Memantine shifts cancer cell metabolism via ampk1/2 mediated energetic switch in a549 lung cancer cells

Memantine is used to prevent glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. As glutamine is one of the major source of anabolism in fast growing cancer cells, we aimed to interfere with the cancer cell metabolism in A549 lung cancer cells by using memantine. The effects of memantine on cell cycle progression and cell death in A549 cells were assessed by MTT assay and PI staining. Cells were treated with 0.25 mM memantine for 48 hours and then cell metabolism (AMPKA1, AMPKA2, HIF1A, B-catenin, PKM), apoptosis (p53, p21, Bax, Bcl-XL, NOXA, PUMA) and autophagy related (LC3B-I, LC3B-II, SQSTM1) mRNA and protein expressions were investigated by RT-qPCR and western blotting. Memantine decreased cell viability significantly in a concentration-dependent manner by inducing G0/G1 cell cycle arrest. Our results suggest that memantine activates AMPK1/2 significantly (p=0.039 and p=0.0105) that led cells through apoptosis and au tophagy by decreasing cancer cell metabolism regulators like HIF1A, B-catenin and PKM as the consequence of this energetic shift. Memantine represents a useful tool to target metabolism in cancer cells. Therefore, it might be used a new repurposed drug in cancer treatment

Alzheimer's drug Memantine inhibits metastasis and p-Erk protein expression on 4T1 breast cancer cells

OBJECTIVES: Drug repurposing studies enable shorter routes to the clinic by skipping the steps like in vitro in vivo screening, chemical optimization and toxicological studies. In our study, we investigated the potent anti-cancer effect of Alzheimer's drug Memantine on 4T1 breast cancer cells. METHODS: Memantine's effect on proliferation of 4T1 cells was evaluated by using the MTT assay. Memantine inhibited 4T1 cell proliferation in a concentration-dependent manner at 24 and 48 hours. We investigated the drug's effect on the protein expressions of Bax, Bcl-2, Casp-3, Casp-9, E-Cad, Vimentin, B-Cat, GSK3B, p-ERK, ERK, p-GS, GS that are involved in apoptosis, metastasis and cell survival. RESULTS: Memantine altered the Bcl-2, Bax, Casp3, Casp-9 apoptotic protein expression levels. We found that memantine inhibited p-Erk expression and that result suggested a plausible mechanism of action for memantine's antineoplastic effect. Memantine also inhibited wound closure at 24 h, significantly (p = 0.0055). CONCLUSIONS: Memantine inhibited 4T1 breast cancer cell proliferation at significantly lower doses than mostly studied re-purposed drug Metformin. Therefore, we believe that memantine might hold a great promise as a new repositioned drug in cancer treatment and it is our further interest to investigate its effects in vivo (Fig. 3, Ref. 22). Text in PDF www.elis.s

The outcomes of an impaired powerhouse in KRAS mutant lung adenocarcinoma cells by Elesclomol

Objectives: Lung cancer stands out as the most common cancer type worldwide. The most common genetic alteration detected in adenocarcinoma patients is KRAS. KRAS mutated patients still cannot get benefit from precision medicine approaches andlackatargetedtherapy.Elesclomolisaninvestigationalagentformelanomaand other malignancies. In this study, we evaluated its effect on cellular apoptosis, survival, and metastasis mechanisms on KRAS mutant A549 and Calu-1 cell lines. Methods: The cytotoxic effects of Elesclomol on A549 and Calu-1 cells were determinedby3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide(MTT) cell viability test. Cells were treated with IC50 concentration and then apoptosisrelated (Casp-3, Casp-9, Bcl-2, and Bcl-xL), survival-related (Akt, p-Akt, Erk, and pErk), and metastasis-related (E-cadherin, Vimentin, MMP-2, and MMP-9) protein expressions were determined by Western blot analysis. Elesclomol’s effect on cell migration was evaluated by wound healing. Total oxidant, malondialdehyde (MDA), and glutathione (GSH) levels after Elesclomol treatment were assessed. Results: Elesclomolnotonlyinducedapoptoticproteinsbutalsoinhibitedmetastatic protein expressions and migration in both cells. Also, p-Erk activity was diminished by Elesclomol treatment as a reflection of decreased proliferation. However, p-Akt was enhanced as a cellular survival mechanism. Although Elesclomol’s effects on oxidative stress parameters were puzzling, it induced total oxidant status (TOS), and MDA in Calu-1 cells. Conclusion: Elesclomol might provide an alternative treatment approach for patients with KRAS mutant lung adenocarcinoma and other solid tumor malignancies that harbor KRAS mutations. This would enable the development of biomarker-driven targeted therapy for KRAS mutant adenocarcinoma patient

Impaired global and segmental myocardial deformation assessed by two-dimensional speckle tracking echocardiography in patients with vitamin B12 deficiency

Background: Contrary effects of vitamin B12 deficiency have been shown on the cardiovascular system. Aim of our study was to analyze left ventricular (LV) myocardial deformation, by using the two dimensional (2D) speckle tracking echocardiography (STE) in patients with vitamin B12 deficiency and normal LV ejection fraction.Methods: Twenty-five patients with vitamin B12 deficiency (B12 levels < 200 pg/mL; meanage: 29.6 ± 8.2 years, 15 female), and 27 healthy controls (B12 levels > 200 pg/mL; meanage: 30.1 ± 6.9 years, 13 female) were included in the study. 2D echocardiography images were transferred to a workstation for further offline analysis. Longitudinal peak systolic (LPSS) and global strain (LGS) was obtained from 4 chamber and apical long axis (APLAX) views.Results: Standard echocardiographic parameters and tissue Doppler imaging (TDI) velocities were compared between the groups. All LPSS values in the patient group except for apical 4C septal wall longitudinal strain were significantly decreased than those in the control group. There was a positive correlation between B12 levels and strain values except apical 4C septal wall strain values.Conclusions: We found that in patients with vitamin B12 deficiency, global and segmental myocardial deformation was impaired and this impairment was correlated with the levels of vitamin B12

Wellesley College 1875-1975: A Century of Women

https://repository.wellesley.edu/wellesleyhistories/1000/thumbnail.jp

Association of serum and follicular fluid leptin and ghrelin levels with in vitro fertilization success

 Objectives: The aim of this study was to evaluate the relationship between in vitro fertilization (IVF) cycle outcomes, serum and follicular fluid (FF) levels of leptin and ghrelin. Material and methods: Forty-four women who underwent intracytoplasmic sperm injection cycles (ICSI) were enrolled in the study. On the third day (D3) of the menstrual cycle, venous blood samples were drawn for serum measurements of leptin and ghrelin. The follicular fluid (FF) and the corresponding oocyte were obtained from a single dominant preovulatory follicle at the time of oocyte pick-up. The FF and D3 serum leptin and ghrelin concentrations were measured by enzyme-linked immunosorbent assay. The relationship between pregnancy rate and serum, follicular fluid levels of leptin and ghrelin were analyzed. Results: Of the 44 cases included, nineteen achieved clinical pregnancy (43.18%). Follicular fluid ghrelin levels were significantly lower in the pregnant group than non-pregnant group (p < 0.05) With respect to FF leptin, there was no statistically significant differences between the pregnant and non-pregnant women (p > 0.05). There was no statistically significant difference in D3 serum ghrelin between pregnant and non-pregnant groups (p > 0.05). However, D3 serum leptin levels were significantly lower in pregnant women than non-pregnant women (p < 0.05). Conclusions: Lower ghrelin levels in the follicular fluid were associated with higher pregnancy rates. Also, D3 serum leptin levels were inversely correlated with clinical pregnancy rates. These findings support the potential role of these molecules on IVF outcomes

Comparação de Soluções Cardioplégicas em Cirurgia de Revascularização Miocárdica sobre Mecanismos de Autofagia e Apoptose

Resumo Fundamento A doença arterial coronariana (DAC) devido à isquemia miocárdica causa perda permanente de tecido cardíaco. Objetivos Nosso objetivo foi demonstrar o possível dano ao miocárdio em nível molecular através dos mecanismos de autofagia e apoptose em pacientes submetidos à cirurgia de revascularização miocárdica. Métodos Um grupo recebeu uma solução de cardioplegia Custodiol e o outro grupo uma solução de cardioplegia sanguínea. Duas amostras miocárdicas foram coletadas de cada paciente durante a operação, imediatamente antes da parada cardíaca e após a liberação do pinçamento aórtico. Foram avaliadas as expressões de marcadores de autofagia e apoptose. O nível de significância estatística adotado foi de 5%. Resultados A expressão do gene BECLIN foi significativa nos tecidos miocárdicos do grupo CS (p=0,0078). Os níveis de expressão dos genes CASPASE 3, 8 e 9 foram significativamente menores no grupo CC. Os níveis pós-operatórios de TnT foram significativamente diferentes entre os grupos (p=0,0072). As expressões dos genes CASPASE 8 e CASPASE 9 foram semelhantes antes e depois do pinçamento aórtico (p=0,8552, p=0,8891). No grupo CC, os níveis de expressão gênica de CASPASE 3, CASPASE 8 e CASPASE 9 não foram significativamente diferentes em amostras de tecido coletadas após pinçamento aórtico (p=0,7354, p=0,0758, p=0,4128, respectivamente). Conclusões Com nossos achados, acreditamos que as soluções CC e CS não apresentam diferença significativa em termos de proteção miocárdica durante as operações de by-pass

The efficacy of cinacalcet in the treatment of hyperparathyroidism in Turkish hemodialysis patient population

WOS: 000393291900012OBJECTIVE: Cinacalcet reduces parathyroid hormone levels by increasing the sensitivity of the parathyroid gland to calcium. in this study, we firstly aimed to evaluate the efficacy of cinacalcet in Turkish hemodialysis patients. MATERIAL and METHODS: 4483 hemodialysis patients were screened and 469 patients who had used cinacalcet were included in the study. the patients were divided into 4 groups according to drug usage durations (Group 1: 3 months, Group 2: 6 months, Group 3: 9 months and Group 4: 12 months). the patients' Parathormone, Ca, P and CaxP levels at the 3rd, 6th, 9th and 12th months were compared to the start of treatment and previous months. RESULTS: the levels of Parathormone, Ca, P and CaxP significantly decreased compared to their initial levels in all groups (from 1412 pg/ml to 1222 pg/mL for Parathormone, p< 0,001) in the 3rd month. However, this reduction was not continued in the subsequent months (Parathormone: 1381 pg/ml for the 12th month). CONCLUSION: Cinacalcet may not provide adequate benefit in control of hyperparathyroidism in Turkish hemodialysis patient population

Assesment of genotoxic effects of Titanium dioxide and Zinc oxide nanoparticles in human lymphocytes in vitro

Bu çalışmada kullanılan titanyum dioksit nanopartikülleri (TiO2 NP) ve çinko oksit nanopartiküllerinin (ZnO NP) taramalı elektron mikroskobunda küresel yapıda ve 10-300 nm arasında değişen partiküller içerdiği gözlenmiştir. Bu nanopartiküllerin, dinamik ışık saçılımı ile negatif elektrik yüklü ve ortalama hidrodinamik çaplarının TiO2 NP'nde 804,30±15,06 nm, ZnO NP'nde ise 495,80±51,15 nm ebatlarında olduğu tespit edilmiştir. Genotoksik etkilerin değerlendirilmesi için TiO2 NP'nin 20, 40, 60, 80 ve 100 µg/ml'lik, ZnO NP'nin 1, 5, 10, 20 ve 30 µg/ml'lik konsantrasyonları kullanılmıştır. TiO2 NP kromozom anormallikleri (KA) frekansını 24 saatlik uygulamada en düşük iki konsantrasyonda (20 ve 40 ?g/ml) önemli düzeyde artırmış, 48 saatlik uygulamada ise önemli bir artış oluşturmamıştır. ZnO NP, KA frekansını 24 saatlik uygulamada en yüksek iki konsantrasyonda (20 ve 30 ?g/ml), 48 saatlik uygulamada ise tüm konsantrasyonlarda önemli düzeyde artmıştır. TiO2 NP kardeş kromatid değişimi (KKD) frekansını her iki uygulama süresinde de negatif kontrole göre önemli düzeyde artırmıştır. Bu artışlar çözücü kontrol ile kıyaslandığında, 24 saatlik uygulamada 20, 60 ve 100 µg/ml'lik, 48 saatlik uygulamada ise 20, 60, 80 ve 100 µg/ml'lik konsantrasyonlarda anlamlıdır. ZnO NP, KKD frekansını her iki uygulama süresinde de doza bağlı olarak artırmıştır. Bu artış 24 saatlik muamelede en yüksek üç dozda, 48 saatlik uygulamada ise en yüksek iki dozda anlamlıdır. TiO2 NP, mikronükleus (MN) frekansında en düşük üç konsantrasyonda anlamlı olmayan bir artış oluşturmuştur. ZnO NP MN frekansını tüm konsantrasyonlarda artırmıştır, fakat bu artış en yüksek iki konsantrasyonda (20 and 30 ?g/ml) anlamlıdır. TiO2 NP 24 saatlik uygulamada mitotik indeksi kontrole göre düşürmüştür, ancak bu düşüş 60 ve 80 µg/ml'lik konsantrasyonlarda anlamlıdır. TiO2 NP 48 saatlik uygulamada mitotik indekste önemli bir değişikliğe sebep olmamıştır. ZnO NP, mitotik indeksi her iki uygulama süresinde de düşürmüştür. Bu düşüş 24 saatlik uygulamada 5, 10 ve 30 µg/ml'lik konsantrasyonlarda, 48 saatlik uygulamada 30 µg/ml'lik konsantrasyonda anlamlıdır. TiO2 NP, replikasyon indeksi üzerinde önemli bir etki göstermez iken, ZnO NP, her iki uygulama süresinde de en yüksek konsantrasyonda (30 µg/ml) anlamlı olmayan bir azalmaya sebep olmuştur. TiO2 NP ve ZnO NP, nükleer bölünme indeksini etkilememiştir. TiO2 NP kuyruk uzunluğunda en yüksek konsantrasyonda (100 µg/ml) kontrole göre anlamlı bir artışa sebep olmuştur, fakat kuyruk yoğunluğu ve kuyruk momenti üzerinde önemli bir etki göstermemiştir. ZnO NP uygulaması ile kuyruk yoğunluğu en yüksek konsantrasyonda önemli düzeyde azalmıştır. Kuyruk yoğunluğu ve kuyruk momenti benzer artış ve azalışlar gösterirken, kuyruk uzunluğu ZnO NP'nin 5 ve 20 µg/ml'lik konsantrasyonlarında önemli ölçüde artmıştır. Bu sonuçlar, TiO2 NP'lerinin nisbeten zayıf bir genotoksik etkiye sahip olduğunu, bunun aksine ZnO NP'nin yüksek konsantrasyonlarda hem güçlü bir genotoksik etkiye ve hem de sitotoksik etkiye sahip olduğunu göstermektedir.Titanium dioxide nanoparticles (TiO2 NPs) and zinc oxide nanoparticles (ZnO NPs), used in this study, were observed to be spherical in shape and contained particles ranging from 10-300 nm by scanning electron microscopy. These nanoparticles were found to be negatively charged and the mean hydrodynamic diameters were found to be 804.30±15.06 nm for TiO2 NPs and 495.80±51.15 nm for ZnO NPs by dynamic light scattering. 20, 40, 60, 80 ve 100 µg/ml concentrations of TiO2 NPs and 1, 5, 10, 20 ve 30 µg/ml concentrations of ZnO NPs were used to assess genotoxic effects. TiO2 NPs significantly increased the frequency of chromosomal aberrations (CAs) at two lowest concentrations (20 ve 40 ?g/ml) at 24 h treatment, however they did not show a significant increase at 48 h treatment. ZnO NPs significantly increased the frequency of CAs at two highest concentrations (20 and 30 ?g/ml) at 24 h and at all concentrations at 48 h treatment. TiO2 NPs significantly increased the frequency of sister chromatid exchanges (SCEs) at both treatment periods compared to negative control. These increases were significant at 20, 60 ve 100 µg/ml concentrations for 24 h treatment and, 20, 60, 80 ve 100 µg/ml concentrations for 48 h treatment compared to solvent control. ZnO NPs, increased the frequency of sister chromatid exchanges (SCEs) at both treatment periods in a dose dependent manner. These increases were significant at the three highest concentrations for 24 h and at the two highest concentrations for 48 h treatment. TiO2 NPs induced a non-significant increase in the the frequency of micronuclei at three lowest concentrations. ZnO NPs increased the frequency of MN at all concentrations, however these increases were significant at the two highest concentrations (20 and 30 ?g/ml). TiO2 NPs caused reduction in mitotic index at 24 h treatment compared to control. However these reductions were significant at 60 and 80 µg/ml concentrations. TiO2 NPs did not induced a significant effect on mitotic index at 48 h treatment. ZnO NPs reduced mitotic index at both treatment periods. These decreases were significant at 5, 10 and 30 µg/ml concentrations at 24 h and 30 µg/ml concentrations at 48 h treatments. While TiO2 NPs did not show any effect on replication index, ZnO NPs caused a non-significant decrease at the highest concentrations at both treatment periods. Neither TiO2 NPs nor ZnO NPs effect nuclear division index. TiO2 NPs caused a significant increase in tail lenght at the highest concentration (100 µg/ml) compared to control, however they did not show a significant effect on tail intensity and tail moment. Tail intensity reduced significantly at the highest concentrations with ZnO NPs treatment. Although tail intensity and tail moment displayed similar decreases and increases, tail lenght increased significantly at 5 and 20 µg/ml concentrations in ZnO NPs treatment. These results show that TiO2 NPs have a relatively weak genotoxic effect, by contrast, ZnO NPs have a strong genotoxic effect as well as cytotoxic effect at high concentrations

Ağız gargaralarının sonicfill ve bir nanohibrid kompozitin renklenme dayanıklılığı üzerindeki etkileri

Purpose: The aim of this study was to evaluate the effects of 4 mouth rinses on the color stability of two different resin composites. Materials and Methods: A2 shade sonic-activated bulk fill material SonicFill (Kerr) and conventional nanohybrid composite Filtek Z550 (3M ESPE) were used. Forty disc-shaped specimens (10 mm x 2 mm) were fabricated for both composites and finished using 400-grit SiC paper and polished. After polishing and immersing in distilled water for 24h all specimens were subjected to color measurements. The baseline color values (L*, a*, b*) of each specimen were measured with a colorimeter. Following baseline measurement each composite group was divided into 5 groups: Oral-B Pro Expert Clinic Line Alcoholfree (Oral-B) group, Listerine Tooth Defense Rinse (Listerine) group, Pharmol Zn Mouth rinse (Çözümilaç) group, Nilera Mouth rinse (Nilera) group and Distilled water (control) group. The specimens were incubated in mouth rinses (20 ml) at 37°C for 12 hours and subjected to color measurement. Two-way ANOVA was used for statistical analysis (p<0.05). Results: SonicFill showed significantly higher discoloration when exposed to Oral-B Pro Expert Clinic Line Alcohol-free, Listerine Tooth Defense Rinse and Pharmol Zn Mouth rinse. The color differences of two resin composites were not statistically significant for distilled water and Nilera Mouth rinse. Conclusion: Within the limits of this study it can be concluded that the SonicFill showed higher discoloration than nanohybrid resin composite Filtek Z550.Amaç: Bu çalışmanın amacı, dört farklı ağız gargarasının iki farklı kompozit rezinin renklenme dayanıklığı üzerine etkisinin değerlendirilmesidir. Gereç ve Yöntem: Çalışmada, A2 renginde sonikle aktive edilen bulk-fill materyal SonicFill (Kerr), ile geleneksel nanohibrit kompozit rezin Filtek Z 550 (3M ESPE) kullanılmıştır. Her iki materyal grubundan, kırk adet disk şekilli örnek (10 mm x 2mm) hazırlanmış ve 400-gritlik zımparalar ile bitirilerek parlatılmışlardır. Parlatma ve distile suda 24 saatlik bekletilme aşamalarının ardından, örneklerin renk ölçümleri gerçekleştirilmiştir. Her örneğin ilk ölçüm renk değerleri (L*,a*,b*) kolorimetre ile ölçülmüştür. İlk değerlendirmelerin ardından her kompozit materyali beş gruba ayrılmıştır: Oral B Pro Expert Clinic Line Alkolsüz (Oral-B), Listerine Tooth Defense ağız gargarası (Listerine), Pharmol Zn ağız gargarası, Nilera ağız gargarası (Nilera), ve Distile su (kontrol). Örnekler ağız gargaralarının içerisinde (20 mL) 37 C 0’ de 12 saat bekletildikten sonra tekrar renk ölçümleri yapılmıştır. İstatistiksel analiz için İki yönlü ANOVA kullanılmıştır (p<0.05). Bulgular: SonicFill Oral B Pro Expert Clinic Line Alkolsüz, Listerine Tooth Defense ağız gargarası ve Pharmol Zn ağız gargarasında bekletildiğinde istatistiksel olarak anlamlı derecede renklenme göstermiştir. Hiçbir rezin kompozitin renk değişikliği distile su ve Nilera ağız gargarasında istatistiksel olarak anlamlı bir farklılık göstermemiştir. Sonuç: Bu çalışmanın sınırları dahilinde SonicFill’in nanohibrit rezin kompozit Filtek Z 550’den daha fazla renklenme gösterdiği belirtilebilir