Current Pharmaceutical Design - Volume 24, Issue 27, 2018

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic inflammation within the gastrointestinal tract. It is a multifactorial disease associated with immune-cell mediated oxidative damage to the intestinal mucosa. There is no cure for IBD, but anti-cytokine therapy can limit target inflammation and disease progression. Unfortunately, many patients are nonresponsive or develop resistance to anti-cytokine therapy over time creating a need for new therapeutic agents. Metallothionein (MT) is a small, highly conserved stress response protein that has been shown to modulate the immune response as a pro-inflammatory agent, regulates divalent heavy metal homeostasis, and acts as a reactive metabolite scavenger. Our research, as well as other groups studying MT, has described MT induction and release during IBD inflammatory stress response. The release of MT results in activation of inflammatory responses leading to progressive inflammation and subsequent expansion of MT synthesis. A monoclonal antibody specific for MT has been used in murine models of IBD and should only target the extracellular pool of MT, thus representing a novel therapeutic approach to this disease.

Background: Gastrointestinal (GI) diseases are a major cause of emergency department visits requiring hospitalizations leading to considerable burden on global economy. Several factors contribute to the onset of gastrointestinal diseases such as pathogens (parasites, bacteria, virus, toxins etc.), autoimmune disorders and severe inflammation of intestine. Objective: One common feature among all these diseases is the dysentery and alteration of gut microbiota composition (gut dysbiosis). Apart from conventional therapies such as antibiotics and ORS supplementation, gut microbiota modulation with probiotic supplementation has emerged as a successful and healthy alternative in mitigating GI diseases. In this review our goal is to discuss the causes of gastrointestinal diseases and the present state of various therapeutic strategies such as probiotics as live biotherapeutics and Fecal Microbial Transplants (FMT's). Conclusion: Several reports and clinical trials point out to the beneficial effects of probiotics in modulating the gut microbiota and improving the side effects of gastrointestinal diseases. Live biotherapeutics and FMT’s could be suitable and successful alternatives to conventional therapies in mitigating the gastrointestinal pathogens.

Blastocystis sp. is a unicellular parasitic microorganism commonly found in the gastrointestinal tracts of humans and animals. It causes symptomatic or asymptomatic infection and its route of transmission is via fecal-oral. High prevalence of Blastocystis infection in developing countries is usually due to poor hygiene practices, exposure to animals infected with the parasite and intake of contaminated water or food. Blastocystis infected individuals often suffer from diarrhea, abdominal pain, nausea, and stomach bloating. Even though pathogenicity of Blastocystis is unclear, it is commonly associated with irritable bowel syndrome. In this review, we have analysed the evidence that shows the association between this microorganism and gastrointestinal disorders. There have been a number of studies which showed that the pathogenicity of Blastocystis is related to its different STs. The pathogenicity is speculated to be due to cysteine proteases formation which stimulates mucosal cells to release interleukin-8 which has been associated with extreme dehydration and gut inflammation. In vitro studies on human colonic epithelial cells revealed that incubation of Blastocystis modulated the host immune response by stimulating the formation of pro-inflammatory cytokines and granulocyte macrophage colonystimulating factor. Metronidazole is found to be the first-line drug of choice. Another treatment option is the combination therapy with trimethoprim/sulfamethoxazole.

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

Background: This systematic review and meta-analysis of randomized controlled trials (RCTs), were performed to determine the effects of curcumin intake on glycemic control and lipid profiles among patients with metabolic syndrome (MetS) and related disorders. Methods: We searched the following databases up until January 2018: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. The relevant data were extracted and evaluated for quality of the studies in accordance with the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as standardized mean difference (MDs) with 95% confidence intervals (95% CI). Results: Twenty-six trials with 1890 participants were included in the current meta-analysis. The findings demonstrated the significant association between curcumin intake and reduced fasting glucose levels (SMD -0.78; 95% CI, -1.20, -0.37; P<0.001), homeostasis model of assessment-estimated insulin resistance (SMD -0.91; 95% CI, -1.52, -0.31; P=0.003) and HbA1c (SMD -0.92; 95% CI, -1.37, -0.47; P<0.001). In addition, curcumin supplementation was significantly associated with triglyceride (SMD -1.21; 95 % CI, -1.78, -0.65; P<0.001) and total cholesterol reduction (SMD -0.73; 95 % CI, -1.32, -0.13; P= 0.01). However, curcumin intake significantly increased insulin levels (SMD 0.92; 95% CI, 0.06, 1.78; P=0.036). We found no significant effect of curcumin supplementation on LDL- (SMD -0.52; 95% CI, -1.14, 0.11; P=0.10) and HDL-cholesterol levels (SMD 0.28; 95% CI, -0.22, 0.77; P=0.27). Conclusion: Overall, curcumin consumption was associated with a significant reduction in fasting glucose, HOMA-IR, HbA1c, triglycerides and total cholesterol levels among patients with MetS and related disorders, but did not affect LDL- and HDL-cholesterol levels.

Over the recent years, a particular interest was shown towards understanding the roles of excessive hepatic fat accumulation and the development of obesity-related diseases. While hepatic triacylglycerol accumulation seems to be a response to the systemic increase of insulin release, fatty acid metabolites contribute to the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). It is widely accepted that NAFLD is a polygenic and multifactorial disease under the influence of critical behavioral factors such as overeating and sedentary lifestyles. The progression of the disease is proposed to include the accumulation of lipids in hepatocytes, but liver damage would be mainly initiated through an exaggerated activation of the immune system. This inflammatory response would be triggered by the increase in cytokine production followed by TLR-4 activation and NF-kB pathways. Interestingly, cytokines as IL-1ra, IL-4, IL-6 and IL-10 act as antiinflammatory in response to exercise and thus, could play an important role in the restoration of liver functions in diseased conditions. Strategies for healthy life behaviors including nutrition and regular physical exercise are recommended to counteract the dreadful effects of NAFLD. To beyond the classical effect of exercise for increasing energy expenditure and/or inducing negative energy balance, exercise also prevents and reverses the effects of disorders related to the immunometabolic profile. This suggests that exercise prescription may be an attractive alternative for the prevention of obesity and NAFLD. Thus, this review seeks to shed light on the inflammatory pathways regulating the beneficial effects of physical activity on obesity and NAFLD. We will clarify how physical activity intervenes to normalize inflammatory processes and prevent obesity and NAFLD. Finally, the exercise interventions should be individualized to facilitate behavioral and cognitive strategies in order to promote long-term adherence. A multidisciplinary approach including lifestyles, diet and exercise training interventions is considered as a "best practice" and displays the strongest liver benefits when it occurs simultaneously with weight loss.

Background: Advances in material science and particle engineering have led to the development of a rapidly growing number of nanoparticulate carriers for drug and gene delivery. These carriers are increasingly being investigated in dermal and transdermal routes of drug administration. Objective: To critically examine and summarize the primary factors and mechanisms involved in nanocarriermediated dermal and transdermal delivery of drugs. Method: Thorough literature search was undertaken, spanning the early development of nanocarrier-mediated dermal and transdermal drug delivery approaches, to the current state of the art, using online search tools. Results: Physicochemical, formulation, experimental and morphological factors, such as, material of construction or type of nanoparticle (NP), surface chemistry, particle size, particle shape, surface charge, dispersion medium, duration of exposure of skin to NPs, combination of NPs with physical agents, and aspects related to skin were identified and discussed. Conclusion: The key factors and mechanisms which influence NPs-skin interactions in dermal and transdermal drug delivery are discussed in this article in-line with the current advances in the field.

Objective: To investigate the effect of dapagliflozin on intestinal microflora in MafA-deficient mice using an animal model of diabetes. Methods: Male MafA-deficient mice were administered dapagliflozin (1.0 mg/kg/d) intragastrically for 6 weeks. Mouse body weights and fasting blood glucose levels were measured, and intestinal short-chain fatty acids were measured by gas chromatography. A series of methods was used to analyse the number of primary harmful bacteria in the faeces, and high-throughput sequencing was used to sequence the changes in intestinal flora. Results: The weight of the mice decreased after dapagliflozin gavage, and fasting blood glucose was significantly lower than that in the control group (P < 0.001). Acetic acid and butyric acid contents in the intestinal tracts of the mice increased, and the growth of harmful microorganisms, such as Clostridium perfringens, enterococci, Enterobacteriaceae, and intestinal enterococci, was inhibited. Blautia is a species found in the experimental group and was significantly different from the control and blank groups as determined by the LDA score from highthroughput sequencing. Conclusion: Dapagliflozin can reduce fasting blood glucose, decrease body weight, increase short-chain fatty acid content, regulate the intestinal microecological balance of the body and promote blood glucose and energy homeostasis.

Background: Dietary advanced glycation end products (AGEs) and their interactions with the soluble receptors for AGEs (RAGE) play a crucial role in the pathogenesis of cardiovascular diseases. Objective: This study was set out to assess, whether there was any association between serum sRAGE level and serum uric acid level in children with hyperuricemia. Methods: This case-control study involved 53 patients (12 girls, 41 boys) with hyperuricemia (defined as serum uric acid >4.8 and >5.5 mg/dl in girls and boys, respectively) aged (median [IQR]) (15.5 [13.5-15.5] years). Thirty-six healthy individuals with normal serum uric acid level were selected as a reference group. Additionally, the study group with hyperuricemia was divided into two groups: HU-HT (hypertensive n=25) and HU-NT (normotensive n=28) teenagers. The serum concentration of human sRAGE was measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Results: We found statistically significant differences in serum sRAGE levels between normotensive subjects with hyperuricemia (median [IQR]) (169.8 [148.3-231.1] pg/ml) and reference group (median [IQR]) (129 [107.4-175.3] pg/ml), p<0.01. Univariate analysis of the data revealed a positive correlation between serum sRAGE and serum uric acid in the study group (r=0.306, p<0.05). Conclusion: Our data showed that serum soluble receptors for AGEs are increased in teenagers with hyperuricemia. In contrast, neither hypertension nor increased BMI had a significant influence on serum sRAGE concentration. Further studies are needed to discover the possible mechanism on the influence of uric acid on sRAGE levels and to assess its possible clinical significance.

Background: Cordycepin is an extract from the insect fungus Cordyceps. militaris with various biological function. In previous studies, cordycepin has demonstrated an excellent anti-obesity effect, but the mechanism is unclear. It was also demonstrated that prolactin played an important role in body weight regulation and hyperprolactinemia can promote appetite and accelerate fat deposition. In this study, we explored the molecular mechanism of the anti-obesity effect of cordycepin. Methods: In Vivo, the obese rat model was induced by high fat diet for five weeks, and the serum and liver lipid levels coupled with the serum prolactin levels were reduced following cordycepin treatment (P<0.01). Results: The results suggested that cordycepin is a potential drug that lowers blood and liver lipid levels and reduces body weight related to prolactin. Cordycepin also protects adipocytes from enlargement and hepatocytes from lipotoxicity-induced inflammation. In vitro, cordycepin inhibited prolactin secretion in GH3 cells via upregulating the expression of adenosine A1 receptor, and the inhibition effect was blocked by an antagonist of adenosine receptor A1 DPDPX, demonstrating that cordycepin may work as an adenosine agonist. Additionally, cordycepin inhibited the ERK/AKT/PI3K pathway in GH3 cells. At the same time, cordycepin blocked prolactininduced upregulation of lipogenesis genes PRLR, and phosphorylation of JAK2 in 3T3-L1 cells. In an in vivo study, cordycepin downregulated the expression of prolactin receptor (PRLR) but not the phosphorylation of JAK2. Conclusion: Thus, it was proved that cordycepin modulates body weight by reducing prolactin release via an adenosine A1 receptor.

Objective: Postoperative Pulmonary Complications (PPCs) can contribute to increased mortality and prolonged hospital stay in surgical patients with Gastric Cancer (GC). This study aimed to investigate potential risk factors for PPCs in elderly GC patients following elective laparoscopic gastrectomy. Methods: Eligible consecutive elderly GC patients (aged over 65 years) who were scheduled to undergo elective laparoscopic gastrectomy were enrolled in this study. The demographic, clinicopathological characteristics and laboratory variables were compared in patients with or without PPCs within postoperative 30 days. Risk factors for PPCs were analyzed by multiple logistic regression analysis and receiver operating characteristic (ROC) curve analysis. Results: 35 of all the 262 enrolled patients have developed PPCs with an incidence of 13.4%. Age, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), forced expiratory volume in one second/ forced vital capacity (FEV1/FVC) ratio, duration of operation, hemoglobin, albumin and C-reactive protein (CRP) were potential risk factors for PPCs by univariate analysis. The preoperative albumin level was the only independent risk factor for PPCs (OR: 1.15, 95%CI: 1.06-1.28, P=0.011) by multiple logistic regression analysis. Preoperative albumin level was a predictor for PPCs with an area under the curve (AUC) of 0.728 and a cut-off value of 33.8 mg/dl (specificity: 54.19%, sensitivity: 77.14%, P<0.001). Conclusions: Preoperative albumin level was an independent risk factor for PPCs in elderly GC patients after elective laparoscopic gastrectomy.

Background: Inhibition of hepatic fibrosis is an attainable objective in managing the chronic liver disease. The present study aimed to investigate possible defensive effects of metformin on the activities of antioxidant enzymes, hydroxyproline content, and biochemical factors in bile duct ligation (BDL)-induced cholestatic rats. The interactive behavior of metformin with glutathione peroxidase (GPx) enzyme was also explained by molecular docking and conformation characterization. Methods: The present study was conducted on 28-adult male Wistar rats classified into four 7-animal groups: sham-control, mere BDL, and BDL+ metformin that received daily metformin as gavage in two doses of 250 and 500 mg/kg bw for 10 days. Biochemical analysis, hydroxyproline content, and antioxidant enzymes activity were also determined. Results: The hydroxyproline content significantly increased, but the GPx enzyme activity significantly decreased in the hepatic tissue following BDL, indicating that an oxidative stress-related model in rats was successfully constituted. Administration of metformin at two doses attenuated hydroxyproline content in the cholestatic liver and ameliorated the depletion of GPx enzyme activities compared to the non-treated BDL group (P-value ≤ 0.05). Molecular docking study provides the evidence for metformin ability to regulate enzymatic activity of GPx. Conclusion: The research data indicated that due to novel hepatoprotective effects of metformin in an animal model with BDL-induced liver injury, it was a potential beneficial therapeutic agent for treating the cholestatic liver disease. The main mechanism might contribute to antioxidant actions, particularly via GPx enzyme.

Aim: Estimation of the ocular status in adolescents with diabetes mellitus type 1 (DM1) treated with continuous subcutaneous insulin infusion (CSII), assessment of the development of the diabetic retinopathy (DR) and nephropathy (DN) within 10 years. Methods: 37 patients (74 eyes) aged 16-33 years, treated with CSII were enrolled to the study. Baseline, and a 10- year follow-up evaluation included: best corrected visual acuity (BCVA), tonometry, slit lamp exam and fluorescein angiography (FLA). Additionally, spectral-domain optical coherence tomography (SD-OCT) was done in the 7th year of observation to assess the thickness of the retinal nerve fiber (RNFL) and the ganglion cellinner plexiform layers (GCL-IPL) complex thickness. Glycated haemoglobin (HbA1) and albuminuria were also analysed. Results: During the 10-year observation period DR (non-proliferative - NPDR, proliferative - PDR, diabetic macular edema - DME) was diagnosed in 3 (8%) patients. In the DR group: BCVA was significantly lower, intraocular pressure (IOP) levels and albuminuria were higher. There were no differences in HbA1 in both groups. The thinning of RNFL was observed in both groups. Macular RNFL, GCL-IPL complex thickness assessment showed a significantly higher number of borderline results in the group with DR. Conclusions: Diabetic patients treated with CSII are at a lower risk of developing vascular complications even with poor metabolic control. Increased albuminuria may be a predictive sign for early ocular complications, and requires intense observation. Diagnosis of RNFL and GCL-IPL decreased values is crucial prior to diabetic retinopathy development. SD-OCT is a non-invasive, easy-to-perform, relatively inexpensive procedure, and can be a useful tool to monitor neuropathy progression.

Objective: The objective of the study was to compare cytokine levels in the vitreous body of patients with proliferative diabetic retinopathy (PDR) undergoing posterior vitrectomy. Patients and methods: The study included 39 patients (39 eyes) undergoing pars plana vitrectomy (PPV). Patients were divided into three groups: patients with proliferative diabetic retinopathy (PDR) without aflibercept injection prior to the surgery, PDR patients administered aflibercept injection prior to the surgery, and patients without diabetes mellitus (control group). All patients underwent a comprehensive eye examination one day before and 3 weeks after the surgery, including measurements of: best-corrected visual acuity (BVCA) and intraocular pressure (IOP), slit-lamp examination and spectral domain optical coherence tomography (SOCT). Concentrations of cytokines: IL-6, IL-8, IL-12p70, TNF, IL-10, IL-1β were measured in the vitreous body of patients with BD™ Cytometric Bead Array (CBA) Human Inflammatory Cytokines Kit. Results: PDR patients who received pretreatment with aflibercept injection showed significantly lower concentrations of IL-12p70, TNF, IL-10 and IL-1β in the vitreous body compared to the control group. Meanwhile, patients without prior aflibercept injection had a significantly higher concentration of IL-8. There was also a significant positive correlation between IOP before PPV and IL-8 concentration in both PDR patients’ groups. Conclusion: Findings of our study suggest an important role of IL-8 in the development of severe PDR. Aflibercept administration on the day before elective vitrectomy facilitated the surgery.