Exosome-mediated delivery and regulation in neurological disease progression.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-ß protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Quality by design fostered fabrication of cabazitaxel loaded pH-responsive Improved nanotherapeutics against prostate cancer.

Cabazitaxel has been approved for the treatment of prostate cancer since 2010. However, its poor solubility and permeability pitfalls prevent its accumulation at the target site and promote severe adverse effects. About 90% of prostate cancer (PCa) patients suffer from bone metastasis. This advent reports the development of CBZ-loaded pH-responsive polydopamine nanoparticles (CBZ NP) against metastatic PCa cells. Quality by design (QbD) and multivariate analysis tools were employed for the optimization of CBZ NP. Amorphisation of CBZ along with metastatic microenvironment responsive release was observed thereby imparting spatial release and circumventing solubility pitfalls. CBZ NP retained its cytotoxic potential, with a significant increase in quantitative cellular uptake. Apoptotic markers observed from nuclear staining with elevated reactive oxygen species (ROS) and mitochondrial damage revealed by JC-1 staining demonstrated the efficacy of CBZ NP against PC-3 cells with good serum stability and diminished hemolysis. Cell cycle analysis revealed substantial S and G2/M phase arrest with enhancement in apoptosis was observed. Western blot studies revealed an elevation in caspase-1 and suppression in Bcl-2 indicating enhanced apoptosis compared to the control group. Substantial reduction in the diameter of 3D-Tumoroid and enhanced cell proliferation inhibition indicated the efficacy of CBZ NP in PCa. Thus, we conclude that CBZ NP could be a promising Nanotherapeutic approach for PCa.

Effect of weight loss on ventricular repolarization in normotensive severely obese patients with and without heart failure.

BACKGROUND: Obesity has been reported to be associated with delayed ventricular repolarization. The purpose of this study was to assess ventricular repolarization in normotensive severely obese subjects with and without heart failure (HF) and to assess the effect of weight loss on ventricular repolarization in such patients. METHODS: Twenty-eight patients with and 39 patients without HF (body mass index ≥ 40 kg/m(2)) were studied before and after weight loss from bariatric surgery. Corrected QT interval (QTc) was measured on 12-lead electrocardiograms using Bazett's formula. QTc dispersion was calculated by subtracting the minimum from the maximum QTc on each 12-lead electrocardiogram. Electrocardiograms and transthoracic echocardiograms were performed preoperatively and at the nadir of postoperative weight loss. RESULTS: Mean QTc and QTc dispersion were significantly longer/greater in subjects with HF than in those without HF (P < 0.0001). Weight loss produced significant reductions in mean QTc and QTc dispersion in both subgroups (P < 0.0001). Pre-weight loss left ventricular (LV) mass/height and presence or absence of HF independently predicted pre-weight loss QTc and QTc dispersion (P < 0.0001). Weight loss-induced decrease in LV mass/height independently predicted weight loss-induced decreases in QTc and QTc dispersion (P < 0.0001). CONCLUSIONS: HF independently predicts QTc and QTc dispersion in normotensive severely obese patients. Decrease in the LV mass resulting from weight loss independently predicts reduction in QTc and QTc dispersion in such patients.

Impact of obesity and weight loss on cardiac performance and morphology in adults.

Obesity, particularly severe obesity is capable of producing hemodynamic alterations that predispose to changes in cardiac morphology and ventricular function. These include increased cardiac output, left ventricular hypertrophy and diastolic and systolic dysfunction of both ventricles. Facilitated by co-morbidities such as hypertension, the sleep apnea/obesity hypoventilation syndrome, and possibly certain neurohormonal and metabolic alterations, these abnormalities may predispose to left and right heart failure, a disorder known as obesity cardiomyopathy.

Utilization of phase II cardiac rehabilitation in Veterans Administration patients.

Cardiac rehabilitation (CR) is underutilized across the United States. Reported national average varies from 14-35% after acute myocardial infraction and 31% after coronary artery bypass grafting surgery. No study to date has examined the utilization of CR in eligible veteran population. In this retrospective study, computerized veteran medical records at a single Veterans Administration (VA) hospital were screened between January 1, 2006 and December 31, 2009. Patients who met the inclusion and exclusion criteria were surveyed telephonically and asked a series of questions relating to delivery and utilization of phase II CR. Data was collected using a pre-printed questionnaire and patient responses were number coded. Utilization rate of phase II CR in veterans was noted to be 21%. Common reasons reported for underutilization of CR included time and distance problems, orthopedic- and stroke-related muscle weakness and lack of motivation. Participation in Phase II CR led to better adherence to exercise long term. Also, 65-70% of the veterans expressed interest in a tailored home based CR program. CR is underutilized in eligible veterans. Compliance could possibly be improved if the veterans were offered a tailored CR program.

Acute left ventricular dysfunction in the critically ill.

Acute left ventricular (LV) dysfunction is common in the critical care setting and more frequently affects the elderly and patients with comorbidities. Because of increased mortality and the potential for significant improvement with early revascularization, the practitioner must first consider acute coronary syndrome. However, variants of stress (takotsubo) cardiomyopathy may be more prevalent in ICU settings than previously recognized. Early diagnosis is important to direct treatment of complications of stress cardiomyopathy, such as dynamic LV outflow tract obstruction, heart failure, and arrhythmias. Global LV dysfunction occurs in the critically ill because of the cardio-depressant effect of inflammatory mediators and endotoxins in septic shock as well as direct catecholamine toxicity. Tachycardia, hypertension, and severe metabolic abnormalities can independently cause global LV dysfunction, which typically improves with addressing the precipitating factor. Routine troponin testing may help early detection of cardiac injury and biomarkers could have prognostic value independent of prior cardiac disease. Echocardiography is ideally suited to quantify LV dysfunction and determine its most likely cause. LV dysfunction suggests a worse prognosis, but with appropriate therapy outcomes can be optimized.