Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM ...multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR.
A dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Globally, it is estimated that 290,000 patients infected with hepatitis C virus (HCV) died from hepatitis C consequences, including cirrhosis and hepatocellular carcinoma in 2019. Although ...daclatasvir (DCV), combined with sofosbuvir (SOF), is effective in HCV patients, the new pan-genotypic combinations are considered by many as more cost-effective and successful in eradicating HCV infection.
This review discusses the safety, efficacy, and cost-effectiveness of DCV as an HCV treatment option based on real-world studies and pharmacoeconomic evaluations.
Real-life studies suggest that SOF/DCV has acceptable sustained virological response and can be used successfully to manage HCV. Nonetheless, the use of SOF/DCV is limited by the longer treatment duration in genotype (GT)-3 patients and the need for ribavirin (RBV) in treatment-experienced patients which increases the likelihood of adverse effects. DCV is likely to remain as a therapeutic option for the management of GT-1, GT-2, and GT-4 patients in resource limited settings, while GT-3 patients are more likely to benefit from RBV-free direct-acting antiviral combinations such as SOF/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8 weeks. The introduction of generics for these new pan-genotypic drugs would likely eliminate the need for SOF/DCV in the near future.
Summary
Background: Coagulopathy and thromboembolic events are common in Covid‐19 patients and are poor prognostic factors. Controversy exists regarding the potential of anticoagulation (AC) to ...reduce mortality and incidence of thromboembolic events in Covid‐19 patients. The current systematic review and meta‐analysis investigated the association between anticoagulants and mortality in adult hospitalized COVID‐19 patients using the available published non‐randomized studies. Methods: Google Scholar, PubMed, Scopus, the Cochrane Library and Clinical Trials.gov were searched for relevant studies. A meta‐analysis of adjusted and unadjusted estimates was performed. The relative risk was used as a measure of effect. The random‐effects model was used to pool estimates using the generic inverse variance method. Results: Sixteen studies were included in the quantitative data synthesis. Results showed a statistically significant association between AC and mortality (RR = 0.56, 95% CI 0.36; 0.92, p = 0.02). Both therapeutic (Relative risk RR = 0.4, 95% CI 0.27; 0.57) and prophylactic AC (RR = 0.54, 95% CI 0.41; 0.71) were associated with lower risk of mortality. Pre‐admission AC was not associated with mortality (RR = 0.84, 95% CI 0.49; 1.43, p > 0.05) while prophylactic AC was associated with higher risk of mortality compared to therapeutic AC (RR = 1.58, 95% CI 1.34; 1.87, p < 0.001). Conclusion: Findings support the association of AC with mortality in Covid‐19 patients. The results, synthesized from mostly low‐quality studies, show that prophylactic and therapeutic AC might reduce mortality in Covid‐19 patients. Findings suggest that therapeutic doses might be associated with better survival compared to prophylactic doses.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
It is necessary to have an energy management system based on one or more control strategies to sense, monitor, and control the behavior of the hybrid energy sources. In renewable hybrid power systems ...containing fuel cells and batteries, the hydrogen consumption reduction and battery state of charge (SOC) utilizing are the main objectives. These parameters are essential to get the maximum befits of cost reduction as well as battery and hydrogen storage lifetime increasing. In this paper, a novel hybrid energy management system (HEMS) was designed to achieve these objectives. A renewable hybrid power system combines: PV, PEMFC, SC, and Battery was designed to supply a predetermined load with its needed power. This (REHPS) depends on the PV power as a master source during the daylight. It uses the FC to support as a secondary source in the night or shading time. The battery is helping the FC when the load power is high. The supercapacitor (SC) is working at the load transient or load fast change. The proposed energy management system uses fuzzy logic and frequency decoupling and state machine control strategies working together as a hybrid strategy where the switching over between both strategies done automatically based on predetermined values to obtain the minimum value of hydrogen consumption and the maximum value of SOC at the same time. The proposed HEMS achieves 19.6% Hydrogen consumption saving and 5.4% increase in SOC value compared to the results of the same two strategies when working as a stand-alone. The load is designed to show a surplus power when the PV power is at its maximum value. This surplus power is used to charge the battery. To validate the system, the results were compared with the results of each strategy if working separately. The comparison confirms the achievement of the hybrid energy management system goal.
•Hybrid energy management system designed to minimize hydrogen consumption in FC.•Hybrid energy management system designed to optimize the battery state of charge.•A battery is helping the FC when the load power is high.•A supercapacitor (SC) is working at the load transient or load fast change.•The proposed management systems decreased hydrogen consumption by 20%.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the last decades, pharmaceutical interested researches aimed to develop novel and innovative drug delivery techniques in the medical and pharmaceutical fields. Recently, phospholipid vesicles ...(Liposomes) are the most known versatile assemblies in the drug delivery systems. The discovery of liposomes arises from self-forming enclosed phospholipid bilayer upon coming in contact with the aqueous solution. Liposomes are uni or multilamellar vesicles consisting of phospholipids produced naturally or synthetically, which are readily non-toxic, biodegradable, and are readily produced on a large scale. Various phospholipids, for instance, soybean, egg yolk, synthetic, and hydrogenated phosphatidylcholine consider the most popular types used in different kinds of formulations. This review summarises liposomes composition, characterisation, methods of preparation, and their applications in different medical fields including cancer therapy, vaccine, ocular delivery, wound healing, and some dermatological applications.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
The surgical management of multinodular goiter is the treatment of choice for the majority of cases. There is controversy between radical resection with the lifelong thyroxine substitution ...and function-preserving resection with the risk for recurrence, and the complications associated with total thyroidectomy.
Objective
The aim of the present study was to compare the outcome of total thyroidectomy (TT) in comparison with subtotal thyroidectomy (ST) as regards hypocalcemia, transient nerve injury, and recurrence rate.
Patients and methods
This study included published English medical articles in the last 20 years, concerning the treatment of multinodular goiter.
Results
Meta-analysis was for the evaluation of surgical outcomes after surgical management of multinodular goiter including total thyroidectomy versus subtotal thyroidectomy by comparing the TT versus ST in our study including 23 studies included of the total number of patients (4485) who underwent subtotal thyroidectomy versus the total number of patients (7116) who underwent total thyroidectomy; a comparison was done as regards postoperative complications including RLN injury (transient or permanent), rate of recurrence, need for reoperation, and incidence of postoperative hypocalcemia. The incidence of RLN injury is lower in ST compared to TT, and its recurrence is much lower in TT than in ST.
Conclusion
This meta-analysis showed that the advantages of total thyroidectomy include adequate eradication of the disease, prevention of recurrent goiter, and avoidance of the need for completion surgery in case of occult malignancy, but it is associated with higher morbidity (postoperative thyroidectomy complications: RLN palsy and hypoparathyroidism) and the need for lifelong replacement therapy (L-thyroxin supplementation).
Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer’s and Parkinson’s diseases. Vilda‘s ...effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington’s disease (HD). However, Vilda’s role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (
p
Y458/199)-PI3K,
p
S473-Akt. Together, it boosted striatal neurotrophic factors and receptor;
p
S133-CREB, BDNF,
p
Y515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.
Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). ...Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Left ventricular hypertrophy is a common finding in patients with ischemic heart disease and is associated with mortality in patients with cardiovascular disease (CVD). Metformin, ...an antidiabetic drug, has been shown to reduce oxidative stress and left ventricular mass index (LVMI) in animal hypertrophy models. We summarized evidence regarding the effect of metformin on LVMI and LVEF.
Methods
Electronic databases were searched for randomized clinical trials (RCTs) that used metformin in non-diabetic patients with or without pre-existing CVD. The standardized mean change using change score standardization (SMCC) was calculated for each study. The random-effects model was used to pool the SMCC across studies. Meta-regression analysis was used to assess the association of heart failure (HF), metformin dose, and duration with the SMCC.
Results
Data synthesis from nine RCTs (754 patients) showed that metformin use resulted in higher reduction in LVMI after 12 months (SMCC = −0.63, 95% CI − 1.23; − 0.04, p = 0.04) and an overall higher reduction in LVMI (SMCC = −0.5, 95% CI − 0.84; − 0.16, p < 0.01). These values equate to absolute values of 11.3 (95% CI 22.1–0.72) and 8.97 (95% CI 15.06–2.87) g/m
2
, respectively. The overall improvement in LVEF was also higher in metformin users after excluding one outlier (SMCC = 0.26, 95% CI 0.03–0.49, P = 0.03) which translates to a higher absolute improvement of 2.99% (95% CI 0.34; 5.63). Subgroup analysis revealed a favorable effect for metformin on LVEF in patients who received > 1000 mg/day (SMCC = 0.28, 95% CI 0.04; 0.52, P = 0.04), and patients with HF (SMCC = 0.23; 95% CI 0.1; 0.36; P = 0.004). These values translate to a higher increase of 2.64% and 3.21%, respectively.
Conclusion
Results suggest a favorable effect for metformin on LVMI and LVEF in patients with or without pre-existing CVD. Additional trials are needed to address the long-term effect of metformin.
Registration
The study was registered on the PROSPERO database with the registration number CRD42021239368 (
https://www.crd.york.ac.uk/prospero
).
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