Functional candesartan loaded lipid nanoparticles for the control of diabetes-associated stroke: In vitro and in vivo studies.

Diabetes mellitus is a metabolic disease that raises the odds of developing stroke. Candesartan has been used to prevent stroke due to its inhibitory effects on blood pressure, angiogenesis, oxidative damage, and apoptosis. However, oral candesartan has very limited bioavailability and efficacy due to its weak solubility and slow release. The study aimed to develop a nasal formulation of candesartan-loaded liposomes containing ethanol and propylene glycol (CLEP) to improve candesartan's delivery, release, permeation, and efficacy as a potential diabetes-associated stroke treatment. Using design expert software, different CLEP formulations were prepared and evaluated in vitro to identify the optimum formulation, which. The selected optimum formulation composed of 3.3% phospholipid, 10% ethanol, and 15% propylene glycol significantly increased the release and permeation of candesartan relative to free candesartan by a factor of 1.52 and 1.47, respectively. The optimum formulation significantly reduced the infarction after stroke in rats; decreased flexion, spontaneous motor activity, and time spent in the target quadrant by 70%, 64.71%, and 92.31%, respectively, and enhanced grip strength by a ratio of 2.3. Therefore, nasal administration of the CLEP formulation could be a potential diabetes-associated stroke treatment.

Design, optimization, and in vivo evaluation of invasome-mediated candesartan for the control of diabetes-associated atherosclerosis.

Atherosclerosis is an inflammatory disease characterized by the accumulation of arterial plaque. Diabetes mellitus stands out as a major risk factor for atherosclerosis. Candesartan is a potent angiotensin II receptor antagonist that enhances arterial blood flow and reduces insulin resistance. However, oral candesartan has limited activity because of its low bioavailability, water solubility, hepatic first-pass degradation, and efficacy. The current study aims to develop nasal candesartan-loaded invasome (CLI) drops to improve candesartan's permeation, release, and bioavailability as a potential treatment for diabetes-associated atherosclerosis. Design expert software was used to prepare various CLI formulations to determine the impact of the concentrations of ethanol, cineole, and phospholipid. The desirability index was used to estimate the optimized formulation composition to maximize entrapment efficiency and minimize vesicle size. The optimized formulation had a 1% ethanol concentration, a 1.5% cineole concentration, and a 2.32% phospholipid concentration. The selected optimized formulation was then tested in a rat model of diabetes and atherosclerosis to evaluate its activity. The results showed that nasal CLI drops significantly raised serum HDL levels by a ratio of 1.42 and lowered serum glucose, cholesterol, triglycerides, LDL, and VLDL levels by 69.70%, 72.22%, 36.52%, 58.0%, and 65.31%, respectively, compared with diabetic atherosclerotic rats, throwing an insight on the potential for promising anti-diabetic and anti-atherosclerotic activities. Additionally, atherosclerotic lesions were improved in rats treated with CLI, as shown in histopathology. In conclusion, the results of this investigation showed that treatment with nasal CSN-loaded invasome formulation drops prevented the initiation and progression of diabetes-associated atherosclerosis.

The long weight: association between distressed communities index and long-term weight outcomes following bariatric surgery.

BACKGROUND: Socioeconomic status (SES) is multifactorial, and its effect on post-bariatric weight recurrence is unclear. Distressed Community Index (DCI) is a composite SES score measuring community economic well-being. This study aims to evaluate the effect of DCI on long-term post-bariatric weight outcomes. METHODS: Retrospective analysis of patients undergoing primary laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy between 2015 and 2020 was performed. All weights in the electronic medical record (EMR), including non-bariatric visits, were captured. Patients were stratified into low tier (LT) and high tier (HT) DCI groups. RESULTS: Of 583 patients, 431 (73.9%) were HT and 152 (26.1%) were LT. Average bariatric follow up was 1.78 ± 1.6 years and average postoperative weight in the EMR was 3.96 ± 2.26 years. Rates of bariatric follow up within the last year were similar (13.8% LT vs 16.2% HT, p = 0.47). LT had higher percent total body weight loss (%TWL; 26% LT vs 23% HT, p < 0.01) and percent excess weight loss (%EWL; 62% vs 57%, p = 0.04) at 1 year on univariate analysis. On multivariate linear regression adjusting for baseline characteristics and surgery type, there were no differences in %EWL between groups at 1 year (p = 0.22), ≥ 3 years (p = 0.53) or ≥ 5 years (p = 0.34) postop. While on univariate analysis LT only trended towards greater percentage of patients with > 15% increase from their 1-year weight (33.3% LT vs 21.0% HT, p = 0.06), on multivariate analysis this difference was significant (OR 2.0, LT 95%CI 1.41-2.84). There were no differences in the percentage of patients with > 15% decrease in %EWL from 1 to 3 + years postop between groups (OR 0.98, LT 95% CI 0.72-1.35). CONCLUSIONS: While low tier patients had similar weight loss at 1 year, they were twice as likely to have weight recurrence at ≥ 3 years. Further studies are needed to identify factors contributing to greater weight recurrence among this population.

Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical: improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats.

Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (-) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity.

Perindopril ameliorates experimental Alzheimer's disease progression: role of amyloid ß degradation, central estrogen receptor and hyperlipidemic-lipid raft signaling.

Accumulating evidence indicates that over-stimulation of angiotensin-converting enzyme 1 (ACE1) activity is associated with ß-amyloid (Aß) and phosphorylated tau (p-tau)-induced apoptosis, oxido-nitrosative neuroinflammatory stress and neurodegeneration in Alzheimer's disease (AD). Alternatively, activation of the ACE2, the metalloprotease neprilysin (Neutral Endopeptidase; NEP) and the insulin-degrading enzyme (IDE) could oppose the effects of ACE1 activation. We aim to investigate the relationship between ACE1/ACE2/NEP/IDE and amyloidogenic/hyperlipidemic-lipid raft signaling in hyperlipidemic AD model. Induction of AD was performed in ovariectomized female rats with high-fat high fructose diet (HFFD) feeding after 4 weeks following D-galactose injection (150 mg/kg). The brain-penetrating ACE1 inhibitor perindopril (0.5 mg/kg/day, p.o.) was administered on a daily basis for 30 days. Perindopril significantly decreased hippocampal expression of ACE1 and increased expression of ACE2, NEP and IDE. Perindopril markedly decreased Aß1-42, improved lipid profile and ameliorated the lipid raft protein markers caveolin1 (CAV1) and flotillin 1 (FLOT1). This was accompanied by decreased expression of p-tau and enhancement of cholinergic neurotransmission, coupled with decreased oxido-nitrosative neuroinflammatory stress, enhancement of blood-brain barrier (BBB) functioning and lower expression of the apoptotic markers glial fibrillary acidic protein (GFAP), Bax and ß-tubulin. In addition, perindopril ameliorated histopathological damage and improved learning, cognitive and recognition impairment as well as depressive behavior in Morris water maze, Y maze, novel object recognition and forced swimming tests, respectively. Conclusively, perindopril could improve cognitive defects in AD rats, at least through activation of ACE2/NEP/IDE and inhibition of ACE1 and subsequent modulation of amyloidogenic/hyperlipidemic-lipid raft signaling and oxido-nitrosative stress.

Role of curcumin in regulating p53 in breast cancer: an overview of the mechanism of action.

p53 is a tumor suppressor gene involved in various cellular mechanisms including DNA repair, apoptosis, and cell cycle arrest. More than 50% of human cancers have a mutated nonfunctional p53. Breast cancer (BC) is one of the main causes of cancer-related deaths among females. p53 mutations in BC are associated with low survival rates and more resistance to the conventional therapies. Thus, targeting p53 activity was suggested as an important strategy in cancer therapy. During the past decades, cancer research was focused on the development of monotargeted anticancer therapies. However, the development of drug resistance by modulation of genes, proteins, and pathways was the main hindrance to the success of such therapies. Curcumin is a natural product, extracted from the roots of Curcuma longa, and possesses various biological effects including anticancer activity. Previous studies proved the ability of curcumin to modulate several signaling pathways and biomolecules in cancer. Safety and cost-effectiveness are additional inevitable advantages of curcumin. This review summarizes the effects of curcumin as a regulator of p53 in BC and the key molecular mechanisms of this regulation.

Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients.

BACKGROUND: During mechanical ventilation medical aerosol delivery has been reported to be upto two fold greater with dry inhaled gas than with heated humidity. Urine levels at 0.5 h post dose (URSAL0.5%) has been confirmed as an index of lung deposition and 24 h (URSAL24%) as index of systemic absorption. Our aim was to determine the effect of humidification and aerosol device type on drug delivery to ventilated patients using urine levels. METHODS: In a randomized crossover design, 36 (18female) mechanically ventilated patients were assigned to one of three groups. Groups 1 and 2 received 5000 µg salbutamol using vibrating mesh (VM) and jet nebulizers (JN), respectively, while group 3 received 1600 µg (16 puffs) of salbutamol via metered dose inhaler with AeroChamber Vent (MDI-AV). All devices were placed in the inspiratory limb of ventilator downstream from the humidifier. Each subject received aerosol with and without humidity at >24 h intervals with >12 h washout periods between salbutamol doses. Patients voided urine 15 min before each study dose and urine samples were collected at 0.5 h post dosing and pooled for the next 24 h. RESULTS: The MDI-AV and VM resulted in a higher percentage of urinary salbutamol levels compared to the JN (p < 0.05). Urine levels were similar between humidity and dry conditions. CONCLUSIONS: Our findings suggest that in-vitro reports overestimate the impact of dry vs. heated humidified conditions on the delivery of aerosol during invasive mechanical ventilation.