Effect of Tumor Suppressor MiR-34a Loaded on ZSM-5 Nanozeolite in Hepatocellular Carcinoma: In Vitro and In Vivo Approach.

BACKGROUND: MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge. OBJECTIVE: We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo. METHODS: In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo. RESULTS: ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo. CONCLUSION: Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery.

Redox dysregulation, immuno-inflammatory alterations and genetic variants of BDNF and MMP-9 in schizophrenia: Pathophysiological and phenotypic implications.

BACKGROUND: Although a clear mechanism underlying the pathophysiology of schizophrenia (SZ) remains elusive, oxidative stress, inflammatory syndrome and immune activation have become an attractive hypothesis for explaining the pathophysiology of SZ. Data from prior studies on the role of matrix metalloproteinase 9 (MMP-9) and brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms (SNPs) in SZ are contradictory. We aimed to investigate whether oxidative stress, inflammatory and immune activation markers as well as MMP-9 levels may be implicated in SZ pathogenesis. The association of MMP-9 and BDNF SNPs with the clinical expression of SZ was examined. SUBJECTS AND METHODS: Ninety-four subjects were recruited, including 44 SZ patients and 50 healthy controls. Serum levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), nitrite, C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), Beta-2 microglobulin (Β2M), complement component 3 (C3), C4 and MMP-9 were measured. The MMP-9 -1562C>T and BDNF196G>A SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay. Psychopathology was assessed using the positive and negative syndrome scale (PANSS). RESULTS: SZ patients showed significantly higher TBARS, PCC, nitrite, CRP, IL-6, TNF-α, Β2M, C3 and MMP-9 levels than controls. In distinguishing SZ patients from healthy controls, CRP and MMP-9 yielded similar discriminatory performance, and both perform better than IL-6, Β2M, C3, nitrite, TBARS, PCC, TNF-α and C4. The MMP-9 -1562C>T SNP genotypes distribution didn't differ significantly between controls and SZ patients. As compared to controls, SZ patients harbor a significantly higher frequency of the BDNF196GG genotype and a lower frequency of the BDNF196GA/AA genotype. Patients carrying the MMP-9 -1562CC or BDNF196GG genotype revealed a significantly higher PANSS than those carrying MMP-9 -1562CT/TT or BDNF196GA/AA genotype. Male gender and the MMP-9 -1562CC genotype were identified as independent predictive factors for higher PANSS. CONCLUSIONS: Redox dysregulation and alterations in the immuno-inflammatory pathways are major culprits in the pathogenesis of SZ. MMP-9 and BDNF SNPs are associated with the clinical phenotype of SZ and, thus, may be a useful marker predicting the phenotypic expression and prognosis of SZ patients.

Activated Leukocyte Cell Adhesion Molecule (ALCAM) in Saudi Breast Cancer Patients as Prognostic and Predictive Indicator.

BACKGROUND: Activated leukocyte cell adhesion molecules (ALCAMs) play an essential role in tumor metastasis and are higher in some patients with breast cancer. AIM: This study aimed to evaluate ALCAM as an early diagnostic biomarker for breast cancer and how it compares with other markers. SUBJECTS AND METHODS: One-hundred and sixty-one women were selected for this study. They were divided into three groups: Group 1 consisted of 42 healthy individuals (control) while a patients groups divided into two groups according to tumour grade, Group II, Include 58 breast cancer patient's grade II and Group III, Include 61 patients with grade III of breast cancer. Tumour markers CEA, CA 15-3 and s ALCAM levels were determined and Group 2 consisted of breast cancer patients. RESULTS: A highly significant elevation was recorded in s ALCAM, CA 15-3 and CEA. Percent change for grade II and grade III were [sALCAM (90, 127)], [CA15-3 (40, 72)] and [CEA (33, 156)]. Operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the biomarkers ALCAM, CA15-3 and CEA with area under the curve (AUC) of (0.99 & 1.0) (AUC 0.947 & 0.99) and (AUC 0.88 & 0.94) for grade II and grade III respectively the incremental values of AUC were statistically highly significant (p < 0.001). CONCLUSION: It could be concluded that serum ALCAM concentration represents a suitable biomarker for Saudi arabian breast carcinoma with high sensitivity and has the potential to be used as a diagnostic tool comparable to CA15-3 and CEA.