Biomedicine & Aging Pathology最新文献

The role of glutathione peroxidase-1 (GPx1) in limiting the oxidative risk for atherogenesis is increasingly recognized. Therapeutic strategies, designed to augment cellular endogenous defense systems have been identified as a promising approach to control oxidative stress-associated diseases, including atherosclerosis. Ozone therapy regulates oxidative metabolism and prevents oxidative stress-associated-chronic diseases. Thus, the present study was aimed to test the hypothesis that ozone-oxidative conditioning up-regulates GPx1 synthesis in apolipoprotein E deficient mice (apoE^−/−), protecting the vasculature against atherosclerosis. Male apoE^−/− mice were treated with 1 mL of ozone/oxygen containing 40 μg/mL of ozone by rectal insufflation. As controls, mice were untreated or insufflated with oxygen only. Results showed a significant increase (P < 0.05) of aortic GPx1 gene expression in ozone-treated mice, whereas only minor atherosclerotic lesions were observed. Furthermore, GPx1 activity and GSH levels were significant increased (P < 0.05) in ozone receiving group compared with controls. In addition, lipid peroxidation was attenuated by ozone treatment, whereas serum lipids were similar among experimental groups. These results altogether suggest that ozone therapy attenuated atherogenesis by a mechanism that involved, at least, the improvement of aortic GPx1 expression/activity. Further studies are needed in order to assess the possible link of cellular redox-sensitive pathways with the antiatherogenic effect of ozone therapy.

Aim of the study

The present study was designed to investigate the possible association of concomitant administration of trigonelline (TRIG) and sitagliptin (SITA) on cardiomyopathy in diabetic rats.

Methods

Diabetes was induced in Wistar rats by administration of nicotinamide (NICO; 110 mg/kg) and streptozotocin (STZ; 65 mg/kg) intraperitonelly (i.p.). After confirmation of diabetes, rats were divided into following groups i.e. group 1: non-diabetic rats (ND); Group 2: diabetic rats (DC); Group 3: TRIG (50 mg/kg, p.o.); Group 4: SITA (5 mg/kg, p.o.); Group 5: TRIG + SITA (50 + 5 mg/kg, p.o.). Treatment with selected dose of TRIG and SITA was started from 3rd week after NICO–STZ injection and was continued up to 11th week. Cardiomyopathy was assessed by measuring serum glucose level, enzymatic cardiac markers, electrographic abnormalities, heamodynamic changes, lipid levels and histological examination of isolated heart tissue of treated animals.

Results

NICO–STZ diabetic rats showed extensive hyperglycemia, hyperlipidemia, and elevated levels of enzymatic cardiac markers compared to non-diabetic rats. Concomitant and monotherapy treatment of TRIG and SITA exhibited significant decrease in hyperglycemia as compared to diabetic rats. Whereas TRIG + SITA considerably reduced hyperlipidemia, alteration in levels enzymatic cardiac markers and improvement in cardiac function by improved electrographic abnormalities and heamodynamic changes. Overall, the findings revealed in this investigation demonstrated that concomitant administration of TRIG + SITA can be strong pharmacological therapy as compared to monotherapy used for the treatment of hyperglycemia, hyperlipidemia and cardiac dysfunctions in NICO–STZ-induced cardiomyopathy in Wistar rats.

Conclusion

We conclude that concomitant administration of TROG and SITA showed additive cardioprotective effect compared to monotherapy.

There is an unmet clinical need to develop neuroprotective agents for cerebrovascular procedures requiring transient cerebral artery occlusion. This study aims to investigate the effects of a single pre-treatment dose of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a glycogen synthase kinase-3β (GSK-3β) inhibitor, in a transient focal cerebral ischemia model. Twenty-eight male adult Wistar rats were subjected to right middle cerebral artery (MCA) occlusion via intraluminal thread technique for 60 min under continuously cortical perfusion monitoring by laser-Doppler flowmetry. Rats were divided into two groups: control or treatment groups. In the treated group, TDZD-8 (5 mg/kg; intravenously) was administered 10 min before the onset of the MCA ischemia. At 24-h reperfusion, the following parameters were evaluated: neurological deficits, brain infarct volume, ipsilateral hemispheric oedema, neuron specific enolase (NSE) plasma levels, parenchyma histology (H–E staining), Fluoro-Jade positive neurons, p-Akt and total Akt expression by western blot analysis and p-Akt-positive nuclei by immunohistochemistry. Infarct volume (P < 0.001) and neurological deficits severity (P < 0.001) were reduced in TDZD-8 treated group. TDZD-8 attenuated hemispheric oedema (P < 0.001), prevented the NSE plasma level increase (P < 0.001) and diminished the number of degenerated neurons in the infarct area (P < 0.001), as shown by Fluoro-Jade staining. TDZD-8 treated rats showed few signs of perivascular oedema when compared to control group. No variations in total Akt and p-Akt expression were observed; instead immunohistochemistry showed increased p-Akt nucleus translocation in TDZD-8 treated rats (P < 0.05). TDZD-8 is a potential pre-treatment intraoperative drug to prevent neuronal injury induced by transitory artery occlusion during cerebrovascular procedures.

Neuromuscular blocking drugs are used in anesthesia and intensive care to provide skeletal muscle relaxation. However, literature has revealed that the effects of these drugs on cancer have not been widely studied. We tested the effects of two non-depolarising neuromuscular blocking drugs, vecuronium bromide and cisatracurium besylate on lung cancer cells’ (A549) proliferation, migration and viability in the presence of a cytotoxic drug, cisplatin. We demonstrated in this study that both neuromuscular blocking agents inhibit lung cancer cells’ proliferation. In addition, the study revealed that vecuronium bromide and cisatracurium besylate was synergistic to cisplatin in reducing lung cancer cell proliferation. However, vecuronium inhibits lung cancer cells migration in vitro.

The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Retained lipoproteins are chemically and enzymatically modified, inducing a chronic inflammatory response. Therapeutic approaches for atherosclerosis treatment have been focused on the control of risk factors, such as hypercholesterolemia, hypertension, and diabetes mellitus. Nonetheless, the efficacy of these strategies is limited and unfortunately the health problem persists. On the other hand, development of therapies targeting the interactions between low-density lipoproteins and components of the extracellular matrix has been poorly addressed. In this work, we review the response-to-retention hypothesis and the recent data on therapeutic approaches targeting the retentive process of proatherogenic low-density lipoproteins.

Angiogenesis is the growth of neovessels from existing vasculature. In diseases such as cancer excessive angiogenesis occurs when diseased cells produce abnormally large amounts of angiogenic factors. A wide range of plants contains compounds with angiogenesis modulating properties, which are currently known. The present study explores the screening for antiangiogenic potentials of Argeria elliptica Wight., Ipomoea fistulosa and Leea indica Merr which are native to Western ghats of India. The leaf materials of the plants were subjected for cold ethanolic extraction process. The crude extracts were then screened for preliminary angiogenesis assay like rVEGF₁₆₅ induced in vivo CAM assay, rat corneal micropocket assay and tumor induced peritoneal angiogenesis assay. The molecular basis of modulation of neovessels was verified by the expression of VEGF using RT-PCR and ELISA. The preliminary screening for the angiomodulatory effect of crude extracts revealed that L. indica potentially inhibited the sprouting vessels both in non-tumorigenic and tumorigenic conditions. Inhibition of VEGF expression by L. indica has contributed for tumor inhibitory effect. Findings suggest that, the crude ethanolic extract of L. indica potentially inhibits the angiogenesis by down regulating the expression of VEGF and emerged as a potent angiomodulating plant out of three plants.

Alzheimer's disease (AD) is clinically characterized by progressive loss of cognitive abilities and usually is accompany with elevated oxidative stress. Chamomile is a plant with antioxidant activity with is currently used in Iranian folk medicine as sedative, analgesic, antipyretic and antispasmodic agent. The present study was investigated the effect of Matricaria chamomilla (MC) on learning and memory functions in scopolamine-induced memory deficit in rats. Memory enhancing activity in scopolamine-induced amnesic rats was investigated by assessing the Morris water maze and passive avoidance paradigm. Forty-two male Wistar rats were divided into 6 equal groups as bellow: 1 – control (received water), 2 – SCOP (received scopolamine 1 mg/kg for 15 days), 3 and 4 – SCOP + MC (received scopolamine and MC extract 200 and 500 mg/kg b.w. per day for 15 days), 5 and 6 – intact groups (received MC extract 200 and 500 mg/kg b.w. per day for 15 days). M. Chamomilla ethanolic extract produced significant memory enhancing activity when evaluated by Morris water maze and passive avoidance paradigm models. Our results suggest that M. chamomilla ethanolic extract has repairing effects on memory deficit and might be beneficial in patients with Alzheimer's disease and behavioral disorders. The memory enhancing activity of the extract may be attributed to the free radical scavenging activity, which would have been afforded by the active constituents present in the extract.

The validity of pyrazoline heterocyclic core for the design of inhibitors of monoamine oxidase has been previously established. Recently our group synthesized some novel thiophene based pyrazoline-carbothioamides and found good antidepressant activity. The objective of the current study is to identify the reason for such biological activities of the molecules by using molecular docking studies. In the molecular modeling studies, it is revealed that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B that is an effective target for the treatment of depression.

In the context of the discovery of new potential antidepressant candidates and in the light of promising antidepressant action of pyrazoline nucleus, a new series of thiophene bearing pyrazoline carboxamides were synthesized and examined for their antidepressant effect by two behavioural models viz. Forced Swim Test (FST) and Tail Suspension Test (TST). Neurotoxicity of the compounds were accessed by rotarod test. The titled compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass and elemental analyses. The preclinical evaluation the compounds were predicted by in silico toxicity, blood-brain barrier and human oral absorption. In this series, 5-(3-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxamide (TSe) reduced immobility time 60.43 and 63.47% in both FST and TST, respectively at 10 mg/kg dose level when compared to the standard imipramine. Moreover, it was observed that the compounds possessing electron-releasing groups such as dimethyl amino, methoxy and electron-withdrawing chlorine in the 4th position of aromatic rings of the scaffold showed good antidepressant activity when compared to the pyrazolines having no substituents on the phenyl rings. All the compounds in the series have passed neurotoxicity test.

Sun continuously emits UV radiation which produces series of pathological changes in the body, in long term, this ultimately results in photoaging and skin cancer on long term. Repeated UV exposure increases oxidative stress, nitrosative stress and inflammatory mediators which lead to activation of p38, MMPs and results in photoaging. Lycopene is an antioxidant and very low dose of dexamethasone provides anti-inflammatory effect. Animals were applied with lycopene gel, dexamethasone gel and combination of dexamethasone and lycopene gel after exposing to UV radiation. After experimentation period effectiveness, of treatment were evaluated by morphological, biochemical and histopathological parameters. The animals which had received lycopene and standard treatment showed less wrinkles in comparison to UV irradiated and dexamethasone treated group. Lycopene treatment decreased the TBARS level from 51.2 ± 2.417% to 23.593 ± 3.945%, increased by chronic UV radiation. Similarly, collagen, catalase and GSH level was increased from 56.12 ± 2.626% damage to 20.56 ± 2.029%, 64.59 ± 1.743% damage to 19.507 ± 4.997% and 48.780 ± 1.682% reduction to 21.927 ± 7.248%. Histopathological study and epidermal thickness parameter also revealed that lycopene provide protection against UV radiation. In case of dexamethasone treatment, either alone or in combination did not provide significant (P< 0.001) protection, which may be due to its inherent property to generate oxidative stress in mice. It is noteworthy to report that lycopene provide protection against photoaging by virtue of antioxidant property.