Uncovering SIRT3 and SHMT2-dependent pathways as novel targets for apigenin in modulating colorectal cancer: In vitro and in vivo studies.

Despite significant advances in the treatment of colorectal cancer (CRC), identification of novel targets and treatment options are imperative for improving its prognosis and survival rates. The mitochondrial SIRT3 and SHMT2 have key roles in metabolic reprogramming and cell proliferation. This study investigated the potential use of the natural product apigenin in CRC treatment employing both in vivo and in vitro models and explored the role of SIRT3 and SHMT2 in apigenin-induced CRC apoptosis. The role of SHMT2 in CRC patients' survival was verified using TCGA database. In vivo, apigenin treatment restored the normal colon appearance. On the molecular level, apigenin augmented the immunohistochemical expression of cleaved caspase-3 and attenuated SIRT3 and SHMT2 mRNA expression CRC patients with decreased SHMT2 expression had improved overall and disease-free survival rates. In vitro, apigenin reduced the cell viability in a time-dependent manner, induced G0/G1 cell cycle arrest, and increased the apoptotic cell population compared to the untreated control. Mechanistically, apigenin treatment mitigated the expression of SHMT2, SIRT3, and its upstream long intergenic noncoding RNA LINC01234 in CRC cells. Conclusively, apigenin induces caspase-3-dependent apoptosis in CRC through modulation of SIRT3-triggered mitochondrial pathway suggesting it as a promising therapeutic agent to improve patient outcomes.

Circulating microRNAs, miR-92a, miR-100 and miR-143, as non-invasive biomarkers for bladder cancer diagnosis.

The application of microRNAs (miRNAs) as potential biomarkers and therapy targets has been widely investigated in many kinds of cancers. Recent advantages of serum miRNAs open a new realm of possibilities for non-invasive diagnosis and prognosis of bladder cancer (BC). The aim of our study was to identify plasma miR-92a, miR-100 and miR-143 expression signatures in patients with BC to introduce new markers for establishing BC diagnosis and prognosis. Blood samples were collected from 70 BC patients and 62 controls. An expression of three target miRNAs (miR-92a, miR-100 and miR-143) was measured using quantitative real-time PCR method. Results were correlated with clinicopathological data and analysed. Plasma levels of miR-92a, miR-100 and miR-143 were significantly lower in BC patients than in control group. Receiver operator characteristic analysis revealed that the sensitivity and specificity values of miR-92a were 97·1% and 76·7%, respectively, with a cut-off value of 0·573. The sensitivity and specificity values of miR-100 were 90% and 66·7%, respectively, with a cut-off value of 0·644. The sensitivity and specificity values of miR-143 were 78·6% and 93·3%, respectively, with a cut-off value of 0·164. This study explores the existence of specific plasma miRNAs as early diagnostic biomarkers for BC in Egyptian patients; and these findings suggest that plasma miR-92a, miR-100 and miR-143 could be promising novel circulating biomarkers in clinical detection of BC.

Alterations in circulating angiogenic and anti-angiogenic factors in type 2 diabetic patients with neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. There is an increased attention directed towards the role of angiogenic factors including vascular endothelial growth factor (VEGF) and anti-angiogenic factors including soluble endoglin (sEng) as contributors to diabetic microvascular complications including neuropathy. The purposes of this study were to determine the role of these angiogenesis regulators in the prognosis of DPN. The study group included 60 patients with type 2 diabetes mellitus (T2DM) and 20 clinically healthy individuals. The patients were divided into two groups. Group I included 20 T2DM patients without peripheral neuropathy, and Group II consisted of 40 T2DM patients with DPN. In all groups, plasma VEGF, sEng and endothelin-1 (ET-1), nitric oxide and ET-1 mRNA were estimated. Plasma levels of VEGF, sEng, ET-1 and nitric oxide were significantly elevated in diabetic patients (Groups I and II) compared with healthy control subjects, with a higher increase in their levels in patients with DPN compared with diabetic patients without peripheral neuropathy. Measurement of plasma levels of angiogenesis-related biomarkers in high-risk diabetic patients might identify who later develop DPN, thus providing opportunities for early detection and targets for novel treatments.

Effect of safranal or candesartan on 3-nitropropionicacid-induced biochemical, behavioral and histological alterations in a rat model of Huntington's disease.

3-nitropropionic acid (3-NP) is a potent mitochondrial inhibitor mycotoxin. Systemic administration of 3-NP can induce Huntington's disease (HD)-like symptoms in experimental animals. Safranal (Safr) that is found in saffron essential oil has antioxidant, anti-inflammatory and anti-apoptotic actions. Candesartan (Cands) is an angiotensin receptor blocker that has the potential to prevent cognitive deficits. The present study aims to investigate the potential neuroprotective efficacy of Safr or Cands in 3-NP-induced rat model of HD. The experiments continued for nine consecutive days. Rats were randomly assigned into seven groups. The first group (Safr-control) was daily intraperitoneally injected with paraffin oil. The second group (Cands- and 3-NP-control) daily received an oral dose of 0.5% carboxymethylcellulose followed by an intraperitoneal injection of 0.9% saline. The third and fourth groups received a single daily dose of 50 mg/kg Safr (intraperitoneal) and 1 mg/kg Cands (oral), respectively. The sixth group was daily treated with 50 mg Safr kg/day (intraperitoneal) and was intraperitoneally injected with 20 mg 3-NP/ kg, from the 3rd till the 9th day. The seventh group was daily treated with 1 mg Cands /kg/day (oral) and was intraperitoneally injected with 20 mg 3-NP/ kg, from the 3rd till the 9th day. The present results revealed that 3-NP injection induced a considerable body weight loss, impaired memory and locomotor activity, reduced striatal monoamine levels. Furthermore, 3-NP administration remarkably increased striatal malondialdehyde and nitric oxide levels, whereas markedly decreased the total antioxidant capacity. Moreover, 3-NP significantly upregulated the activities of inducible nitric oxide synthase and caspase-3 as well as the Fas ligand, in striatum. On the contrary, Safr and Cands remarkably alleviated the above-mentioned 3-NP-induced alterations. In conclusion, Safr and Cands may prevent or delay the progression of HD and its associated impairments through their antioxidant, anti-inflammatory, anti-apoptotic and neuromodulator effects.

Mitochondrial remodeling in colorectal cancer initiation, progression, metastasis, and therapy: A review.

Colorectal cancer (CRC) is a major health concern with multifactorial pathophysiology representing intense therapeutic challenges. It is well known that deregulation of spatiotemporally-controlled signaling pathways and their metabolic reprogramming effects play a pivotal role in the development and progression of CRC. As such, the mitochondrial role in CRC initiation gained a lot of attention recently, as it is considered the powerhouse that regulates the bioenergetics in CRC. In addition, the crosstalk between microRNAs (miRNAs) and mitochondrial dysfunction has become a newfangled passion for deciphering CRC molecular mechanisms. This review sheds light on the relationship between different signaling pathways involved in metabolic reprogramming and their therapeutic targets, alterations in mitochondrial DNA content, mitochondrial biogenesis, and mitophagy, and the role of polymorphisms in mitochondrial genes as well as miRNAs regulating mitochondrial proteins in CRC initiation, progression, metastasis, and resistance to various therapies.

Evaluation of clinical activity and safety of Daflon 500 mg in type 2 diabetic female patients.

BACKGROUND: The incidence of cardiovascular disease in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. AIM: To investigate the hypoglycemic and hypocholesterolemic effects of Daflon(®) 500 mg (DF) administration together with its tolerability and efficacy in reducing the cardiovascular metabolic risk factors in female patients with type 2 diabetes. METHODS: In a well-adequate controlled single-blinded randomized parallel design the tolerability and the efficacy of Daflon(®) (500 mg) either alone or with oral hypoglycemic, twice daily for 45 days, was studied in 36 female patients with type 2 diabetes. RESULTS: None of the patients in the studied groups were reported to have any adverse events throughout the treatment period (45 days), liver and kidney function tests were within normal limits and there was no significant difference between the pre-treatment (day 0) and post-treatment (day 45) values. Female patients receiving Daflon(®) either alone or with oral hypoglycemic showed significant decrease in serum glucose; fructosamine; total cholesterol; LDL-cholesterol; triglycerides; malondialdehydes (as index of lipid peroxidation) and C-reactive protein (CRB) levels along with increase in the levels of nitric oxide and blood glutathione. CONCLUSION: This study has shown that Daflon(®) (500 mg, twice daily for 45 days) is helpful in reducing glucose level and the risk of cardiovascular disease in type 2 diabetic patients. RECOMMENDATION: Further clinical trials are essential for strengthening the evidence base on the role of this drug in the cardiovascular risk in diabetic patients.

Effects of curcumin and Ginkgo biloba on matrix metalloproteinases gene expression and other biomarkers of inflammatory bowel disease.

Treatment of inflammatory bowel disease (IBD) by synthetic active ingredients leads to many side effects. The objective of this study was to manage IBD using natural products as curcumin and Ginkgo biloba. Rats were divided into four groups (control, IBD, curcumin treated, and ginkgo treated). Inflammation was assessed by determination of myeloperoxidase, matrix metalloproteinases, metalloproteinase-1 inhibitor, nitric oxide, hydroxyproline, tumor necrosis factor-alpha, ceruloplasmin, and histopathological scoring. IBD induction significantly increased all measured parameters. Treated groups had significantly lower levels when compared with the IBD group. In conclusion, curcumin and ginkgo were effective in prevention and treatment of IBD.

Effects of curcumin and Ginkgo biloba on matrix metalloproteinases gene expression and other biomarkers of inflammatory bowel disease

Treatment of inflammatory bowel disease (IBD) by synthetic active ingredients leads to many side effects. The objective of this study was to manage IBD using natural products as curcumin andGinkgo biloba. Rats were divided into four groups (control, IBD, curcumin treated, and ginkgo treated). Inflammation was assessed by determination of myeloperoxidase, matrix metalloproteinases, metalloproteinase-1 inhibitor, nitric oxide, hydroxyproline, tumor necrosis factor-alpha, ceruloplasmin, and histopathological scoring. IBD induction significantly increased all measured parameters. Treated groups had significantly lower levels when compared with the IBD group. In conclusion, curcumin and ginkgo were effective in prevention and treatment of IBD (AU)