.9% with partial current density (jC 2+) of 262.9 mA cm-2 at -0.80 V (versus reversible hydrogen electrode, RHE) in 1 m KOH in a flow cell, while Cu@Salen-PIL(Ni) delivers the optimal FEC2+ of 63.8% at jC2+ of 146.7 mA cm-2 at -0.78 V. Mechanistic studies indicates that the presence of Cu-Ni interfaces in Cu@Salen-PIL@Ni(NO3)2 accounts for the preserve of high-valence Cu(I) species under CO2RR conditions. It results in a high activity of both CO2-to-CO conversion and C-C coupling while inhibition of the competitive HER.
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Rosin, a natural resin obtained from conifer trees, has a long history of use in traditional folk medicine for treating abscesses, wounds, carbuncles, and burns, etc. It has been employed in ancient Egypt, China, Nordic countries, and Turkey as a therapeutic remedy. This comprehensive review examines the traditional uses, phytochemistry, and pharmacology of rosin, and it provides a critical update on current knowledge of rosin and identifies potential therapeutic opportunities. The chemical composition of rosin is known to vary depending on factors such as botanical sources, geographical locations, and processing methods. Rosin acids, which account for over 90% of its primary chemical constituents, have been identified as the predominant compounds in rosin. Researchers have isolated approximately 50 compounds from rosin, with terpenoid rosin acids being the most prevalent. Furthermore, the review highlights the potential pharmacological activities of rosin and its constituents. Crude extracts and isolated rosin acids have demonstrated promising properties, including antimicrobial, anti-inflammatory, anti-tumor, insecticidal, wound healing, and anti-obesity effects. However, the review emphasizes that further research is needed, as existing studies are predominantly preliminary. Many of the reported bioactivities require further verification, and the underlying mechanisms of action remain largely unexplored. In conclusion, rosin has been extensively used in traditional medicine across different cultures, and its chemical composition has been confirmed to a significant extent. The pharmacological activities observed in crude extracts and isolated rosin acids support its traditional uses. Nevertheless, additional research is necessary to deepen our understanding of the pharmacological mechanisms underlying its effects.
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Medicina Tradicional , Compostos Fitoquímicos , Resinas Vegetais , Resinas Vegetais/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/química , Estrutura Molecular , Humanos , Animais , Traqueófitas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
A lipidated polysaccharide, HDPS-2II, was isolated from the dried larva of Holotrichia diomphalia, which is used in traditional Chinese medicine. The molecular weight of HDPS-2II was 5.9 kDa, which contained a polysaccharide backbone of â4)-ß-Manp-(1 â 4,6)-ß-Manp-(1 â [6)-α-Glcp-(1]n â 6)-α-Glcpâ with the side chain α-Glcp-(6 â 1)-α-Glcp-(6 â linked to the C-4 of ß-1,4,6-Manp and four types of lipid chains including 4-(4-methyl-2-(methylamino)pentanamido)pentanoic acid, 5-(3-(tert-butyl)phenoxy)hexan-2-ol, N-(3-methyl-5-oxopentan-2-yl)palmitamide, and N-(5-amino-3-methyl-5-oxopentan-2-yl)stearamide. The lipid chains were linked to C-1 of terminal α-1,6-Glcp in carbohydrate chain through diacyl-glycerol. HDPS-2II exhibited DNA protective effects and antioxidative activity on H2O2- or adriamycin (ADM)-induced Chinese hamster lung cells. Furthermore, HDPS-2II significantly ameliorated chromosome aberrations and the accumulation of reactive oxygen species (ROS), reduced γ-H2AX signaling and the expressions of NADPH oxidase (NOX)2, NOX4, P22phox, and P47phox in ADM-induced cardiomyocytes. Mechanistically, HDPS-2II suppressed ADM-induced up-regulation of NOX2 and NOX4 in cardiomyocytes, but not in NOX2 or NOX4 knocked-down cardiomyocytes, indicating that HDPS-2II could relieve intracellular DNA damage by regulating NOX2/NOX4 signaling. These findings demonstrate that HDPS-2II is a new potential DNA protective agent.
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Dano ao DNA , Glicolipídeos , Animais , Dano ao DNA/efeitos dos fármacos , Glicolipídeos/farmacologia , Glicolipídeos/química , Besouros , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Antioxidantes/química , Cricetulus , Polissacarídeos/farmacologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificaçãoRESUMO
Background: AAA is a fatal condition that commonly occurs during vascular surgery. Nutritional status exerts a significant influence on the prognosis of various pathological conditions Scores from the CONUT screening tool have been shown to predict outcomes of certain malignancies and chronic diseases. However, the ramifications of nutritional status on AAA patients undergoing EVAR have not been elucidated in prior studies. In this study, we aimed to elucidate the correlation between CONUT scores and postoperative prognostic outcomes in patients with AAA undergoing EVAR. Methods: This was a retrospective review of 177 AAA patients treated with EVAR from June 2018 to November 2019 in a single center. Patient characteristics, CONUT scores, and postoperative status were collected. These patients were stratified into groups A and B according to CONUT scores. Subsequently, a comparative analysis of the baseline characteristics between the two cohorts was conducted. Cox proportional hazards and logistic regression analyses were employed to identify the autonomous predictors of mid-term mortality and complications, respectively. Results: Compared with group A, patients in group B had higher midterm mortality (p < 0.001). Univariate analysis showed that CONUT scores; respiratory diseases; stent types; preoperative Hb, CRP, PT, and Fb levels were risk factors for death. Multivariate analysis confirmed that CONUT score [HR, 1.276; 95% CI, 1.029-1.584; p = 0.027] was an independent risk factor for mortality. Logistic regression analysis showed that prior arterial disease, smoking, and D-dimer levels were risk factors, although multivariate analysis showed smoking (OR, 3.492; 95% CI, 1.426-8.553; p = 0.006) was an independent risk factor. Kaplan-Meier curves showed that patients in group B had shorter mid-term survival than those in group A (log-rank p < 0.001). Conclusion: Malnutrition was strongly associated with mid-term mortality in patients with infrarenal AAA treated with EVAR.
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BACKGROUND: This study was designed to investigate the clinical outcomes of enhanced recovery after surgery (ERAS) in the perioperative period in elderly patients with non-small cell lung cancer (NSCLC). AIM: To investigate the potential enhancement of video-assisted thoracic surgery (VATS) in postoperative recovery in elderly patients with NSCLC. METHODS: We retrospectively analysed the clinical data of 85 elderly NSCLC patients who underwent ERAS (the ERAS group) and 327 elderly NSCLC patients who received routine care (the control group) after VATS at the Department of Thoracic Surgery of Peking University Shenzhen Hospital between May 2015 and April 2017. After propensity score matching of baseline data, we analysed the postoperative stay, total hospital expenses, postoperative 48-h pain score, and postoperative complication rate for the 2 groups of patients who underwent lobectomy or sublobar resection. RESULTS: After propensity score matching, ERAS significantly reduced the postoperative hospital stay (6.96 ± 4.16 vs 8.48 ± 4.18 d, P = 0.001) and total hospital expenses (48875.27 ± 18437.5 vs 55497.64 ± 21168.63 CNY, P = 0.014) and improved the satisfaction score (79.8 ± 7.55 vs 77.35 ± 7.72, P = 0.029) relative to those for routine care. No significant between-group difference was observed in postoperative 48-h pain score (4.68 ± 1.69 vs 5.28 ± 2.1, P = 0.090) or postoperative complication rate (21.2% vs 27.1%, P = 0.371). Subgroup analysis showed that ERAS significantly reduced the postoperative hospital stay and total hospital expenses and increased the satisfaction score of patients who underwent lobectomy but not of patients who underwent sublobar resection. CONCLUSION: ERAS effectively reduced the postoperative hospital stay and total hospital expenses and improved the satisfaction score in the perioperative period for elderly NSCLC patients who underwent lobectomy but not for patients who underwent sublobar resection.
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BACKGROUND: Elderly giant retrosternal thyroid goiter is a rare yet significant medical condition, often presenting clinical symptoms that can be confused with other diseases, posing diagnostic and therapeutic challenges. This study aims to delve into the characteristics and potential mechanisms of this ailment through pathological diagnosis and immunohistochemical analysis, providing clinicians with more precise diagnostic and treatment strategies. CASE SUMMARY: A 77-year-old male, was admitted to hospital with the chief complaint of finding a goiter in the semilunar month during physical examination, accompanied by dyspnea. Locally protruding into the superior mediastinum, the adjacent structure was compressed, the trachea was compressed to the right, and the local lumen was slightly narrowed. The patient was diagnosed with giant retrosternal goiter. Considering dyspnea caused by trachea compression, our department planned to perform giant retrosternal thyroidectomy. Immunohistochemical results: Tg (+), TTF-1 (+), Calcitonin (CT) (I), Ki-67 (+, about 20%), CD34 (-). Retrosternal goiter means that more than 50% of the volume of the thyroid gland is below the upper margin of the sternum. As retrosternal goiter disease is a relatively rare disease, once the disease is diagnosed, it should be timely surgical treatment, and the treatment is more difficult, the need for professional medical team for comprehensive treatment. CONCLUSION: The imaging manifestations of giant retrosternal goiter are atypical, histomorphology and immunohistochemistry can assist in its diagnosis. This article reviews the relevant literature of giant retrosternal goiter immunohistochemistry and shows that giant retrosternal goiter is positive for Tg, TTF-1, and Ki-67.
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Venous thromboembolism, which includes deep venous thrombosis (DVT) and pulmonary embolism, is the third most common vascular disease in the world and seriously threatens the lives of patients. Currently, the effect of conventional treatments on DVT is limited. Endothelial progenitor cells (EPCs) play an important role in the resolution and recanalization of DVT, but an unfavorable microenvironment reduces EPC function. Non-coding RNAs, especially long non-coding RNAs and microRNAs, play a crucial role in improving the biological function of EPCs. Non-coding RNAs have become clinical biomarkers of diseases and are expected to serve as new targets for disease intervention. A theoretical and experimental basis for the development of new methods for preventing and treating DVT in the clinic will be provided by studies on the role and molecular mechanism of non-coding RNAs regulating EPC function in the occurrence and development of DVT. To summarize, the characteristics of venous thrombosis, the regulatory role of EPCs in venous thrombosis, and the effect of non-coding RNAs regulating EPCs on venous thrombosis are reviewed. This summary serves as a useful reference and theoretical basis for research into the diagnosis, prevention, treatment, and prognosis of venous thrombosis.
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Células Progenitoras Endoteliais , MicroRNAs , Doenças Vasculares , Trombose Venosa , Humanos , MicroRNAs/genética , Trombose Venosa/genética , Trombose Venosa/terapia , Movimento CelularRESUMO
Iliac vein stenting for the treatment of iliac vein compression syndrome (IVCS) has been gradually developed. This article investigated the long-term patency and improvement of clinical symptoms after endovascular stenting for iliac vein obstruction patients. From 2020 to 2022, 83 patients at a single institution with IVCS underwent venous stent implantation and were divided into two groups: non-thrombotic IVCS (n = 55) and thrombotic IVCS (n = 28). The main stent-related outcomes include technical success, long-term patency, and thrombotic events. The technical success rate of all stent implantation was 100%. The mean length of hospital stay and cost were higher in the thrombotic IVCS group than in the non-thrombotic ICVS group, as well as the length of diseased vessel segment and the number of stents implanted were higher than in the control non-thrombotic group. The 1-, 2-, and 3-year patency rates were 85.4%, 80% and 66.7% in the thrombosis group, which were lower than 93.6%, 88.7%, and 87.5% in the control group (P = .0135, hazard ratio = 2.644). In addition, patients in both groups had a foreign body sensation after stent implantation, which resolved spontaneously within 1 year after surgery. Overall, there were statistically significant differences in long-term patency rate outcome between patients with thrombotic and non-thrombotic IVCS, the 1-, 2-, and 3-year patency rates in non-thrombotic IVCS patients were higher than those in thrombotic IVCS patients.
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Síndrome de May-Thurner , Trombose , Trombose Venosa , Humanos , Síndrome de May-Thurner/complicações , Síndrome de May-Thurner/cirurgia , Trombose Venosa/etiologia , Trombose Venosa/cirurgia , Trombose Venosa/diagnóstico , Resultado do Tratamento , Estudos Retrospectivos , StentsRESUMO
OBJECTIVE: The objective of this study was to compare the outcomes of pharmacomechanical thrombolysis and thrombectomy (PCDT) plus catheter-directed thrombolysis (CDT) vs CDT alone for the treatment of acute iliofemoral deep vein thrombosis (DVT) and summarize the clinical experience, safety outcomes, and short- and long-term efficacy. METHODS: We performed a 4-year retrospective, case-control study. A total of 95 consecutive patients with acute symptomatic iliofemoral deep vein thrombosis (DVT) with a symptom duration of ≤7 days involving the iliac and/or common femoral veins underwent endovascular interventions. The patients were divided into two groups according to their clinical indications: PCDT plus CDT vs CDT alone. Statistical analyses were used to compare the clinical characteristics and outcomes between the two groups. Additionally, the patients were followed up for 3 to 36 months after treatment, and the proportions of post-thrombotic syndrome (PTS) and moderate to severe PTS were analyzed using the Kaplan-Meier survival method. RESULTS: A total of 95 consecutive patients were analyzed in this retrospective study, of whom, 51 underwent CDT alone and 44 underwent PCDT plus CDT. Between the two groups, in terms of immediate-term efficacy and safety, significant differences were found in the catheter retention time (60.64 ± 12.04 hours vs 19.42 ± 4.04 hours; P < .001), dosages of urokinase required (5.82 ± 0.81 million units vs 1.80 ± 0.64 million units; P < .001), the detumescence rate at 24 hours postoperatively (48.46% ± 8.62% vs 76.79% ± 7.98%; P = .026), the descent velocity of D-dimer per day (2266.28 ± 1358.26 µg/L/D vs 3842.34 ± 2048.02 µg/L/D; P = .018), total hospitalization stay (6.2 ± 1.40 days vs 3.8 ± 0.70 days; P = .024), number of postoperative angiograms (2.4 ± 0.80 vs 1.2 ± 0.30; P = .042), and grade III venous patency (>95% lysis: 54.5% vs 68.6%; P = .047). Furthermore, during the follow-up period, significant differences were found in the incidence of PTS (Villalta scale ≥5 or a venous ulcer: 47.0% vs 27.7%; P = .037), and the incidence proportion of moderate to severe PTS at 12 months (15.7% vs 4.5%; P = .024) and 24 months (35.3% vs 11.4%; P = .016). CONCLUSIONS: Compared with CDT alone, in the iliofemoral DVT subgroup with a symptom duration of ≤7 days, PCDT plus CDT could significantly relieve early leg symptoms, shorten the hospitalization stay, reduce bleeding complications, promote long-term venous patency, and decrease the occurrence of PTS and the incidence proportion of moderate to severe PTS. Thus, the short- and long-term outcomes both support the superiority of PCDT plus CDT vs CDT in this subgroup.
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Síndrome Pós-Trombótica , Trombose Venosa , Humanos , Estudos Retrospectivos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Fibrinolíticos , Estudos de Casos e Controles , Resultado do Tratamento , Veia Ilíaca/diagnóstico por imagem , Veia Ilíaca/cirurgia , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/terapia , Trombose Venosa/complicações , Síndrome Pós-Trombótica/diagnóstico por imagem , Síndrome Pós-Trombótica/etiologia , Síndrome Pós-Trombótica/terapia , Catéteres/efeitos adversos , Doença AgudaRESUMO
BACKGROUND: Minute Pulmonary Meningothelial-like Nodules (MPMNs) are rare benign pulmonary nodules, which are more common in elderly women and have a higher detection rate in lung tissues of patients with lung malignant diseases. Its origin is not yet clear. At present, there are few reports on the diagnostic methods such as imaging and pathological manifestations of MPMNs. This article reports a 70-year-old female patient with pulmonary adenocarcinoma combined with MPMNs and reviews of the relevant literature. CASE SUMMARY: A 70-year-old women was admitted to our institution with feeling sour in her back and occasional cough for more than 2 mo. Computerized electronic scanning scan and 3D reconstruction images in our institution showed there were multiple ground-glass nodules in both of her two lungs. The biggest one was in the apicoposterior segment of left upper lobe, about 2.5 mm × 9 mm in size. We performed thoracoscopic resection of the left upper lung apicoposterior segment of the patient, and the final pathological report was minimally invasive adenocarcinoma. Re-examination of high resolution computed tomography 21 mo after surgery showed multiple ground-glass nodules in both lungs, and a new ground-glass nodule was found in the superior segment of the right lower lobe. We took pathological biopsy of the right upper lung and right lower lung nodules for the patient under thoracoscopy. The histomorphology of the right lower lobe nodule showed multiple lesions in the lung tissue, and the small foci in the alveolar septum were distributed in mild form of the aggregation of short spindle cells. The immunohistochemistry showed that the lesion was epithelial membrane antigen (EMA) (+), somatostatin receptor 2a (SSTR2a) (+), S-100 (-), chromogranin A (-), Syn (-), cytokeratin (-) and HMB-45 (-). The final diagnosis was minimally invasive adenocarcinoma, accompanied by MPMNs. We recommend that patients continue to receive treatment after surgery and to do regular follow-up observations. CONCLUSION: The imaging manifestations of MPMNs are atypical, histomorphology and immunohistochemistry can assist in its diagnosis. This article reviews the relevant literature of MPMNs immunohistochemistry and shows that MPMNs are positive for EMA, SSTR2a, and progesterone receptor.
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OBJECTIVE: To first induce chronic deep venous thrombosis in the left iliac veins of canines and porcines and then compare these two models to validate endovascular treatment devices. METHODS: Thrombin and fibrinogen were used to produce a solid thrombus in the left iliac veins of a stenosis model. The researchers used venous angiography and histological staining to investigate the progression of thrombosis. RESULTS: A left iliac vein thrombus was successfully formed in all experimental animals, including six Labrador dogs and three Bama miniature pigs, and there was minimal surgical bleeding. All dogs survived until 90 days, and three pigs died on Days 29, 33, and 58. CONCLUSION: The researchers first established the models and then observed the progression of chronic deep venous thrombosis of the iliac vein in large animals for up to 90 days. Dogs are better suited for chronic deep venous thrombosis models due to their uncomplicated anatomy, excellent obedience, and proneness to physical activity compared with pigs.
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The widespread occurrence of tire tread particles (TPs) has aroused increasing concerns over their impacts. However, how they affect the soil fauna remains poorly understood. Here, based on systematically assessing the toxicity of TPs on soil model speciesEnchytraeus crypticusat environmentally relevant concentrations through both soil and food exposure routes, we reported that TPs affected gut microbiota, intestinal histopathology, and metabolites of the worms both through particulate- and leachate-induced effects, while TP leachates exerted stronger effects. The dominant role of TP leachates in TP toxicity was further explained by the findings that worms did not ingest TPs with a particle size of over 150 µm and actively avoided consuming TP particles. Moreover, by comparing the effects of different brands of TPs as well as new and aged TPs, we demonstrated that it was mainly TP leachates that resulted in the ubiquity of the disturbance in the worm's gut microbiota among different brands of TPs. Notably, the large variations in leachate compositions among different brands of TPs provided us a unique opportunity to identify the determinants of TP toxicity. These results provide novel insights into the toxicity of TPs to soil fauna and a reference for toxicity reduction of tires.
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Microbioma Gastrointestinal , Poeira , Tamanho da Partícula , SoloRESUMO
The electrocatalytic reduction of CO2 to CO with high efficiency is one of the most promising approaches for CO2 conversion due to its considerable economic feasibility and broad application prospects. In this study, three Ag@COF-R (R = -H, -OCH3, -OH) hybrids were facilely fabricated by impregnating silver acetate (AgOAc) into respective covalent organic frameworks (COFs) prepared in advance. They differ significantly in the crystallinity, porosity, distribution, size, and electronic configuration of AgOAc species, which thereby influences both the activity and the selectivity of electrolytic CO2-to-CO transformation. Impressively, Ag@COF-OCH3 provided a high FECO of 93.0% with a high jCO of 213.9 mA cm-2 at -0.87 V (vs reversible hydrogen electrode, RHE) in 1 M KOH using a flow cell. In addition, it exhibited long-term durability at 100 mA cm-2 for 30 h.
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Background: Ruptured abdominal aortic aneurysms (rAAAs) are challenging for vascular surgeons because they have a high mortality rate. In many diseases, nutritional status is closely associated with prognosis. The Controlling Nutritional Status (CONUT) screening tool score is a prognostic factor in some malignant and chronic diseases; however, the impact of nutritional status on rAAA has not yet been reported. In this study, we explored the relationship between the CONUT score and the postoperative prognosis of patients with rAAA. Methods: This was a retrospective review of 39 patients with rAAA who underwent surgical treatment from March 2018 to September 2021 at one center. Patient characteristics, nutritional status (CONUT score), and postoperative status were recorded. The patients were divided into groups A and B based on the CONUT score. The baseline characteristics of the two groups were compared, and Cox proportional hazards and logistic regression analyses were used to determine independent predictors of mid-term mortality and complications, respectively. Results: The overall mid-term mortality rate was 28.21% (11/39). Compared with group A, group B had higher intraoperative (P = 0.047) and mid-term mortality (P = 0.033) rates. The univariate analysis showed that age [hazard ratio (HR), 1.098; 95% confidence interval (CI), 1.019-1.182; P = 0.014], CONUT score (HR, 1.316; 95% CI, 1.027-1.686; P = 0.03), and surgical procedure (HR, 0.127; 95% CI, 0.016-0.992; P = 0.049) were associated with mid-term mortality, whereas the multivariate analysis showed that the CONUT score (HR, 1.313; 95% CI, 1.009-1.710; P = 0.043) was an independent predictor of mid-term mortality. The multivariate logistic regression analysis did not reveal any associations with complications. The Kaplan-Meier curves showed that group B had a lower mid-term survival rate (log-rank P = 0.024). Conclusion: Malnutrition is closely associated with the prognosis of patients with rAAA, and the CONUT score can be used to predict mid-term mortality.
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Aims: Transient receptor potential canonical-6 (TRPC6) is a therapeutic target for hepatocellular carcinoma. The authors aimed to synthesize and determine whether indole-2-carboxamide derivatives have anti-hepatocellular carcinoma activities targeting TRPC6. Materials & methods: Molecular docking was carried out to design these derivatives. The top five compounds were synthesized for activity validation using microscale thermophoresis. Cell cytotoxicity, flow cytometry, western blotting and cell transfection were used to investigate the anti-hepatocellular carcinoma activities and mechanisms in vitro. Xenografts of nude mice were used for in vivo evaluation. Results: The indole-2-carboxamide derivative, BP3112, promoted apoptosis and G1-phase arrest in HCCs via inhibiting TRPC6, and dose-dependently inhibit tumor growth in vivo. Conclusion: BP3112 as a specific inhibitor of TRPC6 is a potential therapeutic agent for hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Canal de Cátion TRPC6/uso terapêutico , Camundongos Nus , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Apoptose , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Indóis/farmacologia , Indóis/uso terapêutico , Proliferação de CélulasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Liuwei Dihuang (LWDH) is a classic prescription that has been used to the treatment of "Kidney-Yin" deficiency syndrome for more than 1000 years in China. Recent studies have confirmed that LWDH can prevent the progression of renal fibrosis. Numerous studies have demonstrated the critical role that TRPC6 plays in the development of renal fibrosis. Due to the complex composition of LWDH and its remarkable therapeutic effect on renal fibrosis, it is possible to discover new active ingredients targeting TRPC6 for the treatment of renal fibrosis. AIM OF STUDY: This study aimed to identify selective TRPC6 inhibitors from LWDH and evaluate their therapeutical effects on renal fibrosis. MATERIALS AND METHODS: Computer-aided drug design was used to screen the biologically active ingredients of LWDH, and their affinities to human TRPC6 protein were detected by microcalorimetry. TRPC6, TRPC3, and TRPC7 over-expressed HEK293 cells were constructed, and the selective activities of the compounds on TRPC6 were determined by measuring [Ca2+]i in these cells. To establish an in vitro model of renal fibrosis, human renal proximal tubular epithelial HK-2 cells were stimulated with TGF-ß1. The therapeutic effects of LWDH compounds on renal fibrosis were then tested by detecting the related proteins. TRPC6 was knocked-down in HK-2 cells to investigate the effects of LWDH active ingredients on TRPC6. Finally, a unilateral ureteral obstruction model of renal fibrosis was established to test the therapeutic effect. RESULTS: From hundreds of LWDH ingredients, 64 active components with oral bioavailability ≥30% and drug-likeness index ≥0.18 were acquired. A total of 10 active components were obtained by molecular docking with TRPC6 protein. Among them, 4 components had an affinity with TRPC6. Piperlonguminine (PLG) had the most potent affinity with TRPC6 and blocking effect on TRPC6-mediated Ca2+ entry. A 100 µM of PLG showed no detectable inhibition on TRPC1, TRPC3, TRPC4, TRPC5, or TRPC7-mediated Ca2+ influx into cells. In vitro results indicated that PLG concentration-dependently inhibited the abnormally high expression of α-smooth muscle actin (α-SMA), collagen I, vimentin, and TRPC6 in TGF-ß1-induced HK-2 cells. Consistently, PLG also could not further inhibit TGF-ß1-induced expressions of these protein biomarkers in TRPC6 knocked-down HK-2 cells. In vivo, PLG dose-dependently reduced urinary protein, serum creatinine, and blood urea nitrogen levels in renal fibrosis mice and markedly alleviated fibrosis and the expressions of α-SMA, collagen I, vimentin, and TRPC6 in kidney tissues. CONCLUSION: Our results showed that PLG had anti-renal fibrosis effects by selectively inhibiting TRPC6. PLG might be a promising therapeutic agent for the treatment of renal fibrosis.
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Nefropatias , Obstrução Ureteral , Humanos , Camundongos , Animais , Canal de Cátion TRPC6/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Vimentina , Células HEK293 , Simulação de Acoplamento Molecular , Nefropatias/metabolismo , Obstrução Ureteral/metabolismo , Fibrose , Colágeno/metabolismo , RimRESUMO
PURPOSE: To summarize experience with and the efficacy of fenestrated/branched thoracic endovascular repair (F/B-TEVAR) using physician-modified stent-grafts (PMSGs) under 3D printing guidance in triple aortic arch branch reconstruction. MATERIALS AND METHODS: From February 2018 to April 2022, 14 cases of aortic arch aneurysms and 30 cases of aortic arch dissection (22 acute aortic arch dissection and 8 long-term aortic arch dissection)were treated by F/B-TEVAR in our department, including 34 males and 10 females, with an average age of 59.84 ± 11.72 years. Three aortic arch branches were affected in all patients. A 3D-printed model was made according to computed tomography angiography images and used to guide the fabrication of PMSGs. All patients were followed up. RESULTS: A total of 132 branches were successfully reconstructed with no case of conversion to open surgery. The average operation time was 4.97 ± 1.40 hours, including a mean 44.05 ± 7.72 minutes for stent-graft customization, the mean postoperative hospitalization duration was 9.91 ± 4.47 days, the average intraoperative blood loss was 480.91 mL (100-2810 mL), and the mean postoperative intensive care unit monitoring duration was 1.02 days (0-5 days). No deaths occurred within 30 days of surgery. Postoperative neurological complications occurred in 1 case (2.3%), and retrograde type A dissection occurred in 1 case (2.3%). CONCLUSION: Compared with conventional surgery, triple aortic arch branch reconstruction under the guidance of 3D printing is a minimally invasive treatment method with the advantages of accurate positioning, rapid postoperative recovery, few complications, and reliable short- to mid-term effects. CLINICAL IMPACT: At present the PMSG usually depend on imaging data and software calculation. With the guidance of 3D printing technology, image data could be transformed into 3D model, which has improved the accuracy of the positioning of the fenestrations. The diameter reduction technique and the internal mini cuff technique have made a complement to the slimed-down fenestration selection process and the low rate of endoleak. As reproducible study, our results may provide reference for TEVAR in different cases.
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Background: The aim of this study was to perform hemodynamic simulations of a three-dimension ideal inferior vena cava-iliac vein model with artificial stenosis to determine the degree of stenosis that requires clinical intervention. Methods: Four three-dimension stenosis models (30%, 50%, 70%, and 90% stenosis) were constructed using commercial software (Solidworks). The inlet flow rates were acquired from previous literatures to perform the hemodynamic simulations. Changes in the old blood volume fraction, as well conventional hemodynamic parameters including pressure, differential pressure, wall shear stress, and flow patterns, over time were recorded. The pressure at the telecentric region of the stenosis increased with increasing degree of stenosis. Results: For the 70% stenosis model, the pressure at the telecentric region of the stenosis reached 341 Pa, and the differential pressure between the two ends of the stenosis was 363 Pa (approximately 2.7 mmHg). Moreover, in the 70% and 90% stenosis models, there was a marked change in wall shear stress in the stenosis and the proximal end region, and the flow patterns began to show the phenomenon of flow separation. Blood stasis analysis showed that the 70% stenosis model had the slowest decrease in old blood volume fraction, while the proximal end region had the largest blood residue (15%). Conclusion: Iliac vein stenosis of approximately 70% is associated with clinically relevant hemodynamic changes, and is more closely related to DVT than other degrees of stenosis.