Effect of IRAK1/4 inhibitor on IL-1β, IL-6, INF-γ and TNF-α expression in breast cancer cells of several lines

Recent studies have shown that inflammation mediated via interleukin-1 receptor-associated kinases (IRAKs) is associated with cancer cells drug resistance. We aimed to evaluate the expression of inflammatory cytokines as the potential mechanism involved in the development of cancer cells resistance to conventional chemotherapy drugs. Breast cancer cells of BT549, BT20 and MB468 lines were treated with IRAK 1/4 inhibitor alone or in combination with chemotherapeutic agents methotrexate and topotecan. Expression of IL-1β, IL-6, TNF-α, and IFN-γ genes was quantified by real-time PCR. It was found that IRAK1/4 inhibitor suppressed IL-1β expression in BT549 cells at most and had minimal effect on IL-6 expression in MB468 cells. For the first time we showed that concomitant use of IRAK1/4 inhibitor with topotecan and methotrexate reduced IL-1β, IFN γ, TNF-α and IL-6 expression in BT-20, BT-549, MB-468 cell lines compared to the controls. It is suggested that specific IRAK inhibitors in combination with conventional chemotherapy can be used in cancer treatment to increase drug sensitivity and decrease the risk of tumor recurrence

Trace elements content of some traditional plants used for the treatment of diabetes mellitus

Diabetes is a public health problem that affects life quality. Trace elements have a critical role in the activity and structure of the enzymes involve in carbohydrate metabolism. Many traditional herbs have been used for the treatment and management of Diabetes Mellitus (DM). Anti-diabetic medicinal plants have a significant lowering effect on blood sugar, then assessment of mineral content of these plants has a great value to judge their mechanism of action. Determination of Cobalt (Co), Chromium (Cr), Ferrum (Fe), Manganese (Mn), Molybdenum (Mo), Selenium (Se), Vanadium (V), and Zinc (Zn) values in twenty-eight anti-diabetic plants were conducted and the estimation carried out by atomic absorption spectrophotometry after wet digestion. We found that the levels of Mn, Mo, Co, and Cr were in trace amount, whereas Fe, Se, V and Zn contents were higher. Because of trace elements variations between the studied plants, the hypoglycemic effect of these herbs is not due to a unique element present in the herbs, it rather a synergic effect of several elements might account for the hypoglycemic nature of these plants. Further work is necessary to evaluate this phenomenon. © 2020 by the authors

Effect of the combination of training and errα inhibition on liver metabolism by modulation of pdk4 and lxr-α expression in stz-induced diabetic and healthy rats

Diabetes is a public health problem that affects life quality. Exercise training (ET) and controlled dietary habits improve metabolic diseases such as diabetes. The mechanisms by which exercise training ameliorate metabolic diseases are not fully clear. We designed the current study to evaluate the combination of ERRα suppression and ET effects on the expression of LXR-α, PDK4, and PPARα in healthy and STZ-induced diabetic rats. Fifty-six male Wistar rats were divided into 8 groups (n = 7) as follows; control, diabetic control (a single dose of 45 mg/kg of STZ), ERRα inhibition group (received 0.48 mg/kg of XCT790), endurance training, diabetic rats which received XCT790, diabetic rats which performed endurance training, rats which received XCT790 and performed endurance training, and diabetic rats which received XCT790 and also performed endurance training. Expression of the target gene and protein was carried out on the liver tissue. Our results showed that ET significantly increased PDK4, PPARα, and ERRα expression. ERRα suppression significantly increased LXR-α and PDK4 expression in healthy rats compared to the healthy control group. In the diabetic group with ERRα suppression, LXR-α expression significantly upregulated. The combination of ET and ERRα suppression did not change LXR-α expression compared to healthy and diabetic groups (CTL/ERR), but the expression of PDK4, PPARα, and ERRα was significantly upregulated. © 2020 by the authors

The adaptations induced by Estrogen Related Receptor alpha (ERRα) disruption and exercise training on healthy and diabetic rat�s liver

Diabetes is a widespread metabolic disorder that needs specific management and researchers focused on exercise training and pharmacological interventions for diabetes management. Endurance training (ET) and ERRα gained attention as a potential therapeutic target for diabetes management. We investigated ET and ERRα inhibition effects on the expression of SIRT1 and AMPK in healthy and STZ-induced diabetic rats� liver. Fifty-six Wistar rats were divided into 8 groups as follows (n = 7); group 1, control with no treatment; group 2, diabetic control group that received a single dose of STZ; group 3, ERRα inhibited group that received XCT 790; group 4, endurance training (ET); group 5, diabetic rats with ERRα inhibition; group 6, diabetic rats that performed ET; group 7, ERRα inhibition and ET; and group 8, diabetic rats with ERRα inhibition and performed ET. After 4 weeks, the animals were sacrificed and the liver was used for Real-Time PCR and Western blotting. Our results showed that ET significantly increased AMPK and SIRT1 gene and protein, and ERRα gene expression in healthy and diabetic rats compared to healthy and diabetic control groups. ERRα inhibition increased AMPK, SIRT1, SREBP-1c and ACC expression compared to control and ET groups. In healthy and diabetic rats, the combination of ERRα inhibition and ET significantly increased AMPK, SIRT1, SREBP-1c and ACC expression compared to healthy and diabetic control animals. Briefly, the combination of ET and ERRα disruption probably can be considered as a potential therapeutic intervention in diabetes but this hypothesis needs more evaluation to be cleared. © 2020, Institute of Molecular Biology, Slovak Academy of Sciences

Screening of plants hydro-alcoholic extracts from kerman for their inhibition of β-glucuronidase activity

In neonatal jaundice, β-glucuronidase converts conjugated bilirubin into the unconjugated form and increases its level in the blood. Many natural compounds have been identified as β-glucuronidase inhibitors. The aim of this study was to evaluate the effect of hydro-methanolic extracts of 100 plants on β-glucuronidase. The β-glucuronidase activity was measured by a spectrophotometric method using Phenolphthalein glucuronide and 4-nitrophenyl β-D-glucuronide. Kinetic study of the enzyme was performed in the presence and absence of the plant extract. It was revealed that from hydro-methanolic (70) extracts, Rosa damascena and Ipomoea tricolor showed more than 85 inhibitory effect on β-glucuronidase. Rosa damascena showed competitive inhibition, and Ipomoea tricolor showed non-competitive inhibition. The Km and Vmax values for β-glucuronidase were 23.32 mM and 0.814 mM min-1, respectively. When using 4-nitrophenyl β-D-glucuronide, Stevia and Cerasus avium showed more than 65 inhibitory effect on β-glucuronidase. Both Stevia and Cerasus avium showed non-competitive inhibition. The Km and Vmax values for β-glucuronidase were 16.98 mM and 0.936 mM min-1, respectively. None of the plant extracts showed an activation effect on the enzyme. The data suggest that these plants might be good candidates for the treatment of neonatal jaundice and its related diseases. © 2020, AMG Transcend Association. All rights reserved

L-carnitine administration effects on AMPK, APPL1 and PPARγ genes expression in the liver and serum adiponectin levels and HOMA-IR in type 2 diabetes rat model induced by STZ and nicotinamide

Diabetes is a chronic disease and public health problem globally. L-Carnitine is synthesized in the liver, promotes fatty acids oxidation and currently is used as a supplement against weight gain. Carnitine level is found to be reduced in diabetic patients and to be beneficial as a supplement at diabetes, but the mechanisms of this effect is not fully understood. Therefore, we evaluated the oral L-carnitine supplemen-tation on expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPARγ), adaptor protein APPL1 genes in the liver and insulin and adiponectin levels in the serum of diabetic rats. Rats were randomly divided into three groups (n = 8) as follow: group 1 � control without any treatment, group 2 � diabetic control rats which received STZ (45 mg/kg) and nicotinamide (200 mg/kg) by i.p. injection, group 3 � diabetic rats which received 600 mg/kg/day carnitine orally for 35 days. It was found that L-carnitine supplementation reduced the level of fasting glucose compared to that in control and diabetic groups (p = 0.001, p = 0.0001 respectively) and increased adiponectin level compared to diabetic nontreated rats (p = 0.0001). Homeostasis model assessment of insulin resistance (HOMA-IR) was significantly increased in the diabetic group and reduced in the group that received L-carnitine. These promising beneficial effect of L-carnitine on the type 2 diabetes in rats� model was shown to be conducted through the up-regulation of AMPK, PPARγ and APPL1 genes expression in the liver and elevation of serum adiponectin level. © 2020 Shahouzehi B. et al

The effects of pdk4 inhibition on ampk protein levels and pgc-1α gene expression following endurance training in skeletal muscle of wistar rats

There are regulatory networks in cells which surveil the physiological and environmental states. These cellular regulations are conducted through gene expression modulation. Skeletal muscle is able to adapt shortly and produce ATP at different conditions. AMPK (AMP-activated protein kinase) and PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) are important regulators of cellular energy homeostasis. We designed this study to examine the effects of interactions between endurance training­ and PDK4 (pyruvate dehydrogenase kinase 4) inhibition on AMPK and PGC-1α expression in rat skeletal muscle. Thirty-two male Wistar rats were randomly selected and divided into 4 groups (n = 8); Group 1 control which did not receive any treatment, Group 2 received dichloroacetic acid (DCA) (150 mg/kg/day), Group 3 (endurance training group), Group 4 which received DCA and performed endurance training. AMPK protein expression, PDK4 and PGC-1α gene expression were measured by western blotting and real-time PCR, respectively. Our data showed that PDK4 inhibition caused AMPK protein elevation. Endurance training­ (group 2) and PDK4 inhibition (group 4) induce significant enhancement of PGC-1α gene expression compared to control group. The group which received DCA showed significant elevation of PDK4 gene expression compared to control group (P = 0.001), also other two groups (groups 2 & 3) showed significant elevation of PDK4 gene expression compared to control (P = 0.006). It seems that the combination of endurance training and PDK4 inhibition by up-regulation of PGC-1α expression, effectively improves energy state and performance in skeletal muscle