Ameliorative effect of Metformin / alpha-lipoic acid combination on diabetic nephropathy via modulation of YAP/ miR-29a/PTEN/p-AKT axis.

Diabetic nephropathy (DN) is the most frequent and serious complication of type 2 diabetes (T2DM). Lack of a precise remedy and socio-economic burden of DN patients implements searching about alternative therapies. This study aims to evaluate the possible beneficial effect of alpha-lipoic acid (α-LA) alone or in combination with metformin (Met) in ameliorating STZ/High fat diet (HFD)-induced DN. T2DM was induced via HFD administration for 15 weeks and single ip injection of STZ (35 mg/kg) at week 7. Male Sprague-Dawley rats were randomly grouped as follows: control group, STZ/HFD-induced DN, Met/T; daily treated with 150 mg/kg Met, α-LA/T group; daily treated with 100 mg/kg α-LA, and Met/T + α-LA/T group; daily treated with Met and α-LA at same doses. Administration of Met and α-LA succeeded in attenuating STZ/HFD-induced DN as manifested by significant decrease in kidney weight as well as renal and cardiac hypertrophy index. Moreover, Met and α-LA improved glycemic control, kidney functions and lipid profile as well as restored redox balance. Additionally, Met and α-LA administration significantly upregulated PTEN level accompanied by significant downregulation in renal p-AKT and miR-29a levels. Histopathologically, Met and α-LA administration mitigated STZ/HFD-induced histopathological alterations in kidney and heart. Moreover, immunohistochemical examination revealed a significant decrease in renal YAP, collagen I and Ki-67. Taken together, these observations revealed that Met and α-LA administration could protect against STZ/HFD-induced DN.

Pramipexole protects against diabetic neuropathy: Effect on oxidative stress, TLR4/IRAK-1/TRAF-6/NF-κB and downstream inflammatory mediators.

BACKGROUND: Diabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN. METHODS: Sprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators. RESULTS: PPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1ß and ICAM-1). CONCLUSION: Collectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation.

Betanin protects against bleomycin-induced pulmonary fibrosis by regulating the NLRP3/IL-1ß/TGF-ß1 pathway-mediated epithelial-to-mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease that leads to dyspnea and progressive loss of lung function. This study aimed to investigate the protective effect of betanin (BET), the major pigment in red beetroot, on pulmonary fibrosis induced by bleomycin (BLM) in rats and to assess the underlying mechanisms. In this view, total and differential cell counts and LDH activity in bronchoalveolar lavage fluid were estimated. Furthermore, MDA and GSH contents in the lungs were colorimetrically measured, while hydroxyproline, NLRP3, ASC, caspase-1, TGF-ß1, and vimentin levels in lung tissue were evaluated using the ELISA technique. Moreover, IL-1ß, E-cadherin, and α-SMA expressions were analyzed by immunostaining of lung specimens. BET treatment protects against pulmonary fibrosis as indicated by the reduction in total and differential cell counts, LDH activity, hydroxyproline, NLRP3, ASC, caspase-1, IL-1ß, and TGF-ß1 levels. MDA content was also decreased following BET administration, while GSH content was elevated. Additionally, BET suppressed the EMT process as evidenced by an increase in E-cadherin expression besides the reduction in vimentin and α-SMA expressions. To conclude, these results revealed the protective effect of BET against pulmonary fibrosis that might be attributed to the attenuation of the NLRP3/IL-1ß/TGF-ß1 signaling pathway and EMT process.

Novel doxorubicin / folate-targeted trans-ferulic acid-loaded PLGA nanoparticles combination: In-vivo superiority over standard chemotherapeutic regimen for breast cancer treatment.

AIM: Doxorubicin/Cyclophosphamide (AC) is one of the standard adjuvant anthracycline-containing regimens that is still in use for breast cancer treatment. Cancer cell resistance and AC-induced side effects make treatment suboptimal and worsen patients' quality of life. This study aimed to improve trans-ferulic acid's (TFA) efficiency via loading into folate-receptor-targeted-poly lactic-co-glycolic acid nanoparticles (FA-PLGA-TFA NPs). Also, investigating both the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-TFA NPs combination against dimethylbenz[a]anthracene (DMBA)-induced breast cancer and its safety profile. METHODS: FA-PLGA-TFA NPs were optimally fabricated and characterized. Levels of Notch1, Hes1, Wnt-3a, ß-catenin, MMP-9, cyclin D1, Permeability-Glycoprotein (P-gp), ERα, PR, and HER2 were assessed as a measure of the antitumor efficacy of different treatment protocols. Histopathological examination of heart and bone, levels of ALT, AST, ALP, CK-MB, and WBCs count were evaluated to ensure the combination's safety profile. KEY FINDINGS: Dox/FA-PLGA-TFA NPs not only inhibited Notch signaling but also suppressed Notch synergy with Wnt, estrogen, progesterone, and HER2 pathways. Interestingly, Dox/FA-PLGA-TFA NPs decreased P-gp level and preserved heart, bone, and liver health as well as WBCs count. SIGNIFICANCE: Dox/FA-PLGA-TFA NPs reduced the side-effects of each single drug, and at the same time exerted excellent antitumor activity that surpass the AC regimen in evading cancer cell resistance and having a superior safety profile.

Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model.

AIMS: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Indeed, chemotherapeutic drugs-induced systemic toxicity results in suboptimal cancer treatment. Consequently, there is a need for exploring of a safe and effective therapy for cancer patients. This study aimed to evaluate the hepatoprotective effect of thymoquinone (TQ) against thioacetamide (TAA)-induced HCC. Also, we investigated TQ's ability to sensitize cancer cells toward TRAIL/TRAILR2 apoptotic pathway. MAIN METHODS: Forty male Sprague Dawley rats were divided into 4 groups (n = 10) as follows: control group, CMC group, HCC group and HCC + TQ group. Serum levels of liver function biomarkers and Alpha-Fetoprotein (AFP), as well as hepatic levels of glutathione (GSH) and Alpha-Fetoprotein (MDA) were measured. Transforming growth factor-beta 1 (TGF-ß1), TRAILR2, TRAIL, caspase-3, caspase-9, caspase-8 and B cell lymphoma-2 (Bcl-2) mRNA levels were assessed by Quantitative, Real-Time PCR. Fibrosis percentage and necroinflammation were quantified by histopathological examination. KEY FINDINGS: Our results indicated improvement in liver functions, decrease in AFP level and attenuation of HCC progression in TQ treated rats. TQ upregulated TRAIL/TRAILR2 and subsequently enhanced apoptosis as hinted by caspase-3 upregulation and Bcl-2 downregulation. Also, TQ decreased TGF-ß1 gene expression level. Moreover, HCC + TQ group showed significant increase in hepatic GSH level and marked decrease in hepatic MDA level. SIGNIFICANCE: This study proved that TQ is able to suppress HCC development via decreasing oxidative stress, suppression of TGF-ß1 and induction of TRAIL-mediated apoptosis.

Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-ß1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect.