Steatosis regression assessed by cap after Vitamin 'D' supplementation in NAFLD patients with Vitamin 'D' deficiency.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and previous studies suggested a relationship between vitamin D deficiency and NAFLD. It is suggested that vitamin D supplementation may have significant beneficial effect on liver biochemistry and histology. OBJECTIVE: This study aims to assess the degree of possible steatosis regression using controlled attenuation parameter (CAP) in NAFLD patients with vitamin D deficiency after vitamin D supplementation and evaluating its effect on lipid profile and transaminases. PATIENTS AND METHODS: This study was conducted on 100 NAFLD patients with vitamin D deficiency. They received 10000 IU/week of vitamin D orally for 3 months. CAP was used to assess hepatic steatosis and fibrosis before/after intervention. Transaminases, lipid profile, and vitamin D levels were evaluated before/after treatment. RESULTS: Serum AST, ALT, cholesterol, TG, LDL and HDL showed a significant reduction posttreatment in patients with both normal and elevated baseline levels ( P < 0.001). The posttreatment mean CAP showed a significant reduction (300.44 ±â€…37.56 vs. 265 ±â€…36.19 dB/ml) ( P  < 0.001), and there was a significant improvement in the mean fibrosis values by LSM (5.32 ±â€…1.53 vs. 4.86 ±â€…1.28 KPa) ( P  = 0.001). After supplementation, serum vitamin D level was raised significantly in the majority of patients ( P  < 0.001); however, only 13% of them reached sufficient levels (>30 ng/ml), insufficient levels (20-29 ng/ml) was reached in 83% and 5% showed vitamin D deficiency (<20 ng/ml). CONCLUSION: A significant improvement was detected in hepatic steatosis (by CAP); mean values of LSM, transaminases and lipid profile after three months of oral vitamin D supplementation.

Design and synthesis of multifunctional microtubule targeting agents endowed with dual pro-apoptotic and anti-autophagic efficacy.

Autophagy is a lysosome dependent cell survival mechanism and is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Targeting autophagy in cancer therapy attracted considerable attention in the past as stress-induced autophagy has been demonstrated to contribute to both drug resistance and malignant progression and recently interest in this area has re-emerged. Unlocking the therapeutic potential of autophagy modulation could be a valuable strategy for designing innovative tools for cancer treatment. Microtubule-targeting agents (MTAs) are some of the most successful anti-cancer drugs used in the clinic to date. Scaling up our efforts to develop new anti-cancer agents, we rationally designed multifunctional agents 5a-l with improved potency and safety that combine tubulin depolymerising efficacy with autophagic flux inhibitory activity. Through a combination of computational, biological, biochemical, pharmacokinetic-safety, metabolic studies and SAR analyses we identified the hits 5i,k. These MTAs were characterised as potent pro-apoptotic agents and also demonstrated autophagy inhibition efficacy. To measure their efficacy at inhibiting autophagy, we investigated their effects on basal and starvation-mediated autophagic flux by quantifying the expression of LC3II/LC3I and p62 proteins in oral squamous cell carcinoma and human leukaemia through western blotting and by immunofluorescence study of LC3 and LAMP1 in a cervical carcinoma cell line. Analogues 5i and 5k, endowed with pro-apoptotic activity on a range of hematological cancer cells (including ex-vivo chronic lymphocytic leukaemia (CLL) cells) and several solid tumor cell lines, also behaved as late-stage autophagy inhibitors by impairing autophagosome-lysosome fusion.

The Potential of Raman Spectroscopy in the Diagnosis of Dysplastic and Malignant Oral Lesions.

Early diagnosis, treatment and/or surveillance of oral premalignant lesions are important in preventing progression to oral squamous cell carcinoma (OSCC). The current gold standard is through histopathological diagnosis, which is limited by inter- and intra-observer errors and sampling errors. The objective of this work was to use Raman spectroscopy to discriminate between benign, mild, moderate and severe dysplasia and OSCC in formalin fixed paraffin preserved (FFPP) tissues. The study included 72 different pathologies from which 17 were benign lesions, 20 mildly dysplastic, 20 moderately dysplastic, 10 severely dysplastic and 5 invasive OSCC. The glass substrate and paraffin wax background were digitally removed and PLSDA with LOPO cross-validation was used to differentiate the pathologies. OSCC could be differentiated from the other pathologies with an accuracy of 70%, while the accuracy of the classifier for benign, moderate and severe dysplasia was ~60%. The accuracy of the classifier was lowest for mild dysplasia (~46%). The main discriminating features were increased nucleic acid contributions and decreased protein and lipid contributions in the epithelium and decreased collagen contributions in the connective tissue. Smoking and the presence of inflammation were found to significantly influence the Raman classification with respective accuracies of 76% and 94%.

Biomedical applications of vibrational spectroscopy: Oral cancer diagnostics.

Vibrational spectroscopy, based on either infrared absorption or Raman scattering, has attracted increasing attention for biomedical applications. Proof of concept explorations for diagnosis of oral potentially malignant disorders and cancer are reviewed, and recent advances critically appraised. Specific examples of applications of Raman microspectroscopy for analysis of histological, cytological and saliva samples are presented for illustrative purposes, and the future prospects, ultimately for routine, chairside in vivo screening are discussed.

Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation.

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.

Iron chelators in cancer therapy.

Iron chelators have long been a target of interest as anticancer agents. Iron is an important cellular resource involved in cell replication, metabolism and growth. Iron metabolism is modulated in cancer cells reflecting their increased replicative demands. Originally, iron chelators were first developed for use in iron overload disorders, however, their potential as anticancer agents has been gaining increasing interest. This is due, in part, to the downstream effects of iron depletion such as the inhibition of proliferation through ribonucleotide reductase activity. Additionally, some chelators form redox active metal complexes with iron resulting in the production of reactive oxygen species and oxidative stress. Newer synthetic iron chelators such as Deferasirox, Triapine and di-2-pyridylketone-4,4,-dimethyl-3-thiosemicrbazone (Dp44mt) have improved pharmacokinetic properties over the older chelator Deferoxamine. This review examines and discusses the various iron chelators that have been trialled for cancer therapy including both preclinical and clinical studies. The successes and shortcomings of each of the chelators and their use in combination therapies are highlighted and future potential in the cancer therapy world is considered.

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents.

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.

Recent advances in optical diagnosis of oral cancers: Review and future perspectives.

Optical diagnosis techniques offer several advantages over traditional approaches, including objectivity, speed, and cost, and these label-free, noninvasive methods have the potential to change the future workflow of cancer management. The oral cavity is particularly accessible and, thus, such methods may serve as alternate/adjunct tools to traditional methods. Recently, in vivo human clinical studies have been initiated with a view to clinical translation of such technologies. A comprehensive review of optical methods in oral cancer diagnosis is presented. After an introduction to the epidemiology and etiological factors associated with oral cancers currently used, diagnostic methods and their limitations are presented. A thorough review of fluorescence, infrared absorption, and Raman spectroscopic methods in oral cancer diagnosis is presented. The applicability of minimally invasive methods based on serum/saliva is also discussed. The review concludes with a discussion on future demands and scope of developments from a clinical point of view. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2403-E2411, 2016.

Liver Enzymes in Children with beta-Thalassemia Major: Correlation with Iron Overload and Viral Hepatitis.

BACKGROUND: Beta Thalassemia is the most common chronic hemolytic anemia in Egypt (85.1%) with an estimated carrier rate of 9-10.2%. Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of Alanine transaminase (ALT) and Aspartate transaminase (AST). AIM: Evaluating the potentiating effect of iron overload & viral hepatitis infection on the liver enzymes. PATIENTS AND METHODS: Eighty (80) thalassemia major patients were studied with respect to liver enzymes, ferritin, transferrin saturation, HBsAg, anti-HCV antibody and HCV-PCR for anti-HCV positive patients. RESULTS: Fifty % of the patients were anti-HCV positive and 55% of them were HCV-PCR positive. Patients with elevated ALT and AST levels had significantly higher mean serum ferritin than those with normal levels. Anti-HCV positive patients had higher mean serum ferritin, serum ALT, AST and GGT levels and higher age and duration of blood transfusion than the negative group. HCV-PCR positive patients had higher mean serum ferritin and serum ALT and also higher age and duration of blood transfusion than the negative group. CONCLUSION: Iron overload is a main leading cause of elevated liver enzymes, and presence of HCV infection is significantly related to the increased iron overload.

Genetic polymorphisms of glutathione-S-transferase and microsomal epoxide hydrolase in egyptian acquired aplastic anemia patients.

Exposure to various environmental toxins with a reduced ability to metabolize them may lead to acquired aplastic anemia (AA). Genetic polymorphism of the detoxifying enzymes, the glutathione-S-transferase (GST) and microsomal epoxide hydrolase (mEh), with alteration in their activities could explain the genetic interindividual risks for AA. We aimed to characterize the genetic polymorphisms of the GST and mEh and to test their impact on the susceptibility, disease severity, and prognosis in Egyptian patients with AA. The GST and mEh genotypes were determined by multiplex-polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism analysis, respectively, in 21 patients with AA and 20 healthy control subjects. The mEh functional phenotypes were assessed. The frequency of GST θ1-null genotype was found significantly higher in AA patients compared with the controls (odds ratio=2.8, 95% confidence interval = 1.1-7.8; P = 0.001). The frequency of heterozygous 139A--G of the mEh gene was significantly higher in AA patients compared with the controls (odds ratio=3.07, 95% confidence interval = 1.23-7.7; P = 0.018). Moreover, the patients with normal functional phenotype of the mEh had significantly favorable prognosis than those with abnormal enzyme activity (P = 0.027). Thus, the GST θ1-null genotype and the 139A--G mEh gene polymorphism may enhance the susceptibility to AA and provide an evidence of gene-environmental interaction.