Effects of mesenchymal stem cells versus curcumin on sonic hedgehog signaling in experimental model of Hepatocellular Carcinoma.

BACKGROUND: Sonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC. METHODS, AND RESULTS: The present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology. CONCLUSIONS: In conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.

Circulating hsa-miR-221 as a possible diagnostic and prognostic biomarker of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN), which is a chronic outcome of diabetes mellitus (DM), usually progresses to end-stage renal disease (ESRD). The DN pathophysiology, nevertheless, is not well-defined. Several miRNAs were reported to be either risk or protective factors in DN. METHODS, AND RESULTS: The present study sought to inspect the potential diagnostic and prognostic value of hsa-miR-221 in DN. The study included 200 participants divided into four groups: Group 1 (50 patients with DN), Group 2 (50 diabetic patients without nephropathy), Group 3 (50 nondiabetic patients with CKD), and Group 4 (50 healthy subjects as a control group). Patients in groups 1 and 3 were further classified based on the presence of macroalbuminuria and microalbuminuria. Hsa-miR-221 expression was measured by RT- qRT-PCR. DN patients had significantly elevated serum hsa-miR-221 levels than the other groups, while diabetic patients without nephropathy exhibited elevated levels compared to both nondiabetic patients with CKD, and the control group. The DN patients with macroalbuminuria revealed significantly higher mean values of hsa-miR-221 relative to the patients with microalbuminuria. Significant positive associations were observed in the DN group between serum hsa-miR-221 and fasting insulin, fasting glucose, HOMA IR, ACR, and BMI. The ROC curve analysis of serum hsa-miR-221 in the initial diagnosis of DN in DM revealed high specificity and sensitivity. CONCLUSIONS: It is concluded that hsa-miR-221 has the potential to be a useful biomarker for prognostic and diagnostic purposes in DN.

Evaluation of gene expression of PLEKHS1, AADAC, and CDKN3 as novel genomic markers in gastric carcinoma.

Gastric cancer (GC) is considered lethal aggressive cancer. In Egypt, GC has a low incidence but unfortunately, it is mostly diagnosed at an advanced stage with a poor prognosis. Assessment of novel markers that can be used in the early detection of GC is an urgent need. The present study was performed to assess the association of the Pleckstrin homology domain-containing S1 (PLEKHS1)، arylacetamide deacetylase (AADAC, and Cyclin-dependent kinase inhibitor 3 (CDKN3) genes with GC and to correlate their gene expression levels with tumor stage, grade, and other clinicopathological features. The current work was performed on forty gastric tissue samples; twenty in Group 1 with GC tissues at different stages, and grades and twenty in Group 2 (control group) with non-tumorous tissue. PLEKHS1, AADAC, and CDKN3 gene expression were assessed by RT-qPCR. AADAC, CDKN3 genes were significantly (p<0.001) upregulated, while PLEKHS1 gene was significantly (p<0.001) downregulated in the GC group than the control group. AADAC gene expression exhibited a high significant (p<0.001) positive correlation with the tumor grades and the tumor stages. A high significant negative correlation between AADAC, and CDKN3 gene expression (r = -.760, p<0.001) was found. The three studied parameters showed high significant sensitivity and specificity in the prediction of the presence of GC. PLEKHS1, AADAC, and CDKN3 gene expressions were suggested to be used as diagnostic and predictive biomarkers of GC, additionally, AADAC may be used as a prognostic marker in these patients for further future confirming studies.

Protective Effects of Quercetin and Melatonin on Indomethacin Induced Gastric Ulcers in Rats.

BACKGROUND: Medications to prevent the development of NSAID-induced gastric ulcers have a large range of unpleasant side effects. Recent efforts have been focused on determining safer alternative nontoxic and natural forms of anti-ulcer treatments. METHODS: Twenty-four male rats were divided into 4 groups: 1: control group that received no treatment; 2: the ndomethacin-treated group that received 20 mg/kg of indomethacin for 2 days to induce the development of gastric ulcers; 3: quercetin-treated group that in addition to the indomethacin treatment, received 50 mg/kg of quercetin 6 hours after and then daily for 14 days and; 4: the melatonin-treated group which received 20 mg/kg of melatonin 6 hours after each indomethacin treatment and then daily for 14 days. All drugs were administered orally. The following parameters were assessed in each group: mean ulcer index of gastric tissue, gastric acid volume and pH, oxidative stress markers: malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH), inflammatory markers: PGE-2, TNF-α, and IL-10, nitric oxide (NO) levels and the relative gene expression of BAX, BCL-2 and COX-2 by real time PCR. RESULTS: Our findings revealed that the indomethacin-treated group had a significantly increased (p< 0.05) ulcer index, gastric acid volume, and elevated levels of stress, inflammatory, and apoptotic markers compared to controls. In the groups that received quercetin or melatonin, these factors were all significantly decreased (p< 0.05). Between quercetin and melatonin, there was no significant difference in their gastroprotective effect. CONCLUSION: Both quercetin and melatonin had protective antioxidant, anti-inflammatory and antiapoptotic activity against indomethacin-induced gastric ulcers.

Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4.

BACKGROUND: Neuroprotective mechanisms triggered by peroxisome proliferator-activated receptor-gamma agonist: pioglitazone (PIO) and glucagon-like peptide 1 analog: exendin-4 (Ex-4) in neurological diseases were reported, but whether mitochondrial biogenesis is involved or not in their neuro-protective mechanisms in type 1 Diabetes Mellitus (T1DM); has not been studied before. To bridge this gap, we investigated the effect of PIO and Ex-4 on brain mitochondrial biogenesis in streptozotocin- induced diabetes in rats. METHODS: Seven weeks after induction of diabetes in rats, serum fasting glucose and insulin were measured in studied groups. The brain was removed for histological analysis and assessment of: mitochondrial complexes I and II, ATP, H2O2, brain derived neurotrophic factor (BDNF), cytochrome c and hemeoxygenase (HO)-1 activity, and relative gene expression of the nuclear factor; Nrf2 and the apoptotic markers: bax & bcl2 and mitochondrial biogenesis markers; peroxisome proliferator-activated receptor γ coactivator (PGC) 1-α and sirtuin 1 (SIRT-1) and AMP-activated protein kinase (AMPK) and c-Jun-N-terminal kinase (JNK) proteins. RESULTS: Brain in untreated rats showed neurodegeneration area and significantly rising H2O2 and JNK, up-regulation of bax, down-regulation of bcl2. These changes were paralleled with significant reduction in Nrf2, HO-1, BDNF, complex I, II and ATP and SIRT-1/ PGC1-α expression. PIO and Ex-4 significantly improved the reported changes. Combined modality showed better improvement relative to each drug alone. CONCLUSION: PIO and Ex-4 may have neuroprotective effects in T1DM, via targeting altered mitochondrial biogenesis probably due to modulation of brain SIRT-1 signaling, improvement of oxidative stress and equilibrating the balance between pro-apoptotic and anti-apoptotic mediators.