scholarly journals AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Eslam E. Abd El-Fattah ◽  
Sameh Saber ◽  
Mahmoud E. Youssef ◽  
Hanan Eissa ◽  
Eman El-Ahwany ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Ki 67 ◽  
Tissue Invasion ◽  
Novel Approach ◽  
Promising Target ◽  
Tnf Α ◽  
Key Factor ◽  
Potential Basis ◽  
Α Level

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

scholarly journals Cerium-Containing N-Acetyl-6-Aminohexanoic Acid Formulation Accelerates Wound Reparation in Diabetic Animals

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 834
Author(s):  
Ekaterina Blinova ◽  
Dmitry Pakhomov ◽  
Denis Shimanovsky ◽  
Marina Kilmyashkina ◽  
Yan Mazov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Topical Therapy ◽  
Skin Defect ◽  
Ki 67 ◽  
Fgfr3 Gene ◽  
White Rats ◽  
Tnf Α ◽  
Acid Formulation ◽  
Healing Property

Background: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. Methods: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl6 mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1β and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. Results: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1β, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. Conclusions: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment.

scholarly journals The Role of Thymoquinone in Mitigating Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Rats: Targeting the CHOP-1/JNK/P38 MAPK, NFκB/TNF-α/IL-10, and Bax/Bcl-2/Caspase-3 Signalling Pathways

2021 ◽  
Vol 69 (1) ◽  
pp. 1-9
Author(s):  
Rania Elsayed Hussein ◽  
Laila Ahmed Rashed ◽  
Basma Emad Aboulhoda ◽  
Ghada Mahmoud Abdelaziz ◽  
Ebtehal Gamal Abdelhady ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
P38 Mapk ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Mitogen Activated Protein Kinase ◽  
Lipid Peroxidation Product ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Bax Gene

The present study was conducted to evaluate the effect of thymoquinone (TQ) on hepatocellular carcinoma (HCC) in rats. Our study has reported that TQ treatment of experimentally-induced HCC results in the up-regulation of the Jun-N-terminal kinase and p38 mitogen activated protein kinase pathway (JNK/p38 MAPK) and the enhancement of anti-inflammatory, anti-oxidant, and pro-apoptotic machineries. TQ resulted in a significant decrease in the levels of nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB), tumor necrosis factor-α (TNF-α), and a significant increase in the anti-inflammatory interleukin-10 (IL-10). The pro-apoptotic effect of TQ was demonstrated through stimulating the apoptotic Bcl-2-associated X (Bax) gene and inhibiting the anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene together with increasing the level of caspase 3 and up-regulating the C/EBP homologous protein (CHOP-1) gene expression. TQ treatment also enhanced the activity of the ROS scavenger, superoxide dismutase (SOD), and decreased the level of the lipid peroxidation product malondialdehyde (MDA). TQ-dependent suppression of HCC was associated with the up-regulation of JNK/p38 MAPK, enhanced CHOP-1 expression, and subsequently increased Bax gene expression.

scholarly journals Mebendazole augments sensitivity to sorafenib by targeting MAPK and BCL-2 signalling in n-nitrosodiethylamine-induced murine hepatocellular carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nancy S. Younis ◽  
Amal M. H. Ghanim ◽  
Sameh Saber
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Hepatic Inflammation ◽  
Novel Approach ◽  
Tnf Α ◽  
Mapk Signalling ◽  
Cancer Types ◽  
Tgf Β1

AbstractSorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed that MBZ decreased AFP levels, improved liver function and histology and increased survival in HCC mice, particularly when administered in combination with SO. MBZ also reduced hepatic inflammation and fibrogenesis as evidenced by reductions in TNF-α and TGF-β1 levels, respectively. Increased hepatic caspases-3 and -9 and decreased BCL-2 levels suggest induced-cell death. In addition, MBZ demonstrated anti-angiogenic, anti-metastatic, and anti-proliferative effects, as indicated by reduced VEGF levels, MMP-2:TIMP-1 ratios, and reduced cyclin D1 levels and Ki67 immunostaining, respectively. Our main finding was that MBZ targeted downstream signal of the MAPK pathway by inhibiting ERK1/2 phosphorylation. Targeting downstream MAPK signalling by MBZ and upstream signalling by SO is a novel approach to minimizing resistance and prolonging survival.

Trans Fatty Acids Suppress TNF-α-Induced Inflammatory Gene Expression in Endothelial (HUVEC) and Hepatocellular Carcinoma (HepG2) Cells

Lipids ◽  
2017 ◽  
Vol 52 (4) ◽  
pp. 315-325 ◽  
Author(s):  
Marine S. Da Silva ◽  
Pierre Julien ◽  
Jean-François Bilodeau ◽  
Olivier Barbier ◽  
Iwona Rudkowska
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Fatty Acids ◽  
Hepg2 Cells ◽  
Trans Fatty Acids ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Tnf Α

scholarly journals Antioxidant activity and apoptotic induction as mechanisms of action of Withania somnifera (Ashwagandha) against a hepatocellular carcinoma cell line

2018 ◽  
Vol 46 (4) ◽  
pp. 1358-1369 ◽  
Author(s):  
Wafaa Ahmed ◽  
Dina Mofed ◽  
Abdel-Rahman Zekri ◽  
Nasr El-Sayed ◽  
Mohamed Rahouma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Withania Somnifera ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Carcinoma Cell ◽  
Antioxidant Activities ◽  
Tnf Α ◽  
Hepatocellular Carcinoma Cell Line ◽  
Hepatocellular Carcinoma Cell ◽  
Α Level

Objective To evaluate the antioxidant and apoptotic inductive effects of Withania somnifera (Ashwagandha) leaf extract against a hepatocellular carcinoma cell line. Methods After treating HepG2cells with Ashwagandha water extract (ASH-WX; 6.25 mg/ml–100 mg/ml), cell proliferation was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activities (total antioxidant, glutathione S-transferase and glutathione reductase), Fas-ligand level, tumour necrosis factor-α (TNF-α) level and caspase-3, -8, and -9 activities were measured. Molecular modelling assessed the binding-free energies of Ashwagandha in the cyclin D1 receptor. Results The MTT assay demonstrated increased cytotoxicity following treatment of HepG2 cells with ASH-WX compared with control untreated cells and theIC50was 5% (approximately 5.0 mg/ml). Antioxidant activities, Fas-ligand levels and caspase-3, -8 and -9 activities significantly increased, while TNF-α level significantly decreased following ASH-WX treatment compared with control untreated cells. Molecular docking analysis revealed a good prediction of binding between cyclin D1 and Ashwagandha. There was significant accumulation of ASH-WX-treated HepG2cells in the G0/G1 and G2/M phases compared with the control untreated cells. Conclusion Ashwagandha could be a powerful antioxidant and a promising anticancer agent against HCC.

Potential of ephedrine to suppress the gene expression of TNF-α, IL-1β, IL-6 and PGE2: A novel approach towards management of rheumatoid arthritis

Life Sciences ◽  
2021 ◽  
pp. 119825
Author(s):  
Haseeb Ahsan ◽  
Hafiz Muhammad Irfan ◽  
Alamgeer ◽  
Shah Jahan ◽  
Muhammad Shahzad ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Novel Approach ◽  
Tnf Α

The TNF-α level variation in the aqueous humour of the anterior chamber inindividuals with cataract

2020 ◽  
pp. 86-87
Author(s):  
V.S. Shevchenko ◽  
◽  
A.S. Prilutskii ◽  
K.Y. Tkachenko ◽  
◽  
...  
Keyword(s):  
Anterior Chamber ◽  
Aqueous Humour ◽  
Level Variation ◽  
Tnf Α ◽  
Α Level

Актуальность. Фактор некроза опухоли(TNF-α) является провоспалительным цитокином, продуцирующимся макрофагами и многими другими клетками. Данные о вариации концентрацииTNF-α во влаге передней камеры глаза у лиц, не имеющих выраженных воспалительных и аутоиммунных процессов практически единичны. Цель. Исследование диапазона вариации фактора некроза опухоли альфа во влаге передней камеры глаза у пациентов с возрастной катарактой. Материал и методы. Отобраны и обследованы 33 пациента, в возрасте от 47 до 82 лет, госпитализированных для плановой экстракции катаракты не имеющих выраженных сопутствующих воспалительных заболеваний (аутоиммунных, острых инфекционных болезней, обострением хронических заболеваний, глаукомы, перенесенного увеита и др.). Влага передней камеры забиралась при вскрытии передней камеры глаза во время факоэмульсификации катаракты. Исследование TNF-αпроводилось с помощью иммуноферментны хтест-систем, разработанных при участии сотрудников кафедры клинической иммунологии, аллергологии и эндокринологии ГОО ВПО «ДонНМУ им.М. Горького». Вышеуказанные тест-системы характеризует высокая чувствительность (0,5 пикограмм в миллилитре) и хорошая воспроизводимость. Результаты. При исследовании уровня TNF-αво влаге передней камеры глаза у пациентов с возрастной катарактой, мы выявили колебания данного показателя от 0 до 2,49 пкг/мл. Следует отметить, что полученные нами результаты показывают небольшую вариацию (в пределах низких значений) данного провоспалительного цитокина в исследованной жидкости у пациентов в возрасте от 47 до80 лет, не имеющих выраженной воспалительной(аутоиммунной и др.) патологии. Выводы. Показана низкая вариация TNF-α во влаге передней камеры глаза у пациентов с возрастной катарактой (у обследуемых исключена сопутствующая выраженная воспалительная патология). Результаты можно также использовать как контрольные при проведении сравнительныхисследований этого цитокина в данной среде у лицс различными заболеваниями глаза.

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