Molecular mechanisms underlying cyclophosphamide-induced cognitive impairment and strategies for neuroprotection in preclinical models.

Cyclophosphamide has drastically enhanced the expectancy and quality of life of cancer patients. However, it is accompanied by diverse neurological complications which are considered a dose-limiting adverse effect. Neurotoxicity caused by cyclophosphamide can manifest in numerous manners including anxiety, depression, motor dysfunction and cognitive deficits. This review article offers an overview on cyclophosphamide-induced neurotoxicity, providing a unified point of view on the possible underlying molecular mechanisms including oxidative brain damage, neuroinflammation, apoptotic neuronal cell death as well as disruption of the balance of brain neurotransmitters and neurotrophic factors. Besides, this review sheds light on the promising protective agents that have been investigated using preclinical animal models as well as their biological targets and protection mechanisms. Despite promising results in experimental models, none of these agents has been studied in clinical trials. Thus, there is lack of evidence to advocate the use of any neuroprotective agent in the clinical setting. Furthermore, none of the protective agents has been evaluated for its effect on the anticancer activity of cyclophosphamide in tumor-bearing animals. Therefore, there is a great necessity for adequate well-designed clinical studies for evaluation of the therapeutic values of these candidates. Conclusively, this review summarizes the molecular mechanisms accounting for cyclophosphamide-induced neurotoxicity together with the potential protective strategies seeking for downgrading this neurological complication, thus enhancing the quality of life and well-being of cancer patients treated with cyclophosphamide.

Design of nanoconstructs that exhibit enhanced hemostatic efficiency and bioabsorbability.

Hemorrhage is a prime cause of death in civilian and military traumatic injuries, whereby a significant proportion of death and complications occur prior to paramedic arrival and hospital resuscitation. Hence, it is crucial to develop hemostatic materials that are able to be applied by simple processes and allow control over bleeding by inducing rapid hemostasis, non-invasively, until subjects receive necessary medical care. This tutorial review discusses recent advances in synthesis and fabrication of degradable hemostatic nanomaterials and nanocomposites. Control of assembly and fine-tuning of composition of absorbable (i.e., degradable) hemostatic supramolecular structures and nanoconstructs have afforded the development of smart devices and scaffolds capable of efficiently controlling bleeding while degrading over time, thereby reducing surgical operation times and hospitalization duration. The nanoconstructs that are highlighted have demonstrated hemostatic efficiency pre-clinically in animal models, while also sharing characteristics of degradability, bioabsorbability and presence of nano-assemblies within their compositions.

Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure.

Pulmonary administration provides a useful alternative to oral and invasive routes of administration while enhancing and prolonging the accumulation of drugs into the lungs and reducing systemic drug exposure. In this study, chloroquine, as a model drug, was loaded into niosomes for potential pulmonary administration either via dry powder inhalation or intratracheally. Chloroquine-loaded niosomes have been prepared and extensively characterized. Furthermore, drug-loaded niosomes were lyophilized and their flowing properties were evaluated by measuring the angle of repose, Carr's index, and Hausner ratio. The developed niosomes demonstrated a nanosized (100-150 nm) spherical morphology and chloroquine entrapment efficiency of ca. 24.5%. The FT-IR results indicated the incorporation of chloroquine into the niosomes, whereas in vitro release studies demonstrated an extended-release profile of the drug-loaded niosomes compared to the free drug. Lyophilized niosomes exhibited poor flowability that was not sufficiently improved after the addition of lactose or when cryoprotectants were exploited throughout the lyophilization process. In vivo, intratracheal administration of chloroquine-loaded niosomes in rats resulted in a drug concentration in the blood that was 10-fold lower than the oral administration of the free drug. Biomarkers of kidney and liver functions (i.e., creatinine, urea, AST, and ALT) following pulmonary administration of the drug-loaded nanoparticles were of similar levels to those of the control untreated animals. Hence, the use of a dry powder inhaler for administration of lyophilized niosomes is not recommended, whereas intratracheal administration might provide a promising strategy for pulmonary administration of niosomal dispersions while minimizing systemic drug exposure and adverse reactions.

Correction to: Protection from doxorubicin-induced nephrotoxicity by clindamycin: novel antioxidant, anti-inflammatory and anti-apoptotic roles.

The published online version contains mistake in the author list for the author "Nermeen N. El-Agroudy" was incorrectly presented.

Protection from doxorubicin-induced nephrotoxicity by clindamycin: novel antioxidant, anti-inflammatory and anti-apoptotic roles.

This study was performed to examine whether clindamycin could protect against doxorubicin (DOX)-induced acute nephrotoxicity, and if so, what molecular mechanisms responsible for this protective effect. Male albino rats were pretreated with clindamycin once per day for 5 consecutive days at a dose of 300 mg/kg, i.p, then received a single dose of DOX (15 mg/kg; i.p) on the 5th day. DOX-induced marked renal injury as indicated by the presence of inflammatory cell infiltration, congestion, and edema accompanied by elevation in serum levels of creatinine and urea. These effects were alleviated by clindamycin pretreatment. DOX caused glutathione depletion and reduction in level of the antioxidant enzyme, catalase. Pretreatment with clindamycin markedly prohibited DOX-induced oxidative damage in renal tissue. Moreover, DOX provoked inflammatory responses in renal tissues as confirmed by increased expressions of NF-κB and COX-2 which were significantly reduced by clindamycin pretreatment. Besides, DOX-triggered apoptotic cascades in renal tissues as evidenced by elevated expression of pro-apoptotic proteins; Bax and cytochrome c, enhancing activity of caspase-3 enzyme whereas reducing the expression of anti-apoptotic Bcl-2 protein. Clindamycin pretreatment counteracts these apoptotic effects of DOX. Summarily, our results provide an evidence for the first time that clindamycin has a potential protective action against DOX-induced acute nephrotoxicity through inhibiting oxidative stress, inflammatory cascades, and apoptotic tissue injury.