Cardioprotective and renoprotective effects of venlafaxine on cisplatin-induced cardiotoxicity and nephrotoxicity in rats

Ali, Maha Ismail Mohammed; Imbaby, Samar; Arafat, Horeya Erfan Korayem; Maher, Shymaa Ahmed; Kolieb, Eman; Ali, Shrouk Mohamed

doi:10.1016/j.lfs.2023.121561

Cited by 11 publications

(4 citation statements)

References 44 publications

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“…Taken together, these observations suggest that the combination of cisplatin/methotrexate and benzamil could provide several advantages over cisplatin or methotrexate alone, such as enhanced anticancer activity and reduced risks of renal and cardiac toxicities from high or accumulated cisplatin and methotrexate dosages. [40][41][42] Integrins are signalling molecules that act upstream of FAK and STAT3. 27,43 Moreover, integrins α5, 44 αV, [45][46][47] and β1 48 are known to be involved in the development of osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Repurposing the diuretic benzamil as an anti-osteosarcoma agent that acts by suppressing integrin/FAK/STAT3 signalling and compromising mitochondrial function

Lin,

Chen,

et al. 2024

Bone Joint Res

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AimsOsteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro.MethodsMG63 and U2OS cells were treated with benzamil for 24 hours. Cell viability was evaluated with the MTS/PMS assay, colony formation assay, and flow cytometry (forward/side scatter). Chromosome condensation, the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, cleavage of poly-ADP ribose polymerase (PARP) and caspase-7, and FITC annexin V/PI double staining were monitored as indicators of apoptosis. Intracellular calcium was detected by flow cytometry with Fluo-4 AM. The phosphorylation and activation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) were measured by western blot. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), SOD1, and SOD2 were also assessed by western blot. Mitochondrial status was assessed with tetramethylrhodamine, ethyl ester (TMRE), and intracellular adenosine triphosphate (ATP) was measured with BioTracker ATP-Red Live Cell Dye. Total cellular integrin levels were evaluated by western blot, and the expression of cell surface integrins was assessed using fluorescent-labelled antibodies and flow cytometry.ResultsBenzamil suppressed growth of osteosarcoma cells by inducing apoptosis. Benzamil reduced the expression of cell surface integrins α5, αV, and β1 in MG63 cells, while it only reduced the expression of αV in U2OS cells. Benzamil suppressed the phosphorylation and activation of FAK and STAT3. In addition, mitochondrial function and ATP production were compromised by benzamil. The levels of anti-apoptotic proteins XIAP, Bcl-2, and Bcl-xL were reduced by benzamil. Correspondingly, benzamil potentiated cisplatin- and methotrexate-induced apoptosis in osteosarcoma cells.ConclusionBenzamil exerts anti-osteosarcoma activity by inducing apoptosis. In terms of mechanism, benzamil appears to inhibit integrin/FAK/STAT3 signalling, which triggers mitochondrial dysfunction and ATP depletion.Cite this article: Bone Joint Res 2024;13(4):157–168.

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Section: Discussionmentioning

confidence: 99%

Repurposing the diuretic benzamil as an anti-osteosarcoma agent that acts by suppressing integrin/FAK/STAT3 signalling and compromising mitochondrial function

Lin,

Chen,

et al. 2024

Bone Joint Res

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“…This combination can be attributed to the effect of doxorubicin on the left ventricles of the heart, which is represented by the QRS and PR intervals. Two types of histological testing are used to validate the results of machine learning algorithms: Hematoxylin and eosin (H&E) staining and Masson's trichrome staining [33], [34]. Degenerated cardiomyocytes with missing myofibrils and many sarcoplasmic vacuoles, nuclei displayed aberrant chromatin distribution, and karyolitic alterations were seen in (DOX, 6 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

Machine Learning-Based ECG Signal Classification for Enhanced Early Detection of Doxorubicin-Induced Cardiotoxicity in Rats

Mohammed,

H.Hanafy,

abdo

et al. 2024

Preprint

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Cardiotoxicity, which leads to irreversible myocardial damage, is a major adverse effect associated with chemotherapy. Electrocardiogram (ECG) is an inexpensive, rapid, and simple tool that may provide valuable diagnostic information pertinent to cardiotoxicity. An automatic interpretation and classification of the ECG signals by machine learning algorithms is considered superior to human interpretation of the ECG which may not be able to early detect subtle alterations in the ECG and vary according to the experience of the specialist. The present work aimed at using different machine learning algorithms to classify ECG signals recorded from doxorubicin-injected rats. Rats were divided into four groups and each group was intraperitoneally injected with different cumulative doses of doxorubicin (0, 6, 12, and 18 mg/kg). ECG signal classification depended on multiple features that were extracted from the recorded signals under different conditions. K nearest neighbors’ algorithm achieved higher classification accuracy (99.83 %) than random forest (99.56 %), decision tree (99.54 %), artificial neural network (99.50 %), and support vector machine (99.38 %). Furthermore, the dose-dependent cardiotoxicity was validated via a histopathological examination of the left ventricle that indicated significant pathological alterations in the cardiac tissue. The present findings emphasized the potential of the machine learning-based enhanced detection of cardiotoxicity and validated the dose-dependent toxicity of doxorubicin in the cardiac left ventricle. This approach might be applicable clinically to avoid cardiotoxicity in chemotherapy-treated patients.

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“…The tissue sections were dewaxed using xylene (Beyotime, Shanghai, China) and rehydrated using gradient alcohol. Histological staining was performed using a haematoxylin and eosin (H&E) staining kit and a Masson’s staining kit (Solarbio, Beijing, China), followed by dehydration and transparency [ 25 , 26 ]. Neutral resin was used to seal the slices, which were observed under a light microscope (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2

Jiang,

Xu,

Zeng

et al. 2024

ABBS

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Myocardial damage is a critical complication and a significant contributor to mortality in sepsis. MicroRNAs (miRNAs) have emerged as key players in sepsis pathogenesis. In this study, we explore the effect and mechanisms of miR-29b-1-5p on sepsis-induced myocardial damage. Sepsis-associated Gene Expression Omnibus datasets (GSE72380 and GSE29914) are examined for differential miRNAs. The mouse sepsis-induced cardiac injury was established by Lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). LPS-treated HL-1 mouse cardiomyocytes simulate myocardial injury in vitro . miR-29b-1-5p is co-upregulated in both datasets and in cardiac tissue from sepsis mouse and HL-1 cell models. miR-29b-1-5p expression downregulation was achieved by antagomir transduction and confirmed by real-time quantitative reverse transcription PCR. Survival analysis and echocardiography examination show that miR-29b-1-5p inhibition improves mice survival cardiac function in LPS- and CLP-induced sepsis mice. Hematoxylin and eosin and Masson’s trichrome staining and Immunohistochemistry analysis of mouse myocardial α-smooth muscle actin show that miR-29b-1-5p inhibition reduces myocardial tissue injury and fibrosis. The inflammatory cytokines and cardiac troponin I (cTnI) levels in mouse serum and HL-1 cells are also decreased by miR-29b-1-5p inhibition, as revealed by enzyme-linked immunosorbent assay. The expressions of autophagy-lysosomal pathway-related and apoptosis-related proteins in the mouse cardiac tissues and HL-1 cells are evaluated by western blot analysis. The sepsis-induced activation of the autophagy-lysosomal pathway and apoptosis are also reversed by miR-29b-1-5p antagomir. MTT and flow cytometry measurement further confirm the protective role of miR-29b-1-5p antagomir in HL-1 cells by increasing cell viability and suppressing cell apoptosis. Metascape functionally enriches TargetScan-predicted miR-29b-1-5p target genes. TargetScan prediction and dual luciferase assay validate the targeting relationship between miR-29b-1-5p and telomeric repeat-binding factor 2 (TERF2). The expression and function of TERF2 in HL-1 cells and mice are also evaluated. MiR-29b-1-5p negatively regulates the target gene TERF2 . TERF2 knockdown partly restores miR-29b-1-5p antagomir function in LPS-stimulated HL-1 cells. In summary, miR-29b-1-5p targetedly inhibits TERF2, thereby enhancing sepsis-induced myocardial injury.

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Cardioprotective and renoprotective effects of venlafaxine on cisplatin-induced cardiotoxicity and nephrotoxicity in rats

Cited by 11 publications

References 44 publications

Repurposing the diuretic benzamil as an anti-osteosarcoma agent that acts by suppressing integrin/FAK/STAT3 signalling and compromising mitochondrial function

Repurposing the diuretic benzamil as an anti-osteosarcoma agent that acts by suppressing integrin/FAK/STAT3 signalling and compromising mitochondrial function

Machine Learning-Based ECG Signal Classification for Enhanced Early Detection of Doxorubicin-Induced Cardiotoxicity in Rats

miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2

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