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Abdullah Acikgoz,1 Ramazan Asci,2 Oguz Aydin,3 Hikmet Çavuş,4 Gamze Donmez,5 Recep Buyukalpelli2 1Department of Urology, School of Medicine, Kemerburgaz University, Istanbul, Turkey; 2Department of Urology, 3Department of Pathology, School of Medicine, Ondokuz Mayis University, Samsun, Turkey; 4Department of Urology, Medical Park Samsun Hospital, Samsun, Turkey; 5Department of Pathology, School of Medicine, Ondokuz Mayis University, Samsun, Turkey Abstract: The aims of this study conducted on rats were to determine mast cell (MC) proliferation on undescended testes (UDTs); whether there is a correlation between MC proliferation and testicular damage; and whether testicular damage can be prevented with administration of an MC blocker. Sixty-five newborn male rats were divided into three groups. During the neonatal period, unilateral UDTs were experimentally induced in Group 2 and Group 3. The rats in Group 3 were given 1 mg/kg/day ketotifen orally until the end of the study. Groups 2 (n=30) and 3 (n=15) were divided into groups of ten and five rats, respectively, each of which underwent bilateral orchiectomy in either the prepubertal, pubertal, or adult period. Group 1 (n=15) underwent a sham operation followed by bilateral orchiectomy, with five rats in each of the prepubertal, pubertal, and adult periods. Testicular MCs in the interstitial and subtubular areas, biopsy scores, interstitial connective tissue, seminiferous tubule (ST) diameters, and the basement membrane thickness of STs were evaluated. In Group 2 the ST diameters in the UDTs decreased, the number of MCs in the interstitial and subtubular areas increased, ST basement membranes thickened, and spermatogenesis decreased. The number of MCs in the interstitial and subtubular areas of the descended testes increased and spermatogenesis decreased. In Group 3, the number of MCs in the interstitial and subtubular areas decreased. In unilateral UDTs, the number of MCs in the interstitial and subtubular areas increased in both testes. Fibrosis developed in the ST basement membranes and interstitial areas, and spermatogenesis deteriorated. Testicular fibrosis may be prevented with administration of an MC blocker. Keywords: rat, unilateral undescended testis, MC, spermatogenesis, atrophic testis

Purpose: to evaluate ankle function following endoscopically guided percutaneous Achilles tendon repair. The hypoth- esis of this study was that patients with percutaneous repair of the Achilles tendon would still display impaired involved side ankle proprioception. Methods: nineteen male patients with percutaneous Achilles tendon surgery were tested for bilateral ankle active angle reproduction at 10° dorsiflexion and 15° plantar flexion, peak concentric isokinetic ankle dorsi- and plantar flexor torque, one-leg hop for distance, single leg vertical jump height. Dominant sides of age and sex matched 19 healthy controls were evaluated for ankle active angle reproduction at 10° dorsiflexion and 15° plantar flexion, peak concentric isokinetic ankle dorsi- and plantar flexor torque. Results: peak isokinetic torque, one-leg hop for distance, single leg vertical jump for height and ankle joint position sense at 10° dorsiflexion did not differ between the affected and unaffected side. Ankle joint position sense for active angle replication at 15° plantar flexion revealed a significant side-to-side difference. Joint position sense at 10° dorsiflexion and at 15° plantar flexion at affected side was poor in patients compared with the controls while joint position sense at 10° dorsiflexion and at 15° plantar flexion at unaffected side was same in patients compared with the controls. Conclusions: it has revealed a significant difference in joint position sense at plantarflexion of the patients at least one year after percutaneous Achilles tendon surgery compared to their unaffected limb. Large prospective longitudinal stuies are needed to evaluate therapeutic interventions designed to improve proprioception. [ABSTRACT FROM AUTHOR]

Aim: Functional polymorphisms located in FOXP3 intron 1 was recently found to be associated with rheumatoid arthritis (RA). Although RA is an autoimmune disease, there is supporting evidence that activated maladaptive responses including pro-inflammatory pathways play roles in osteoarthritis (OA), similar to RA. The aim of this study was to explore the relationship between rs2232365 (-924A/G) and rs3761548 (-3279A/C) polymorphisms as well as possible changes in the 600 bp promoter region of FOXP3 and knee OA., Methods: Patients with primary knee OA (n = 300) and healthy individuals (n = 300) were examined for rs3761548 and rs2232365 FOXP3 gene polymorphisms by the polymerase chain reaction-restriction fragment-length polymorphism method. The 600 bp promoter region (between -500 and +100) of the gene was also sequenced with direct sequencing in 50 knee OA patients and 50 healthy individuals., Results: There were no sequence variants in the promoter region tested both in OA patients and healthy controls. The SNP rs2232365 showed no association with OA susceptibility and severity and the results of other genetic models were also nonsignificant. On the other hand, rs3761548 AC (P = 0.003), AA + CC (P = 0.0014) as well as AC + AA (P = 0.40) genotypes showed association with Grade 4 knee OA patients., Conclusion: Our findings indicated that the association between FOXP3 rs2232365 polymorphism and knee OA tended to yield negative results but the FOXP3 rs3761548 C allele was associated with elevated risk of OA in Grade 4 knee OA patients in a Turkish population., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Breast cancer is a leading cause of death in women worldwide. Genetic polymorphisms have been reported to be important etiological factors. Murine double minute 2 (MDM2) T309G interacts with p53 and mutations in p53 are present in approximately 50% of all cancers. However, it has been reported that effect of the polymorphism on breast cancer risk may vary in different populations. Here, we therefore investigated whether there is an association between MDM2 T309G (rs2279744) polymorphism and breast cancer in a Turkish population. Materials and Methods: We analysed 110 patients with breast cancer and 138 matched? controls. For genotyping, polymerase chain reaction and restriction length fragment polymorphism methods were used. Results: A significant difference was observed between case and control groups with regard to the distribution of the MDM2 T309G polymorphism (p<0.05). There was a significantly higher frequency of the TT genotype in the control group (p=0.028; OR, 2.42; 95% CI, 1.09-5.37). However, we did not find any relationships among tumor grade and metastasis status and this polymorphism. Conclusion: This study indicates that the MDM2 T309G polymorphism GG genotype and the TG+GG combination may be risk factors for breast cancer in our Turkish population., (Creative Commons Attribution License)

Background: Hypertension (HT) is associated with atrial electrophysiological abnormalities. Echocardiographic pulsed wave tissue Doppler imaging (TDI) is one of the noninvasive methods for evaluation of atrial electromechanical properties. The aims of our study were to investigate the early changes in atrial electromechanical conduction in patients with HT and to assess the parameters that affect atrial electromechanical conduction., Methods: Seventy-six patients with HT (41 males, mean age 52.6 ± 9.0 years) and 41 controls (22 males, mean age 49.8 ± 7.9 years) were included in the study. Atrial electromechanical coupling at the right (PRA), left (PLA), interatrial septum (PIS) were measured with TDI. Intra- (right: PIS-PRA, left: PLA-PIS) and inter-atrial (PLA-PRA) electromechanical delays were calculated. Maximum P-wave duration (Pmax) was calculated from 12-lead electrocardiogram., Results: Atrial electromechanical coupling at PLA (76.6 ± 14.1 ms vs. 82.9 ± 15.8 ms, P = 0.036), left intra-atrial (10.9 ± 5.0 ms vs. 14.0 ± 9.7 ms, P = 0.023), right intra-atrial (10.6 ± 7.8 ms vs. 14.5 ± 10.1 ms, P = 0.035), and interatrial electromechanical (21.4 ± 9.8 ms vs. 28.3 ± 12.7 ms, P = 0.003) delays were significantly longer in patients with HT. The linear regression analysis showed that left ventricular (LV) mass index and Pmax were significantly associated with PLA (P = 0.001 and P = 0.002, respectively), and the LV mass index was the only related factor for interatrial delay (P = 0.001)., Conclusions: Intra- and interatrial electromechanical delay, PLA were significantly prolonged in hypertensive patients. LV mass index and Pmax were significantly associated with PLA, and the LV mass index was the only related factor for interatrial delay. The atrial TDI can be a valuable method to assess the early changes of atrial electromechanical conduction properties in those patients.

Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondria. Mutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases.

Further elucidation of the molecular mechanisms underlying lung cancer (LC) is essential for the development of new effective therapeutic agents. Recently, involvement of Wnt antagonists in oncogenesis has been demonstrated in several cancers. The investigation of their contribution to lung carcinogenesis is still under investigation. We aimed to investigate whether there is a susceptibility or preventive effect of Wnt antagonist gene polymorphisms on the development and/or prognosis of LC. We investigated 110 LC patients and 160 controls. Single-nucleotide polymorphisms of Wnt antagonist genes including DKK2 (rs17037102), DKK3 (rs3206824), DKK3 intron4 G/C (rs7396187), DKK4 (rs2073664), and sFRP4 (rs1802074) were analyzed using nested polymerase chain reaction and restriction fragment length polymorphism. Results showed that patients with DKK3 AA compared with controls have a decreased risk of LC (adjusted for smoking habit, body mass index, and familial history) (P = 0.02; odds ratio [OR],0.08; 95% confidence interval [95% CI], 0.01-0.7). It was found that, for sFRP4 polymorphism, patients with GG and GA genotypes versus AA genotype controls showed a decreased risk for LC (P = 0.01; [OR, 0.19; 95% CI, 0.05-0.73 for GG genotype]; [OR = 0.18, 95% CI, 0.04-0.72 for GA genotype]). In addition, a decreased risk of LC was also found for the genotype combination of DKK3 (rs3206824) GG and sFRP4 AG + GG (P = 0.004; OR, 0.12; 95% CI, 0.02-0.58). We suggest that these 2 polymorphisms have a protective effect on LC in this study.

Traumatic dental and facial injuries are frequent in sports and often cause esthetic, functional, psychological, and economic problems. The term "weekend warrior" is used to describe people who participate in physically demanding activities only on the weekend, or part-time. In this prospective cohort study, we examined the prevalence of dental trauma and knowledge of traumatic dental injuries among weekend warriors in Ankara, Turkey. A detailed questionnaire on mouthguard awareness and knowledge and experience of dental trauma was distributed to 1,007 weekend warrior athletes participating in a soccer tournament. The results showed that 9.8% of participants had experienced orofacial trauma, 21.7% were aware of mouthguards, 2.9% reported using mouthguards, 15.4% were aware of the field of sports dentistry, and 19.6% were aware of emergency treatment for dental trauma. Participation in sports, especially contact sports, greatly increases the risk of dental injury. The present results show that knowledge of traumatic orofacial and dental injuries is limited among weekend warriors. Public health authorities should develop relevant educational programs, including broad dissemination of information on the risks of traumatic dental injuries and methods for protection against such injuries.

Parkinson's disease (PD) is characterized by progressive loss of nigrostriatal dopaminergic neurons that results in motor deficits including resting tremor, rigidity, bradykinesia, and postural instability. Despite decades of intensive study, the underlying molecular mechanisms are not fully understood. Multiple lines of evidence indicate that mitochondrial dysfunction and oxidative stress contribute to neuronal death, which is the key feature of neurodegeneration. Mitochondria are pivotal organelles that host essential functions in neuronal viability including energy production, oxidative phosphorylation, calcium buffering, redox homeostasis and apoptosis. SIRT5, which localizes in the mitochondrial matrix, is nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase. The physiological and pathophysiological functions of SIRT5 in vivo remain elusive although it is known to be an important energy sensor. Here, we investigated the role of SIRT5 in the pathogenesis of PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We present evidence that SIRT5 deficiency, by itself, does not affect motor and non-motor functions; however, lack of SIRT5 exacerbates MPTP-induced motor deficits. Consistently, MPTP-exposed SIRT5 knockout mice exhibited more severe nigrostriatal dopaminergic degeneration than that observed in wild-type controls. Furthermore, deletion of SIRT5 leads to a larger decrease, relative to control, in the expression level of manganese superoxide dismutase (SOD2), a mitochondria-specific antioxidant enzyme, after MPTP induction. These findings indicate that SIRT5 ameliorates MPTP-induced nigrostriatal dopaminergic degeneration via preserving mitochondrial antioxidant capacity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. There is a growing consensus that mitochondrial dysfunction and oxidative stress play a crucial role in PD pathogenesis. Sirtuin3 (SIRT3) is the major mitochondria NAD(+)-dependent deacetylase that acts as a regulator of mitochondrial protein function; it is essential for maintaining mitochondrial integrity. Although SIRT3 was reported to have anti-oxidative stress activity in an in vitro study, there is no explicit in vivo evidence for the involvement of SIRT3 in the etiology of PD. The present study shows that SIRT3 null mice do not exhibit motor and non-motor deficits compared with wild-type controls. However, SIRT3 deficiency dramatically exacerbated the degeneration of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. SIRT3 null mice exposed to MPTP also exhibited decreased superoxide dismutase 2, a specific mitochondrial antioxidant enzyme, and reduced glutathione peroxidase expression compared with wild-type controls. Taken together, these findings strongly support that SIRT3 has a possible role in MPTP-induced neurodegeneration via preserving free radical scavenging capacity in mitochondria.

Glutamate transport is a critical process in the brain that maintains low extracellular levels of glutamate to allow for efficient neurotransmission and prevent excitotoxicity. Loss of glutamate transport function is implicated in epilepsy, traumatic brain injury, and amyotrophic lateral sclerosis. It remains unclear whether or not glutamate transport can be modulated in these disease conditions to improve outcome. Here, we show that sirtuin (SIRT)4, a mitochondrial sirtuin, is up-regulated in response to treatment with the potent excitotoxin kainic acid. Loss of SIRT4 leads to a more severe reaction to kainic acid and decreased glutamate transporter expression and function in the brain. Together, these results indicate a critical and novel stress response role for SIRT4 in promoting proper glutamate transport capacity and protecting against excitotoxicity., (© 2014 International Society for Neurochemistry.)

Sirtuins are NAD-dependent protein deacetylases that were shown to have protective effects against different age-related diseases. SIRT2 is a strong deacetylase that is highly expressed in brain. It has been associated with neurodegenerative diseases. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a dopaminergic neurotoxin that displays clinical features of Parkinson's Disease (PD). MPTP leads to the degeneration of nigrostriatal dopaminergic pathway after its systemic administration. Chronic administration of MPTP induces lesion via apoptosis. We show here that SIRT2 deacetylates Foxo3a, increases RNA and protein levels of Bim, and as a result enhances apoptosis in the MPTP model of PD. We also show that neurodegeneration induced by chronic MPTP regimen is prevented by genetic deletion of SIRT2 in mouse. Deletion of SIRT2 leads to the reduction of apoptosis due to an increase in acetylation of Foxo3a and a decrease in Bim levels. We demonstrate that SIRT2 deacetylates Foxo3a, activates Bim, and induces apoptosis only in MPP(+)-treated cells. Therefore, designing SIRT2 inhibitors might be helpful in developing effective treatments for PD.

Purpose: Aim of this study was to investigate the prognostic significance of absence of septal Q waves in patients scheduled for aortic valve replacement., Material and Methods: Sixty-one patients who underwent isolated aortic valve replacement for aortic stenosis were retrospectively evaluated. Septal Q waves were defined as Q waves of<2mm in amplitude and<40ms in width and absence of septal Q waves was defined as simultaneous loss of Q waves from at least three of the leads I, aVL, V5 and V6. Septal Q waves were absent in 17 patients (Group AQ, 27.8%) and were present in 44 patients (Group PQ, 72.1 %) preoperatively. Newly developed AV block>1st degree and newly developed left bundle branch block were primary endpoints., Results: Preoperatively, absence of normal septal Q waves was significantly associated with increased risk of postoperative AV block (HR: 11.18, range 1.37-91.21, 95% CI, p=0.02) whereas it was not associated with increased risk for newly developed LBBB (HR: 3.15 0.62-15.83, 95% CI, p=0.16)., Conclusion: Absence of normal septal Q waves in the preoperative ECG may predict further delay in conduction which might develop in the early postoperative course of aortic valve replacement., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To evaluate ankle function following endoscopically guided percutaneous Achilles tendon repair. The hypothesis of this study was that patients with percutaneous repair of the Achilles tendon would still display impaired involved side ankle proprioception., Methods: Nineteen male patients with percutaneous Achilles tendon surgery were tested for bilateral ankle active angle reproduction at 10° dorsiflexion and 15° plantar flexion, peak concentric isokinetic ankle dorsiflexor and plantar flexor torque, one-leg hop for distance, and single-leg vertical jump height. Dominant sides of age- and sex-matched 19 healthy controls were evaluated for ankle active angle reproduction at 10° dorsiflexion and 15° plantar flexion, peak concentric isokinetic ankle dorsiflexor and plantar flexor torque., Results: Peak isokinetic torque, one-leg hop for distance, single-leg vertical jump for height and ankle joint position sense at 10° dorsiflexion did not differ between the affected and unaffected side. Ankle joint position sense for active angle replication at 15° plantar flexion revealed a significant side-to-side difference. Joint position sense at 10° dorsiflexion and at 15° plantar flexion at affected side was poor in patients compared with the controls, while joint position sense at 10° dorsiflexion and at 15° plantar flexion at unaffected side was same in patients compared with the controls., Conclusions: It has revealed a significant difference in joint position sense at plantar flexion of the patients at least 1 year after percutaneous Achilles tendon surgery compared to their unaffected limb. Large prospective longitudinal studies are needed to evaluate therapeutic interventions designed to improve proprioception.

Age-related diseases pose as an enormous problem on aging populations of the world. Despite the fact that many advances have been made on understanding of the neurodegeneration, there is still no cure available for the age-related brain disorders. Sirtuins are NAD-dependent protein deacetylases that were shown to have beneficial effects against age-related diseases. SIRT1 and SIRT2 have been studied mostly in terms of neurodegenerative diseases and seem to have opposite effects. According to the recent findings, activators of SIRT1 and inhibitors of SIRT2 would benefit the brain from neurodegeneration. Despite the enormous amount of research that has been conducted so far, there is still no cure or treatment for almost all of the neurodegenerative disorders. In addition, the mechanisms underlying brain aging and also the link between aging and neurodegeneration are not understood. This review focuses on the role of sirtuins as possible drug targets for neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's Diseases.

Sirtuins are highly conserved NAD(+)-dependent enzymes that were shown to have beneficial effects against age-related diseases. Alzheimer's Disease (AD) is the most common neurodegenerative disorder associated with aging and the effects of sirtuins on AD have been investigated using different mouse and cell culture models. In most of these studies, it has been found that the overexpression of SIRT1 has protective effects against the AD phenotype. Therefore, designing therapeutics based on SIRT1 activity might be important to investigate treatment methods for this disease. In this review, we summarize the recent research regarding the functions of sirtuins and their potential roles in designing therapeutics for AD.

Sirtuins are NAD-dependent protein deacetylases known to have protective effects against age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. In mammals, there are seven sirtuins (SIRT1-7), which display diversity in subcellular localization and function. While SIRT1 has been extensively investigated due to its initial connection with lifespan extension and involvement in calorie restriction, important biological and therapeutic roles of other sirtuins have only recently been recognized. Here, we review the potential roles and effects of SIRT1 and SIRT2 in neurodegenerative diseases. We discuss different functions and targets of SIRT1 and SIRT2 in a variety of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's Disease (HD). We also cover the role of SIRT1 in neuronal differentiation due to the possible implications in neurodegenerative conditions, and conclude with an outlook on the potential therapeutic value of SIRT1 and SIRT2 in these disorders., (Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

Sirtuins are NAD-dependent protein deacetylases that were shown to have beneficial effects against age-related diseases. SIRT2 is a strong deacetylase that is highly expressed in brain. It has been associated with neurodegenerative diseases. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a dopaminergic neurotoxin that replicates most of the clinical features of Parkinson disease (PD) and produces a reliable and reproducible lesion of the nigrostriatal dopaminergic pathway and neurodegeneration after its systemic administration. Chronic administration of MPTP induces lesion via apoptosis. We show here that SIRT2 deacetylates Foxo3a, increases RNA and protein levels of Bim, and as a result, enhances apoptosis in the MPTP model of PD. We also show that neurodegeneration induced by chronic MPTP regimen is prevented by genetic deletion of SIRT2 in mouse. Deletion of SIRT2 leads to the reduction of apoptosis due to an increase in acetylation of Foxo3a and a decrease in Bim levels. We demonstrate that SIRT2 deacetylates Foxo3a, activates Bim, and induces apoptosis only in 1-methyl-4-phenylpyridinium-treated cells. Therefore, designing SIRT2 inhibitors might be helpful to develop effective treatments for PD.

Sirtuins are highly conserved NAD(+)-dependent enzymes that have beneficial effects against age-related diseases. Aging is the major unifying risk factor for all neurodegenerative disorders. Sirtuins modulate major biological pathways, such as stress response, protein aggregation, and inflammatory processes, that are involved in age-related neurodegenerative diseases. Therefore, sirtuins have been widely studied in the context of the nervous system and neurodegeneration. They are especially interesting because it is possible to alter the activities of sirtuins using small molecules that could be developed into drugs. Indeed, it has been shown that manipulation of SIRT1 activity genetically or pharmacologically impacts neurodegenerative disease models. This review summarizes recent research in sirtuin neurobiology and neurodegenerative diseases and analyzes the potential of therapeutic applications based on sirtuin research., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

α-Synuclein is a key molecule in the pathogenesis of synucleinopathy including dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. Sirtuins are NAD(+)-dependent protein deacetylases that are highly conserved and counter aging in lower organisms. We show that the life span of a mouse model with A53T α-synuclein mutation is increased by overexpressing SIRT1 and decreased by knocking out SIRT1 in brain. Furthermore, α-synuclein aggregates are reduced in the brains of mice with SIRT1 overexpression and increased by SIRT1 deletion. We show that SIRT1 deacetylates HSF1 (heat shock factor 1) and increases HSP70 RNA and protein levels, but only in the brains of mice with A53T and SIRT1 expression. Thus, SIRT1 responds to α-synuclein aggregation-induced stress by activating molecular chaperones to protect against disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD(+)-dependent deacetylase that has been proposed to deacetylate α-tubulin, histone H4 K16 and to regulate cholesterol biogenesis - a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of α-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD.

Sirtuins are highly conserved NAD(+)-dependent enzymes that were shown to have beneficial effects against age-related diseases. Aging is the major risk factor for all neurodegenerative disorders including Alzheimer's Disease (AD). Sirtuins have been widely studied in the context of AD using different mouse models. In most of these studies, overexpression of SIRT1 has been shown to have protective effects against AD. Therefore, designing therapeutics based on increasing SIRT1 activity might be important for investigating the ways of treatment for this disease. This paper summarizes the recent research on the effect of SIRT1 in AD animal models and also the potential of SIRT1 being a therapeutical target for AD.

Polymorphism of AXIN2, a component of Wnt signaling, has been shown to play a role in tumorigenesis and dysregulated in cancer cells. In order to find out if AXIN2 polymorphism is a risk factor for prostate cancer, we analyzed eight polymorphic regions of this gene in 84 patients with prostate cancer and compared the results with 100 healthy controls in a Turkish population using PCR-RFLP methods. The genotype frequencies and risk factors of prostate cancer and control groups were analyzed by Chi-square test. We found a statistically significant result between prostate cancer risk and AXIN2 Intron2-956+16A/G (rs35285779) SNP. The frequency of the homozygous G/G (0%) and heterozygous A/G (18%) genotypes was significantly less in patients with prostate cancer than in healthy controls (7 and 32%, respectively) (P<0.05) for this SNP. When compared with the wild-type A/A genotype of the controls, prostate cancer patients with the A/G and G/G genotype showed reduced risk of cancer; the adjusted odds ratio (OR) for patients with the homozygous G/G genotype was 0.87 (95% CI: 0.81-0.95) and for heterozygous A/G genotype was 0.42 (95% CI: 0.20-0.85). We found no statistically significant association between controls and prostate cancer for other seven SNPs of AXIN2 including Exon1-148 C/T (rs2240308), Exon1-432 T/C (rs2240308), Exon5-1365 G/A (rs9915936), Exon5-1386 C/T (rs1133683), Intron5-1712+19 T/G, Exon7-2062 C/T, and Intron7-2141+73 G/A (rs4072245) (P>0.05). These results suggest that the AXIN2 Intron2 rs35285779 SNP is associated with development of prostate cancer as a protective SNP, while an association between other seven SNPs of the AXIN2 and risk of prostate cancer was not observed.

Purpose: The objective of this study was to evaluate the effects of synovium on the proliferation of the cartilage tissue and chondrocytes using a rabbit knee model as an in vivo synovial culture medium., Methods: Twelve New Zealand rabbits were used as the animal model in this investigation. Standard size chondral and osteochondral cartilage grafts were taken from, respectively, the left and right knees of all the animals. Two groups of 6 animals were formed: in Group I (synovium group), grafts were placed into the synovial tissue and in group II (patellar tendon group) behind the patellar tendon of the corresponding knees. After 4 months, samples were collected and evaluated macroscopically by measuring their dimensions (vertical = D1, horizontal = D2, and depth = D3) and volumes, and histologically by counting the chondrocyte number using camera lucida method., Results: Macroscopically, the increase in average D1, D2, and D3 measurements and volume in the osteochondral specimens were significantly higher compared to the chondral specimens in both groups (P < 0.05). However, no significant difference was observed between the two groups in terms of macroscopic values. Histologically, the mean chondrocyte counts in osteochondral and chondral specimens for Group I (synovium) were 20.2 and 18.1, and for Group II (patellar tendon) were 18.7 and 15.6, respectively. The mean number of chondrocytes was found to be significantly higher in osteochondral specimens than that of chondral specimens in either group (P < 0.05). Overall average chondrocyte count was significantly higher for Group I compared to Group II (P < 0.05)., Conclusion: Transplantation of the cartilage grafts into the synovial tissue in rabbit knees significantly enhanced the chondrocyte production compared with the group where the grafts were transplanted into intra-articular patellar tendon. The results of this study indicate that native synovial tissue may have the potential to be used as an in vivo culture medium for osteochondral tissue growth.

Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of human type 2 diabetes (T2DM). Although SIRT1 has a therapeutic effect on metabolic deterioration in T2DM, the precise mechanisms by which SIRT1 improves insulin resistance remain unclear. Here, we demonstrate that adenovirus-mediated overexpression of SIRT1 in the liver of diet-induced insulin-resistant low-density lipoprotein receptor-deficient mice and of genetically obese ob/ob mice attenuates hepatic steatosis and ameliorates systemic insulin resistance. These beneficial effects were associated with decreased mammalian target of rapamycin complex 1 (mTORC1) activity, inhibited the unfolded protein response (UPR), and enhanced insulin receptor signaling in the liver, leading to decreased hepatic gluconeogenesis and improved glucose tolerance. The tunicamycin-induced splicing of X-box binding protein-1 and expression of GRP78 and CHOP were reduced by resveratrol in cultured cells in a SIRT1-dependent manner. Conversely, SIRT1-deficient mouse embryonic fibroblasts challenged with tunicamycin exhibited markedly increased mTORC1 activity and impaired ER homeostasi and insulin signaling. These effects were abolished by mTORC1 inhibition by rapamycin in human HepG2 cells. These studies indicate that SIRT1 serves as a negative regulator of UPR signaling in T2DM and that SIRT1 attenuates hepatic steatosis, ameliorates insulin resistance, and restores glucose homeostasis, largely through the inhibition of mTORC1 and ER stress.

A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Abeta 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the beta and gamma-secretases. The production of Abeta peptides is avoided by alternate cleavage of APP by the alpha and gamma-secretases. Here we show that production of beta-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the alpha-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor beta, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases., (Copyright 2010 Elsevier Inc. All rights reserved.)

The sirtuins are highly conserved NAD-dependent deacetylases that were shown to regulate lifespan in lower organisms and affect diseases of aging in mammals, such as diabetes, cancer, and inflammation. Most relevant to the amelioration of disease, the SIR2 ortholog SIRT1 has been shown to deacetylate many important transcription factors to exert an overarching influence on numerous metabolic pathways. Here we discuss several diseases of aging for which SIRT1 has been recently shown to confer protection. These findings suggest that manipulating sirtuin activity pharmacologically may be a fruitful area to improve human health.

Mammalian life span can be extended by both calorie restriction (CR) and mutations that diminish somatotropic signaling. Sirt1 is a mediator of many effects of CR in mammals, but any role in controlling somatotropic signaling has not been shown. Since the somatotropic axis is controlled by the brain, we created mice lacking Sirt1 specifically in the brain and examined the impacts of this manipulation on somatotropic signaling and the CR response. These mutant mice displayed defects in somatotropic signaling when fed ad libitum, and defects in the endocrine and behavioral responses to CR. We conclude that Sirt1 in the brain is a link between somatotropic signaling and CR in mammals.