Silencing of tissue factor by antisense deoxyoligonucleotide mitigates thioacetamide-induced liver injury.

BACKGROUND: Retinoid receptors (RRs), RAR-α and RXR-α, work as transcription factors that regulate cell growth, differentiation, survival, and death. Hepatic stellate cells (HSCs) store retinoid and release its RRs as lipid droplets upon their activation. PURPOSE: We test the hypothesis that loss of retinoid receptors RAR-α and RXR-α from HSCs is dependent on tissue factor (TF) during thioacetamide (TAA)-induced liver injury. METHODS: Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated. RESULTS: Increased TF, fibrin, cleaved caspase-3, and cyclin D1 protein expression is seen in zone of central vein after TAA injection compared with vehicle-treated mice. A strong downregulation of RAR-α and RXR-α is seen in TAA-induced liver injury. In addition, histopathological obliteration and pericentral expression of cleaved caspase 3 and cyclin D1 are observed after TAA injection compared with the normal vehicle-treated mice. No changes have been seen in TAA/TF-sense (SC) in whole parameters compared with TAA-treated animals. TAA/TF-antisense (AS)-treated mice show normal expression of all parameters and normal histopathological features when compared with the control mice. In conclusion, this study declares that the strong downregulation of RAR-α and RXR-α may cause liver injury and particularly activation of HSCs in TAA-induced toxicity. TF-AS treatment not only downregulates TF protein expression but also alleviates loss of liver RAR-α and RXR-α and suppresses the activated apoptosis signals in TAA-induced liver toxicity. Finally, TF and RAR-α/RXR-α are important regulatory molecules in TAA induced acute liver injury.

Comparative study of cholinergic and oxidative stress biomarkers in brains of diabetic and hypercholesterolemic rats.

OBJECTIVE: Diabetes mellitus (DM) and hypercholesterolemia (HC) when poorly controlled lead to debilitating central nervous system complications including cognitive deficits and memory impairment. In the present study, we investigated the mechanisms that may be responsible for such deficits. METHODS: Both diabetes and HC were induced in two groups of rats independently using alloxan and high cholesterol diet, respectively. RESULTS: Acetyl cholinesterase was significantly increased in brain of diabetic rats. Also, brain malondialdehyde level was extremely elevated in both diabetic and hypercholesterolemic groups. Meanwhile, brain albumin was markedly decreased in both of them. However, the brain iron level was significantly increased in DM with concomitant increase in total antioxidant capacity in the same group as compared to the normal control. The concentration of brain calcium was noticeably increased in HC group. Our results were confirmed by the increased activity of lactate dehydrogenase in both DM and HC groups, indicating major brain cytotoxicity. CONCLUSIONS: Overall, our results suggested that both DM and HC have deleterious effects on the brain which may be attributed to oxidative stress and dysregulation of both cholinergic function and calcium level. Administration of antioxidant is recommended in both cases.

Carbon tetrachloride-induced liver injury in mice is tissue factor dependent.

Tissue factor (TF) is a membranous glycoprotein that activates the coagulation system when blood vessels or tissues are damaged. TF was up-regulated in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. The present study aimed to test the hypothesis that TF-dependent fibrin deposition occurs in liver toxicity induced by CCl4 in mice. Pericentral deposition of TF and fibrin is induced after CCl4-induced liver toxicity. The toxicity was evaluated by determination of serum activities of ALT, AST and ALP as well as GSH content and histopathological changes. The results showed that injection of mice with TF-antisense deoxyoligonucleotide (TF-AS) prevented the accumulation of TF and fibrin in the hepatic tissues. Furthermore, it significantly restored blood biochemical parameters, GSH content and distorted histopathological features caused by CCl4. The current study demonstrates that TF activation is associated with CCl4-induced liver injury. Furthermore, administration of TF-AS successfully prevented this type of liver injury.

Thymol and carvacrol prevent cisplatin-induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

The aim of the present study is to assess the possible protective effects of thymol and carvacrol against cisplatin (CP)-induced nephrotoxicity. A single dose of CP {6 mg/kg, intraperitoneally (i.p.)} injected to male rats revealed significant increases in serum urea, creatinine, and tumor necrosis factor alpha levels. It also increased kidney contents of malondialdehyde and caspase-3 activity with significant reduction in serum albumin, kidney content of reduced glutathione as well as catalase, and superoxide dismutase activity as compared to that of the control group. In contrast, administration of thymol {20 mg/kg, orally (p.o.)} and/or carvacrol (15 mg/kg, p.o.) for 14 days before CP injection and for 7 days after CP administration restored the kidney function and examined oxidative stress parameters. In conclusion, thymol was more effective nephroprotective than carvacrol. Moreover, a combination of thymol and carvacrol had a synergistic nephroprotective effect that might be attributed to antioxidant, anti-inflammatory, and antiapoptotic activities.

Inhibitory effect of yoghurt and soya yoghurt containing bifidobacteria on the proliferation of Ehrlich ascites tumour cells in vitro and in vivo in a mouse tumour model.

The effect of yoghurt and soya yoghurt containing Bifidobacterium lactis Bb-12 or B. longum Bb-46 on Ehrlich ascites tumour cell proliferation was investigated in vitro and in vivo. Tumour cells were incubated with B. lactis Bb-12 or B. longum Bb-46 cultivated in de Mann Rogosa Sharpe (MRS) broth medium, or with their centrifuged supernatant fractions or sediments, for 2 h at 37 degrees C. Treatment resulted in the inhibition of tumour cell proliferation by 85.42 (SD 0.78) and 85.10 (SD 1.28) % by intact micro-organisms, 77.61 (SD 0.29) and 71.43 (SD 1.75) % by their supernatant fractions, but only 4.00 (SD 0.19) and 9.09 (SD 1.24) % by the two sedimented bacteria, respectively. The incubation of tumour cells with yoghurt and soya yoghurt containing Bb-12 for 2 h resulted in 83.01 (SD 0.11) and 88.23 (SD 0.06) % inhibition, respectively, while it was 83.82 (SD 0.24) and 86.36 (SD 0.06) %, respectively for the same products containing Bb-46. Corresponding values for plain yoghurt and soya milk (without bifidobacteria) were 32.81 (SD 0.14) and 5.55 (SD 0.12) %, respectively. The differences between yoghurt or soya yoghurt containing Bb-12 or Bb-46 and plain yoghurt, soya milk or control treatments were statistically significant (n 3; P<0.05). Female Swiss albino mice were injected intraperitoneally with the same tumour cells. The lifespan of mice fed diets supplemented with yoghurt or soya yoghurt containing Bb-12 or Bb-46 was prolonged by 16, 23, 34 and 39 %, respectively compared with that of the positive control group (n 6; P<0.05). The lifespan of groups fed plain yoghurt or soya milk was prolonged by 15 and 8 %, respectively. Prolongation of lifespan was positively correlated with faeces bifidobacterial count in the groups fed yoghurt or soya yoghurt containing bifidobacteria (r 0.917; P<0.05).

Prevention of cisplatin-induced nephrotoxicity by methimazole.

Nephrotoxicity is a dose-limiting factor in the use of cisplatin against solid tumours. Methimazole, an antithyroid drug containing a free SH group, has a nephroprotective potential against chemically-induced nephrotoxicity. We tried to explore the nephrotoxic effect of the experimentally therapeutic dose of cisplatin (7 mg kg(-1), i.p.), particularly on the nuclear level of kidney cells in male albino rats, as well as the possible protective effect of methimazole. Furthermore, the drug interaction regarding the oncolytic effect of cisplatin was examined in Ehrlich ascites carcinoma (EAC)-bearing mice. A single dose of cisplatin caused kidney damage, 6 days after injection, manifested by 219% increase in serum creatinine, 384% increase in blood urea nitrogen and 170% increase in kidney content of lipid peroxides. Kidney DNA showed clear fragmentations detected by gel electrophoresis. However, kidney reduced glutathione was unchanged at that time period. Histological examination of kidney confirmed the toxic effect of cisplatin. Methimazole (40 mg kg(-1), i.p., 30 min before cisplatin injection) significantly protected the kidney from the nephrotoxic effect of cisplatin as judged from the biochemical parameters investigated as well as the histopathological examination. On the other hand, the survival data in EAC-bearing mice treated with both drugs indicated the persistence of an effective cytotoxic action. This study points to a promising use of this combination and necessitates further experimental and clinical studies.

Effect of bromocriptine on uterine contractility in near-term pregnant rats.

Treatment of pregnant albino rats at gestation day 9 with the dopamine agonist, bromocriptine, in a dose of 0.7 mg kg-1 day-1, i.p. for 11 days produced a significant increase in the normal uterine contractions both in vitro and in vivo. The increase in frequency (F), amplitude (A) and area under the curve (AUC) in the in vitro experiment amounted to 35, 80 and 58%, respectively; while the increase in F and A in the in vivo experiment was 36 and 25%, respectively, in comparison with the corresponding control group. Addition of oxytocin (5x10(-12)-4x10(-11) m) to the uterus isolated from rats pretreated with bromocriptine resulted in marked uterotonic effect (24, 35 and 49% increase in F; 25, 35 and 46% increase in A and 42, 62 and 122% increase in AUC of contractions). Also, the in vivo experiment showed that an injection of oxytocin at the time of investigation (0.125-1.0 I.U. kg-1, i.v.) into rats pretreated with bromocriptine caused a marked increase in F (33, 40 and 81%) and A (33, 37 and 75%) of uterine contractions compared to the values of bromocriptine-treated animals. These results indicate that bromocriptine should be used with caution during pregnancy. In addition, this must be considered when using oxytocin during delivery of females pretreated with bromocriptine.

Effect of different types of textile fabric on spermatogenesis: electrostatic potentials generated on the surface of the human scrotum by wearing different types of fabric.

This study was conducted to evaluate the effect of the electrostatic potentials generated on the surface of the scrotal area when different types of textile fabric were worn. Twenty-one healthy volunteers were divided into three equal groups. The first group was dressed in underpants made of 100% polyester, the second wore underpants of 100% cotton, and the third wore a 50/50% polyester/cotton mixture. With an electrostatic kilovoltmeter, the electrostatic potentials were measured 1 h after wearing the pants once during the day and a second time at night. The test was repeated 4 times, each on a separate day. No electrostatic potentials were detected on the cotton underpants. The polyester pants showed the highest potentials (mean 338.9 +/- 25 SD V/cm2), while the mixed polyester/cotton pants produced less than half that level (mean 148.3 +/- 16 SD V/cm2). The readings during the day were higher than those at night, probably due to the higher temperature during the day. This study could explain the cause of diminished spermatogenesis in dogs dressed in polyester pants. A new theory is put forward holding that the polyester underpants create an "electrostatic field" across the scrotal sac that disturbs the testicular and/or epididymal function.

Effect of different types of textile fabric on spermatogenesis. I. Electrostatic potentials generated on surface of human scrotum by wearing different types of fabric.

This paper comprises a study of the electrostatic potentials generated on the surface of the scrotal area when different types of textile fabric were worn. 21 healthy volunteers were divided into 3 equal groups. The first group was dressed in underpants made of 100% polyester, the second of 100% cotton, and the third of a 50:50% polyester:cotton mixture. With an electrostatic kilovoltmeter, the electrostatic potentials were measured 1 h after wearing the pants once at daytime and a second time at night. The test was repeated 4 times, each on a separate day. No electrostatic potentials were detected on the cotton underpants. The polyester pants showed the highest potentials (mean 338.9 +/- 25 SD Volt cm-2) while the mixed polyester:cotton pants produced less than half that level (mean 148.3 +/- 16 SD Volt cm-2). The readings at daytime were higher than at night, probably due to the higher temperature during the day. The accumulated electrostatic charges on the pants are due to the friction of the pants with the skin. As a result of friction, equal and opposite charges are accumulated on the skin surface and on the inner surface of the pants facing the skin. Eventually, an 'electrostatic field' is produced traversing the scrotal contents and may disturb the testicles and/or epididymis leading to disordered spermatogenesis.

[Effect of acetycholine chloride and chlorocholine chloride on the resting potential and membrane resistance of identified mollusk A and B neurons]. / Deistvie atsetilkholinkhlorida na potentsial pokoia i soprotivlenie membrany identifitsirovannykh neironov A i B molliuska.

Chlorcholine chloride (CCC) the molecule of which has no other group, characteristic of acetylcholine (Ach), causes an effective cholinomimetic action on the surface membrane of the mollusc neurons A and B. As the concentration of Ach and CCC increases from 10(-6) to 10(-3) M the resting potential (RP) and the membrane resistance (R) of the neuron A first increases then decreases. The increase of Ach and CCC concentration causes in the neuron B only a decrease of the above mentioned parameters. The data point to the necessity of improving the ideas about the structure of cholinoreceptors and mechanism of cholinoreceptor-cholinomimetic interaction.

[Bioelectric characteristics of A and B neurons in the mollusc Coretus corneus with different calcium and sodium contents in the medium]. / Bioélektricheskie kharakteristiki neironov A i B molliuska Coretus corneus pri razlichnom soderzhanii kal'tsiia i natriia v srede

Action potentials (AP) of neurons A and B could be only elicited in the presence of Na-+ ions. An increase in [Ca-++]0 led to depolarization of neurons, enhancement of their excitability, AP, overshoot, of positive afterpotential, AP duration, AP maximal rate of fall (Vf) and to decrease in AP maximal rate of rise (Vr). After addition of CaCl2 up to 50 mmoles into the Ringer solution, the membrane resistance (R) increased. If the [Na-+]0 was equimolarly diminished, R increased up to the [Ca-++]0 30 mmoles, but at greater [Ca-++]0 R fall below the initial value. The regularities were independent of the initial value of resting potential (RP). At high [Ca-++]0 Ca-++ contributed to the generation of the inward current during AP while Na-+ caused an increase in ionic (calcium) membrane permeability at rest. At high [Ca-++]0, Na-+ was also necessary for support of membrane channels which maintained the inward and outward currents during the AP.