Naringin is one of the most interesting phytopharmaceuticals that has been widely investigated for various biological actions. Yet, its low water solubility, limited permeability, and suboptimal bioavailability limited its use. Therefore, in this study, polymeric micelles of naringin based on pluronic F68 (PF68) were developed, fully characterized, and optimized. The optimized formula was investigated regarding in vitro release, storage stability, and in vitro cytotoxicity vs different cell lines. Also, cytoprotection against ethanol-induced ulcer in rats and antitumor activity against Ehrlich ascites carcinoma in mice were investigated. Nanoscopic and nearly spherical 1:50 micelles with the mean diameter of 74.80±6.56 nm and narrow size distribution were obtained. These micelles showed the highest entrapment efficiency (EE%; 96.14±2.29). The micelles exhibited prolonged release up to 48 vs 10 h for free naringin. The stability of micelles was confirmed by insignificant changes in drug entrapment, particle size, and retention (%) (91.99±3.24). At lower dose than free naringin, effective cytoprotection of 1:50 micelles against ethanol-induced ulcer in rat model has been indicated by significant reduction in mucosal damage, gastric level of malondialdehyde, gastric expression of tumor necrosis factor-alpha, caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, and interleukin-6 with the elevation of gastric reduced glutathione and superoxide dismutase when compared with the positive control group. As well, these micelles provoked pronounced antitumor activity assessed by potentiated in vitro cytotoxicity particularly against colorectal carcinoma cells and tumor growth inhibition when compared with free naringin. In conclusion, 1:50 naringin–PF68 micelles can be represented as a potential stable nanodrug delivery system with prolonged release and enhanced antiulcer as well as antitumor activities.

No abstract

Neuron‐immune interaction in the dorsal root ganglia (DRG) plays a pivotal role in the neuropathic pain development after nerve injury. Sigma‐1 receptor (Sig‐1R) is expressed by DRG neurons but its role in neuropathic pain is not fully understood. We investigated the effect of peripheral Sig‐1R on neuroinflammation in the DRG after spared (sciatic) nerve injury (SNI) in mice. Nerve injury induced a decrease in NeuN staining along with the nuclear eccentricity and ATF3 expression in the injured DRG. Sig‐1R was present in all DRG neurons examined, and after SNI this receptor translocated to the periphery of the soma and the vicinity of the nucleus, especially in injured ATF3 + neurons. In WT mice, injured DRG produced the chemokine CCL2, and this was followed by massive infiltration of macrophages/monocytes, which clustered mainly around sensory neurons with translocated Sig‐1R, accompanied by robust IL‐6 increase and mechanical allodynia. In contrast, Sig‐1R knockout (Sig‐1R‐KO) mice showed reduced levels of CCL2, decreased macrophage/monocyte infiltration into DRG, and less IL‐6 and neuropathic mechanical allodynia after SNI. Our findings point to an important role of peripheral Sig‐1R in sensory neuron‐macrophage/monocyte communication in the DRG after peripheral nerve injury; thus, these receptors may contribute to the neuropathic pain phenotype.

The goal of the current study was to explore the potential benefits of Acitretin (Act) nanovesicular gel as a prospective antipsoriatic topical delivery system counteracting the drug challenges in terms of its extremely low aqueous solubility, instability, skin irritation, and serious systemic adverse effects. Act-loaded niosomes were successfully developed, entirely characterized, and optimized. Further evaluation of the optimized formula was conducted regarding its stability and ex vivo cytotoxicity on different cell lines. The optimized niosomal vesicles were then incorporated in gel base matrix and investigated by sequential ex vivo (skin permeation and deposition) and in vivo (skin irritation and antipsoriatic activity using mouse tail model) experiments. The optimized Act-loaded niosomes (span 60:cholesterol molar ratio 1:1) were spherical in shape and exhibited the highest entrapment efficiency (90.32±3.80%) with appropriate nanosize and zeta potential of 369.73±45.45 nm and −36.33±1.80 mV, respectively. Encapsulation of the drug in the nanovesicles was further emphasized by differential scanning calorimetric and powder X-ray diffraction studies. After 3 months storage at 4±1°C, the optimized formula preserved its stability. Act nano niosomal gel produced a remarkable enhanced ex vivo permeation profile up to 30 h and significant drug deposition in the viable epidermal–dermal layers compared with those of Act gel. The pronounced antipsoriatic activity of the medicated nano niosomes was proved ex vivo in HaCaT cells (a keratinocyte cell line). Topical application of Act nano niosomal gel to mouse tail model further established its distinct in vivo antipsoriatic superiority in terms of significantly higher orthokeratosis, drug activity, and reduction in epidermal thickness compared with the control and other gel formulations. Also, negligible skin irritation and better skin tolerability of Act nanovesicular gel were revealed by primary irritation index and histopathologic examination.

No abstract

Acetaminophen (APAP) overdose leads to liver injury. NLRP3 inflammasome is a key player in APAP-induced inflammation. Also, apoptosis and liver regeneration play an important role in liver injury. Therefore, we assessed allicin's protective effect on APAP-induced hepatotoxicity and studied its effect on NLRP3 inflammasome and apoptosis. Mice in the APAP group were injected by APAP (250 mg/kg, intraperitoneal). The allicin-treated group received allicin orally (10 mg/kg/d) during 7 days before APAP injection. Serum and hepatic tissues were separated 24 hours after APAP injection. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA) were assessed using the colorimetric method. Hepatic NLRP3 inflammasome, caspase-1, and interleukin-1β (IL-1β) were estimated using enzyme-linked immunosorbent assay. Hepatic Bcl-2 and Ki-67 were investigated by immunohistochemistry. APAP significantly increased AST, ALT, and ALP, whereas allicin significantly decreased their levels. Also, APAP significantly decreased albumin and allicin significantly improved it. APAP produced changes in liver morphology, including inflammation and massive coagulative necrosis. Allicin protected the liver from APAP-induced necrosis, apoptosis, and hepatocellular degeneration via increasing Bcl-2 and Ki-67 levels. APAP significantly increased the hepatic MDA, whereas allicin significantly prevented this increase. APAP markedly activated the NLRP3 inflammasome pathway and consequently increased the production of caspase-1 and IL-1β.Interestingly, we found that allicin significantly inhibited NLRP3 inflammasome activation, which resulted in decreased caspase-1 and IL-1β levels. Allicin has a hepatoprotective effect against APAP-induced liver injury via the decline of oxidative stress and inhibition of the inflammasome pathway and apoptosis. Therefore, allicin might be a novel tool to halt the progression of APAP-stimulated hepatotoxicity.

There is a great demand to introduce new approaches into cancer treatment field due to incidence of increased breast cancer all over the world. The current study was designed to evaluate the role of imatinib mesylate (IM) and/or hesperidin (HES) nanoparticles alone or in combination in enhancing the anticancer activity and to investigate the ability of nanoencapsulation to reduce cardiotoxicity of IM in solid Ehrlich carcinoma (SEC)‐bearing mice. IM and HES were loaded into PLGA (poly(lactic‐co‐glycolic acid) polymer. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n = 10). On day 28 from tumor inoculation, mice were sacrificed and blood samples were collected in heparinized tubes for hematological studies, biochemical determination of lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (SGOT) levels. In addition, tumor and cardiac tissues were utilized for histopathological examination as well as determination of MDR‐1 gene expression. Immunohistochemical staining of BAX and BCL‐2 was done. Nano IM‐ and/or Nano HES‐treated groups showed a significant reduction in tumor volume, weight, hematological, cardiac markers, and tumor MDR‐1 gene downregulation compared to free conventional treated groups. In conclusion, the use of HES as an adjuvant therapy with IM could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, nanoencapsulation of IM and/or HES with PLGA polymer showed a remarkable anticancer activity.

Lipopolysaccharide (LPS) is a component of the outer membrane of gram negative bacteria. LPS challenging allows switching transcription of proinflammatory cytokines on via over stimulation of Toll-like receptors (TLRs) signaling pathway with subsequent pathogenic inflammatory response. We investigated the possible reproductive toxicity of LPS in male Wister albino rats. Oxidative stress markers, antioxidant status and caspase-3 activity were analyzed in testicular tissues of rats exposed to either saline or LPS (4 mg/kg BW, ip; 0.18 of the LD 50 ). The samples were collected at 6 h and 72 h after injection of LPS. A significant reduction in testicular reduced glutathione (GSH), glutathione-S-transferase (GST) and superoxide dismutase (SOD) was observed at 72 h compared to control group. Total antioxidant capacity was decreased at 6 h with additional significant reduction at 72 h. Catalase activity was reduced significantly at both 6 and 72 h. Malondialdehyde (MDA) was increased (P ≤ 0.05) in LPS injected rats without variation between 6 and 72 h. A significant increase in nitric oxide (NO) was observed at 72 h after injection. A time-dependent increase in LPS-treated groups was observed in the concentration of caspase-3.Histopathological analysis revealed degenerative changes and necrosis of seminiferous tubules after 6 h with further accumulation of eosinophilic edematous transudate in its lumen after 72 h. In conclusion, by increasing time of exposure, LPS induced lipid peroxidation, oxidative stress, reduced testicular antioxidant capacity and encouraged testicular apoptosis which could be possible mechanisms for impairment of testicular function.