Evaluation of Anatomoradiological Findings on Trigeminal Neuralgia Patients Using Computed Tomography and Cone-Beam Computed Tomography.

The study aimed to establish and evaluate anatomoradiological landmarks in trigeminal neuralgia patients using computed tomography (CT) and cone-beam CT. CT images of 40 trigeminal neuralgia (TN) and 40 healthy individuals were retrospectively analyzed and enrolled in the study. The width and length of the foramen rotundum (FR), foramen ovale (FO), foramen supraorbitale, and infraorbitale were measured. The distances between these foramen, between these foramen to the median plane, and between the superior orbital fissure, FO, and FR to clinoid processes were also measured bilaterally. Variations were evaluated according to groups. Significant differences were found for width and length of the foramen ovale, length of the foramen supraorbitale, and infraorbitale between TN and control subjects (p < 0.05). On both sides, FO gets narrower and the length of the infraorbital and supraorbital foramen shortens in the TN group. In most of the control patients, the plane which passes through the infraorbital and supraorbital foramen intersects with impression trigeminale; 70% on the right-side, and 67% in the left-side TN groups. This plane does not intersect with impression trigeminale and deviates in certain degrees. The determination of specific landmarks allows customization to individual patient anatomy and may help the surgeon achieve a more selective effect with a variety of percutaneous procedures in trigeminal neuralgia patients.

Squalene attenuates the oxidative stress and activates AKT/mTOR pathway against cisplatin-induced kidney damage in mice.

The clinical use of cisplatin, which is a first-line anticancer agent, is highly restricted due to its adverse effects on kidneys that lead to nephrotoxicity. Therefore, some potential reno-protective substances have been used in combination with cisplatin to cope with nephrotoxicity. Due to its high antitumor activity and oxygen-carrying capacity, we investigated the molecular effects of squalene against cisplatin-induced oxidative stress and kidney damage in mice. Single dose of cisplatin (7 mg/kg) was given to male Balb/c mice. Squalene (100 mg/kg/day) was administered orogastrically to mice for 10 days. Following sacrification, molecular alterations were investigated as analysis of the levels of oxidative stress index (OSI), inflammatory cytokines and cell survival-related proteins in addition to histopathological examinations in mice kidney tissue. The level OSI and Interferon-gamma (IFN-γ) decreased in the cisplatin and squalene cotreated mice compared to cisplatin-treated mice. Squalene treatment also increased the activation of protein kinase B (AKT). Furthermore, cisplatin-induced inactivation of mammalian target of rapamycin (mTOR) and histopathological damages were reversed by squalene. It may be suggested that squalene ameliorated the cisplatin-induced histopathological damages in the kidney through activation of AKT/mTOR signaling pathway by regulating the balance of the redox system due to its antioxidative effect.

Specific alterations in the circulating levels of the SIRT1, TLR4, and IL7 proteins in patients with dementia.

Sirtuins have gained considerable attention as epigenetic regulators for slowing aging and age-related disorders. The growing association between neurodegeneration and inflammation has led researchers to investigate interactions of sirtuins with inflammatory markers in neurodegenerative diseases. We analyzed SIRT1's association with chronic inflammation in dementia as an age-related neurodegenerative condition through Toll-like receptor 4 (TLR4) and interleukin-7 (IL7) for the first time. In the present study, we observed a significant increase in the level of SIRT1 in patients with all types of dementia. Interestingly, the level of TLR4 protein was significantly lower in only the patients with Alzheimer's disease (AD) compared to the healthy elderly subjects. There was no significant change in the level of IL7 between the diseased and healthy elderly subjects. A significant positive correlation between SIRT1 level and age in healthy elderly subjects was evident according to Pearson's correlation test. However, this correlation was not observed in the dementia patients. Furthermore, the positive correlation between the levels of IL7 and TLR4 in the healthy elderly subjects was absent in the dementia patients. However, there was no direct association between the examined single nucleotide polymorphisms (SNPs) and dementia at the molecular level. According to logistic regression analysis, dementia risk increases 1.16 times due to an increase in the SIRT1 level and 24.23 times due to a decrease in the TLR4 level. Interestingly, a high level in the total antioxidant status (TAS) increases the risk of dementia approximately 33.32 times. Therefore, the current study, for the first time, provides a much better molecular understanding of the interaction between decreasing TLR4 levels and increasing SIRT1 levels in dementia, especially in AD. Furthermore, it highlights the importance of epigenetics in several age-related diseases and suggests that developing novel therapies to prevent or slow down the progression of dementia may support healthy aging.

A pyridoindole antioxidant SMe1EC2 regulates contractility, relaxation ability, cation channel activity, and protein-carbonyl modifications in the aorta of young and old rats with or without diabetes mellitus.

We studied the effects of treatment with SMe1EC, a hexahydropyridoindole antioxidant, on vascular reactivity, endothelial function, and oxidonitrosative stress level of thoracic aorta in young and old rats with or without diabetes mellitus. The rats were grouped as young control (YC 3 months old), old control (OC 15 months old), young diabetic (YD), old diabetic (OD), young control treated (YCT), old control treated (OCT), young diabetic treated (YDT), and old diabetic treated (ODT). Diabetes was induced by streptozotocin injection and subsequently SMe1EC2 (10 mg/kg/day, p.o.) was administered to YCT, OCT, YDT, and ODT rats for 5 months. In young and old rats, diabetes resulted in hypertension, weight loss, hyperglycemia, and hypertriglyceridemia, which were partially prevented by SMe1EC2. SMe1EC2 also inhibited the diabetes-induced increase in aorta levels of AGEs (advanced glycosylation end-protein adducts), 4-HNE (4-hydroxy-nonenal-histidine), 3-NT (3-nitrotyrosine), and RAGEs (receptors for AGEs). The contractions of the aorta rings to phenylephrine (Phe) and KCL did not significantly change, but acetylcholine (ACh) and salbutamol relaxations were reduced in OC compared to YC rats. Diabetes induction increased Phe contractions in YC and OC rats, KCL contractions in YC rats, and did not cause further inhibition in already inhibited ACh and salbutamol relaxations in OC rats. We have achieved the lowest levels of ACh relaxation in YD rats compared to other groups. SMe1EC2 did not change the response of aorta to ACh, salbutamol and Phe in YC rats, and ameliorated ACh relaxations in OC and YD but not in OD rats. In YDT and ODT rats, increased Phe and KCL contractions, high blood pressure, and impaired salbutamol relaxations were amended by SMe1EC2. Phe contractions observed in YD and OD rats as well as KCl contractions observed in OC rats were the lowest levels when the rats were treated with SMe1EC2. When the bath solution was shifted to cyclopiazonic acid (CYP) or CYP plus Ca2+-free medium, the contraction induced by a single dose of Phe (3 × 10-6 M) was more inhibited in YD and OD than in YC but not in OC rats. In SMe1EC2-treated rats, neither the presence of CFM nor CFM plus CYP exhibited a significant change in response of aorta to a single dose of Phe. These findings suggest that α1-adrenergic receptor signaling is activated in both age groups of diabetic rats, diabetes activates K+-depolarization and calcium mobilization via CaV especially in the aorta of young rats, and sensitizes the aorta of old rats to the regulating effect of SMe1EC2. ACh relaxations were inhibited in YC rats, increased in OC rats and unchanged in YD and OD rats when aortic rings pretreated with TEA, an inhibitor of calcium-activated K+ channels (KCa), or 4-aminopyridine (4-AP), an inhibitor of voltage-sensitive K+ channels (KV). ACh relaxations were inhibited in YCT, OCT, and YDT rats in the presence of 4-AP or TEA. In ODT rats, 4-AP did not change ACh relaxation but TEA inhibited. These findings suggest that the contribution of Kv and KCa to ACh relaxation is likely upregulated by SMe1EC2 when the relaxations were inhibited by aging or diabetes. We conclude that SMe1EC2 might be a promising agent for aging and diabetes related vascular disorders.

Antioxidant SMe1EC2 modulates pentose phosphate pathway and glutathione-dependent enzyme activities in tissues of aged diabetic rats.

The pentose phosphate pathway and glutathione-associated metabolism are the main antioxidant cellular defense systems. This study investigated the effects of the powerful antioxidant SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b] indolinium dichloride) on pentose phosphate pathway (PPP) and glutathione-dependent enzyme activities in aged diabetic and aged matched control rats. Diabetes was induced by streptozotocin injection in rats aged 13-15 months. Diabetic and control rats were divided into two subgroups, one untreated and one treated with SMe1EC2 (10 mg/kg/day, orally) for 4 months. SMe1EC2 ameliorated body weight loss, but not hyperglycemia of aged diabetic rats. Diabetes resulted in decreased glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD) and glutathione-S-transferase (GST), yet in unchanged glutathione reductase (GR) in the liver of aged diabetic rats. In the liver of the aged control rats, SMe1EC2 did not affect G6PDH, 6PGDH and GR, but it inhibited GST. SMe1EC2 also failed to affect diabetes-induced decline in 6PGDH, it ameliorated G6PDH but produced further decline in GST in the liver of aged diabetic rats. In the kidney of aged rats, G6PDH and GST were found to be comparable among the groups, but diabetes up-regulated 6PGDH and GR; these alterations were prevented by SMe1EC2. In the heart of aged diabetic rats, while GST remained unchanged, the recorded increase in G6PD, 6PGD, GR was prevented by SMe1EC2. Furthermore, an unchanged GR and remarkable increases in G6PD, 6PGD and GST were found in the lung of the aged diabetic group. These alterations were completely prevented by SMe1EC2. The results suggest that in aged rats SMe1EC2 can ameliorate the response of the kidney, heart and lung but not that of the liver against diabetes-induced glucotoxicity by interfering with the activity of redox network enzymes.

Age- and diabetes-induced regulation of oxidative protein modification in rat brain and peripheral tissues: consequences of treatment with antioxidant pyridoindole.

The increased glyco- and lipo-oxidation events are considered one of the major factors in the accumulation of non-functional damaged proteins, and the antioxidants may inhibit extensive protein modification and nitrosylated protein levels, enhancing the oxidative damage at the cellular levels in aging and diabetes. Because of its central role in the pathogenesis of age-dependent and diabetes-mediated functional decline, we compared the levels of oxidatively modified protein markers, namely AGEs (Advanced Glycation End-protein adducts), 4-HNE (4-hydroxy-nonenal-histidine) and 3-NT (3-nitrotyrosine), in different tissues of young and old rats. Separately, these three oxidative stress parameters were explored in old rats subjected to experimentally induced diabetes and following a long-term treatment with a novel synthetic pyridoindole antioxidant derived from stobadine-SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolinium dichloride). Diabetes induced by streptozotocin injection in rats aged 13-15 months, and SMe1EC2 treatment was applied during 4months to aged diabetic rats. AGEs and 4-HNE levels were significantly elevated in brain, ventricle and kidney, but not in lens and liver of aged rats when compared with young rats. Diabetes propagated ageing-induced increase in AGEs and 4-HNE in brain, ventricle and kidney, and raised significantly lens and liver AGEs and 4-HNE levels in aged rats. In aged diabetic rats, SMe1EC2 protected only the kidney against increase in AGEs, and inhibited significantly 4-HNE levels in brain, kidney, liver and lens that were observed more pronounced in lens. 3-NT was significantly increased in brain of aged rats and in kidney, lens and ventricle of aged diabetic rats, while SMe1EC2 has no protective effect on 3-NT increase. Results demonstrate that (1) the responsiveness of different tissue proteins to glyco-lipo-oxidative and nitrosative stress in the course of normal aging was miscellaneous. (2) Diabetes is a major factor contributing to accelerated aging. (3) SMe1EC2 selectively inhibited the generation of oxidatively modified proteins, only in a limited number of tissues.