Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 May 9:15:1380057.
doi: 10.3389/fphar.2024.1380057. eCollection 2024.

New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model

May Almukainzi  1 , Thanaa A El-Masry  2 , Hanaa A Ibrahim  2 , Hebatallah M Saad  3 , Enas I El Zahaby  4 , Asmaa Saleh  1 , Maysa M F El-Nagar  2
Affiliations

New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model

May Almukainzi et al. Front Pharmacol. .

Abstract

Background: Cardiotoxicity is one of the limiting side effects of the commonly used anticancer agent cyclophosphamide (Cyclo).

Materials and methods: The possible protective effects of telmisartan and nanoformulated Spirulina platensis (Sp) methanolic extract against Cyclo-induced cardiotoxicity were examined in this study. Experimental groups of rats were randomly divided into nine groups as control vehicle, control polymer, telmisartan (TEL, 10 mg/kg), free Sp extract (300 mg/kg), nano Sp extract (100 mg/kg), Cyclo (200 mg/kg), TEL + Cyclo, free Sp + Cyclo, and nano Sp + Cyclo. The groups with Cyclo combinations were treated in the same manner as their corresponding ones without Cyclo, with a single dose of Cyclo on day 18.

Results: The results indicate that Cyclo causes significant cardiotoxicity, manifesting in the form of notable increases of 155.49%, 105.74%, 451.76%, and 826.07% in the serum levels of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and cardiac troponin I (cTnI) enzyme activities, respectively, as compared to the control. In addition, the cardiac glutathione (GSH) content and activity of glutathione peroxidase-1 (GPX-1) enzyme decreased by 65.94% and 73.85%, respectively. Treatment with nano Sp extract showed the most prominent restorations of the altered biochemical, histopathological, and immunohistochemical features as compared with those by TEL and free Sp; moreover, reductions of 30.64% and 43.02% in the p-AKT content as well as 60.43% and 75.30% of the endothelial nitric oxide synthase (eNOS) immunoreactivity were detected in the TEL and free Sp treatment groups, respectively. Interestingly, nano Sp boosted the autophagy signal via activation of beclin-1 (36.42% and 153.4%), activation of LC3II (69.13% and 195%), downregulation of p62 expressions (39.68% and 62.45%), and increased gene expressions of paraoxonase-1 (PON-1) (90.3% and 225.9%) compared to the TEL and free Sp treatment groups, respectively.

Conclusion: The findings suggest the protective efficiency of telmisartan and nano Sp extract against cardiotoxicity via activations of the antioxidant, antiapoptotic, and autophagy signaling pathways.

Keywords: PON-1; Spirulina platensis; autophagy; cardiotoxicity; cyclophosphamide; nanoformulation; telmisartan.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
GC-MS chromatogram of the Sp methanolic extract.
FIGURE 2
FIGURE 2
SEM images of (A) free Sp and (B, C) different magnifications of nano Sp.
FIGURE 3
FIGURE 3
FTIR spectra of (A) free Sp, (B) nano Sp, and (C) chitosan.
FIGURE 4
FIGURE 4
Impacts of different treatments on ROS biomarkers in cardiac tissues: (A) MDA content, (B) GSH content, and (C) GPX-1 enzyme activity. The values were recorded as mean ± SD (n = 6). * means significant vs. control group, a means significant vs. Cyclo group, b means significant vs. TEL + Cyclo group, and c means significant vs. free Sp + Cyclo group. Cyclo: cyclophosphamide, Sp: Spirulina platenesis extract, nano Sp: nanoformulated Sp extract. p ≤ 0.05.
FIGURE 5
FIGURE 5
Impacts of different treatments on p-AKT content in cardiac tissues. The values were recorded as mean ± SD (n = 6). * means significant vs. control group, a means significant vs. Cyclo group, b means significant vs. TEL + Cyclo group, and c means significant vs. free Sp + Cyclo group. Cyclo: cyclophosphamide, Sp: Spirulina platenesis extract, nano Sp: nanoformulated Sp extract. p ≤ 0.05.
FIGURE 6
FIGURE 6
Impacts of different treatments on various gene expressions in cardiac tissues: (A) Bax, (B) Bcl2, (C) LC3II, and (D) p62 gene expressions. The values were recorded as mean ± SD (n = 6). * means significant vs. control group, a means significant vs. Cyclo group, b means significant vs. TEL + Cyclo group, and c means significant vs. free Sp + Cyclo group. Cyclo: cyclophosphamide, Sp: Spirulina platensis extract, nano Sp: nanoformulated Sp extract. p ≤ 0.05.
FIGURE 7
FIGURE 7
Impacts of different treatments on PON-1 gene expression in cardiac tissues. The values were recorded as mean ± SD (n = 6). * means significant vs. control group, a means significant vs. Cyclo group, b means significant vs. TEL + Cyclo group, and c means significant vs. free Sp + Cyclo group. Cyclo: cyclophosphamide, Sp: Spirulina platenesis extract, nano Sp: nanoformulated Sp extract. p ≤ 0.05.
FIGURE 8
FIGURE 8
Impacts of different treatments on Cyclo-induced myocardial histopathological alterations: (A, B) vehicle control (VC), (C, D) polymer control (PC), (E, F) TEL, (G, H) free Sp, and (I, J) nano Sp showing typical myocardial histoarchitectures. (K–N) Cyclo-treated group showing vascular congestion (arrow) and myocardial necrosis with interstitial mononuclear inflammatory infiltrates (arrowhead). (O, P) TEL + Cyclo-treated group shows nearly normal histoarchitecture with mild congestion; (Q, R) free Sp + Cyclo-treated group shows moderate vascular congestion with mild interstitial inflammatory infiltrates; (S, T) nano Sp + Cyclo-treated group shows nearly normal myocardial histoarchitecture. (U) The scoring system is a scale ranging from negative (representing normal findings) to positive (indicating varying degrees of abnormality), including borderline ±, mild +, moderate ++, and severe levels +++. Scale bar = 100 µm and 50 µm. Hematoxylin and eosin (H&E).
FIGURE 9
FIGURE 9
Impacts of different treatments on eNOS immunoreactivity in Cyclo-induced myocardial injury: (A) vehicle control (VC), (B) polymer control (PC), (C) TEL, (D) free Sp, and (E) nano Sp showing weak eNOS immunoreactivity. (F) Cyclo-treated group with nano Sp showing marked eNOS immunoreactivity. (G) TEL + Cyclo-treated group with nano Sp showing mild eNOS immunoreactivity. (H) Free Sp + Cyclo-treated group with nano Sp showing moderate eNOS immunoreactivity. (I) Nano Sp + Cyclo-treated group with nano Sp showing weak eNOS immunoreactivity. (J) Semiquantitative statistical analyses for the percentage area of eNOS immunoreactivity. Scale bar = 50 µm. The values are expressed as mean ± SD. Endothelial nitric oxide synthase (eNOS) immunostain.
FIGURE 10
FIGURE 10
Impacts of different treatments on caspase-3 immunoreactivity in Cyclo-induced myocardial injury: (A) vehicle control (VC), (B) polymer control (PC), (C) TEL, (D) free Sp, and (E) nano Sp showing negative caspase-3 immunoreactivity. (F) Cyclo-treated group showing marked caspase-3 immunoreactivity. (G) TEL + Cyclo-treated group showed weak caspase-3 immunoreactivity. (H) Free Sp + Cyclo-treated group showing moderate caspase-3 immunoreactivity. (I) Nano Sp + Cyclo-treated group showing nearly negative caspase-3 immunoreactivity. (J) Semiquantitative statistical analysis for the percentage area of caspase-3 immunoreactivity. Scale bar = 50 µm. The values are expressed as mean ± SD.
FIGURE 11
FIGURE 11
Impacts of different treatments on p62 immunoreactivity in Cyclo-induced myocardial injury: (A) vehicle control (VC), (B) polymer control (PC), (C) TEL, (D) free Sp, and (E) nano Sp showing negative p62 immunoreactivity. (F) Cyclo-treated group showing marked p62 immunoreactivity. (G) TEL + Cyclo-treated group showing mild p62 immunoreactivity. (H) Free Sp + Cyclo-treated group showing moderate p62 immunoreactivity. (I) Nano Sp + Cyclo-treated group showing little p62 immunoreactivity. (J) Semiquantitative statistical analysis for the percentage area of p62 immunoreactivity. Scale bar = 50 µm. The values are expressed as mean ± SD.
FIGURE 12
FIGURE 12
Impacts of different treatments on beclin-1 immunoreactivity in Cyclo-induced myocardial injury: (A) vehicle control (VC), (B) polymer control (PC), (C) TEL, (D) free Sp, and (E) nano Sp showing intense beclin-1 immunoreactivity. (F) Cyclo-treated group showing weak beclin-1 immunoreactivity. (G) TEL + Cyclo-treated group showing marked beclin-1 immunoreactivity. (H) Free Sp + Cyclo-treated group showing moderate beclin-1 immunoreactivity. (I) Nano Sp + Cyclo-treated group showing intense beclin-1 immunoreactivity. (J) Semiquantitative statistical analysis for the percentage area of beclin-1 immunoreactivity. Scale bar = 50 µm. The values are expressed as mean ± SD.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Adeyemi D. H., Hamed M. A., Oluwole D. T., Omole A. I., Akhigbe R. E. (2024). Acetate attenuates cyclophosphamide-induced cardiac injury via inhibition of NF-kB signaling and suppression of caspase 3-dependent apoptosis in Wistar rats. Biomed. Pharmacother. 170, 116019. 10.1016/j.biopha.2023.116019 - DOI - PubMed
    1. Afkhami-Ardakani M., Hassanzadeh S., Shahrooz R., Asadi-Samani M., Latifi E., Luther T. (2017). Phytotherapy and phytopharmacology for reduction of cyclophosphamide-induced toxicity in the male urinary system. J. Ren. Inj. Prev. 6, 164–170. 10.15171/jrip.2017.32 - DOI
    1. Agoramoorthy G., Chandrasekaran M., Venkatesalu V., Hsu M. J. (2007). Antibacterial and antifungal activities of fatty acid methyl esters of the blind-your-eye mangrove from India. Braz. J. Microbiol. 38, 739–742. 10.1590/S1517-83822007000400028 - DOI
    1. Ahmed R. A., Alam M. F., Alshahrani S., Jali A. M., Qahl A. M., Khalid M., et al. (2023). Capsaicin ameliorates the cyclophosphamide-induced cardiotoxicity by inhibiting free radicals generation, inflammatory cytokines, and apoptotic pathway in rats. Life 13, 786. 10.3390/LIFE13030786 - DOI - PMC - PubMed
    1. Aiba S., Ogawa T. (1977). Assessment of growth yield of a blue-green alga, Spirulina platensis, in axenic and continuous culture. J. Gen. Microbiol. 102, 179–182. 10.1099/00221287-102-1-179 - DOI