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Pharmaceuticals (Basel, Switzerland) May 2024Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle...
BACKGROUND
Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle (ASM). Previous studies have demonstrated that γ-tocotrienols reduce ASM proliferation and migration by inhibiting the activation of RhoA. In this present study, we investigate the effect of another vitamin E isoform, β-tocotrienols, on human ASM cell proliferation and migration stimulated by platelet-derived growth factor-BB (PDGF-BB).
METHODS
Human ASM cells were pre-treated with β-tocotrienol prior to being stimulated with PDGF-BB to induce ASM cell proliferation and migration. The proliferation and migration of PDGF-BB-induced human ASM cells were assessed using colorimetric and transwell migration assays. The intracellular ROS assay kit was employed to quantify reactive oxygen species (ROS) in human ASM cells. Additionally, we explored the effect of β-tocotrienols on the signaling pathways involved in PDGF-BB-induced ASM proliferation and migration.
RESULTS
β-tocotrienol inhibited PDGF-BB-induced ASM cell proliferation and migration by reducing RhoA activation and ROS production. However, in this present study, β-tocotrienol did not affect the signaling pathways associated with cyclin D1, phosphorylated Akt1, and ERK1/2.
CONCLUSIONS
In conclusion, the inhibition of RhoA activation and ROS production by β-tocotrienol, resulting in the reduction in human ASM proliferation and migration, suggests its potential as a treatment for asthma airway remodeling.
PubMed: 38931379
DOI: 10.3390/ph17060712 -
Pharmaceuticals (Basel, Switzerland) May 2024Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective...
Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, -, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds - were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds -. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is . Biological results revealed that all the screened compounds - might serve as selective COX-1 inhibitors. They showed IC values ranging from 0.71 μM to 4.82 μM against COX-1 and IC values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of -forms with respect to -forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.
PubMed: 38931377
DOI: 10.3390/ph17060710 -
Pharmaceuticals (Basel, Switzerland) May 2024The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population...
AIMS
The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile.
METHODS
Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges.
RESULTS
A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CL), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM.
CONCLUSIONS
We found that qCRP, CRRT, CL, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.
PubMed: 38931333
DOI: 10.3390/ph17060665 -
Microorganisms Jun 2024The study aimed to determine liver fibrosis in human immunodeficiency virus (HIV) positive individuals using transient elastography (FibroScan), Fibrosis-4 (FIB-4)...
The study aimed to determine liver fibrosis in human immunodeficiency virus (HIV) positive individuals using transient elastography (FibroScan), Fibrosis-4 (FIB-4) score, and aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) in the HIV Department from Infectious Diseases Hospital "Victor Babeș" Craiova, Romania. Of the analyzed HIV-positive subjects ( = 161), 93 (57.76%) had HIV mono-infection, and 68 (42.24%) had Hepatitis B Virus (HBV) co-infection. The prevalence of advanced liver fibrosis was higher (F2: 11.76% and F3: 13.24%, F4: 4.41%) in the HIV-HBV co-infected group compared to the HIV mono-infected group. The univariate and multivariate analysis identified HBV co-infection (OR = 5.73) male sex (OR = 5.34), serum aspartate amino-transferase levels (Pearson's rho = 0.273), low platelet count (Pearson's rho = -0.149) and erythrocyte sedimentation rate (OR = 1.030) as risk factors for the presence of liver fibrosis. Body mass index (OR = 1.08), serum lipid levels (OR = 0.96), viral load at diagnosis (OR = 1.00005), and low CD4+ cell count (OR = 0.977) were also correlated with liver fibrosis. The FIB-4 and APRI scores were strongly correlated with each other. In conclusion, HBV co-infection seems to be a determinant factor for liver fibrosis development in people living with HIV, together with other risk factors.
PubMed: 38930595
DOI: 10.3390/microorganisms12061213 -
Journal of Clinical Medicine Jun 2024Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and...
Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Here, we evaluated the GOS population 12 years after the registry initiation. As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 10/L to >450 × 10/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.
PubMed: 38930117
DOI: 10.3390/jcm13123588 -
Journal of Clinical Medicine Jun 2024Medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN) are associated with severe disability and continuous pain, both of which are very...
Medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN) are associated with severe disability and continuous pain, both of which are very difficult to control. This study aims to evaluate the outcome of platelet-rich fibrin (PRF) treatment compared to iodoform gauze packing and the primary suture of oral mucosa in patients with both MRONJ and ORN. Patients suffering from MRONJ and ORN who were treated in the Oral and Maxillofacial Surgery Clinic of Cluj-Napoca in the last 10 years were selected for this study from the hospital database. PRF treatment proved to be a reliable method to help heal the necrotic bone sites. High-ASA risk patients and immunosuppressed patients are more prone to recurrence and persistent signs and symptoms. Intravenous bisphosphonates produce more intense symptomatology compared to oral administration. The posterior mandible is more difficult to treat compared to other sites. The quality of life of MRONJ and ORN patients may be improved by a protocol that reduces pain and hospitalization.
PubMed: 38930013
DOI: 10.3390/jcm13123473 -
Journal of Personalized Medicine Jun 2024Surgical resection is the key treatment for colorectal cancer, but the extent of surgical trauma has been implied as a key factor for the oncologic outcome. The immune...
Surgical resection is the key treatment for colorectal cancer, but the extent of surgical trauma has been implied as a key factor for the oncologic outcome. The immune stress response to surgical trauma generates a cascade of immunological events implying neutrophils' perioperative change generating NETosis, N killer decrease, and platelets' activation that may influence postoperative surgical outcome, tumor cell growth, and future oncogenesis. The present study aimed to investigate the correlation between intraoperative oxygen consumption (VO) and the dynamic variation of neutrophils, lymphocytes, and platelets in the perioperative period to identify an intraoperative tool that could predict the postoperative immune response. Twenty-six colorectal oncological surgical patients were enrolled in an observational, prospective, monocentric study, over 18 months. Serum neutrophils, lymphocytes, and thrombocytes values were collected in the preoperative period and on the third postoperative day, oxygen consumption was measured and recorded every 15 min during surgery using indirect calorimetry. We compared oxygen consumption measurements registered 30 min after induction of anesthesia (VOa) and the first value registered after abdominal wall closure (VOb) to perioperative variation of absolute neutrophils (VNC), lymphocytes (VLC), and platelets (VPC) count. Our results proved a significant correlation between VO variation and neutrophils' perioperative dynamic assessed by VNC (correlation coefficient = 0.547, < 0.01, 95% confidence interval (CI) =0.175, 0.783). We also noticed a correlation between VPC and VO (correlation coefficient = -0.603, < 0.01, 95% CI = -0.815, -0.248). No correlation could be shown between VO2 and VLC variation ( = 0.39). In conclusion, intraoperative VO variation measured by indirect calorimetry correlates well with perioperative neutrophils and platelets count dynamic variations and can be used as an early prognosis marker of postoperative immune response and surgical outcome in colorectal oncological surgery.
PubMed: 38929815
DOI: 10.3390/jpm14060594 -
Journal of Personalized Medicine May 2024We investigated the type of blood component transfusion associated with increased postoperative delirium. Adult patients who underwent total knee arthroplasty (TKA) or...
We investigated the type of blood component transfusion associated with increased postoperative delirium. Adult patients who underwent total knee arthroplasty (TKA) or total hip arthroplasty (THA) between 2017 and 2022 were included. Delirium was evaluated and treated within two days after surgery. A total of 6737 patients (4112 TKA/2625 THA) were retrospectively studied; 2.48% of patients in the TKA (n = 102) and THA (n = 65) groups had postoperative delirium. The blood transfusion (BT) and non-BT groups had similar percentages of patients who experienced postoperative delirium (3.34 vs. 2.35%, = 0.080). In the multivariable logistic regression model, BT was not associated with postoperative delirium-adjusted odds ratio (aOR): 1.03, confidence interval (CI): 0.62, 1.71; = 0.917. Moreover, transfusion of packed red blood cells ( = 0.651), platelets ( = 0.998), and cryoprecipitate ( = 0.999) were not associated with delirium. However, transfusion of fresh frozen plasma was associated with a 5.96-fold higher incidence of delirium-aOR: 5.96, 95% CI: 2.72, 13.04; < 0.001. In conclusion, perioperative BT was not associated with postoperative delirium in patients who underwent TKA or THA. However, FFP transfusion was associated with an increased incidence of postoperative delirium.
PubMed: 38929797
DOI: 10.3390/jpm14060576 -
Journal of Personalized Medicine May 2024Patellar tendinopathy (PT) involves anterior knee pain and functional. Platelet-rich fibrin matrix (PRFM) is a promising biological therapy for tendinopathies. We...
BACKGROUND
Patellar tendinopathy (PT) involves anterior knee pain and functional. Platelet-rich fibrin matrix (PRFM) is a promising biological therapy for tendinopathies. We examined a cohort of PT patients treated with tendon debridement and autologous PRFM at the 24-month follow-up to assess whether the combined treatment facilitated return to sports and yielded satisfactory clinical and functional scores.
METHODS
Baseline and 24-month visual analogue scale (VAS), Victorian Institute of Sport Assessment Scale for Patellar Tendinopathy (VISA-P), Tegner Activity Scale (TAS), and Blazina scores were compared to evaluate treatment effectiveness. The Friedman test was used to compare repeated observations of VAS, VISA-P, TAS, and Blazina Score values. Return to sport rate, Tampa Scale of Kinesiophobia (TKS) score and patient satisfaction were collected at 24 months.
RESULTS
The postoperative clinical scores demonstrated significant improvement compared with their preoperative values (all < 0.001). Specifically, the VISA-P score was 80.32 (±20.58), 92.10% of patients had resumed sports activities and patient satisfaction was 9.21 (±1.21) at 24 months.
CONCLUSIONS
Surgical debridement and autologous PRFM application in patients with chronic PT resulted in a higher rate of return to sports when compared to solely surgical treatment, significantly improved clinical outcomes and excellent patient satisfaction at 24 months.
PubMed: 38929787
DOI: 10.3390/jpm14060567 -
Journal of Personalized Medicine May 2024Inflammation-related parameters serve as pivotal indicators in the prognosis and management of lung cancer. This retrospective investigation aimed to explore the...
Inflammation-related parameters serve as pivotal indicators in the prognosis and management of lung cancer. This retrospective investigation aimed to explore the relationship between inflammatory markers and diverse clinical variables in non-small-cell lung cancer patients. A cohort of 187 individuals undergoing elective lobectomy for lung cancer was retrospectively analyzed, spanning an 11-year data collection period. Six inflammation ratios derived from complete peripheral blood counts were assessed. Significantly elevated levels of neutrophil-to-lymphocyte ratio (NLR) ( = 0.005), platelet-to-lymphocyte ratio (PLR) ( = 0.001), Aggregate Index of Systemic Inflammation (AISI) ( = 0.015), Systemic Inflammation Response Index (SIRI) ( = 0.004), and Systemic Immune Inflammation Index (SII) ( = 0.004) were observed in patients with advanced T stages. Significantly, elevated values ( < 0.05) of these parameters were observed in the study's smoker patients compared to non-smokers. A statistically significant correlation was identified between the NLR parameter and tumor size ( = 0.07, r = 0.204), alongside a significant elevation in SIRI ( = 0.041) among patients experiencing postoperative complications. Inflammatory biomarkers emerge as invaluable prognostic indicators for patients with non-small-cell lung cancer, offering potential utility in forecasting their prognosis.
PubMed: 38929773
DOI: 10.3390/jpm14060552