GOAT rs10096097 and CREB1 rs6740584 single nucleotide polymorphisms are associated with type 2 diabetes mellitus in Egyptians.

Diabetes mellitus (DM) is a chronic disorder that affects nearly half a billion people around the world and causes millions of deaths annually. Treatment of diabetes or related complications represents an economic burden not only for developing countries but also for the developed ones. Hence, new efficient therapeutic and preventive strategies and screening tools are necessary. The current work aimed to assess the potential association of single nucleotide polymorphisms (SNPs) in ghrelin O-acyltransferase (GOAT) rs10096097, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) rs6740584, and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) rs62521874 genes with type 2 DM susceptibility in Egyptians. A total of 96 patients with type 2 DM along with 72 healthy individuals participated in this study. Genotyping was executed via real-time polymerase chain reaction (PCR), and the serum protein levels of GOAT, CREB, and MafA were measured by enzyme-linked immunosorbent assay (ELISA). Genotyping revealed a significant association of GOAT rs10096097 and CREB1 rs6740584 SNPs with type 2 diabetes risk, with significantly higher GOAT rs10096097 G allele and CREB1 rs6740584 T allele frequencies in diabetic patients than in controls. However, insignificant association was identified between the MafA rs62521874 SNP and diabetes in the examined sample of the Egyptian residents. Serum GOAT, CREB1, and MafA protein levels did not vary significantly between diabetic and control individuals. Yet, significant variation in serum GOAT and CREB1 levels was detected between CREB1 rs6740584 genotypes within the diabetic group, with CT and TT genotype carriers showing higher levels than AA genotype patients. GOAT rs10096097 and CREB1 rs6740584, but not MafA rs62521874, SNPs are associated with type 2 diabetes risk in the studied Egyptians.

From NAFLD to NASH: Understanding the spectrum of non-alcoholic liver diseases and their consequences.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases worldwide in recent decades. Metabolic diseases like excessive blood glucose, central obesity, dyslipidemia, hypertension, and liver function abnormalities cause NAFLD. NAFLD significantly increases the likelihood of liver cancer, heart disease, and mortality, making it a leading cause of liver transplants. Non-alcoholic steatohepatitis (NASH) is a more advanced form of the disease that causes scarring and inflammation of the liver over time and can ultimately result in cirrhosis and hepatocellular carcinoma. In this review, we briefly discuss NAFLD's pathogenic mechanisms, their progression into NASH and afterward to NASH-related cirrhosis. It also covers disease epidemiology, metabolic mechanisms, glucose and lipid metabolism in the liver, macrophage dysfunction, bile acid toxicity, and liver stellate cell stimulation. Additionally, we consider the contribution of intestinal microbiota, genetics, epigenetics, and ecological factors to fibrosis progression and hepatocellular carcinoma risk in NAFLD and NASH patients.

Exosomal miR-122, miR-128, miR-200, miR-298, and miR-342 as novel diagnostic biomarkers in NAFL/NASH: Impact of LPS/TLR-4/FoxO3 pathway.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder affecting a quarter of the global residents. Progression of NAFL into nonalcoholic steatohepatitis (NASH) may cause cirrhosis, liver cancer, and failure. Gut microbiota imbalance causes microbial components translocation into the circulation, triggering liver inflammation and NASH-related fibrosis. MicroRNAs (miRNAs) regulate gene expression via repressing target genes. Exosomal miRNAs are diagnostic and prognostic biomarkers for NAFL and NASH liver damage. Our work investigated the role of the gut microbiota in NAFLD pathogenesis via the lipopolysaccharide/toll-like receptor 4/Forkhead box protein O3 (LPS/TLR-4/FoxO3) pathway and certain miRNAs as noninvasive biomarkers for NAFL or its development to NASH. miRNA expression levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 50 NAFL patients, 50 NASH patients, and 50 normal controls. Plasma LPS, TLR-4, adiponectin, peroxisome proliferator-activated receptor γ (PPAR-γ), and FoxO3 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). In NAFL and NASH patients, miR-122, miR-128, FoxO3, TLR-4, LPS, and PPAR-γ were upregulated while miR-200, miR-298, miR-342, and adiponectin were downregulated compared with the normal control. The examined miRNAs might distinguish NAFL and NASH patients from the normal control using receiver operating characteristic analysis. Our study is the first to examine these miRNAs in NAFLD. Our findings imply that these are potentially promising biomarkers for noninvasive early NAFL diagnosis and NASH progression. Understanding the LPS/TLR-4/FoxO3 pathway involvement in NAFL/NASH pathogenesis may aid disease management.

Short Versus Regular Periods of Cast Immobilization for Distal Radial Fractures: A Systematic Review and Meta-Analysis.

The current research on the recommended durations for cast immobilization in adults with distal radial fractures (DRFs) lacks a clear consensus or definitive conclusion. The standard practice involves casting immobilization for five to six weeks. The debate revolves around the potential benefits of shorter periods (three to four weeks) without compromising patient outcomes. While previous research has delved into this subject through systematic reviews, our study stands out by conducting a meta-analysis, aiming for a more precise understanding of whether short or regular cast immobilization duration proves more effective for treating DRFs. A systematic search was conducted across PubMed, Embase, and the Cochrane Library databases to identify relevant studies. The focus was on comparing the outcomes of DRFs between short (three to four weeks) and regular (five to six weeks) periods of cast immobilization. The evaluated parameters include the shortened disabilities of the arm, shoulder, and hand questionnaire (quick (q) DASH); patient-rated wrist evaluation (PRWE); visual analog scale (VAS) score after cast removal; total complications; and the occurrence of complex regional pain syndrome (CRPS). Data synthesis employed the random-effects models, presenting the results as mean difference (MD) and weighted odds ratio (OR) with corresponding 95% confidence intervals (CI). We included three randomized controlled trials (RCTs) with 252 patients, of whom 125 (49.6%) were immobilized in a cast for three to four weeks. The average age of participants was 61.20 years, and the follow-up duration was one year. The QDASH scores were significantly lower at 12 weeks (MD -6.72; 95% CI -10.76 to -2.69; p = 0.001), six months (MD -4.46; 95% CI -7.42 to -1.50; p = 0.003), and one year (MD -4.89; 95% CI -7.45 to -2.33; p = 0.0002) in patients treated with short periods compared to those with regular periods. The PRWE scores at six months (MD -2.33; 95% CI -8.10 to 3.43; p=0.43) did not significantly differ between groups. Also, the PRWE scores were significantly lower at one year (MD -4.93; 95% CI -9.03 to -0.82; p = 0.02) in the shorter cast-immobilization-period group. There were no significant differences in VAS score after cast removal, total complications, or CRPS. The meta-analysis of RCTs on DRFs reveals that shorter periods of cast immobilization lead to better patient-reported functional outcomes (qDASH and PRWE). This suggests a potential benefit of reducing the immobilization duration for DRF patients, offering clinicians valuable insights for improved patient care and informed decision-making in clinical practice.

Renoprotective Potency of Sitagliptin versus Pioglitazone in Type 2 Diabetic Patients: Impact on LncMIAT.

Background: Diabetes mellitus (DM) represents one of the most important reasons for chronic kidney diseases due to the high level of blood glucose that destructs blood vessels. Objective: The present study focused on investigating the protective impact of sitagliptin on kidney complication in type 2 diabetes mellitus (T2DM) patients in comparison to pioglitazone to examine which has the superior effect against the nephritic complication of DM. Methods: Eighty adult subjects were classified into four groups: control group, pioglitazone-treated T2DM patients (P group), sitagliptin-treated T2DM patients for less than one year (SL group), and sitagliptin-treated T2DM patients for more than one year (SM group). Blood samples were withdrawn from all subjects for analysis of neutrophil gelatinase-associated lipocalin (NGAL), vanin-1, kidney injury molecule-1 (KIM-1), glyoxalase-1 (Glo-1), methylglyoxal (MG), cystatin-C, and interleukin-18 (IL-18) using competitive ELISA kits. Also, long noncoding myocardial infarction associated transcript (lncMIAT) was measured in whole blood using qRT-PCR. Results: The present study revealed that the lncMIAT expression level was significantly higher in the P group as compared to the SL group, SM group, or healthy control group. Additionally, serum NGAL, vanin-1, KIM-1, Glo-1, MG, and cystatin-C were significantly higher in the P group and SL group as compared to the SM group and healthy control group. Conclusion: Sitagliptin protected the kidney through downregulation of lncMIAT besides amelioration of kidney injury marker levels, which was more preferable than in pioglitazone therapy.

Intratracheally Inhalable Nifedipine-Loaded Chitosan-PLGA Nanocomposites as a Promising Nanoplatform for Lung Targeting: Snowballed Protection via Regulation of TGF-ß/ß-Catenin Pathway in Bleomycin-Induced Pulmonary Fibrosis.

Pulmonary fibrosis is a serious ailment that may progress to lung remodeling and demolition, where the key participants in its incidence are fibroblasts responding to growth factors and cellular calcium swinging. Calcium channel blockers, like nifedipine (NFD), may represent auspicious agents in pulmonary fibrosis treatment. Unfortunately, NFD bears complicated pharmacodynamics and a diminished systemic bioavailability. Thus, the current study aimed to develop a novel, non-invasive nanoplatform for NFD for direct/effective pulmonary targeting via intratracheal instillation. A modified solvent emulsification-evaporation method was adopted for the fabrication of NFD-nanocomposites, integrating poly(D,L-lactide-co-glycolide) (PLGA), chitosan (CTS), and polyvinyl alcohol, and optimized for different physiochemical properties according to the 32 full factorial design. Additionally, the aerodynamic behavior of the nanocomposites was scrutinized through cascade impaction. Moreover, the pharmacokinetic investigations were conducted in rats. Furthermore, the optimum formulation was tested in bleomycin-induced pulmonary fibrosis in rats, wherein fibrotic and oxidative stress parameters were measured. The optimum nanocomposites disclosed a nanosized spherical morphology (226.46 nm), a high entrapment efficiency (61.81%) and a sustained release profile over 24 h (50.4%). As well, it displayed a boosted in vitro lung deposition performance with a mass median aerodynamic diameter of 1.12 µm. Pharmacokinetic studies manifested snowballed bioavailability of the optimal nanocomposites by 3.68- and 2.36-fold compared to both the oral and intratracheal suspensions, respectively. The intratracheal nanocomposites revealed a significant reduction in lung fibrotic and oxidative stress markers notably analogous to normal control besides repairing abnormality in TGF-ß/ß-catenin pathway. Our results conferred a compelling proof-of-principle that NFD-CTS-PLGA nanocomposites can function as a promising nanoparadigm for pulmonary fibrosis management.

Physiological Roles of Red Carrot Methanolic Extract and Vitamin E to Abrogate Cadmium-Induced Oxidative Challenge and Apoptosis in Rat Testes: Involvement of the Bax/Bcl-2 Ratio.

The precise analysis of the contents of the red carrot is still ambiguous and its role in the maintenance of male fertility needs to be further reconnoitered. Hence, this study targets the physiological impacts of either red carrot methanolic extract (RCME) or vitamin E (Vit. E), co-administrated with cadmium chloride (CdCl2) on rat testes, specifically those concerned with apoptosis and oxidative challenge. Four groups of adult male rats (n = 12) are used; control, CdCl2, CdCl2 + Vit. E and CdCl2 + RCME. LC-MS analysis of RCME reveals the presence of 20 different phytochemical compounds. Our data clarify the deleterious effects of CdCl2 on testicular weights, semen quality, serum hormonal profile, oxidative markers and Bax/Bcl-2 ratio. Histopathological changes in testicular, prostatic and semen vesicle glandular tissues are also observed. Interestingly, our data clearly demonstrate that co-administration of either RCME or Vit. E with CdCl2 significantly succeeded in the modulation (p < 0.05) of all of these negative effects. The most striking is that they were potent enough to modulate the Bax/Bcl-2 ratio as well as having the ability to correct the impaired semen picture, oxidant status and hormonal profile. Thus, RCME and Vit. E could be used as effective prophylactic treatments to protect the male reproductive physiology against CdCl2 insult.

MET canonical transcript expression is a predictive biomarker for chemo-sensitivity to MET-inhibitors in hepatocellular carcinoma cell lines.

PURPOSE: Long interspersed nuclear element 1 (LINE-1 or L1) is a dominant non-long terminal repeat (non-LTR) retrotransposon in the human genome that has been implicated in the overexpression of MET. Both the canonical MET and L1-MET transcripts are considered to play a role in hepatocellular carcinoma (HCC) development. The aim of this study was to assess the utility of canonical MET, L1-MET, and MET protein expressions as predictive biomarkers for chemo-sensitivity to MET-inhibitors in HCC cell lines in vitro. Additionally, we assessed their expression in tumour tissues from Egyptian HCC patients. METHODS: MET and L1-MET expressions were assessed by qRT-PCR in six liver cancer cell lines (SNU-387, SNU-475, SK-HEP-1, PLC/PRF/5, SNU-449 and SNU-423) and 47 HCC tumour tissues. MET protein expression was measured by western blot in cell lines and immunohistochemistry in the tumours. Cell proliferation assay was used to assess the effect of crizotinib and tivantinib on the six liver cancer cell lines in correlation with the expression of MET, L1-MET and MET. RESULTS: The antitumor effect of crizotinib and tivantinib correlated with MET gene expression but not with L1-MET transcript or MET protein expressions. No significant difference was observed between HCC tumours and non-tumour samples in MET and L1-MET transcripts expression. There were no significant correlations between the 2-year overall survival rate and the MET, L1-MET transcripts and the MET protein expression. CONCLUSION: MET RNA expression could be useful biomarker for tivantinib and crizotinib targeted therapy in HCC. The value of assessment of MET protein expression is limited.

The effect of some natural antioxidants against cisplatin-induced neurotoxicity in rats: behavioral testing.

BACKGROUND: Cisplatin (CP) is a common antineoplastic agent widely used to treat a broad spectrum of cancers. However, its usage for cancer treatment was restricted due to various side effects such as neurotoxicity, nephrotoxicity, hepatotoxicity and ototoxicity. Neurotoxicity in patients who have undergone a complete course of chemotherapy is clinically evident. CP administration caused problems in rats with memory and learning. METHODS: The effect of combination of CP with either thymoquinone (TQ) or geraniol (Ger) on cell viability of human breast cancer cells (MCF-7) was detected by MTT assay. Forty male Wistar albino rats, healthy and adult, were divided into four groups: normal control, CP-treated group, CP + TQ-treated group and CP + Ger-treated group. RESULTS: Our results demonstrated that prophylactic treatment with either TQ or Ger plus CP enhanced the anticancer effect of CP in MCF-7 cell line. In vivo study showed that CP-treated rats had higher depressives like behavior in open field and Morris water maze test while prophylactic treatment with either TQ or Ger and CP significantly enhanced the performance of depressive-like behavior. Also, histopathological evaluation of brain tissues proved the neurotoxic effect of CP and the possible protective activity of either TQ or Ger. CONCLUSION: The findings of the present work revealed that TQ or Ger along with CP may enhance the antitumor effect of CP. Also, spontaneous administration of CP with either TQ or Ger as natural antioxidants may prevent CP-induced neurotoxicity in rats through diminishing the memory and learning impairment.

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition.

Although integrin alpha 2 subunit (ITGA2) mediates cancer progression and metastasis, its transfer by exosomes has not been investigated in prostate cancer (PCa). We aimed to determine the role of exosomal ITGA2 derived from castration-resistant PCa (CRPC) cells in promoting aggressive phenotypes in androgen receptor (AR)-positive cells. Exosomes were co-incubated with recipient cells and tested for different cellular assays. ITGA2 was enriched in exosomes derived from CRPC cells. Co-culture of AR-positive cells with CRPC-derived exosomes increased their proliferation, migration, and invasion by promoting epithelial-mesenchymal transition, which was reversed via ITGA2 knockdown or inhibition of exosomal uptake by methyl-ß-cyclodextrin (MßCD). Ectopic expression of ITGA2 reproduced the effect of exosomal ITGA2 in PCa cells. ITGA2 transferred by exosomes exerted its effect within a shorter time compared to that triggered by its endogenous expression. The difference of ITGA2 protein expression in localized tumors and those with lymph node metastatic tissues was indistinguishable. Nevertheless, its abundance was higher in circulating exosomes collected from PCa patients when compared with normal subjects. Our findings indicate the possible role of the exosomal-ITGA2 transfer in altering the phenotype of AR-positive cells towards more aggressive phenotype. Thus, interfering with exosomal cargo transfer may inhibit the development of aggressive phenotype in PCa cells.

Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview.

BACKGROUND: Worldwide, hepatocellular carcinoma (HCC) is a universal problem and its epidemiological data showed variation from place to place. Hepatocellular carcinoma (HCC) is the sixth and fourth common cancer in worldwide and Egypt, respectively. Egypt ranks the third and 15th most populous country in Africa and worldwide, respectively. The aim of this review is to compare the status of HCC in Egypt to that in the worldwide from different issues; risk factors, screening and surveillance, diagnosis and treatment, prevention, as well as research strategy. MAIN BODY: The risk factors for HCC in Egypt are of great importance to be reported. The risk factor for HCC are either environmental- or host/genetic-related risk factors. In the last years, there is a tangible improvement of both screening and surveillance strategies of HCC in Egypt. The unprecedented national screening campaign launched by the end of 2018 is a mirror image of this improvement. While the improvement of the HCC prevention requires the governmental health administration to implement health policies. Although the diagnosis of Egyptian HCC patients follows the international guidelines but HCC treatment options are limited in terms of cost. In addition, there are limited Egyptian reports about HCC survival and relapse. Both basic and clinical HCC research in Egypt are still limited compared to worldwide. SHORT CONCLUSION: Deep analysis and understanding of factors affecting HCC burden variation worldwide help in customization of efforts exerted to face HCC in different countries especially large country like Egypt. Overall, the presence of a research strategy to fight HCC in Egyptian patients will help in the optimum allocation of available resources to reduce the numbers of HCC cases and deaths and to improve the quality of life.

Preparation and appraisal of self-assembled valsartan-loaded amalgamated Pluronic F127/Tween 80 polymeric micelles: Boosted cardioprotection via regulation of Mhrt/Nrf2 and Trx1 pathways in cisplatin-induced cardiotoxicity.

This study aimed to develop valsartan (VAL)-loaded mixed micelles and investigate their cardioprotective potential and molecular mechanisms through Mhrt/Nrf2 and Trx1 pathways. VAL-loaded mixed micelles have not been elaborated and their impact on Mhrt/Nrf2 and Trx1 pathways has not been yet inspected. VAL-loaded mixed micelles were prepared, incorporating Pluronic F127 and Tween 80, adopting thin-film hydration method. The micelles were evaluated for drug entrapment efficiency, loading characteristics, particle size, morphology, in vitro drug release and micelles storage stability. The pharmacokinetic studies were explored in rats. Also, VAL suspension and mixed micelles were tested in cisplatin-induced cardiotoxicity in rats either pre to or simultaneously with cisplatin. RNA expression of lnc Mhrt and protein expression of Nrf2, Trx1, Ask1, AMPK and caspase 3, oxidative stress and cardiac injury markers besides tailed DNA% by comet assay were assessed. Pharmacokinetic studies evoked a 3.75-fold increase in oral bioavailability as compared with VAL suspension. Overall, treatment with VAL-loaded mixed micelles was superior to VAL suspension in decreasing oxidative stress and cardiac injury markers and restoring the abnormalities occurred in Mhrt/Nrf2 and Trx1 pathways. Thus, mixed micelles would be promising nanocarrier for the engineering of VAL with reinforced pharmacokinetics and cardioprotection characteristics.

Zingiber officinale extract and omega-3 fatty acids ameliorate endoplasmic reticulum stress in a nonalcoholic fatty liver rat model.

Endoplasmic reticulum (ER) stress was reported to play a major role in non-alcoholic fatty liver disease (NAFLD) induction and progression. Here, we study the effect of Zingiber officinale and omega-3 fatty acids on ER stress for treating NAFLD. Male Wistar rats were fed on a normal diet (control group) or high-fat diet (HFD) for 8 weeks. The HFD rats were later treated with vehicle, omega-3 or with Z. officinale extract. HFD group demonstrated significantly more body weight gain and higher plasma lipid profile, glucose, and hepatic enzymes. The expressions of lipogenic ChREBP and ER stress genes CHOP, XBP1, and GRP78 were increased. This was accompanied by intrahepatic fat accumulation visualized by hepatic morphology and H&E-stained sections. Treatment with Z. officinale and omega-3 fatty acids reverted these changes into a normal healthy state. From these results, we prove that both therapeutic approaches can be potential drugs for treating NAFLD besides other ER stress-associated diseases. PRACTICAL APPLICATIONS: The effect of Zingiber officinale extract and omega-3 fatty acid on ER stress associated with NAFLD was investigated. The results revealed that Z. officinale extract and omega-3 fatty acids significantly inhibited ER stress and intrahepatic fat accumulation with the upper hand for Z. officinale extract. Both can be used as future promising therapies for the treatment of NAFLD patients and also treating different diseases that involve ER stress as a pathological modulator like diabetes mellitus, Alzheimer's disease, Parkinson's disease, and cancer.

Thymoquinone and geraniol alleviate cisplatin-induced neurotoxicity in rats through downregulating the p38 MAPK/STAT-1 pathway and oxidative stress.

AIMS: Cisplatin (CP) is a widely used broad-spectrum antineoplastic agent used to treat a variety of human malignancies. Neurotoxicity is clinically evident in patients who have undergone a full course of chemotherapy. The aim of this study was to investigate the possible protective effects of thymoquinone (TQ) and geraniol (Ger) against CP-induced neurotoxicity in rats. MAIN METHODS: Forty male Wistar albino rats were allocated into four groups as follows: normal control, CP-induced neurotoxicity, CP + TQ and CP + Ger. KEY FINDINGS: Our results demonstrated that simultaneous treatment with either TQ or Ger and CP significantly abrogated oxidative stress and downregulated the apoptotic markers p38 mitogen-activated protein kinase (MAPK), STAT-1, p53, p21 and MMP9; FMO3, however, was insignificantly decreased. In addition to the biochemical results, we assessed the histopathological findings, which confirmed the protective effect of TQ and Ger against the brain damage induced by CP. SIGNIFICANCE: The results of the present study indicate that simultaneous treatment with either TQ or Ger as natural antioxidants can provide protection against cisplatin-induced neurotoxicity in rats by attenuating oxidative stress and cell apoptosis.

Alpha lipoic acid protects against dexamethasone-induced metabolic abnormalities via APPL1 and PGC-1 α up regulation.

BACKGROUND: Glucocorticoids (GCs) have various uses in the medicine in different specialties. However, GCs administration is usually accompanying with multiple side effects such as hyperglycemia and hyperlipidemia. Alpha lipoic acid (ALA) has been documented to posse anti-diabetic properties. AIM OF THE STUDY: this study highlights the role of ALA in avoiding dexamethasone induced metabolic disturbance. MATERIALS & METHODS: 30 rats were randomly divided into 5 groups: Group (1): Control group; Groups 3, 4, and 5: rats received dexamethasone 1 mg/kg/day for 10 days; Groups 2, 4, and 5: Rats received ALA 100 mg/kg/day all the duration of the study, 2 weeks before dexamethasone, or concomitant with dexamethasone respectively. For each rat, we collected blood samples for measurement of glucose, lipid profiles, adiponectin, irisin, and Phosphoinositide 3-kinase (PI3K). We also isolated gastrocnemius muscles for measurement of insulin receptor substrate-1(IRS-1), peroxisome proliferator-activated receptor γ coactivator 1 α(PGC1-α), and adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1(APPL) gene expression. RESULTS: Dexamethasone administration caused hyperglycemia, hyperlipemia, decrease the level of adiponectin, irisin, and PI3K besides decreasing the gene expression of IRS-1, PGC-1 α, and APPL1. ALA administration pre or concomitant to dexamethasone avoided these results. CONCLUSION: ALA can prevent metabolic abnormalities induced by dexamethasone via PGC1α and APPL1 upregulation.

Balanites aegyptiaca ameliorates insulin secretion and decreases pancreatic apoptosis in diabetic rats: Role of SAPK/JNK pathway.

SAPK-JNK pathway performs a significant role in the pathogenesis of type 2 diabetes. Balanites aegyptiaca (BA) is used as an anti-diabetic agent in folk medicine however its hypoglycemic mechanism is not fully elucidated. The current study aimed to evaluate the effect of crude extract, butanol, and dichloromethane fractions from BA on the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK-JNK) pathway in experimental diabetic rats. Six groups of male Wistar rats were included: normal control, diabetic, diabetic rats treated with crude, butanol or dichloromethane fraction from BA (50 mg/kg BW) and diabetic rats treated with gliclazide as a reference drug for one month. Our results suggested a protective role of treatment of diabetic rats with BA against oxidative stress-induced SAPK-JNK pathway. Moreover, BA treatment produced a reduction in plasma glucose, HbA1c, lactic acid, lipid profile, malondialdehyde levels and produced an increase in insulin, reduced glutathione levels, catalase and superoxide dismutase activities compared with untreated diabetic rats. Moreover, it decreased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase 1, protein 53 and increased insulin receptor substrate 1 in rat pancreas while it increased glucose transporter 4 in rat muscle. Analysis of BA extracts by LC-HRMS revealed the presence of different saponins with reported hypoglycemic effect. In conclusion, BA exerted hypoglycemic, hypolipidemic, insulinotropic and antioxidant effects. Additionally, it reduced apoptosis in pancreatic ß-cells and increased glucose uptake in muscle. These results suggest that the hypoglycemic effect of BA is due to the inhibition of the SAPK-JNK pathway.

Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats.

CONTEXT: Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle. OBJECTIVE: The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route. METHODS: The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits. RESULTS: The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186-583nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity. CONCLUSION: The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV.

Effect of silibinin and vitamin E on the ASK1-p38 MAPK pathway in D-galactosamine/lipopolysaccharide induced hepatotoxicity.

Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensor mitogen-activated protein kinase kinase kinase (MAPKKK) that activates p38 MAPK pathways in oxidative stress-induced hepatotoxicity in D-galactosamine/lipopolysaccharide (D-GalN/LPS) model, is a key central pathway in which specific targeting of ASK1 deactivation is of a great therapeutic potential. We tested the effect of silibinin and vitamin E in curative and prophylactic manner of treatment on the negative modulators of ASK1, thioredoxin1 (Trx1), thioredoxin reductase1 (TrxR1), and the protein phosphatase (PP5), whereas they have previously proven to have hepatoprotective effect. Either curative or prophylactic silibinin and vitamin E groups significantly decreased ASK1 and p38 MAPK levels through increasing the gene expression of Trx1, TrxR1, and PP5 to reduce the oxidative stress as demonstrated by decreasing the levels of NADPH oxidase 4 (NOX4), TBARS and conjugated diene with a concomitant increase in the levels of GSH, CAT, and SOD. These results were confirmed by histopathology examination which illustrated progressive degenerative changes of hepatocytes such as hydropic degeneration, vacuolation, pyknosis, karyolysis, and loss of architecture of some cells in D-GalN/LPS treatment, and these features were alleviated with silibinin and vitamin E administration. In conclusion, silibinin and vitamin E decreased ASK1-p38 MAPK pathway through deactivating the upstream signalling ASK1 molecule via increasing the levels of Trx1 and TrxR1 as well as the PP5 to alleviate in D-GalN/LPS induced hepatotoxicity.

Effect of glycemic control on soluble RAGE and oxidative stress in type 2 diabetic patients.

BACKGROUND: The interaction of advanced glycation end products (AGEs) and its receptor (RAGE) has played an important role in the pathogenesis of diabetes and its complications. A soluble form of RAGE (sRAGE) has been reported as a decoy receptor for AGEs. Oxidative stress is demonstrated in pathological condition such as atherosclerosis and diabetes mellitus. It has been suggested to be involved in the pathogenesis of both macro- and microvascular complications. This study was designed to evaluate the effect of glycemic control on sRAGE and oxidative stress markers in type 2 diabetic patients. METHODS: Seventy patients with type 2 diabetes and 20 healthy subjects were recruited into the study. Blood glutathione (GSH) and plasma total nitric oxide (NOx) levels were measured using commercially available colorimetric kits, blood superoxide dismutase (SOD) activity was measured by the method of Marklund and Marklund, and plasma C-peptide, oxidized LDL (ox-LDL), sRAGE, and VCAM-1 levels were measured using competitive ELISA kits. RESULTS: Plasma sRAGE levels were significantly lower (p < 0.05) while VCAM-1 levels were significantly higher (p < 0.05) in poorly controlled diabetic patients compared with healthy control. Blood GSH levels were significantly lower in diabetic patients compared with healthy control (p < 0.05). Plasma C-peptide, NOx, ox-LDL levels, and SOD activity were not significantly different in diabetic patients compared with healthy control. Plasma levels of sRAGE were negatively associated with circulating VCAM-1 levels in diabetic patients. CONCLUSION: Poor glycemic control decreases plasma sRAGE and increases VCAM-1 levels while good glycemic control improves these abnormalities which provides benefit to diabetic patients.