Archerthomasen2000
Celastrol (CEL) has a great potential in the treatment of a wide variety of metabolic diseases. However, whether CEL protects pancreatic β cells and its underlying mechanism are not yet clear.
This study investigates to determine the effects of CEL on the pathogenesis of pancreatic β cells damage.
C57BLKS/Lepr
(db/db) mice and rat insulinoma INS-1 cell line or mouse J774A.1 cell line were used as in vivo and in vitro models for investigating the protective effect of CEL on pancreatic β cells under high glucose environment and the related mechanism. The phenotypic changes were evaluated by immunofluorescence, immunohistochemical staining, flow cytometry and the measurement of biochemical indexes. The molecular mechanism was explored by biological techniques such as western blotting, qPCR, ChIP-qPCR, co-immunoprecipitation and lentivirus infection.
Our results showed that CEL at the high dose (CEL-H, 0.2 mg/kg) protects db/db mice against increased body weight and blood glucose. CEL-H inhibits pancreatic β cell apoptosis in db/db mice and high glucose-induced INS-1 cells. CEL-H also reduced IL-1β production in islet macrophages. The further study found that CEL suppressed TXNIP expression and NLRP3 inflammasome activation in pancreatic β cells and islet macrophages. Importantly, the inhibitory effect of CEL on pancreatic β cell apoptosis and IL-1β production was also dependent on TXNIP. Mechanically, CEL inhibits Txnip transcription by promoting the degradation of ChREBP.
Celastrol inhibits TXNIP expression to protect pancreatic β cells in vivo and in vitro. Our research pointed out another mechanism by which celastrol functions under the condition leptin signaling is ineffective.
Celastrol inhibits TXNIP expression to protect pancreatic β cells in vivo and in vitro. Our research pointed out another mechanism by which celastrol functions under the condition leptin signaling is ineffective.
Recent studies revealed a substantial role of carotenoids to treat respiratory diseases. This review aimed to give an updated overview of the investigational evidence on the preventive properties of carotenoids against respiratory diseases both in vitro and in vivo along with their pathophysiology and mechanisms of action.
Carotenoids as a potential therapeutic class of bioactive compounds to treat respiratory diseases.
Carotenoids such as β-carotene, lycopene, crocin, bixin, lutein, and astaxanthin show beneficial effects against chronic lung diseases (e.g., asthma, emphysema, fibrosis, COPD, acute lung injury, and lung cancer). Moreover, in vitro and in vivo studies also supported the preventive role of carotenoids. These carotenoids showed a beneficial role by activation of the NRF2/HO-1 pathway and inhibition of the NF-кB, MAPK, JAK/STAT-3, and PI3K/AKT pathways. Additionally, epidemiological studies also showed that dietary intake of carotenoids lowers the risk of lung diseases.
Carotenoids may be used as drugs or can be given in combination with other drugs to prevent and treat respiratory diseases. Although in vitro and in vivo results are encouraging, further well-conducted randomized clinical trials are required to approve carotenoids as drug candidates.
Carotenoids may be used as drugs or can be given in combination with other drugs to prevent and treat respiratory diseases. Although in vitro and in vivo results are encouraging, further well-conducted randomized clinical trials are required to approve carotenoids as drug candidates.
Tetrandrine (TET), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, is the only approved medicine in China for silicosis. However, TET-induced hepatotoxicity has raised safety concerns. The underlying toxic targets and mechanism induced by TET remain unclear; there are no targeted detoxification strategies developed for TET-induced hepatotoxicity. Ursolic acid (UA), a pentacyclic triterpene with liver protective effects, may have detoxification effects on TET-induced hepatotoxicity.
This study aims to explore toxic targets and mechanism of TET and present UA as a potential targeted therapy for alleviating TET-induced hepatotoxicity.
A TET-induced liver-injury model was established to evaluate TET toxicity and the potential UA detoxification effect. Alkenyl-modified TET and UA probes were designed to identify potential liver targets. Pharmacological and molecular biology methods were used to explore the underlying toxicity/detoxification mechanism.
TET induced liver injury b alleviate hepatotoxicity caused by GST inhibition.
To evaluate the feasibility and acceptability of exercise and patient education for patients with hip dysplasia not receiving surgery.
Feasibility study.
The participants received exercise instruction and patient education over six months. read more Feasibility covered recruitment, retention, and mechanisms of change (MC). MC were measured with Hip and Groin Outcome Score (HAGOS), muscle strength tests, Y-balance test, and hop for distance test (HDT) over six months. Acceptability covered adherence, expectations, perceptions, benefits, and harms.
Thirty of 32 were recruited (median age 30 years); six were lost to follow-up. Twenty-four participants improved by a mean of 11 (95%CI 5-17) HAGOS pain points, improvements in all subscales were 1-11 points. Mean hip abduction strength improved 0.2 (95%CI 0.04-0.4) Nm/kg, similar to flexion and extension. Median Y-balance test improvements anterior 70 (IQR 64-74) to 75 (IQR 72-80) centimetres; posteromedial 104 (IQR 94-112) to 119 (IQR 112-122) centimetres and posterontrolled trial.
To evaluate the effectiveness and tolerability of perampanel (PER) in real-world settings in patients between 1 month and 18 years of age with drug resistant epilepsy (DRE) waiting for epilepsy surgery.
In this multicenter study, patients between 1 month and 18 years of age with DRE treated with PER between January 2020 and June 2021 were selected. The study outcome was effectiveness of PER treatment reported as reduction in seizure frequency and seizure freedom rate. Effectiveness was assessed at 30, 60, 90, 120, 150 and 180 days after initiation of PER. Tolerability profiles were reported as adverse events according to the observations of the patients' family members and physician.
Eighty-five patients treated with PER were included in the study. The mean initial dose and mean maximum dose of adjunctive PER was 2 mg/day and 5.8 mg/day, respectively. The mean seizure frequency (rate/week) was 41.3, 25.4, 18.9, 14.3, 11.2, 11.1 and 8.9 seizures at baseline, 30, 60, 90, 120, 150 and 180 days, respectively; the reduction in the mean seizure frequency at all timepoints was significant compared at the baseline (p<0.001). At 180 days, ≥75% seizure reduction was seen in 64.9% (37/57) of the patients and seizure freedom was achieved in 36.8% (21/57). Drowsiness, ataxia, and behavioral changes were the common adverse events observed, and these improved after the dose of PER was reduced. No discontinuation of PER was required due to side effects or intolerance.
In real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE.
In real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE.
The average human lifespan has increased dramatically over the past century. However, molecular and physiological alterations of the healthy brain during aging remain incompletely understood. Generalized synaptic restructuring may contribute to healthy aging and the reduced metabolism observed in the aged brain. The aim of this study was to assess healthy brain aging using [
F]FDG as a measure of cerebral glucose consumption and [
C]UCB-J PET as an indicator of synaptic density.
Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [
C]UCB-J alongside with the fluorodeoxyglucose radioligand [
F]FDG, we obtained SUVR-1 values for 14 pre-defined volume-of-interest brain regions defined on MRI T1 scans. Regional differences in relative [
F]FDG and [
C]UCB-J uptake were investigated using a voxel-wise approach. Finally, correlations between [
C]UCB-J, [
F]FDG PET, and age were examined.
We found widespread cortical reduction of synaptic density in a cohort of olc density levels during aging. Thus, loss of synaptic density may be unrelated to aging and does not seem to be a sufficient explanation for the recognized reduction in brain metabolism during aging. Our study also demonstrates that the relationship between glucose consumption and synaptic density is not uniform throughout the human brain with implications for our understanding of neuroenergetics.Thermoluminescence (TL), kinetic parameters and dosimetric features of Pakistani limestone (CaCO3) is reported in this study. Both compositional and structural analyses reveal that the material has a crystalline nature with rhombohedral structure and non-uniform crystallite size having major content of CaCO3. A powdered limestone sample of 30 mg is found to be the optimized weight for TL and other dosimetric studies. After irradiating the samples with a test dose of 100 Gy using a β source three composite glow peaks termed as P1, P2 and P3 are visible at 100, 230 and 330 °C respectively using a linear heating rate of 1 °C/s during the TL readout. The Coefficient of Variation (COV) is found to be about 4%. Kinetic parameters (i.e., frequency factor (f), activation energy (E), and the kinetic order (b)) are estimated using both first and second Order of kinetics using an in-house Computerized Glow Curve Deconvolution (GCD) software. The figure-of-merit (FOM) is found to be 2.12%. The distribution of continuum traps with activation energy in the range of 0.77-2.59 eV is observed in the kinetic parameter analysis of the glow peaks of the sample. The TL response in the dose range of 1-5 Gy (not reported previously) and linearity in the dose response in the dose range of 1-10 Gy is observed in samples of Pakistani limestone. The Minimum Detectable Dose (MDD) is 1.01 Gy clearly resembling the experimentally linear fitted results. After a fading study for a period of thirty days, only the first peak i.e., P1 majorly fades while no major change is observed in the amplitude of peaks P2 and P3. In addition, P1 is the main contributor fading by 92% within the first 24 h of irradiation while P2 fades by 30 %. However, P3 shows stability with a very minor fading of 0.05% within 24 h of irradiation. This study concludes that Pakistani limestone can be further assessed as a potential radiation dosimeter for various applications.
To evaluate the effect of irregular screening behaviour on the risk of advanced stage breast cancer at diagnosis in Flanders.
All women aged 50-69 who were invited to the organized breast cancer screening and diagnosed with breast cancer before age 72 from 2001 to 2018 were included. All prevalent screen and interval cancers within 2 years of a prevalent screen were excluded. Screening behaviour was categorized based on the number of invitations and performed screenings. Four groups were defined regular, irregular, only-once, and never attenders. Advanced stage cancer was defined as a stage III+breast cancer. The association between screening regularity and breast cancer stage at diagnosis was evaluated in multivariable logistic regression models, taking age of diagnosis and socio-economic status into account.
In total 13.5% of the 38,005 breast cancer cases were diagnosed at the advanced stage. Compared to the regular attenders, the risk of advanced stage breast cancer for the irregular attenders, women who participated only-once, and never attenders was significantly higher with OR
1.
