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Oxyhydrogen nanobubbles attenuate angiogenesis, inflammation, and immunosuppression in Wistar rats hepatocellular carcinoma model

Jurnal Medik Veteriner · Vol. 9 No. 2 (2026) · hlm. 409–423

DOI
10.20473/jmv.vol9.iss2.2026.409-423
ISSN
2581-012X, 2615-7497
Terbit
2026-10-01
Penerbit
Universitas Airlangga
Bahasa
eng
Lisensi
creativecommons.org/licenses/by-nc-sa/4.0

Abstrak

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, while currently available first-line therapies are often constrained by systemic toxicity, resistance, and limited single-target mechanisms. Therefore, safer and broader-spectrum therapeutic strategies are urgently needed. This study evaluated the antitumor efficacy of oxyhydrogen nanobubbles (HHOnbs), an innovative multigas nanosystem that simultaneously delivers O₂, H₂, and low-dose H₂O₂, and hypothesized that HHOnbs would suppress HCC progression through multitarget modulation of the tumor microenvironment. A true experimental study was conducted using diethylnitrosamine/carbon tetrachloride (DEN/CCl₄)-induced HCC in male Wistar rats. Six groups were assigned: negative control, positive control, HHOnbs (200 million particles/mL; 0.1 mL per intravenous injection) administered every 2 days for a total of 12 or 24 treatments, and Lenvatinib (1.2 mg/kg body weight, orally) administered in 3- or 5-dose regimens. Antitumor activity was evaluated by immunohistochemical analysis of CD31, CD68, and FoxP3 expression, representing angiogenesis, macrophage-mediated inflammation, and regulatory T-cell-associated immunosuppression, respectively. In addition, TERT gene amplification was quantified using PCR. Compared with the positive control, HHOnbs significantly reduced CD31 by 42.07–43.55%, CD68 by 42.61–48.02%, and FoxP3 by 44.96–48.71% (all p < 0.001), with greater effects observed at higher treatment frequencies. TERT gene amplification was suppressed by up to 47.89% in the 24-administration group. These effects were comparable to those of Lenvatinib, while HHOnbs showed more consistent frequency-dependent responses across all biomarkers. In conclusion, HHOnbs demonstrated significant multitarget antitumor activity in experimental HCC and represent a promising nanotherapeutic candidate for liver cancer management.

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  • University of Brawijaya
  • State University of Malang
  • Diponegoro University
  • Ministry of Agriculture
  • UIN Sunan Ampel Surabaya
  • Lambung Mangkurat University
  • Dr. Hasan Sadikin General Hospital
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Rekan penulisOrganisasiArtikel bersama
Muhaimin Rifa’iUniversity of Brawijaya2
Putri Fitri AlfiantyaUniversity of Brawijaya2
Alif Fariz JazmiUniversity of Brawijaya2
Sitti Ayu Hemas NurarifahUniversity of Brawijaya2
Mohammad HidayatUniversity of Brawijaya2
Zairin NoorLambung Mangkurat University2
Agus Hadian RahimDr. Hasan Sadikin General Hospital2
. WIDJIATIAfiliasi tidak diketahui2
Arief BoedionoIPB University2
Aucky HintingUniversitas Airlangga2
Trinil SusilowatiUniversity of Brawijaya2
Kusworini HandonoUniversity of Brawijaya2
Siti ZubaidahState University of Malang1
Ahmad FauziUniversitas Muhammadiyah Malang1
Deny SetiawanState University of Medan1
Muhammad Roil BiladUniversiti Brunei Darussalam1
Muhamad Justitia RamadhanState University of Malang1
Sindi KharomahState University of Malang1
Sinta KharomahState University of Malang1
Hikmah BuroidahUniversitas Jember1
Luchman HakimUniversity of Brawijaya1
Abdul Hamid A. TohaUniversitas Papua1
Widodo WidodoState University of Jakarta1
Ambariyanto AmbariyantoDiponegoro University1
Agustina L. N. AmininDiponegoro University1
Sri RahayuUniversity of Brawijaya1
Maftuch MaftuchUniversity of Brawijaya1
Daniar KusumawatiNational Research and Innovation Agency1
Sapti PuspitariniUniversitas Negeri Surabaya1

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Sumber metadata: OAI-PMH (metadata jurnal) https://e-journal.unair.ac.id/JMV/oai, pertama di-harvest 9 Nov 2026, terakhir terlihat 9 Nov 2026.
Metadata asli (oai_dc) 
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	<dc:title xml:lang="en-US">Oxyhydrogen nanobubbles attenuate angiogenesis, inflammation, and immunosuppression in Wistar rats hepatocellular carcinoma model</dc:title>
	<dc:creator>Aulanni'am, Aulanni'am</dc:creator>
	<dc:creator>Zahrah, Natasya Adiba</dc:creator>
	<dc:creator>Widyarti, Sri</dc:creator>
	<dc:creator>Indrajani, Olly</dc:creator>
	<dc:creator>Wuragil, Dyah Kinasih</dc:creator>
	<dc:creator>Riawan, Wibi</dc:creator>
	<dc:creator>Prasetyo, Dodik</dc:creator>
	<dc:creator>Mustika, Syifa</dc:creator>
	<dc:creator>Hernowo, Aditya</dc:creator>
	<dc:creator>Sumitro, Sutiman Bambang</dc:creator>
	<dc:creator>Lubab, Ahmad</dc:creator>
	<dc:subject xml:lang="en-US">hepatocellular carcinoma</dc:subject>
	<dc:subject xml:lang="en-US">oxyhydrogen nanobubbles</dc:subject>
	<dc:subject xml:lang="en-US">TERT</dc:subject>
	<dc:subject xml:lang="en-US">tumor microenvironment</dc:subject>
	<dc:description xml:lang="en-US">Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, while currently available first-line therapies are often constrained by systemic toxicity, resistance, and limited single-target mechanisms. Therefore, safer and broader-spectrum therapeutic strategies are urgently needed. This study evaluated the antitumor efficacy of oxyhydrogen nanobubbles (HHOnbs), an innovative multigas nanosystem that simultaneously delivers O₂, H₂, and low-dose H₂O₂, and hypothesized that HHOnbs would suppress HCC progression through multitarget modulation of the tumor microenvironment. A true experimental study was conducted using diethylnitrosamine/carbon tetrachloride (DEN/CCl₄)-induced HCC in male Wistar rats. Six groups were assigned: negative control, positive control, HHOnbs (200 million particles/mL; 0.1 mL per intravenous injection) administered every 2 days for a total of 12 or 24 treatments, and Lenvatinib (1.2 mg/kg body weight, orally) administered in 3- or 5-dose regimens. Antitumor activity was evaluated by immunohistochemical analysis of CD31, CD68, and FoxP3 expression, representing angiogenesis, macrophage-mediated inflammation, and regulatory T-cell-associated immunosuppression, respectively. In addition, TERT gene amplification was quantified using PCR. Compared with the positive control, HHOnbs significantly reduced CD31 by 42.07–43.55%, CD68 by 42.61–48.02%, and FoxP3 by 44.96–48.71% (all p &amp;lt; 0.001), with greater effects observed at higher treatment frequencies. TERT gene amplification was suppressed by up to 47.89% in the 24-administration group. These effects were comparable to those of Lenvatinib, while HHOnbs showed more consistent frequency-dependent responses across all biomarkers. In conclusion, HHOnbs demonstrated significant multitarget antitumor activity in experimental HCC and represent a promising nanotherapeutic candidate for liver cancer management.</dc:description>
	<dc:publisher xml:lang="en-US">Universitas Airlangga</dc:publisher>
	<dc:date>2026-10-01</dc:date>
	<dc:type>info:eu-repo/semantics/article</dc:type>
	<dc:type>info:eu-repo/semantics/publishedVersion</dc:type>
	<dc:format>application/pdf</dc:format>
	<dc:format>text/xml</dc:format>
	<dc:identifier>https://e-journal.unair.ac.id/JMV/article/view/91736</dc:identifier>
	<dc:identifier>10.20473/jmv.vol9.iss2.2026.409-423</dc:identifier>
	<dc:source xml:lang="en-US">Jurnal Medik Veteriner; Vol. 9 No. 2 (2026): October; 409-423</dc:source>
	<dc:source>2581-012X</dc:source>
	<dc:source>2615-7497</dc:source>
	<dc:language>eng</dc:language>
	<dc:relation>https://e-journal.unair.ac.id/JMV/article/view/91736/40680</dc:relation>
	<dc:relation>https://e-journal.unair.ac.id/JMV/article/view/91736/41192</dc:relation>
	<dc:rights xml:lang="en-US">Copyright (c) 2026 Aulanni'am Aulanni'am, Natasya Adiba Zahrah, Sri Widyarti, Olly Indrajani, Dyah Kinasih Wuragil, Wibi Riawan, Dodik Prasetyo, Syifa Mustika, Aditya Hernowo, Sutiman Bambang Sumitro, Ahmad Lubab</dc:rights>
	<dc:rights xml:lang="en-US">http://creativecommons.org/licenses/by-nc-sa/4.0</dc:rights>
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