ABSTRACT
PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications. METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression. RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6 %, P < 0.05), NLRP3 (46.8 %, P < 0.05), and p-P38/P38 (37.1 %, P < 0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0 %, P < 0.01), TNF-α (30.3 %, P < 0.05), and NLRP3 (43.3 %, P < 0.05). CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-κB pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.
Subject(s)
Acetylcysteine , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Drug Therapy, Combination , Insulin , NF-kappa B , Pyroptosis , Signal Transduction , Spleen , Animals , Dogs , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/drug therapy , NF-kappa B/metabolism , Pyroptosis/drug effects , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Signal Transduction/drug effects , Male , Spleen/drug effects , Spleen/pathology , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Splenic Diseases/drug therapy , Splenic Diseases/etiology , Splenic Diseases/complications , MAP Kinase Signaling System/drug effectsABSTRACT
Background: Cardiovascular surgery is usually associated with higher degree of postoperative pain that influences a patient's physical recovery. Multiple clinical measures have been taken to avoid overuse of opioid agents for postoperative pain management, which led to the development of clinical pathways for analgesic drug treatment using a multimodal approach. Objective: To evaluate the effectiveness and safety of a multimodal postoperative analgesic drug pathway (ADP) for pain management following cardiovascular surgery. Methods: This retrospective, controlled, nonrandomized study evaluated a postoperative ADP in patients undergoing cardiovascular surgery in a tertiary general hospital in Qingdao, China. Effectiveness and safety outcomes were compared before and after the implementation of the ADP. Outcome indicators included postoperative pain scores, consumption of opioids in analgesic pumps, and incidence of adverse events. Results: Patients who underwent cardiovascular surgery from September to November 2021 before the implementation of the ADP (nâ¯=â¯193) and from September to November 2022 after the implementation of the ADP (nâ¯=â¯218) were enrolled. Pain scores were reduced on day 1, 3, and 5 after surgery and the reduction was most significant in mild pain (P < .001). Opioids in analgesic pumps consumption was also significantly reduced and there was decreased incidence of adverse events such as nausea and vomiting (Pâ¯=â¯.026), respiratory inhibition (Pâ¯=â¯.027), and dizziness and headache (Pâ¯=â¯.028) in cardiovascular surgery patients after implementation of the ADP. Conclusions: Improved effectiveness and safety were observed following the implementation of the ADP. Multimodal analgesic ADP methodology can be effectively used for postoperative pain management in patients undergoing cardiovascular surgery.
ABSTRACT
Acute myocardial injury (AMI) induced by lipopolysaccharide (LPS) can cause cardiovascular dysfunction and lead to death in poultry. Traditional antibiotic therapy has been found to have many limitations and negative effects. Asiatic acid (AA) is a naturally occurring pentacyclic triterpenoid that is extracted from Centella asiatica and has anti-inflammatory, antioxidant, and anticancer pharmacological properties. Previously, we studied the effect of AA on LPS-induced liver and kidney injury; however, the impact of AA on LPS-induced AMI remained unclear. Sixty 1-day-old broilers were randomly divided into control group, LPS group, LPS + AA 15 mg/kg group, LPS + AA 30 mg/kg group, LPS + AA 60 mg/kg group, and control + AA 60 mg/kg group. The histopathology of cardiac tissues was detected by hematoxylin and eosin (H&E) staining. The mRNA and protein expressions related to mitochondrial dynamics and mitophagy were detected by quantitative real-time PCR, western blot, immunofluorescence, and immunohistochemistry. Disorganized myocardial cells and fractured myocardial fibers were found in the LPS group, and obvious red-blood-cell filling can be seen in the gaps between the myocardial fibers in the low-dose AA group. Nevertheless, the medium and high dose of AA obviously attenuated these changes. Our results showed that AA significantly restored the mRNA and protein expressions related to mitochondrial dynamic through further promoting mitophagy. This study revealed the effect of AA on LPS-induced AMI in broilers. Mechanically, AA regulated mitochondrial dynamic homeostasis and further promoted mitophagy. These novel findings indicate that AA may be a potential drug for LPS-induced AMI in broilers.
El ácido asiático como mitigante de las lesiones miocárdicas agudas inducidas por lipopolisacáridos al promover la mitofagia y regular la dinámica mitocondrial en pollos de engorde. La lesión miocárdica aguda (con siglas en inglés IAM) inducida por lipopolisacáridos (LPS) puede causar disfunción cardiovascular y provocar la muerte en las aves comerciales. Se ha descubierto que la terapia tradicional con antibióticos tiene muchas limitaciones y efectos negativos. El ácido asiático (AA) es un triterpenoide pentacíclico natural que se extrae de la planta Centella asiática y que tiene propiedades farmacológicas antiinflamatorias, antioxidantes y anticancerígenas. Anteriormente, se estudió el efecto del ácido asiático sobre la lesión hepática y renal inducida por lipopolisacáridos; sin embargo, el impacto del ácido asiático en las lesiones miocárdicas agudas inducidas por lipopolisacáridos continua sin estar completamente determinada. Sesenta pollos de engorde de un día de edad se dividieron aleatoriamente en los siguientes grupos experimentales: grupo control, grupo que recibió LPS solamente, grupo LPS + ácido asiático 15 mg/kg, grupo LPS + ácido asiático 30 mg/kg, grupo LPS + ácido asiático 60 mg/kg y control + ácido asiático 60 mg./kg grupo. La histopatología de los tejidos cardíacos se detectó mediante tinción con hematoxilina y eosina (H&E). Las expresiones de ARN mensajero y proteínas relacionadas con la dinámica mitocondrial y la mitofagia se detectaron mediante PCR cuantitativa en tiempo real, inmunotransferencia Western, inmunofluorescencia e inmunohistoquímica. Se encontraron células miocárdicas desorganizadas y fibras miocárdicas fracturadas en el grupo que recibió lipopolisacáridos, y se puede observar un evidente acúmulo de glóbulos rojos en los espacios entre las fibras miocárdicas en el grupo de dosis bajas de ácido asiático. Sin embargo, las dosis medias y altas de ácido asiático obviamente atenuaron estos cambios. Nuestros resultados mostraron que el ácido asiático restableció significativamente las expresiones de ARN mensajero y proteínas relacionadas con la dinámica mitocondrial mediante la promoción adicional de la mitofagia. Este estudio reveló el efecto del ácido asiático sobre las lesiones miocárdicas agudas inducidas por lipopolisacáridos en pollos de engorde. Basicamente, el ácido asiático reguló la homeostasis dinámica mitocondrial y promovió aún más la mitofagia. Estos nuevos hallazgos indican que el ácido asiático puede ser un fármaco potencial para mitigar lesiones miocárdicas agudas inducidas por lipopolisacáridos en pollos de engorde.
Subject(s)
Chickens , Lipopolysaccharides , Mitophagy , Pentacyclic Triterpenes , Poultry Diseases , Animals , Pentacyclic Triterpenes/pharmacology , Pentacyclic Triterpenes/administration & dosage , Poultry Diseases/chemically induced , Mitophagy/drug effects , Mitochondrial Dynamics/drug effects , Random AllocationABSTRACT
Inflammatory response induced by biological stress usually occurs in weaning piglets, it reduces the production performance of piglets and even causes death. Tert-butylhydroquinone (TBHQ) is a food additive that has the effect of anti-inflammation and anti-oxidation. However, there are few reports related to the protective mechanisms of TBHQ on lipopolysaccharide (LPS) induced injury in intestinal porcine epithelial (IPEC-J2) cells. Quantitative real-time polymerase chain reaction and western blot analysis, respectively, detected the mRNA levels and protein expressions related to pyroptosis, tight junction (TJ) protein and high-mobility group box 1/toll-like receptor 4/nuclear factor kappa-B (HMGB1/TLR4/NF-κB) axis. Localisation and expression of NOD-like receptor pyrin domain containing 3 (NLRP3), HMGB1 and P-NF-κB proteins detected by immunofluorescence. The results showed that TBHQ (12.5 and 25 µM) can increase cell activity and reduce intracellular lactate dehydrogenase (LDH) levels in a dose-dependent manner. LPS significantly decreases cell viability and increases the LDH level. However, pretreatment with TBHQ evidently increases cell viability and decreases the LDH level of IPEC-J2 cells. In addition, treatment with LPS decreased the mRNA level and protein expression of zonula occludens-1, occludin and claudin-1, and increased the mRNA level and protein expression of pyroptosis and HMGB1/TLR4/NF-κB axis. Interestingly, pretreatment with TBHQ increased the TJ protein expressions as well as decreased the mRNA level and protein expressions of pyroptosis and HMGB1/TLR4/NF-κB axis. Moreover, the results of immunofluorescence showed that TBHQ significantly reduced the expression of NLRP3, HMGB1 and P-NF-κB in LPS-induced injury of IPEC-J2 cells. Therefore, we come to the conclusion that TBHQ attenuates LPS-induced pyroptosis in IPEC-J2 cells through downregulation of the HMGB1/TLR4/NF-κB axis, TBHQ may become a potential feed additive for preventing inflammatory diarrhoea in piglets.
Subject(s)
HMGB1 Protein , NF-kappa B , Animals , Swine , NF-kappa B/genetics , NF-kappa B/metabolism , Lipopolysaccharides/toxicity , NLR Family, Pyrin Domain-Containing 3 Protein , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Pyroptosis , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , RNA, MessengerABSTRACT
The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1ß-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.
Subject(s)
Diabetes Mellitus, Type 1 , NF-kappa B , Humans , Animals , Dogs , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha , Insulin/metabolism , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/drug therapy , Apoptosis , UbiquitinationABSTRACT
Nanoplastics (NPs) are defined as a group of emerging pollutants. However, the adverse effect of NPs and/or heavy metals on mammals is still largely unclear. Therefore, we performed a 35-day chronic toxicity experiment with mice to observe the impacts of exposure to Cadmium (Cd) and/or polystyrene nanoplastics (PSNPs). This study revealed that combined exposure to Cd and PSNPs added to the mice's growth toxicity and kidney damage. Moreover, Cd and PSNPs co-exposure obviously increased the MDA level and expressions of 4-HNE and 8-OHDG while decreasing the activity of antioxidase in kidneys via inhibiting the Nrf2 pathway and its downstream genes and proteins expression. More importantly, the results suggested for the first time that Cd and PSNPs co-exposure synergistically increased iron concentration in kidneys, and induced ferroptosis through regulating expression levels of SLC7A11, GPX4, PTGS2, HMGB1, FTH1 and FTL. Simultaneously, Cd and PSNPs co-exposure further increased the expression levels of Pink, Parkin, ATG5, Beclin1, and LC3 while significantly reducing the P62 expression level. In brief, this study found that combined exposure to Cd and PSNPs synergistically caused oxidative stress, ferroptosis and excessive mitophagy ultimately aggravating kidney damage in mice, which provided new insight into the combined toxic effect between heavy metals and PSNPs on mammals.
Subject(s)
Cadmium , Ferroptosis , Animals , Mice , Cadmium/toxicity , Microplastics , Polystyrenes/toxicity , Mitophagy , Oxidative Stress , Kidney , MammalsABSTRACT
The development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lyciumbarbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes IâV. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.
Subject(s)
Chemical and Drug Induced Liver Injury , Mitochondria , Oxidative Stress , Polysaccharides , Animals , Dogs , Antioxidants/metabolism , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury/drug therapy , Kelch-Like ECH-Associated Protein 1/metabolism , Liver , Metabolic Networks and Pathways , Mitochondria/metabolism , NF-E2-Related Factor 2/metabolism , Polysaccharides/pharmacology , Lycium/chemistryABSTRACT
Recurrence and distant metastasis after paclitaxel (PTX)-based chemotherapy in ovarian cancer (OC) patients remains a clinical obstacle. Flavokawain A (FKA) is a novel chalcone from kava plant that can induce G2/M arrest and inhibit invasion and metastasis in different tumor cells. In this study, we examined the effects and the molecular mechanism of sodium aescinate (Aes)-stabilized nanoparticles FKA-A NPs in enhancing the efficacy of PTX-A NPs in vitro and in vivo. We showed that FKA-A NPs combined with PTX-A NPs notably inhibited the proliferation and migration and reduced the expression of EMT-related markers in OCs. YAP nuclear translocation and its downstream signaling pathway were remarkably activated after PTX-A NPs treatment in OCs. FKA-A NPs obviously inhibited YAP nuclear translocation and reduced the transcriptional activity of YAP target genes. Simultaneously, FKA-A NPs dose and time dependently inhibited Skp2 expression in A2780 and Skov3 cells. In contrast, overexpression of Skp2 significantly attenuated the inhibition of FKA-A NPs on YAP nuclear translocation. In OC homograft mice, treatment with FKA-A NPs and PTX-A NPs significantly suppressed the growth of homograft tumor compared with PTX-A NPs but did not decrease mice's body weight. In summary, we demonstrate that FKA-A NPs enhance the efficacy of PTX-A NPs against OCs in vitro and in vivo via reducing Skp2 expression, thus suppressing YAP nuclear translocation and activity of its target genes.
Subject(s)
Nanoparticles , Ovarian Neoplasms , Humans , Mice , Animals , Female , Paclitaxel/pharmacology , Cell Line, Tumor , Ovarian Neoplasms/drug therapy , Apoptosis , G2 Phase Cell Cycle CheckpointsABSTRACT
Asiatic acid (AA), a triterpenoid compound isolated from Centella asiatica, has anti-inflammatory, antioxidant and anticancer biological characteristics. To explore the effect of AA on LPS-induced acute kidney injury (AKI) in broilers, a total of 60 one-day-old broilers were randomly divided into 6 groups, including the normal group, AKI model group, AKI + AA 15 mg/kg group, AKI + AA 30 mg/kg group, AKI + AA 60 mg/kg group and normal + AA 60 mg/kg group. Hematoxylin-eosin staining was used to observe the histopathology in kidney tissue, and the mRNA and protein expressions related to oxidative stress and ferroptosis were tested by qPCR and western blotting respectively. AA mitigated vacuolar degeneration and enlarged glomerular space caused by LPS in kidney tissue. Additionally, AA significantly increased the mRNA levels of Nrf2, HO-1, NQO1, GCLC, GCLM, GPX4, SLC7A11 and FTH1, and decreased the mRNA levels of Keap1 and PTGS2 in LPS-induced AKI. Likewise, AA significantly upregulated the protein expressions of Nrf2, HO-1, NQO1, GPX4, SLC7A11 and FTH1, and downregulated the protein expressions of Keap1 and PTGS2 in LPS-induced AKI. These results suggested that AA alleviated LPS-induced AKI by inhibiting oxidative stress and ferroptosis through targeting regulation of the Nrf2 pathway in broilers.
Subject(s)
Acute Kidney Injury , Ferroptosis , Animals , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Lipopolysaccharides/adverse effects , Chickens/metabolism , Cyclooxygenase 2/metabolism , Oxidative Stress , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , RNA, Messenger/metabolismABSTRACT
PURPOSE: To investigate the perioperative clinical nursing experience and application effect of small incision phacoemulsification with topical anesthesia. METHODS: Retrospectively analysis of 126 patients who came to our hospital for small incision phacoemulsification with topical anesthesia from November 2018 to November 2019. These patients were randomly divided into a study group and a control group, with 63 patients in each group. Patients from both groups underwent small incision phacoemulsification with topical anesthesia. The control group used routine nursing care during the perioperative period, and the study group used comprehensive nursing care. The clinical intervention effects of the two groups were compared. RESULTS: The visual acuity of the two groups of patients after intervention was significantly improved (P<0.001), and the visual acuity of the study group after intervention was significantly better than that of the control group (P<0.001); the astigmatism of the study group after intervention was obviously lower (P<0.001); the Self-rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores of the two groups of patients after intervention were significantly lower than those before the intervention, and the decrease of SAS and SDS scores of the study group were more significant (P<0.001); The clinical nursing satisfaction of the study group was significantly higher than that of the control group (P<0.05); the postoperative complication rate of the study group was significantly lower than that of the control group (P<0.05); the cataract knowledge scores of the two groups of patients after intervention were both significantly higher than before the intervention, and the increase of cataract knowledge score of the study group was more remarkable (P<0.001). CONCLUSION: The comprehensive nursing mode used in small incision phacoemulsification with topical anesthesia for cataract extraction can effectively improve the patient's visual acuity, reduce the astigmatism, and have a lower incidence of postoperative complications, which has high clinical application value.
ABSTRACT
BACKGROUND: The purpose of the study is to identify off-pump patients who are at higher risk of mortality after re-exploration for bleeding or tamponade. METHODS: We analyzed the data of 3256 consecutive patients undergoing isolated off-pump coronary artery bypass grafting (OPCABG) in our heart center from 2013 through 2020. Fifty-eight patients underwent re-exploration after OPCABG. The 58 patients were divided into death group and survival group according to their discharge status. Propensity score matching (PSM) was performed to analysis the risk factors of death. 15 pairs of cases of two groups were matched well. RESULTS: The mortality rate of patients underwent re-exploration after OPCABG for bleeding or tamponade was 27.59% (16/58). In the raw data, we found the patients in death group had higher body mass index (BMI) (P = 0.030), higher cardiac troponin T (cTnT) (P = 0.028) and higher incidence of heart failure before OPCABG (P = 0.003). After PSM, the levels of lactic acid before and after re-exploration (P = 0.028 and P < 0.001) were higher in death group. And the levels of creatinine (P = 0.002) and cTnT (P = 0.017) were higher in the death group after re-exploration. The death group had longer reoperation time (P = 0.010). In addition, the perioperative utilization rate of intra-aortic ballon pump (IABP) (P = 0.027), continuous renal replacement therapy (CRRT) (P < 0.001) and platelet transfusion (P = 0.017) were higher than survival group. CONCLUSIONS: The mortality rate of patients undergoing re-exploration for bleeding or tamponade after isolated OPCABG is high. More attention should be paid to patients with above risk factors and appropriate measures should be taken in time.
Subject(s)
Cardiac Tamponade/surgery , Coronary Artery Bypass, Off-Pump/mortality , Coronary Artery Disease/surgery , Postoperative Hemorrhage/surgery , Reoperation/mortality , Aged , Cardiac Tamponade/diagnostic imaging , Cardiac Tamponade/etiology , Cardiac Tamponade/mortality , Coronary Artery Bypass, Off-Pump/adverse effects , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/mortality , Female , Humans , Male , Middle Aged , Postoperative Hemorrhage/diagnostic imaging , Postoperative Hemorrhage/etiology , Postoperative Hemorrhage/mortality , Reoperation/adverse effects , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: 5-fluorouracil (5-FU) is a cytotoxic antimetabolite that interferes with nucleic acid metabolism in both normal and cancer cells. Capecitabine is a prodrug of 5-FU, and S-1 is an oral 5-FU derivative. Patients usually tolerate treatment with one fluorouracil drug well. However, simultaneous application of two or more fluorouracil drugs such as capecitabine and S-1 can lead to life-threatening toxicities. CASE REPORT: A 73-year-old male with gastric and rectal cancer was admitted to the emergency department because of severe oral mucositis, hand-foot syndrome, and fever after concurrently taking capecitabine (1.5 g twice a day) and S-1 (50 mg twice a day) for 3 days at home. He was immediately given recombinant human granulocyte colony-stimulating factor (200 mg SC once a day) and recombinant human thrombopoietin (15,000 IU SC once a day). Hemagglutinin (1 unit IM once a day) was administered. Anti-infection and mucosal care were started promptly. A few days later, he developed supraventricular premature beats and short flutter requiring cardioversion. After comprehensive treatment, the patient's infection was effectively controlled, and mucosal damage and cardiac toxicity were significantly alleviated. CONCLUSION: 5-FU overdose caused by the combination of capecitabine and S-1 can cause serious adverse reactions. Careful checking of the medical orders and extensive education of patients to recognize the symptoms of toxicity may reduce the occurrence of such adverse reactions.
Subject(s)
Antineoplastic Agents , Prodrugs , Aged , Capecitabine , Fluorouracil/adverse effects , Humans , MaleABSTRACT
BACKGROUND: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo. MATERIALS AND METHODS: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs. RESULTS: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg-1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells. CONCLUSION: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Resistance, Neoplasm/drug effects , Nanoparticles/chemistry , Paclitaxel/pharmacology , Saponins/chemistry , Triterpenes/chemistry , A549 Cells , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cell Line, Tumor , Chalcone/administration & dosage , Chalcone/analogs & derivatives , Chalcone/pharmacokinetics , Drug Stability , Drug Synergism , Female , Humans , Hydrophobic and Hydrophilic Interactions , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Nanoparticles/therapeutic use , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Particle Size , Polymers/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Lung cancer is one of the most common cancers, which is the leading cause of cancer-related death among various cancers worldwide. Flavokawain A (FKA), a chalcone found in the kava plant, exerts potent anticancer activity. However, the activity and mechanisms of FKA in inhibiting the viability of paclitaxel (PTX)-resistant lung cancer A549 (A549/T) have not been investigated. In the present study, the effect of FKA on the viability of A549/T and hepatotoxicity in normal liver epithelial cells was detected by Cell Counting Kit-8 assay. Flow cytometry, western blot analysis and Annexin V-FITC/PI apoptosis detection kit were used to assess cell apoptosis. The effect of FKA on permeability-glycoprotein (P-gp) expression was measured by reverse transcription-PCR and western blot analysis. The results indicated that FKA dose-dependently inhibited cell proliferation and induced cell apoptosis in PTX-resistant A549/T cells, with an IC50 value of ~21 µM, while the IC50 value of A549/T cells to PTX was 34.64 µM. FKA had no hepatic toxicity in liver epithelial cells. P-gp, which contributes to the chemoresistant phenotype, was not expressed in A549 cells but was remarkably enhanced in A549/T cells. FKA (30 µM) decreased P-gp protein expression at 24 h by 3-fold. Furthermore, FKA downregulated P-gp expression by blocking the PI3K/Akt pathway. These findings suggest FKA as a potential candidate for the treatment of PTX-resistant lung cancer.
ABSTRACT
Tuberculosis (TB), a chronic infectious disease, is one of the greatest risks to human beings and 10 million people were diagnosed with TB and 1.6 million died from this disease in 2017. In addition, with the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the TB situation has become even worse, which has aggravated the mortality and spread of this disease. To overcome this problem, research into novel antituberculosis agents with enhanced activities against MDR-TB, reduced toxicity, and shortened duration of therapy is of great importance. Fortunately, many novel potential anti-TB drug candidates with five-membered rings, which are most likely to be effective against sensitive and resistant strains, have recently entered clinical trials. Different five-membered rings such as furans, pyranoses, thiazoles, pyrazolines, imidazoles, oxazolidinone, thiazolidins, isoxazoles, triazoles, oxadiazoles, thiadiazoles, and tetrazoles have been designed, prepared, and evaluated for their antimycobacterial activity against Mycobacterium tuberculosis. In this article, we highlight the recent advances made in the discovery of novel five-membered ring compounds and focus on their antitubercular activities, toxicity, structure-activity relationships, and mechanisms of action.
Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Tuberculosis/drug therapy , Antitubercular Agents/adverse effects , Antitubercular Agents/chemistry , Drug Design , Drug Discovery , Humans , Structure-Activity Relationship , Tuberculosis/epidemiology , Tuberculosis/microbiologyABSTRACT
Two series of novel 4â³-O-aralkylacetylhydrazineacyl azithromycin derivatives were synthesized and evaluated for their in vitro antibacterial activities. Among them, compound B4, B5, B13 and B18 were found to display significantly improved activity than control drugs (MIC > 128 µg/mL) against methicillin-resistant strain S. aureus ATCC 43,300 with an MIC value 2-4 µg/mL. Remarkably, compound B5 and B13 showed potent activity against penicillin-resistant S. aureus ATCC31007 (MIC = 4 µg/mL) and methicillin-resistant S. aureus ATCC 43,300 (MIC = 2 µg/mL).
Subject(s)
Anti-Bacterial Agents/pharmacology , Azithromycin/pharmacology , Drug Resistance, Bacterial/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Azithromycin/analogs & derivatives , Azithromycin/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
The present study investigated the anti-atherosclerotic potential of myricitrin in hypercholesterolemic rats. Rats were divided into the following groups: sham (standard food), control [1% high-cholesterol diet (HCD)], 1 µM myricitrin + 1% HCD, 10 µM myricitrin + 1% HCD, 100 µM myricitrin + 1% HCD, and the positive control (10 mg/kg body weight atorvastatin). The dose was given to rats via oral gavage for 45 consecutive days. Feeding of rats with 1% HCD caused substantial increases in the levels of LDL, cholesterol, and triglycerides (TG), while high-density lipoprotein (HDL) was reduced. However, rats supplemented with myricitrin had reduced levels of cholesterol, LDL, and TG to near-normal levels, whereas HDL was increased. Catalase, superoxide dismutase (SOD), glutathione peroxidase (Gpx), and reduced glutathione (GSH) levels were substantially reduced in the HCD-fed rats compared with sham rats. However, the rats supplemented with 100 µM myricitrin showed > 50% increases in these levels. Lipid peroxidation and reactive oxygen species (ROS) levels were reduced following myricitrin treatment. The aortic cell wall area was significantly increased by 14.5% in HCD-fed rats. However, rats supplemented with 1, 10, and 100 µM myricitrin showed significant reductions in the aortic cell wall area of 2.3%, 4%, and 27.5%, respectively. This is the first report of the anti-atherosclerotic and hypolipidemic effects of myricitrin in hypercholesterolemic rats. Myricitrin decreased the level of total serum cholesterol and the role of aortic atherosclerosis in hypercholesterolemic rats.
ABSTRACT
Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-ß-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was â¼17 µM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 µM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.
Subject(s)
Drug Resistance, Neoplasm/drug effects , Prostatic Neoplasms/drug therapy , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Triterpenes/therapeutic use , Animals , Apoptosis/drug effects , Cell Line, Tumor , Docetaxel/pharmacology , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice, Inbred C57BL , Neoplastic Stem Cells/drug effects , Triterpenes/pharmacologyABSTRACT
A standard fingerprint containing twelve common peaks was constructed from ten batches of Yifei Tongluo granules to evaluate batch-to-batch consistency by using HPLC-DAD. Additionally, the corresponding medicinal material attributes of these chemical constituents were analyzed according to the data acquired from the HPLC method and the identification was further carried out using the LC-MS/MS method. Comparing the retention time or accurate mass with previous studies or standards, the common components were tentatively identified in 50 min for ten batches of samples. At the same time, a reliable LC-MS/MS method was established to quantify marker substances simultaneously in 25 min, and the linear relationship of the standard curves was good in the experimental range. The validations of the method were successfully applied to the quality control and pharmacokinetic study. The results obtained from this study suggest that militarine was most abundant and the components in the granules caused pharmacokinetic herb-drug interactions in rats. This study provides a meaningful basis for evaluating the viability of Yifei Tongluo granules for clinical applications.
Subject(s)
Drug Compounding/standards , Drugs, Chinese Herbal/analysis , Quality Control , Succinates/analysis , Animals , Chemical Fractionation/instrumentation , Chemical Fractionation/methods , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Drug Interactions , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization/instrumentation , Spectrometry, Mass, Electrospray Ionization/methods , Succinates/chemistry , Succinates/pharmacokinetics , Tandem Mass Spectrometry/instrumentation , Tandem Mass Spectrometry/methodsABSTRACT
The transport of calcium and phosphorus is mainly relied on their corresponding transporters. The aim of this study was to determine the effect of dietary phosphorus level on the expression of the relevant calcium and phosphorus transporters in laying hens, which has a large amount of calcium and phosphorus input from intestine and output from kidney and eggshell gland. Thirty-six 25-week-old Hy-line Brown hens were fed diets with different available phosphorus level (AP, 0.15, 0.41, and 0.82%), respectively. The expression of phosphorus transporters type IIa and type IIb Na/Pi co-transporter (NPt2a, NPt2b), calcium transporter calbindin-D28k (CaBP-D28k), and plasma membrane Ca ATPase 1b (PMCA1b) were measured in small intestine, kidney, and eggshell gland by RT-PCR and western blot. The results showed that serum calcitriol and PTH concentrations were not affected (P > 0.05) by dietary AP levels. Duodenum had the highest mRNA and protein expression level of NPt2b than jejunum and ileum (P < 0.05). The protein expression abundance of CaBP-D28k and PMCA1b were higher in duodenum than that in jejunum and ileum (P < 0.05). 0.15%-AP diet upregulated the ileal mRNA expression level of NPt2b and renal mRNA expression level of NPt2a (P < 0.05), while downregulated the protein abundance of NPt2b and CaBP-D28k mRNA expression in shell gland (P < 0.05). In conclusion, both the Ca and P transporters were highly expressed in duodenum. Low AP diet decreased protein expression abundance of NPt2b in duodenum while upregulated the mRNA expression level of NPt2a in kidney. The result suggests that both the phosphorus absorption in proximal intestine and its reabsorption in kidney are involved in the adaption to low AP diet.