Band 29, Heft 6

Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine restricted to the rectum and colon. Its clinical course follows an intermittent pattern with episodes of relapse, followed by remission and eventually resulting in mucosal damage. Although there is no permanent cure for UC, the currently available pharmacotherapy aims to induce and maintain clinical remission, promote the healing of colonic mucosa and avert any surgical intervention. The conventional drug therapy comprising of 5-aminosalicylates, thiopurines and corticosteroids has advanced recently in terms of formulations and dosing schedule, resulting in improved efficacy, safety and compliance. Calcineurin inhibitors, such as cyclosporin and tacrolimus, have emerged as steroid sparing agents. The treatment paradigm of UC patients who are refractory to conventional drugs has changed in view of the availability of biologics. Currently, there are four biologics approved by the US FDA for the treatment of UC, namely, infliximab, adalimumab, golimumab and vedolizumab, and several others are undergoing clinical trial. In this comprehensive review, the advantages and limitations of the medical therapy of UC are elaborated with an emphasis on the pharmacokinetic and pharmacodynamic aspects of the drugs.

Background: Bisphenol A (BPA), a chemical used in the manufacture of plastics, has toxic effects on various systems of the human body including the reproductive system. BPA possesses estrogenic activity and is implicated in altering oogenesis, ovulation, and fertility. In addition to ovulatory changes, uterine contractility is an important factor for fertility. However, the effects of BPA on myometrial contractions are not known. Therefore, we examined the effect of BPA on rat uterine contractions. Methods: The uterus was isolated from adult rats showing estrous phase, and spontaneous in vitro contractions were recorded (35±1 °C). The effect of cumulative concentrations of BPA was determined. Further, the involvement of nitric oxide (NO) and guanylyl cyclase (GC) for the BPA-induced changes on uterine contractility was evaluated using the NO synthase inhibitor (L-NAME) or GC inhibitor (methylene blue). Results: BPA decreased the amplitude and frequency of spontaneous uterine contractions in a concentration-dependent manner. A decrease of 50% occurred at 1 and 3 μM for amplitude and frequency, respectively. L-NAME ( N -ω-nitro- l -arginine methyl ester) blocked the BPA-induced decrease in amplitude at all concentrations but antagonized the frequency only at the maximum concentration (10 μM). Methylene blue (a GC inhibitor) did not block the BPA-induced responses but for the frequency at 10 μM of BPA. Conclusions: The results indicate that BPA decreased the amplitude and frequency of spontaneous uterine contractions by involving the nitrergic mechanism; however, the GC mechanism is not involved in the depression.

Background: Anogeissus leiocarpus is a Sahel tree traditionally used by the residents of Burkina Faso for its antihypertensive properties. In this study, experiments were conducted to evaluate whether an aqueous extract of the Anogeissus leiocarpus (AEAL) trunk bark induces a vasorelaxant effect on porcine coronary artery rings and to investigate the underlying mechanism. Methods: AEAL-induced relaxations were assessed using porcine coronary artery rings suspended in organ chambers. The phosphorylation levels of Src, Akt and endothelial nitric oxide synthase (eNOS) were assessed in a primary endothelial cell culture by Western blot. The reactive oxygen species (ROS) formation was assessed using dihydroethidine. Results: In porcine coronary artery rings, AEAL at 0.1–300 μg/mL induced endothelium-dependent relaxations, which were inhibited in the presence of inhibitors of nitric oxide (NO) and the endothelium-derived hyperpolarization pathways. Moreover, the AEAL-induced NO-mediated relaxations were significantly reduced by the inhibitors of Src and PI3-kinase as well as by the membrane-permeant ROS scavengers. In cultured porcine coronary artery endothelial cells, treatment with AEAL is associated with an intracellular generation of ROS. Moreover, the AEAL induced the phosphorylations of Akt (Ser473), eNOS (Ser1177) and a transient phosphorylation of Src (Ser17) in a time-dependent manner. Conclusions: These findings indicate that AEAL is a potent inducer of endothelium-dependent NO-mediated relaxations in porcine coronary arteries through the redox-sensitive Src/PI3-kinase/Akt pathway-dependent activation of eNOS.

Background Glyphae brevis leaf is reported in ethnomedicine as a treatment for hepatitis and jaundice; however, no studies have hitherto investigated the mechanistic basis of these claims. Methods A hepato-protective role of G. brevis hydromethanolic (GBH) leaf extract was established against carbon tetrachloride (CCl 4 )-induced hepatotoxicity. Twenty-four hours after a CCl 4 challenge, rats were sacrificed and serum hematological indices, lipid profile, and biochemical parameters were determined. The antioxidant enzymes parameters (glutathione, catalase, and superoxide dismutase) and lipid peroxidation product (thiobarbituric reactive substances) levels in liver homogenates were evaluated. Changes in the liver cyto-architecture of different treatment groups were also investigated. Results The GBH extract produced no significant impact on weight and hematological indices. Intoxication with CCl 4 significantly (p<0.001–0.05) increased total cholesterol (TC) and low-density lipoproteins (LDL) compared with control rats. Pretreatment with GBH leaf extract significantly reduced triglycerides, TC, and LDL to approaching control levels (p<0.001–0.05). The GBH leaf extract significantly alleviated CCl 4 -induced elevation of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and the CCl 4 -induced depression of total protein, and albumin. Liver antioxidant parameters were significantly increased in plant extract-treated rats, and this antagonized the pro-oxidant effect of CCl 4 . Histopathological studies also supported a hepato-protective effect of GBH. Collectively, the GBH leaf extract alleviated the CCl 4 -induced hepatotoxicity through improvement of innate antioxidant enzyme levels and lipid metabolism and stabilized the hepatocyte cyto-architecture of intoxicated rats. Conclusions This study establishes the ethnomedicinal role of G. brevis leaf in hepatitis and the mechanistic basis of hepato-protection against CCl 4 -induced hepatotoxicity.

Background This study was designed to evaluate the free radical scavenging property of chloroform extract of the bark of Stereospermum chelonoides (SCBC) and to investigate its potential in Alzheimer’s disease and inflammation, two oxidative stress related disorders. Methods Preliminary phytochemical analysis and in vitro antioxidant potential of SCBC were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, ferric reducing antioxidant power (FRAP) assay, cupric reducing antioxidant capacity (CUPRAC) and total antioxidant capacity determination assay. Total phenol and total flavonoid contents were also determined. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based cytotoxicity and cyto-protective assays were performed on human neuroblastoma SH-SY5Y cells. Thioflavin-T assay and caspase activation measurement assay were carried out to elucidate the mechanism of cytoprotection of SCBC observed here. In vivo anti-inflammatory potential was measured using croton oil and xylene induced ear edema tests. Results Phytochemical screening of SCBC revealed the presence of various phytoconstituents. Dose-dependent in vitro antioxidant activity was observed. The extract was enriched in flavonoids and polyphenolic compounds too. SCBC was found to inhibit amyloid-β peptide 1-42 (Aβ42) induced cell death in a dose-dependent manner. Encouraged by the cyto-protective effect, its effects on Aβ42 fibrillogenesis and caspase-3 activated apoptosis were observed. SCBC significantly slowed down the Aβ42 fibrillogenesis and caspase-3 activation in a concentration-dependent manner indicating its probable mechanism of rendering cyto-protection. SCBC has been able to reduce inflammation significantly in croton oil induced ear edema in both doses. Conclusions Thus, this study could form the basis for further study for the potential use of SCBC in oxidative stress associated cell death and inflammation.

Background Iodine is a nonpareil constituent of thyroid hormones (THs) and a prime regulator of thyroid gland functioning. Although essential at recommended levels for the prevention of iodine deficiency disorders (IDDs), exposure to excess iodine reportedly causes hypothyroidism, hyperthyroidism, and several other emerging deleterious impacts. The objective of the present study is to explore the influence of excess iodide exposure on carbohydrate and lipid metabolism along with the histoarchitecture of certain associated organs such as the pancreas, liver, kidney, and skeletal and cardiac muscle because information on those aspects was found to be scanty. Methods Twelve rats were taken, six were fed with iodine through gavage at a dose of 3.5 mg potassium iodide (KI)/100-g body weight, which corresponded to 500 times of the physiological daily dosage of iodide for a period of 60 days, while the other six formed the control group. Results KI-treated rats presented high body weight and urinary iodine with low TH levels, suggesting a primary thyroid dysfunction. There was an increase in blood glucose, cholesterol, triglycerides, low density lipoprotein (LDL), and very low density lipoprotein (VLDL), while high density lipoprotein (HDL) levels decreased. Tissue glycogen content in the liver and skeletal muscle was decreased and was increased in the heart and kidney. Histological sections of the pancreas showed a complete disruption with hardly recognizable histoarchistructure. Treated liver sections displayed the broadened central vein with degenerated hepatocytes, while skeletal muscle sections showed dissolution of muscle fibre cells linked with loss of glycogen from these organs. Histological changes in the heart include features similar to those of a fatty heart with cardiac muscles mutilation, while that of the kidney shows an increase in glomerular tuft size and Bowman’s space expansion with general deterioration. Conclusions It may thus be concluded that excess iodine exposure for a long duration causes the development of a biochemical state of hypothyroidism. The developed hypothyroidism was found responsible for the hyperglycaemic and hypercholestromic status evident by high blood glucose and cholesterol levels and the depletion of glycogen at its storage sites in the liver and skeletal muscle but the extra deposition in the cardiac muscle and kidney; histomicrophotographs showed severe destruction of the pancreatic structure. All these alterations are conducive for the pathogenesis of cardiovascular and kidney diseases.

Background Globally, Termitomyces letestui is used by different communities to treat various illnesses, including bacterial infection, although with limited scientific evidence. The current study aims to assess the immunomodulatory and antibacterial properties of the water extract of a wild mushroom, T. letestui in mice model. Methods The base study was completed following the standard methods and procedures using white mice Mus musculus . The immunomodulatory was investigated for humoral and cell-mediated response in both the normal and dexamethasone-immunosuppressed mice. An immunostimulatory drug, levamisole, was used as reference. The treatment was done daily and the extract doses of 250 and 500 mg/kg bwt were used. Delayed-type hypersensitivity reaction (DTH), mice lethality rate and hemagglutination antibody titer were determined. Disc diffusion assay was performed using the Muller-Hinton agar to assess the effect against Escherichia coli and Staphylococcus aureus . The statistical analysis was performed using GraphPad prism 5.0 a Software. Results T. letestui water extract (TLAE) provided significant inhibition zones against E. coli and S. aureus . TLAE=, along with the antigen ( Salmonella typhi ) showed a significant increase in the circulating antibody titer and reduced the lethality rate in mice. The extract also showed significant increase in the DTH response against S. typhi . Conclusions This preliminary study demonstrated that TLAE caused a significant immunostimulatory effect on both the cell-mediated and humoral immune systems in the mice and antibacterial property against E. coli and S. aureus .

Background: Obese patients have a higher risk of developing different metabolic syndromes (MeS), including acute pancreatitis (AP). Although obese individuals are more prone to MeS and more susceptible to local and systemic inflammation in response to AP, thus causing long-lasting hospitalization, higher morbidity and mortality, their underlying mechanisms remain unclear. This study aimed to investigate the relationship between obesity and the outcomes of AP in the rat model of AP. Methods: To assess the link between obesity and AP, 40 male albino rats were divided into two groups: control and those given a high-fat diet for 12 weeks. This was followed by the injection of a single dose of L-arginine (250 mg/100 gm) in half of each group to induce AP. Results: Data evaluation was done using 2-way ANOVA. Values were considered significant when p≤0.05. Markers of AP were evaluated in the serum and ascitic fluid. Moreover, the systemic inflammatory markers, such as IL-6, TNF-α, HMGB1 and TLR4, were quantified in the liver of all groups. Results showed that the OAP group had the highest levels of liver enzymes and amylase aside from several signs of liver damage, such as fat necrosis and steatosis. Conclusions: The inflammatory cytokine levels are synchronized, creating an early responsive stage and late inflammatory stage to realize the best defense mechanism. Results also indicate that obesity is a main determinant of the severity of AP at the late stage.

Background Our earlier studies had given evidence of the traditional application of Xylopia aethiopica in the management of inflammation. The principal constituent obtained from its bio-fractionation is xylopic acid. It is a crystalline diterpene that belongs to the class of kauranes. This work sets out to investigate the anti-inflammatory potential of the xylopic acid isolated from the dried fruit of X. aethiopica . Methods A preliminary anti-inflammatory study, using the protein denaturation model, and in vivo anti-inflammatory assay were employed in the investigation of acute inflammation. The modulation of the effect of the pro-inflammatory markers histamine, serotonin, bradykinin, and prostaglandin E 2 by xylopic acid was investigated by in vivo mice paw oedema models. Results Xylopic acid showed a concentration-dependent inhibition of albumen denaturation with an IC 50 of 15.55 μg mL −1 . Xylopic acid (10, 30, 100 mg kg −1 ) inhibited the maximal oedema and the average paw thickness (oedema) over the period of each study considerably for all phlogistic agents employed (i.e. carrageenan, histamine, serotonin, bradykinin, and prostaglandin E 2 ) in the inflammation induction for both prophylactic and therapeutic protocols. Conclusion This study establishes that xylopic acid has anti-inflammatory action in acute inflammation.

Background: A prospective observational study was carried out over a period of 6 months among the inpatients and outpatients in the departments of general medicine, urology, obstetrics, and gynecology of a tertiary level referral hospital in south Malabar region of Kerala to assess the prevalence of various bacterial isolates and their changing susceptibility to antimicrobial agents and to evaluate the pattern of antibiotic utilization in urinary tract infection (UTI). Methods: A total of 680 samples were analyzed from December 2015 to May 2016; among them, only 74 patients met the inclusion criteria. Of the 74 patients, 53 were female and 21 were male. Female patients were found to be significantly higher in number in the age group of 61–70years. The maximum number of UTI cases was reported from the general medicine department. Results: The disease was more significantly portrayed in suburbans (47%) and rural (38%) population compared with urbans (15%). Fever (60.81%) and dysuria (48.64%) were the most common symptoms. Diabetes (34%) was found to be the major predisposing factor followed by postmenopausal factors (24%), previous UTI (14%), renal disease (9%), benign prostatic hypertrophy (8%), smoking (7%), and oral contraceptives (4%). Escherichia coli was the major isolate (n=36) followed by Klebsiella (n=13), Citrobacter (n=8), Enterococcus (n=7), Enterobacter (n=4), Pseudomonas (n=3), coagulase-negative Staphylococcus (n=2), and Proteus (n=1). Majority of patients were prescribed with cefoperazone+sulbactum (n=28) followed by levofloxacin (n=25) and nitrofurantoin (n=10). Cumulative antibiogram was prepared as the final step of the study using the WHONET 5.6 software. Gram-negative organisms such as E. coli , Klebsiella , and Citrobacter showed higher susceptibility toward piperacillin-tazobactum, cefoperazone-sulbactam, imipenem, meropenem, amikacin, and netilmicin. Gram-positive organisms such as Enterococcus showed higher susceptibility toward piperacillin-tazobactum, cefoperazone-sulbactam, amoxicillin-clavulanic acid, vancomycin, and linezolid. Conclusions: In our setting, routine culture may be necessary as treatment failure with empirical therapy is likely to occur.

Background: The exploration of the biological assessment of technical azadirachtin, a tetranortritarpinoid from the neem seed kernel, was reviewed. The present study was, therefore, designed to evaluate the dose-dependent in vitro effects of azadirachtin-A, particularly on the functional studies and determination of molecular events, which are critical in the process of sperm capacitation. Methods: To assess the effects of the azadirachtin-A on the functional studies, sperm capacitation, the total sperm adenosine triphosphate levels, acrosome reaction (AR), the sperm-egg interaction and the determination of molecular events like cyclic adenosine-3′,5′-monophosphate and calcium levels, the appropriate volumes of the sperm suspension were added to the medium to a final concentration of 1×10 6 sperm/mL and incubated in a humidified atmosphere of 5% CO 2 in air at 37°C. The increasing quantities 0.5–2.0 mM/mL and the equivalent volumes of 50% dimethyl sulfoxide were added to the control dishes prior to the addition of spermatozoa and then observed at various time-points for motility and other analyses. Results: Results revealed the dose- and time-dependent decrease in the functional consequence of capacitation, i.e. the percentage of motile spermatozoa, motility score and sperm motility index, levels of molecular events in spermatozoa, followed by declined spontaneous AR leading to lesser binding of the cauda epididymal sperm to the Zona pellucida. Conclusions: The findings confirm the inhibition of rat sperm motility by blocking some biochemical pathways like energy utilization. They also demonstrate that sperm capacitation is associated with the decrease in AR and that the levels of molecular events in spermatozoa can guide us towards the development of a new male contraceptive constituent.

Background: Herbs have been used from ages to manage male sexual dysfunction. Hence, this study sought to investigate the effects of Eurycoma longifolia (EL) and Cylicodiscus gabunensis (CG) stem bark extracts on some enzymes implicated in erectile dysfunction in vitro . Methods: The extracts were prepared, and their effects on phosphodiesterase-5 (PDE-5), arginase, and angiotensin-1-converting enzyme (ACE) as well as pro-oxidant-induced lipid peroxidation were assessed. Furthermore, phenolic contents were determined, and their components were characterized and quantified using high-performance liquid chromatography with diode array detector (HPLC-DAD). Results: The results revealed that the extracts inhibited PDE-5, arginase, and ACE in a concentration-dependent manner. However, IC 50 values revealed that CG had higher inhibitory potential on PDE-5 (IC 50 =204.4 μg/mL), arginase (IC 50 =39.01 μg/mL), and ACE (IC 50 =48.81 μg/mL) than EL. In addition, the extracts inhibited pro-oxidant-induced lipid peroxidation in penile tissue homogenate. HPLC-DAD analysis showed that CG is richer in phenolic compounds than EL, and this could be responsible for higher biological activities observed in CG than EL. Conclusions: Hence, the observed antioxidant property and inhibitory action of CG and EL on enzymes relevant to erectile dysfunction in vitro could be part of possible mechanisms underlying their involvement in traditional medicine for the management of male sexual dysfunction.

Background Vaccinium myrtillus leaves are known to be rich in phenols and have been used in traditional medicine as an antidiabetic remedy. This study evaluated the powder extract of V. myrtillus leaves obtained with the use of L-arginine and myo-inositol for anti-obesity and lipid-lowering potential in hamsters. Methods Standard phytochemical methods were used to determine the total phenolic and total flavonoid contents of the extract. The obesity condition was induced in Syrian hamsters by feeding them with highly palatable fat- and sugar-rich diet (40.3 kcal% fat) for 12 weeks. From the 10th week of diet feeding, the obese hamsters were treated with the powder extract of V. myrtillus leaves (15, 25 and 35 mg/kg/day, respectively) and “Styfimol” (6.2 mg/kg/day of hydroxycitric acid) as a positive control drug. At the end of the treatment period, the biochemical parameters as well as visceral fat mass were determined. Results Vaccinium myrtillus leaves powder extract at 25 and 35 mg/kg/day caused a significant reduction in body weight gain and visceral fat mass in obese hamsters. Serum triacylglycerols, free fatty acids, total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels were also significantly lower. Besides, the hamsters treated with powder extract at 25 and 35 mg/kg/day had the closest intact value ratio of high-density lipoprotein cholesterol and LDL-C compared with positive control animals. Conclusions The results showed that V. myrtillus leaves powder extract is a promising therapeutic agent for the treatment of obesity and obesity-induced diseases.