The present study investigates the utilization of nanoparticles based on poly-l-lactide (PLLA) and polyglycerol adipate (PGA), alone and blended, for the encapsulation of usnic acid (UA), a potent ...natural compound with various therapeutic properties including antimicrobial and anticancer activities. The development of these carriers offers an innovative approach to overcome the challenges associated with usnic acid's limited aqueous solubility, bioavailability, and hepatotoxicity. The nanosystems were characterized according to their physicochemical properties (among others, size, zeta potential, thermal properties), apparent aqueous solubility, and in vitro cytotoxicity. Interestingly, the nanocarrier obtained with the PLLA-PGA 50/50 weight ratio blend showed both the lowest size and the highest UA apparent solubility as well as the ability to decrease UA cytotoxicity towards human hepatocytes (HepG2 cells). This research opens new avenues for the effective utilization of these highly degradable and biocompatible PLLA-PGA blends as nanocarriers for reducing the cytotoxicity of usnic acid.
The neurotransmitter glutamate increases cerebral blood flow by activating postsynaptic neurons and presynaptic glial cells within the neurovascular unit. Glutamate does so by causing an increase in ...intracellular Ca2+ concentration (Ca2+i) in the target cells, which activates the Ca2+/Calmodulin‐dependent nitric oxide (NO) synthase to release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in Ca2+i and NO production. The current study assessed whether and how glutamate drives Ca2+‐dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose‐dependent oscillatory increase in Ca2+i, which was maximally activated at 200 μM and inhibited by α‐methyl‐4‐carboxyphenylglycine, a selective blocker of Group 1 metabotropic glutamate receptors. Glutamate‐induced intracellular Ca2+ oscillations were triggered by rhythmic endogenous Ca2+ mobilization and maintained over time by extracellular Ca2+ entry. Pharmacological manipulation revealed that glutamate‐induced endogenous Ca2+ release was mediated by InsP3‐sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two‐pore channel 1. Constitutive store‐operated Ca2+ entry mediated Ca2+ entry during ongoing Ca2+ oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca2+ signals. Of note, glutamate induced Ca2+‐dependent NO release also in hCMEC/D3 cells, an established model of human brain microvascular endothelial cells. This investigation demonstrates for the first time that metabotropic glutamate‐induced intracellular Ca2+ oscillations and NO release have the potential to impact on neurovascular coupling in the brain.
Glutamate induces intracellular Ca2+ oscillations in mouse brain microvascular endothelial cells. Glutamate‐induced intracellular Ca2+ oscillations lead to robust, although delayed, nitric oxide release. Brain microvascular endothelial cells could play a crucial role in neurovascular coupling during synaptic activity.
International and national oncology societies had released recommendations in favor of COVID-19 vaccination in cancer patients. In the context of the national vaccination campaign targeting the so ...called extremely vulnerable, we aimed to assess the safety and efficacy of the mRNA vaccines in a cohort of 623 patients.
Between March 26 and April 04, 2021, the Pfizer and BioNTech BNT162b2 mRNA and the Moderna mRNA-1273 vaccines were given as a two-dose prime-boost regimen. Starting on September 25th 2021 a third dose was offered to patients in whom a suboptimal immunogenicity with COVID-19 vaccination could be expected. Safety assessments were performed by phone call 7 days after each dose. Electronic health records were accessed to review demographic information, disease history, treatment detail, and outcome events of participants patients’.
No toxicities were reported in 63.7%, 54%, and in 48.7% patients with cancer after each dose. Mild-to-moderate pain at the injection site was the most commonly adverse event. After the second dose, 46% of the 610 patients reported toxicity, with more systemic side-effects observed. Fever was reported in 45% of patients, with a temperature ≥ 38 °C in 21.4% of them. Of the 335 patients receiving a third vaccine dose, 51% reported toxicity, with 13% of patients reporting more than one effect. Logistic regression analysis reported mixed results, with limited variables or categories reporting a significant odd ratio. The type of vaccine reported a significant value at first dose (OR = 0.12; CI 0.52, 0.26; p = 0.00). Thirty-four cases of COVID-19 infection were reported with only one patient requiring a short-term hospitalization for monitoring.
The safety profile of the mRNA vaccines does not raise any specific concerns and support prioritization of vaccination for cancer patients.
•COVID-19 vaccination is recommended in patients with cancer.•We observed a first dose-refusal rate of 4.5%.•No safety concerns have emerged in our cohort of patients.•After two-dose prime-boost vaccination 6 cases of COVID-19 infection were reported.
To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate ...(GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND Delapril and Manidipine for Nephroprotection in Diabetes) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range IQR) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.
The neurotransmitter glutamate increases cerebral blood flow by activating postsynaptic neurons and presynaptic glial cells within the neurovascular unit. Glutamate does so by causing an increase in ...intracellular Ca
concentration (Ca
) in the target cells, which activates the Ca
/Calmodulin-dependent nitric oxide (NO) synthase to release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in Ca
and NO production. The current study assessed whether and how glutamate drives Ca
-dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose-dependent oscillatory increase in Ca
, which was maximally activated at 200 μM and inhibited by α-methyl-4-carboxyphenylglycine, a selective blocker of Group 1 metabotropic glutamate receptors. Glutamate-induced intracellular Ca
oscillations were triggered by rhythmic endogenous Ca
mobilization and maintained over time by extracellular Ca
entry. Pharmacological manipulation revealed that glutamate-induced endogenous Ca
release was mediated by InsP
-sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channel 1. Constitutive store-operated Ca
entry mediated Ca
entry during ongoing Ca
oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca
signals. Of note, glutamate induced Ca
-dependent NO release also in hCMEC/D3 cells, an established model of human brain microvascular endothelial cells. This investigation demonstrates for the first time that metabotropic glutamate-induced intracellular Ca
oscillations and NO release have the potential to impact on neurovascular coupling in the brain.
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