Repetitive transcranial magnetic stimulation (rTMS) has gained interest as a non-invasive treatment for stroke based on the data promoting its effects on functional recovery. However, the exact ...action mechanisms by which the rTMS exert beneficial effects in cellular and molecular aspect are largely unknown. To elucidate the effects of high- and low-frequency rTMS in the acute-ischemic brain, we examined how rTMS influences injury development, cerebral blood flow (CBF), DNA fragmentation, neuronal survival, pro- and anti-apoptotic protein activations after 30 and 90 min of focal cerebral ischemia. In addition, inflammation, angiogenesis, growth factors and axonal outgrowth related gene expressions, were analyzed. Furthermore, we have investigated the effects of rTMS on post-acute ischemic brain, particularly on spontaneous locomotor activity, perilesional tissue remodeling, axonal sprouting of corticobulbar tracts, glial scar formation and cell proliferation, in which rTMS was applied starting 3 days after the stroke onset for 28 days. In the high-frequency rTMS received animals reduced DNA fragmentation, infarct volume and improved CBF were observed, which were associated with increased Bcl-xL activity and reduced Bax, caspase-1, and caspase-3 activations. Moreover, increased angiogenesis, growth factors; and reduced inflammation and axonal sprouting related gene expressions were observed. These results correlated with reduced microglial activation, neuronal degeneration, glial scar formation and improved functional recovery, tissue remodeling, contralesional pyramidal tract plasticity and neurogenesis in the subacute rTMS treated animals. Overall, we propose that high-frequency rTMS in stroke patients can be used to promote functional recovery by inducing the endogenous repair and recovery mechanisms of the brain.
Apart from its well-established therapeutic activity on bipolar disorder and depression, lithium exerts neuroprotective activity upon neurodegenerative disorders, such as traumatic brain injury ...(TBI). However, the cellular signaling mechanisms mediating lithium’s neuroprotective activity and long-term dose- and time-dependent effects on close and remote proximity are largely unknown. Herein, we tested prophylactic and acute effects of lithium (2 mmol/kg) after cold- induced TBI. In both conditions, treatments with lithium resulted in reduced infarct volume and apoptosis. Its acute treatment resulted in the increase of Akt, ERK-1/2 and GSK-3 α/β phosphoylations. Interestingly, its prophylactic treatment instead resulted in decreased phosphorylations of Akt, ERK-1/2, p38, JNK-1 moderately and GSK-3 α/β significantly. Then, we tested subacute (35-day follow-up) role of low (0.2 mmol/kg) and high dose (2 mmol/kg) lithium and revealed that high dose lithium group was the most mobile so the least depressed in the tail suspension test. Anxiety level was assessed by light-dark test, all groups’ anxiety levels were decreased with time, but lithium had no effect on anxiety like behavior. When subacute effects of injury and drug treatment were evaluated on the defined brain regions, infarct volume was decreased in the high dose lithium group significantly. In contrast to other brain regions, hippocampal atrophies were observed in both lithium treatment groups, which were significant in the low dose lithium group in both hemispheres, which was associated with the reduced cell proliferation and neurogenesis. Our data demonstrate that lithium treatment protects neurons from TBI. However, long term particularly low-dose lithium causes hippocampal atrophy and decreased neurogenesis.
Cisplatin (CP) is one of the most preferred platinum-containing antineoplastic drugs. However, even in nontoxic plasma concentrations, it may cause kidney injury. To be able to increase its effective ...pharmacological dose, its side effects need to be regarded. Diet restriction (DR) has been demonstrated to improve cellular survival in a number of disorders. In this context, we investigated the role of DR in CP-induced nephrotoxicity (CPN). Besides alternate DR, animals were exposed to DR for 3 days prior or after CP treatment. Here, we observed that both 3 days of DR reverses the nephrotoxic effect of CP, which was associated with improved physiological outcomes, such as serum creatine, blood-urea nitrogen and urea. These treatments significantly increased phosphorylation of survival kinases PI3K/Akt and ERK-1/2 and decreased the level of stress kinase JNK were noted. In addition, the activation level of signal transduction mediator p38 MAPK phosphorylation was higher particularly in both three-day DR groups. Next, animals were fed with carbohydrate-, protein- or fat-enriched diets in the presence of CP. Results indicated that not only fasting but also dietary content itself may play a determinant role in the severity of CPN. Our data suggest that DR is a promising approach to reduce CPN by regulating metabolism and cell signaling pathways.
The circadian rhythm is driven by a master clock within the suprachiasmatic nucleus which regulates the rhythmic secretion of melatonin. Bmal1 coordinates the rhythmic expression of transcriptome and ...regulates biological activities, involved in cell metabolism and aging. However, the role of Bmal1 in cellular- survival, signaling, its interaction with intracellular proteins, and how melatonin regulates its expression is largely unclear. Here we observed that melatonin increases the expression of Bmal1 and both melatonin and Bmal1 increase cellular survival after oxygen glucose deprivation (OGD) while the inhibition of Bmal1 resulted in the decreased cellular survival without affecting neuroprotective effects of melatonin. By using a planar surface immunoassay for PI3K/AKT signaling pathway components, we revealed that both melatonin and Bmal1 increased phosphorylation of AKT, ERK-1/2, PDK1, mTOR, PTEN, GSK-3αβ, and p70S6K. In contrast, inhibition of Bmal1 resulted in decreased phosphorylation of these proteins, which the effect of melatonin on these signaling molecules was not affected by the absence of Bmal1. Besides, the inhibition of PI3K/AKT decreased Bmal1 expression and the effect of melatonin on Bmal1 after both OGD in vitro and focal cerebral ischemia in vivo. Our data demonstrate that melatonin controls the expression of Bmal1 via PI3K/AKT signaling, and Bmal1 plays critical roles in cellular survival via activation of survival kinases.
The phosphodiesterase (PDE) superfamily comprises enzymes responsible for the cAMP and cGMP degradation to AMP and GMP. PDEs are abundant in the brain, where they are involved in several neuronal ...functions. High PDE10A abundance was previously observed in the striatum; however its consequences for stroke recovery were unknown. Herein, we evaluated the effects of PDE10A deactivation by TAK-063 (0.3 or 3 mg/kg, initiated 72 h post-stroke) in mice exposed to intraluminal middle cerebral artery occlusion. We found that PDE10A deactivation over up to eight weeks dose-dependently increased long-term neuronal survival, angiogenesis, and neurogenesis in the peri-infarct striatum, which represents the core of the middle cerebral artery territory, and reduced astroglial scar formation, whole brain atrophy and, more specifically, striatal atrophy. Functional motor-coordination recovery and the long-distance plasticity of pyramidal tract axons, which originate from the contralesional motor cortex and descend through the contralesional striatum to innervate the ipsilesional facial nucleus, were enhanced by PDE10A deactivation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed a set of dopamine receptor-related and neuronal plasticity-related PDE10A targets, which were elevated (e.g., protein phosphatase-1 regulatory subunit 1B) or reduced (e.g., serine/threonine protein phosphatase 1α, β-synuclein, proteasome subunit α2) by PDE10A deactivation. Our results identify PDE10A as a therapeutic target that critically controls post-ischemic brain tissue remodeling and plasticity.
•Deactivation of PDE10A improves functional motor coordination after ischemic stroke.•TAK-063 increases long-term neuronal survival, angiogenesis, and neurogenesis.•TAK-063 reduces astroglial scar formation and Blood-Brain Barrier leakage after MCAO.•PDE10A critically regulates post-ischemic brain tissue remodeling and plasticity.
Ischemic stroke is the leading cause of death and disability. Although stroke mainly affects aged individuals, animal research is mostly one on young rodents. Here, we examined the development of ...ischemic injury in young (9–12-week-old) and adult (72-week-old) C57BL/6 and BALB/c mice exposed to 30 min of intraluminal middle cerebral artery occlusion (MCAo). Post-ischemic reperfusion did not differ between young and adult mice. Ischemic injury assessed by infarct area and blood-brain barrier (BBB) integrity assessed by IgG extravasation analysis was smaller in adult compared with young mice. Microvascular viability and neuronal survival assessed by CD31 and NeuN immunohistochemistry were higher in adult than young mice. Tissue protection was associated with stronger activation of cell survival pathways in adult than young mice. Microglial/macrophage accumulation and activation assessed by F4/80 immunohistochemistry were more restricted in adult than young mice, and pro- and anti-inflammatory cytokine and chemokine responses were reduced by aging. By means of liquid chromatography-mass spectrometry, we identified a hitherto unknown proteome profile comprising the upregulation of glycogen degradation-related pathways and the downregulation of mitochondrial dysfunction-related pathways, which distinguished post-ischemic responses of the aged compared with the young brain. Our study suggests that aging increases the brain’s resilience against ischemic injury.
Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive ...candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 µg/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.
Carbon dioxide reforming of methane (CDRM) is an effective route to utilize CO2 and CH4, the most abundant, thermodynamically stable and hazardous greenhouse gases. To overcome the economical ...impediments to favor CDRM's industrial applicability, its mechanistic features need to be revealed both for developing efficient catalysts and optimizing operational conditions. In this context, this work aims to obtain power‐law type CDRM kinetic expressions over 5%Co–2%Ce/ZrO2 and 10%Co–2%Ce/ZrO2 catalysts and compare and analyze mechanistic routes to elucidate the effect of the Co:Ce ratio on kinetics. The empirical power‐law type rate expressions were estimated with the reaction orders of 1.63 and 1.12 for CH4 and 0.29 and –0.12 for CO2 for 5%Co–2%Ce/ZrO2 and 10%Co–2%Ce/ZrO2 catalysts, respectively. Limited CH4 activation and, thus, carbon formation due to low Co loading lead to accumulation of surface oxygen on ZrO2 as redox ability of Ce becomes suppressed. This causes higher CO2 activation barrier. The presence of H2 in the feed slows down mechanistic steps involving CHx. The reactions including CH4 activation, most probably reversible direct CH4 dissociation, are found to be rate determining.
Background:
Classic Kaposi sarcoma usually remains on the skin and has a slow progression; thus, local treatment methods are preferable. Imiquimod is an immunomodulatory agent with antiviral, ...antitumoural, and antiangiogenic properties that is expedient against Kaposi sarcoma.
Objectives:
We aimed to clarify whether imiquimod is effective on classic Kaposi sarcoma lesions by comparing imiquimod treatment with cryotherapy, which is the most-used treatment method in our department for this disease.
Method:
Patients with classic Kaposi sarcoma were included. All lesions of each patient were evaluated and measured by the blinded investigator considering infiltration and surface diameters. Then, lesions were categorized into 2 groups by the other investigator (nonblinded), and imiquimod 5% cream was administered 3 times per week without occlusion in 1 group. Cryotherapy was performed every 3 weeks in the other group. All lesions were reevaluated and measured at the end of 12 weeks by the blinded investigator. Initial and last measurements were compared between the treatment methods.
Results:
Fifty lesions of 8 patients were included in this study. Imiquimod and cryotherapy were applied to 26 and 24 lesions, respectively. At the end of the study, statistically significant decreases were detected in all scores between weeks 0 and 12 with both treatment methods. Mean percentages of change in scores were not significantly different between the methods.
Conclusions:
Based on a limited number of patients and lesions treated, we believe imiquimod may be a suitable option to use for the treatment of classic Kaposi sarcoma.
Objective: We aimed to examine the technical success, early-stage clinical results and radiological follow up findings of uterine artery embolization (UAE) treatment for symptomatic uterine fibroids ...in patients. Method: In the present study, we retrospectively evaluated the patients who were admitted to our hospital. Between February 2017 and July 2019 with symptoms due to uterine fibroids namely myomas and underwent endovascular embolization treatment. Patients with complaints of excessive, prolonged, irregular, and frequent episodes of uterine bleeding, anemia, abdominal pain, palpable mass, and pollakiuria associated with uterine myoma which impaired quality life of the patients were included in this study. In addition, Magnetic Resonance Imaging (MRI) findings, and clinical symptoms of all patients before UAE, and 6th months after UAE were recorded. Results: In our study, a total of 40 patients aged between 23-50 years (mean 41.3), one of whom had a history of hysterectomy underwent UAE procedure in our hospital. In our series, clinical symptoms, MRI and digital subtraction angiography (DSA) findings were presented. Uterine fibroid volumes as estimated based on MRI images obtained before--and 6 months after UAE were recorded (234,47 + or - 76,48 vs 17,27 + or - 43,53 (p=0,001). Embolization was cancelled due to intense atherosclerotic causes in one patient, and embolization of unilateral uterine artery could be achieved. The remaining 39 patients underwent successful UAE procedure bilaterally. There were no complications associated with endovascular procedure. After the procedure, all of these 39 patients were discharged on the same day following bed rest and one patient could be discharged one week later due to the development of urosepsis. Conclusion: UAE is a novel treatment modality which is being increasingly used in patients with symptomatic uterine fibroids, and it is an important and effective treatment option since it is much less invasive compared to hysterectomy, does not require hospitalization after the procedure and can be performed under simple sedation or spinal anesthesia. Keywords: uterine fibroids, uterine artery, embolization, magnetic resonance imaging Amac: Calismamizda miyom nedeniyle semptomlari olan hasta grubunda Uterin Arter Embolizasyon (UAE) tedavisinin teknik basari, erken donem klinik sonuclari ve radyolojik takip bulgularini gozden gecirmeyi amacladik. Yontem: Subat 2017-Temmuz 2019 tarihleri arasinda hastanemize uterin fibroide yani miyoma bagli semptomlari nedeniyle basvurup UAE tedavi islemi uygulanan hastalari retrospektif olarak inceledik. Calismaya yasam kalitesini bozacak sekilde miyoma bagli miktar olarak fazla, uzun sureli, sik ve duzensiz araliklarla olan uterin kanamalar, anemi, karin agrisi, ele gelen kitle ve sik idrara cikma sikayetleri olan hastalar dahil edildi. Tum hastalarda UAE oncesi ve UAE sonrasi 6. ayda, manyetik rezonans goruntuleme (MRG) ile klinik semptomlari kaydedildi. Bulgular: Calismamizda uterin fibroide bagli semptomlari olan 23-50 yas arasi (ort. 41,3) daha once bir tanesi histerektomi operasyonu gecirmis olmak uzere toplam kirk hastaya UAE islemi yapildi. Serimizde hastalarin klinik semptomlari, MR ve dijital subtraksiyon anjiyografi (DSA) bulgulari sunulmustur. UAE oncesi ve 6. ayda total, MR Uterin fiboid hacmi; 234,47 + or - 76,48 ve 117,27 + or - 43,53 (p=0,001) olup UAE oncesi ve 6. aydaki degerleri kayit altina alindi. Bir hastada yogun aterosklerotik sebeplerden dolayi islem iptal edilmis olup tek tarafli uterin arter embolize edilebilmistir. Otuz dokuz hastada cift tarafli olarak basarili bir sekilde UAE islemi uygulanmistir. Hastalarda endovaskuler islemle iliskili herhengi bir komplikasyon gelismedi. Toplam 39 hasta islemin ertesi gunu yatak istirahatini takiben ayni gun taburcu edilmis olup 1 hastada urosepsis gelismesi nedeniyle 1 hafta sonra tabucu edilebilmistir. Sonuc: UAE miyomu olan hastalarda giderek artar siklikta kullanilmakta olan oncelikle tercih edilmesi gereken alternatif bir tedavi yontemi olup histerektomiye gore cok daha az invaziv olmasi, islem sonrasi hastanede yatis gerektirmemesi ve basit sedasyon ya da spinal anestezi altinda yapilabilir olmasi ile onemli alternatif bir secenektir. Anahtar kelimeler: miyom, embolizasyon, uterin arter, manyetik rezonans
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