Volume 29, Issue 3

The contraction of detrusor smooth muscles depends on the increase in intracellular calcium. The influx of calcium from the plasma membrane calcium channels and calcium release from the sarcoplasmic reticulum give rise to intracellular calcium. Under the pathophysiological conditions, the increased sensitivity of regulatory and contractile proteins to calcium also plays an important role in maintaining the spontaneous detrusor smooth muscle activity. Many proteins have been identified to play a role in calcium sensitization. Both the protein kinase C (PKC) and Rho-kinase (ROCK) signaling pathways are responsible for the induction of calcium sensitization in the detrusor smooth muscles. The balance between the myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) regulates the intracellular calcium-contractile force relationship. The inhibition of MLCP by PKC-mediated phosphatase inhibitor (CPI-17) and myosin phosphatase target subunit (MYPT-1) phosphorylation by both the PKC and ROCK are responsible for calcium sensitization in the detrusor smooth muscles. However, the ROCK pathway predominantly participates in the calcium sensitization induction under pathophysiological situations. Many kinases are well known nowadays to play a role in calcium sensitization. This review aims to enlighten the current understanding of the regulatory mechanisms of calcium sensitization with special reference to the PKC and ROCK pathways in the detrusor smooth muscles. It will also aid in the development of new pharmacological strategies to prevent and treat bladder diseases.

What is an organ and what is an organ system? According to the ‘standard’ hierarchical model of physiology, each living organism comprises of organ systems including those that offer sensory and control functions (nervous system), energy accumulation (gastrointestinal system), internal dissipation (circulatory system) and mobility (musculoskeletal system). Each organ system in turn is comprised of individual organs. This taxonomy has conceptual flaws as not every organ has a single organ system function but may participate in a myriad of physiological functions. To answer this philosophical question, several principles are applied. At one level, the assessment of physiological function and organ system can be considered to have some relation to the broader issue of the species problem in the philosophy of biology. Additionally, however, there is a relationship to the more fundamental issue of the biochemistry of each organ that can be considered through the philosophy of chemistry. The philosophy of physiology can therefore be considered to occupy a position somewhere between these two strata of thought on the path of science reductionism. A distinctive philosophy of physiology and pathophysiology may ultimately offer a myriad of new pathways through which to better explore the metaphysical elements of medicine and science.

Background: In previous studies, we have observed that specific N -methyl- d -aspartic acid (NMDA) antagonists and non-NMDA antagonists injected within the nucleus accumbens septi (NAS) induced an anxiolytic-like effect in the plus maze test in rats. In the present study, the effect of intracanalicular blockade of NMDA receptors using dizocilpine in the plus maze was studied in male rats bilaterally cannulated NAS. Methods: Rats were divided into five groups that received either 1 μL injections of saline or dizocilpine (MK-801, [5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo [ a,d ] cyclohepten-5,10-imine) in different doses (0.5, 1, 2, or 4 μg) 15 min before testing. Results: Time spent in the open arm increased under dizocilpine treatment with the two higher doses (2 and 4 μg, p<0.05), extreme arrivals were increased by the three higher doses (1 μg, p<0.05; 2 and 4 μg, p<0.01), and open arm entries by the three higher doses (1, 2, and 4 μg, p<0.05). A dose-effect relationship was observed in all cases. Conclusions: We conclude that dizocilpine-glutamatergic blockade in the accumbens lead to an anxiolytic-like effect and a behavioral disinhibition related to an increase in some motoric parameters, showing specific behavioral patterns.

Background: The deterioration of male reproductive health may represent an outcome of an active disease and environmental factors. The present study investigated the modulatory role of [6]-gingerol in spermatotoxicity resulting from colitis and benzo[ a ]pyrene (B[ a ]P), an environmental and food-borne pollutant. Methods: Group I (control) mice received corn oil alone, while group II ([6]-gingerol alone) mice orally received [6]-gingerol alone at 100 mg/kg body weight. Group III [benzo[ a ]pyrene+dextran sulfate sodium (BDS) alone] mice were orally exposed to B[ a ]P at 125 mg/kg for 7 days followed by three cycles of 4% dextran sulfate sodium (DSS) in drinking water. A cycle consisted of seven consecutive days of exposure to DSS-treated water followed by 14 consecutive days of normal drinking water. Group IV (BDS+[6]-gingerol) mice were orally treated daily with 100 mg/kg of [6]-gingerol during exposure to B[ a ]P and DSS in the same manner as those of group III. Results: [6]-Gingerol significantly abrogated BDS-mediated increase in disease activity index and restored the colon wet weight, colon length and colon mass index to near normal when compared to BDS alone group. Moreover, [6]-gingerol significantly prevented BDS-induced decreases in the daily sperm production (DSP), testicular sperm number (TSN), epididymal sperm number, sperm progressive motility and sperm membrane integrity when compared with the control. [6]-Gingerol markedly increased the sperm antioxidant enzymes activities and decreased the sperm head, mid-piece and tail abnormalities as well as suppressed oxidative stress and inflammatory biomarkers in BDS-exposed mice. Conclusions: [6]-Gingerol protected against spermatotoxicity in experimental model of interaction of colitis with environmental pollutant B[ a ]P.

Background: Many biological processes are influenced by space weather activity components such as solar activity (SA), geomagnetic activity (GMA) and cosmic ray activity (CRA). Examples are total mortality, acute myocardial infarction (AMI), stroke (cerebrovascular accident), sudden cardiac death, some congenital maladies (congenital heart disease and Down syndrome), many events in neonatology, ophtalmology, blood pressure regulation, blood coagulation, inflammation, etc. The aim of this study was to check if the level of blood troponins (Tns) – markers of myocardial damage and recognized components of modern description of AMI – is connected with the mentioned space weather parameters. Methods: Patients admitted to a 3000-bed tertiary university hospital in Kaunas, Lithuania, with suspected AMI were the object of the study. Data for the time between 2008 and 2013 – 72 consecutive months – were studied. Of the patients, 1896 (1398 male, 498 female) had elevated troponin I (Tn I) or troponin T (Tn T, sensitive Tn) levels. Normal values were 0.00–0.03 ng/mL for Tn I and 0.00–14.00 ng/mL for Tn T. Monthly means and standard deviation of Tn I and Tn T were compared with monthly markers of SA, GMA and CRA. Pearson correlation coefficients and their probabilities were established (in addition to the consecutive graphs of both comparing physical and biological data). The cosmophysical data came from space service institutions in the United States, Russia and Finland. Results: AMI was diagnosed in 1188 patients (62.66%), and intermediate coronary syndrome in 698 patients (36.81%). There were significant links of the Tn blood levels with four SA indices and CRA (neutron activity in imp/min); there was no significant correlation with GMA indices Ap and Cp (p=0.27 and p=0.235). Tn T levels significantly correlated with the GMA indices and not with the SA and CRA levels (Ap: r=0.77, p=0.0021; Cp: r=0.729, p=0.0047). Conclusions: First, the monthly level of blood Tn I in ACS is significantly correlated with the indices of SA (inverse) and with CRA (neutron); second, no significant correlation with the GMA indices was found; and third, the Tn T levels showed significant links with the GMA indices and none with SA and CRA (neutron).

Background: This study was carried out to determine the blood pressure changes in experimentally Trypanosoma brucei brucei -infected Wistar albino rats and diminazene aceturate-treated rats. Methods: Twenty-four rats were purchased and divided into four groups consisting of six rats each. Control group (CON) received 0.5 mL of distilled water, i.m., infected but not treated group (INF) received 2×10 6 trypanosome/mL i.m., infected but diminazene aceturate-treated group (INFDIM) received 2×10 6 trypanosome/mL, 3.5 mg/kg, i.m.) and non-infected but diminazene aceturate-treated group (DIM) received 3.5 mg/kg, i.m. and served as negative control. The blood pressures were measured using a CODA 2 ® non-invasive blood pressure monitor (Kent Scientific, USA). The results were compiled and statistical analysis was done with significance set at p≥0.05. Results: The values of the blood pressure readings of the Trypanosoma -infected INF (137.0±2.0 mmHg) and diminazene-treated rats INFDIM (125.0±7.5 mmHg) when compared to the control group (168.0±3.0 mmHg) were significantly lower (p≤0.05) at the end of day 7. The heart rate was also significantly reduced in the INF (403.5±1.5 beats/min) and DIM (445.0±24 beats/min) groups of rats when compared with the control group (613.0±2.0 beats/min) at the end of day 8. Conclusion: The findings indicate the significant reduction in blood pressure and heart rates during Trypanosoma brucei brucei infection and with diminazene aceturate administration. Hence, caution should be exercised when treating trypanosome-infected patients with diminazene aceturate.

Background The purpose of this study is to examine the dose-dependent effects of vitamin 1,25(OH) 2 D 3 on apoptosis and oxidative stress. Methods In this study, 50 male Balb/c mice were used as control and experiment groups. The mice were divided into 5 groups each consisting of 10 mice. Calcitriol was intraperitoneally administered as low dose, medium dose, medium-high dose and high dose vitamin D groups (at 0.5, 1, 5 and 10 μg/kg, respectively), for three times a week during 14 days. At the end of the study, annexin V was measured by enzyme-linked immunosorbent assay method, and total antioxidant capacity and total oxidant status values were measured by colorimetric method in serum. Hematoxylin eosin staining was performed in liver tissues and periodic acid schiff staining was performed in kidney tissues. Results While comparing the results of medium-high dose (5 μg/kg) and high dose (10 μg/kg) vitamin D administration to that of the control group, it was observed that serum antioxidant status and annexin V levels decreased and glomerular mesenchial matrix ratio increased in kidney (p<0.05). In addition to these findings, in the group receiving high dose vitamin D (10 μg/kg), it was observed that the damage to the liver increased together with the the oxidative stress index values (p<0.05). Conclusions As a result, this study was the first in the literature to report that use of high-dose vitamin D (10 μg/kg) results in oxidant effect, rather than being an antioxidant, and causes severe histopathological toxicity in the liver and kidney.

Background: Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study was designed to examine the treatment effects of losartan on obese ZSF-1 rats and to evaluate the impact of the onset of dosing on efficacy. Methods: The rats (7–10 weeks) underwent a right uninephrectomy (Unx) or sham surgery. Losartan (3, 10, 30 mg/kg) was dosed 3 or 9 weeks post-Unx and continued for 12 weeks. Results: Treatment with losartan reduced urinary protein excretion and blood lipids (triglyceride and cholesterol) dose-dependently in both studies. The glomerular filtration rate (GFR) was significantly lower in obese ZSF-1 rats compared with those in lean rats, and losartan was efficacious against this endpoint, in particular with the earlier onset of treatment. Losartan also decreased tubulointerstitial fibrosis, and similar to GFR, earlier treatment conferred beneficial actions even at the lowest dose of 3 mg/kg. Several urinary biomarkers were elevated in the obese ZSF-1 rats, but the levels of sTNFR1, TIMP-1, L-FABP and KIM-1 were the only markers decreased by losartan. Conclusions: Losartan was renoprotective in the ZSF-1 rats with DN, improving both the pathological and functional parameters of the disease. Importantly, the data also highlight the importance of treatment at earlier stages of the disease for protecting against decline in the GFR and the development of fibrosis.

Background: The present study was planned to investigate the phytochemical, antioxidant, antinociceptive, anticoagulant and cytotoxic activities of the Jacquemontia tamnifolia (L.) Griseb leaf methanol extract (MExJT) in the laboratory using both in vitro and in vivo methods. Methods: Phytochemical values, namely, total phenolic and flavonoid contents, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect and FeCl 3 reducing power effects, were studied by established methods. In vivo antinociceptive activity was performed by acidic acid-induced writhing test and formalin-induced pain test on Swiss albino mice at doses of 125, 250 and 500 mg/kg body weight. The clot lysis and brine shrimp lethality bioassay in vitro were used to evaluate the thrombolytic and cytotoxic activities of the plant extract, respectively. Results: Phytochemical screening illustrates the presence of tannins, saponins, flavonoids, gums and carbohydrates, steroids, alkaloids and reducing sugars in the extract. The results showed the total phenolic content (146.33 g gallic acid equivalents/100 g extract) and total flavonoid content (133.33 g quercetin/100 g). Significant (p<0.05) IC 50 values compared to respective standards were recorded in DPPH radical scavenging (289.5 μg/mL) and FeCl 3 reduction (245.2 μg/mL). The antinociceptive effect was evaluated in the acetic acid-induced writhing test and formalin-induced pain models in Swiss albino mice with doses of 125, 250 and 500 mg/kg body weight. Significant (p<0.05) inhibition (72.87±2.73%) of writhing response compared to diclofenac sodium was achieved by 500 mg/kg body weight. The extract also significantly inhibited the licking response in both the early phase (51.59±1.57%, p<0.05) and the late phase (64.82±1.87%, p<0.05) in the formalin-induced writhing test. MExJT also showed (38.10±1.79%) clot lytic activity in the thrombolytic test and cytotoxicity with an LC 50 value of 31.70 μg/mL in the brine shrimp lethality bioassay. Conclusions: The plant is a potential source of antioxidants and might have one or more secondary metabolite(s) with central and peripheral analgesic activity. The results also demonstrate that MExJT has moderate thrombolytic and lower cytotoxic properties that may warrant further exploration.

Background: In this study, we have investigated whether silymarin intake influences lipid and glycogen content in conjunction with sirtuin1 (SIRT1) and sterol regulatory element-binding protein 1c (SREBP-1c) expressions in liver of type 2 diabetic rat. Methods: Thirty-six male Wistar rats were randomly divided into six groups: control groups (C) and diabetic groups (D); the control groups received 60 or 120 mg/kg silymarin (C+S60 or C+S120), and the diabetic groups received 60 or 120 mg/kg silymarin (D+S60 or D+S120) daily for 8 weeks. Serum biochemical parameters, as well as glycogen, lipid and oxidative stress biomarkers, in the liver tissue were measured by spectrophotometric methods. Additionally, SIRT1 and SREBP-1c messenger RNA (mRNA) expressions were evaluated by quantitative polymerase chain reaction. Results: Diabetes caused a significantly increased fasting blood sugar, homeostasis model assessment for insulin resistance, liver total cholesterol and triglyceride (TG) content, which were attenuated after the administration of silymarin. Dietary silymarin caused the improvement of lipid content in the liver of diabetic rats. Moreover, silymarin administration promoted SIRT1, suppressed SREBP-1c mRNA expression, reduced liver nitric oxide and protein carbonyl content, and increased liver glycogen, catalase and glutathione peroxidase activity. Furthermore, histopathological changes were improved in the treated groups. Conclusions: Silymarin administration considerably restored hepatic changes induced by streptozotocin and nicotinamide. The upregulation of SIRT1 mRNA expression by silymarin may be associated with decreased lipid, increased glycogen content and downregulation of the SREBP-1c gene in the liver.