Selenium suppressed growth of Ehrlich solid tumor and improved health of tumor-bearing mice.

Selenium (Se) is an important micronutritional biomolecule in cancer therapy. The current work evaluated the anticancer effect of Se and its ability to improve health of mice with solid Ehrlich carcinoma implanted subcutaneously. Four groups of five female BALB/c mice each were assembled. Ehrlich tumor cells were engrafted into two of them, either with or without Se therapy. The other groups served as control groups, either with or without Se treatment. Se treatment resulted in a notable decrease in both tumor volume and animal body mass in tumor-bearing mice. Treatment with Se markedly increased oxidative stress in tumor while ameliorating oxidative stress in sera of tumors-bearing mice. Similarly, treatment with Se resulted in downregulation of inflammatory cytokines (TNF-α and IL-6) while increasing IL-10 in serum of tumor-bearing mice. Conversely, selenium increased TNF- α and IL-6 and decreased IL-10 in tumor suggesting disruption of tumor immunity. The increased oxidative stress and inflammation in tumor tissue dysregulated cell cycle phases with increase apoptotic tumor cells population in G0/G1 phase. This is supported by the increased levels apoptotic regulating proteins (Bax and caspase-3 and P-53) while decreasing Bcl-2 in the tumor tissue. Treatment with Se also resulted in increased comet parameters indicating DNA damage of tumor cells. Histopathological examination revealed a significant decrease in a number of neoplastic cells within tumor of mice that treated with Se. In conclusion, these findings suggest that Se therapy significantly suppressed solid tumor proliferation and growth while mitigating the health status of tumor-bearing mice.

A microarray patch SARS-CoV-2 vaccine induces sustained antibody responses and polyfunctional cellular immunity.

Sustainable global immunization campaigns against COVID-19 and other emerging infectious diseases require effective, broadly deployable vaccines. Here, we report a dissolvable microarray patch (MAP) SARS-CoV-2 vaccine that targets the immunoresponsive skin microenvironment, enabling efficacious needle-free immunization. Multicomponent MAPs delivering both SARS-CoV-2 S1 subunit antigen and the TLR3 agonist Poly(I:C) induce robust antibody and cellular immune responses systemically and in the respiratory mucosa. MAP vaccine-induced antibodies bind S1 and the SARS-CoV-2 receptor-binding domain, efficiently neutralize the virus, and persist at high levels for more than a year. The MAP platform reduces systemic toxicity of the delivered adjuvant and maintains vaccine stability without refrigeration. When applied to human skin, MAP vaccines activate skin-derived migratory antigen-presenting cells, supporting the feasibility of human translation. Ultimately, this shelf-stable MAP vaccine improves immunogenicity and safety compared to traditional intramuscular vaccines and offers an attractive alternative for global immunization efforts against a range of infectious pathogens.

Proanthocyanidins attenuated liver damage and suppressed fibrosis in CCl4-treated rats.

Liver damage and fibrosis are serious health problems without effective treatment. Proanthocyanidins (PAs) are flavonoids with several biological effects. We investigated the potential anti-fibrotic effect of proanthocyanidins on carbon tetrachloride (CCl4)-induced liver injury and fibrosis. Liver fibrosis was induced by oral administration of CCl4 three times a week for 5 and 9 weeks. PAs were daily administered in a dose of 500 mg/kg bw. Animals were divided into five groups: control groups, olive oil-treated group, Pas-treated group, CCl4-treated animals, and PAs + CCl4-treated rats. CCl4 and PAs were administered by gavage. Administration of CCl4 caused a significant elevation in alanine aminotransferase and aspartate aminotransferase activities, the concentration of alpha-2-macroglobulin, and bilirubin concentration. In addition, the protein and apolipoprotein contents were significantly decreased in the serum of CCl4-treated rats. These results were accompanied by histopathological alterations and increased inflammation, apoptosis, and DNA damage. Treatment with PAs caused remarkable regression of fibrosis and alpha-2-macroglobulin with improvement in histological characteristics of the liver after 5 and 9 weeks of intoxication. PAs could also maintain redox balance, evidenced by the prevention of lipid peroxidation and mitigation of the decrease in antioxidants. Treatment of intoxicated rats with PAs resulted in a significant decline in pro-inflammatory cytokines, including IL-6, IL-1ß, and TNF-α in serum. This is associated with a remarkable decrease in apoptosis of hepatic cells shown by decreased levels of Bax, caspase-3, and -9, with increased Bcl-2. The protective effect of PAs was also evident by protecting DNA integrity in the intoxicated rats. PAs suppressed hepatic fibrosis, improved liver function and structure via modulating the interdependence between oxidative stress, inflammation, apoptosis, and DNA integrity in CCl4-treated rats.

Microfluidic Systems For Manufacturing of Microparticle-Based Drug-Delivery Systems: Design, Construction, and Operation.

Particles synthesized from biodegradable polymers hold great potential as controlled drug delivery systems. Continuous flow platforms based on microfluidics offer attractive advantages over conventional batch-emulsification techniques for the scalable fabrication of drug-loaded particles with controlled physicochemical properties. However, widespread utilization of microfluidic technologies for the manufacturing of drug-loaded particles has been hindered largely by the lack of practical guidelines toward cost-effective development and reliable operation of microfluidic systems. Here, we present a framework for rational design and construction of microfluidic systems using commercially available components for high-throughput production of uniform biodegradable particles encapsulating drugs. We also demonstrate successful implementation of this framework to devise a robust microfluidic system that is capable of producing drug-carrying particles with desired characteristics. The guidelines provided in this study will likely help broaden the applicability of microfluidic technologies for the synthesis of high-quality, drug-loaded biodegradable particles.

Silymarin inhibits the progression of Ehrlich solid tumor via targeting molecular pathways of cell death, proliferation, angiogenesis, and metastasis in female mice.

BACKGROUND: Plant-derived phytochemicals have been reported to exert anticancer activity. This study investigated the antitumor role of silymarin (Silybum marianum) (SMN) and its molecular targets in Ehrlich solid tumor xenografts in vivo. METHODS AND RESULTS: Female Swiss albino mice were divided into three groups (of five animals each) that were engrafted with Ehrlich tumor (ET) cells with or without SMN treatment. The 3rd groups treated with DMSO only vehicle control group. A significant reduction in animal body mass and tumor volume/weight were observed in xenografted mice treated with SMN. SMN modulated oxidative stress in tumors while enhancing the antioxidant levels in mouse serum. SMN activated both mitochondrial and death receptor-related apoptosis pathways and induced cell cycle arrest, marked by a significant downregulation of cyclin D1 in SMN-treated tumors. Significant decreases in RNA content and protein expression levels of Ki-67 and proliferating cell nuclear antigen were observed in ET cells. Additionally, SMN downregulated vascular endothelial growth factor and nuclear factor-kappa B levels indicating anti-angiogenesis activity of this agent. SMN upregulated the expression of E-cadherin in tumor tissue suggesting, that SMN has potential ability to inhibit metastasis. Tumor tissue from SMN-treated animals showed a remarkable degeneration and reduction in the neoplastic cell density. CONCLUSIONS: The anticancer effect was associated with apparent apoptosis in neoplastic cells with abundance of multifocal necrotic areas. SMN was found to inhibit ET growth via enhancing apoptosis, inhibition of cell division and reduction in angiogenesis in vivo. Hypothetical scheme of SMN antitumor effects (mechanism of signaling) in solid ET in vivo. SMN anticancer effect may be mediated by molecular mediators that affect proliferation, cell cycle activity, apoptotic pathways, angiogenesis, and metastasis.

Self-Adhesive Microneedles with Interlocking Features for Sustained Ocular Drug Delivery.

The interests in sustained ocular drug delivery have grown rapidly in recent years, with hope to replace repeated intravitreal injections. Microneedles (MNs), which are minimally invasive, have been shown to be a feasible vehicle for sustained drug delivery. However, securing an MN patch in the eye remains challenging. In this study, a new design of hydrogel MNs with interlocking features to achieve self-adhesion is proposed. Upon swelling, the swollen interlocking features help secure the MNs in place. A new molding process is developed to fabricate MNs with interlocking features that can cause issues when demolding using the regular micromolding process. MNs with two different interlocking feature designs are used in this study and are made with polyvinyl alcohol. MNs with the interlocking features show an 80% increase in adhesion strength and a small amount of increase in penetration force, in comparison to MNs without any feature. The experiments are performed using both a sclera-mimicking phantom and ex vivo eyes harvested from rabbits and are shown to have comparable results. This study demonstrates the feasibility of incorporating interlocking features to MNs to achieve self-adhesion that can enable sustained drug delivery via MNs.

Nanoformulated ellagic acid ameliorates pentylenetetrazol-induced experimental epileptic seizures by modulating oxidative stress, inflammatory cytokines and apoptosis in the brains of male mice.

The present study evaluated the neuroprotective and antiepileptic efficacy of ellagic acid (EA) encapsulated in calcium-alginate nanoparticles (Ca2+-ALG NPs) in pentylenetetrazol (PTZ)-induced seizures in male mice. EA was encapsulated in ALG NPs using a nanospray drying method followed by ionotropic crosslinking with Ca2+. Characterization of the developed Ca2+-crosslinked EA-ALG NPs showed spherical, high stability NPs; successful loading of EA within crosslinked ALG NPs; and sustained release of EA. Male Swiss albino mice were divided into ten groups as follows; Group I- (control), Group II (50 mg EA /kg) - (EA), Group III polyethylene glycol (PEG), Group IV EA NPs (50 mg/kg) - (EA NP), Group (50 mg/kg alginate) V void V NPs - (void NPs), Group VI: (37.5 PTZ mg/kg) -(PTZ), Group VII: PTZ and EA - (PTZ-EA). Group VIII: animals received PTZ and PEG concurrently (PTZ-PEG). Group IX; animals received PTZ and void NPs concurrently - (PTZ-void). Group X: animals received PTZ and EA NPs concurrently (PTZ-EA NPs). PTZ was used to induce experimental epilepsy. Ca2+-ALG NPs prevented seizures throughout the experimental period and had a more prominent effect than free EA did. Ca2+-ALG NPs prevented increased glutamate, decreased GABA concentrations and ameliorated increased amyloid-ß and homocysteine levels in the serum and brain. Ca2+-EA-ALG NPs were superior to free EA in improving increased IL-6 and TNF-α. Ca2+-ALG NPs ameliorated PTZ-induced oxidative stress, as evidenced by decreased 4HNE levels and enhanced GSH, GR and GPx levels in the brain. These changes were accompanied by amelioration of apoptosis and its regulating proteins, including Cytochrome C, P53, Bax, Bcl2 and caspase-3 and caspase-9, and protected against DNA damage. Histological examination of the hippocampus confirmed that the neuroprotective effect of Ca2+-EA-ALG NPs was superior and more effective than that of free EA.

On the evaporation kinetics of [60] fullerene in aromatic organic solvents.

We investigate the effect of C60 fullerene nanospheres on the evaporation kinetics of a number of aromatic solvents with different levels of molecular association, namely, benzene, toluene, and chlorobenzene. The dependence of the evaporation rate on the fullerene concentration is not monotonic but rather exhibits maxima and minima. The results strongly support the notion of molecular structuring within the liquid solvent controlled by the nature of the fullerene/solvent interaction and the level of molecular association within the solvent itself.

Melatonin controls oxidative stress and modulates iron, ferritin, and transferrin levels in adriamycin treated rats.

AIM: Chemotherapy with adriamycin (ADR) is limited by its iron-mediated pro-oxidant toxicity. Because melatonin (MLT) is a broad spectrum antioxidant, we investigated the ability of MLT to control iron, its binding proteins, and the oxidative damage induced by ADR. MAIN METHODS: ADR was given as single i.p. dose of 10 mg kg(-1) body weight into male rats. MLT at a dose of 15 mg kg(-1) was injected daily for 5 days before ADR treatment followed by another injection for 5 days. Biochemical methods were used for this investigation. KEY FINDINGS: ADR injection caused elevations in plasma creatine kinase isoenzyme, lactic dehydrogenase, and aminotransferases, iron, ferritin, and transferrin. These changes were associated with increases in lipid peroxidation and protein oxidation as well as decreases in glutathione (GSH) levels and glutathione-S-transferase (GST) activity, while glutathione peroxidase (GSH-Px), and catalase (CAT) activity were elevated in the heart and liver of ADR treated rats. In the MLT+ADR group, the cardiac and hepatic function parameters and the levels of iron, transferrin and ferritin in plasma were normalized to control levels. The rats that were subjected to MLT+ADR had normalized CAT and GSH-Px activity and decreased TBARS and protein carbonyl levels compared the group only treated with ADR. GST activity and GSH concentration in the heart and liver were normalized when MLT accompanied ADR treatment. SIGNIFICANCE: MLT ameliorated oxidative stress by controlling iron, and binding protein levels in ADR treated rats demonstrating the usefulness of adriamycin in cancer chemotherapy and allowing a better management of iron levels.

On the development of a confocal Rayleigh-Brillouin microscope.

This Note illustrates how a confocal microscope may be modified to conduct Rayleigh-Brillouin mapping experiments that yield very useful information on the mechanical properties of interfacial materials in small volume elements. While the modifications to the microscope are quite straightforward, they do entail significant changes in the optical design. The instrument described herein consists of an argon ion laser equipped with an actively stabilized intercavity etalon that serves as the excitation source for a modified Zeiss LSM 310 confocal laser scan microscope. The optics of the microscope were reconfigured to enable interfacing of the microscope with a tandem triple-pass Fabry-Perot interferometer. This instrument enables three-dimensional Rayleigh-Brillouin spectral mapping of samples at micron spatial resolution. The performance of the instrument and its ability to perform both lateral and depth scans of the acoustic phonon velocity and, hence, the longitudinal modulus across bonded polymer/polymer and polymer/ceramic interfaces are illustrated and discussed.

Effects of Trifolium alexandrinum extracts on streptozotocin-induced diabetes in male rats.

UNLABELLED: The effects of (water, hexane and ethanolic) extracts prepared from the flower head of Trifolium alexandrinum (Leguminosae) were examined in the treatment of diabetes induced experimentally by streptozotocin (STZ) in rats. A single dose of STZ (50 mg/kg) produced a hyperglycemia, decrease in insulin level and elevation in glycosylated hemoglobin of RBCs as well as elevated serum total lipids, triglycerides and cholesterol levels. Also, a decreased serum high-density lipoprotein and in hepatic glycogen and glutathione GSH contents, concurrent with an increase in the concentration of malondialdehyde in the liver was observed. Daily intake of (water, hexane and ethanolic) extracts of T. alexandrinum in drinking water for 4 weeks immediately after diabetes induction caused significant decreases in glucose and glycated hemoglobin levels and increase in insulin level. It also greatly improved the levels of serum lipid parameters and significantly decreased lipid peroxidation in addition to increase the hepatic GSH content significantly. CONCLUSION: Extracts of T. alexandrinum improved hyperglycemia and other biochemical alterations noticed in STZ-diabetic rats. These effects may be due to the presence of a high content of flavonoids which acts synergistically as antioxidants.

Study of the hydrostatic pressure dependence of the Raman spectrum of single-walled carbon nanotubes and nanospheres.

We have investigated the behavior of single-walled carbon nanotubes and nanospheres (C(60)) under high hydrostatic pressure using Raman spectroscopy over the pressure range 0.2-10 GPa using a diamond anvil cell. Different liquid mixtures were used as pressure transmission fluids (PTF). Comparing the pressure dependence of the Raman peak positions for the nanotubes and the nanospheres in different PTF leads to the observation of a number of new phenomena. The observed shift in Raman peak position of both radial and tangential modes as a function of applied pressure and their dependence on the PTF chemical composition can be rationalized in terms of adsorption of molecular species from the of PTF on to the surface of the carbon nanotubes and/or nanospheres. The peak shifts are fully reversible and take place at a comparatively modest pressure (2-3 GPa) that is far below pressures that might be required to collapse the nanoparticles. Surface adsorption of molecular species on the nanotube or nanospheres provides a far more plausible rational for the observed phenomena than ideas based on the notion of tube collapse that have been put forward in the recent literature.

Laparoscopy-assisted reconstruction to treat severe aortoiliac occlusive disease: early and midterm results.

OBJECTIVES: The purpose of this study was to evaluate the consequences on patient selection and on early and midterm results of the learning curve of a surgical team performing laparoscopy-assisted surgery in the treatment of severe aortoiliac occlusive disease (AIOD). PATIENTS AND METHOD: Between January 1998 and June 2003, 58 patients (53 men, 5 women; mean age, 59.5 years [range, 37-76 years]) were included in a prospective study and underwent a laparoscopy-assisted aortofemoral reconstruction with graft implantation through a 5-cm to 8-cm minilaparotomy. Fifty-one patients (88%) had claudication (category 2 or 3, Rutherford classification), and seven patients (12%) had tissue loss; at presentation they had TransAtlantic Inter-Society Consensus C (n=24, 41.4 %) or D (n=32, 55.2%) iliac lesions, and the last 2 patients (3.4%) had severe aortic lesions. Perioperative data for the first 29 patients, obtained during the first 34 months of the study (group 1), were compared with data for the last 29 patients, obtained during the last 32 months of the study (group 2). Follow-up consisted of clinical examination or duplex scanning, or both, at 1, 3, 6, and 12 months and yearly thereafter, and computed tomography before discharge and then every 2 years. RESULTS: One intraoperative surgical conversion (1.7%) was necessary, and two other patients (3.4%) died in the immediate postoperative period. With experience, initial contraindications such as obesity or suprarenal artery aortic clamping were eliminated, making it possible to increase the percentage of patients included, from 53.7% during the first 34 months to 90.6% during the last 32 months (P=.003). The mean duration of the operative procedure decreased from 285 minutes in group 1 to 192 minutes in group 2 (P<.001), and the mean duration of aortic clamping decreased from 76.4 minutes in group 1 to 31.8 minutes in group 2 (P<.001). The number of early repeat interventions was reduced from three (10.3%) in group 1 to 2 (6.9%) in group 2 (P=NS), and the clinical recovery period decreased from 7 days to 4.5 days (P=.05). During a mean follow-up of 26.7 months (range, 1-66 months) there were 5 repeat surgeries (9%) to treat late graft occlusion, establishing midterm primary and secondary patency rates of 89.3% and 91%, respectively. No aortic false aneurysms were detected, and no major amputations were performed. CONCLUSION: These preliminary results assess the feasability and the safety of this minimally invasive video-assisted technique. A short period of postoperative recovery and good midterm patency rate are the two main benefits of this new surgical option.