Histology and histopathology, Vol.41, Nº3, (2026)

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Open Access
Cardiomyoprotective effect of Tanshinone IIA in diabetic cardiomyopathy achieved through enhancing PINK1-Parkin dependent mitophagy
(2026) Chao Yu; Ping Li; Nannan Li; Ke Wu; Biología Celular e Histología
This study aimed to explore the beneficial effects and underlying protection mechanism of Tanshinone IIA (TSIIA) in diabetic cardiomyopathy (DCM) from the perspectives of mitophagy and mitochondrial integrity. Here, we found that TSIIA significantly increased STZ-induced body weight (L-TSIIA, 299.5 vs. 276.3; H-TSIIA, 308.3 vs. 276.3) and reduced blood glucose concentration (H-TSIIA, 16.1 vs. 21.5). Meanwhile, TSIIA effectively restored the function and morphology of myocardial tissue in diabetes mellitus (DM) rats. Further, TSIIA has been confirmed to have a protective effect on the ultrastructure and function of myocardial mitochondria, which was achieved through activation of mitophagy, as evidenced by enhanced co-localization of LC3 and COX IV (H-TSIIA, 88188.0 vs. 14829.0). Mechanistically, TSIIA alleviated DCM via activation of the PINK1/Parkin axis, increasing PINK1 (H-TSIIA, 0.5 vs. 0.2), Parkin (H-TSIIA, 0.6 vs. 0.3), Beclin-1 (H-TSIIA, 0.6 vs. 0.2) and LC3II/I (H-TSIIA, 0.5 vs. 0.3) expression, as well as decreasing p62 (H-TSIIA, 1.4 vs. 3.6) expression. This study provided a novel insight into the protective effect of TSIIA in DCM and revealed, for the first time, that TSIIA could noticeably improve STZ-induced DCM by enhancing PINK1-Parkin dependent mitophagy.
Open Access
Astrocyte heterogeneity and gliosis in Huntington’s disease: Histopathological insights into striatal and white matter pathology
(2026) Taylor Brown; Rocio Gomez-Pastor; Ross Pelzel; Biología Celular e Histología
Huntington’s disease (HD) is a devastating, autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Among the major pathological hallmarks of HD are mutant huntingtin aggregation, white matter loss and reactive astrogliosis, which together contribute to neuronal dysfunction and death, particularly in the striatum and cortex. Recent studies in HD mouse models have identified a specialized astrocyte subtype that clusters around white matter bundles originating from the secondary cortex and passing through the striatum. While the functional role of these astrocytes remains unclear, they express Glial Fibrillary Acidic Protein (GFAP), a marker typically associated with both fibrous and reactive astrocytes. The discovery of this white matter-associated astrocyte subtype, along with other astrocytic subtypes differing between grey and white matter, underscores the complexity of glial responses in HD. Accurate identification and interpretation of these glial populations are crucial for understanding disease mechanisms and progression. Given the overlapping expression profiles of commonly used astrocyte markers like GFAP, the careful selection and application of both astrocyte and white matter markers in histopathological analyses are essential to advance our understanding of how glial cells contribute to HD pathology. In this review we discuss different histopathological approaches to assess the roles of glia in HD, emphasizing the need for standardized approaches and critical evaluation of marker specificity.
Open Access
Discordance of intrinsic subtype between primary tumor and lymph node metastasis in breast cancer patients
(2026) Tomoko Yamamoto; Yoji Nagashima; Takako Kamio; Kiyomi Horiuchi; Takahiro Okamoto; Yoko Omi; Biología Celular e Histología
The heterogeneity of cancer cells between primary breast tumors and lymph node (LN) metastases at the initial therapy remains unclear. This study aimed to determine whether intrinsic subtypes of LN metastasis differ from those of primary breast tumors and how much additional information is obtained. Ninety-three breast cancer cases with LN metastasis were enrolled in the study. Immunohistochemistry for ER, PgR, HER2, and Ki-67 was performed for primary breast tumors and the largest LN metastases. The intrinsic subtype was determined as luminal A (ER+, PgR+, HER2-, Ki-67 index ≤20%), luminal B (ER+, HER2-, PgR- or PgR+, and Ki-67 index >20%), luminal B HER2 rich (ER+, HER2+), HER2 (ER-, HER2+), and triple-negative (ER-, PgR-, HER2-). The discordance ratios for intrinsic subtypes between the primary tumor and LN metastasis were analyzed. The discordance ratios for ER, PgR, HER2, and Ki 67 were 0/93 (0%), 7/93 (7.5%), 2/93 (2.2%), and 10/93 (10.8%), respectively. The discordance ratio for the intrinsic subtype was 9/93 (9.7%). Considering the intrinsic subtype of LN metastasis, the effects of additional chemotherapy and anti-HER2 therapy could be expected in 4/93 (4.3%) and 1/93 (1.1%) patients, respectively. The discordance ratio for the intrinsic subtype between the primary breast tumor and LN metastasis was 9.7%. Considering the intrinsic subtype of LN metastasis, additional medical therapy could be expected to be effective in 5/93 (5.4%) breast cancer cases with LN metastasis. Immunohistochemistry of metastatic LNs may be useful for planning adjuvant therapy when the analysis of the primary site is inconclusive.
Open Access
USP7 promotes follicular thyroid carcinoma progression and sorafenib resistance by activating NEK2/ATG5-mediated autophagy
(2026) Jutao Zeng; Hong Cao; Jie Luo; Yingcheng Deng; Biología Celular e Histología
Purpose. To investigate the role of ubiquitin-specific protease 7 (USP7) in thyroid cancer (TC) pathogenesis and sorafenib resistance. Methods. USP7 expression was compared in normal human thyroid cells and TC cells. The TC line with maximal differential USP7 expression was selected for further study. The functional interaction between USP7 and never in mitosis A (NIMA)-related kinase 2 (NEK2)/autophagy-related 5 (ATG5) was elucidated through a Pearson correlation coefficient analysis and co-immunoprecipitation assay. The half-inhibitory concentration (IC50) of sorafenib in resistant follicular thyroid (FTC) cells was determined following USP7 knockdown and ATG5 overexpression. Furthermore, the effects of USP7 knockdown and the autophagy inducer rapamycin (RAPA) on FTC cell function were assessed by colony formation and Transwell assays. The function of USP7 was validated in vivo using a xenograft mouse model, and tumor growth was assessed through gross examination and histopathological staining. Results. High USP7 expression promoted the proliferation, migration, and invasion of FTC cells and was positively correlated with NEK2 and ATG5 levels. USP7 enhanced NEK2 stability via deubiquitination. Knocking down USP7 downregulated ATG5, and this effect was reversed by NEK2 overexpression. USP7 inhibition reduced the IC50 of sorafenib in FTC cells, which was reversed by ATG5 overexpression. USP7 knockdown attenuated FTC cell proliferation, migration, and invasion while increasing the apoptosis rate, and these effects were reversed by RAPA treatment. Knocking down USP7 suppressed the growth of TC xenografts in vivo, improved tumor tissue differentiation, and reduced the percentage of Ki-67-positive cells. Conclusion. USP7 promoted the progression of FTC and induced sorafenib resistance by enhancing NEK2/ATG5-mediated autophagy. This study provides novel insights and potential therapeutic strategies for FTC treatment and overcoming drug resistance.
Open Access
Lysimachia christinae Hance aqueous extract ameliorates renal injury in kidney stone rats and calcium oxalate crystal-induced oxidative stress in HK-2 cells via inhibiting the PI3K/Akt/mTOR pathway
(2026) Shengni Lv; Wangen Wang; Liangrong Zhu; Luning Lin; Xintian Zheng; Biología Celular e Histología
Objectives. Kidney stones are a frequent urinary system disorder. Lysimachia christinae Hance is an accepted herb in traditional Chinese medicine for treating kidney stones. However, the effects and mechanisms of Lysimachia christinae Hance aqueous extract (LCH) are yet to be elucidated. Methods. The function of the aqueous extract of LCH was assessed using kidney stone rat models induced by 1% ethylene glycol+2% NH4Cl. Additionally, an in vitro model of human renal tubular epithelial cells (HK-2) treated with calcium oxalate was used. Results. Resultantly, the treatment of aqueous extract of LCH at different concentrations or LCH+LY294002 (PI3K-specific inhibitor) showed significant improve ment in inorganic ions and renal pathological injury in nephrolithiasis rats. Besides, consistent with the in vivo assay, LCH-containing serum increased cell viability and inhibited oxidative stress and deposition of Ca2+ in HK 2 cells, while the influences of LCH-containing serum were attenuated. Mechanistically, the aqueous extract of LCH and LCH-containing serum also promoted Nrf2 and HO-1 levels and inhibited the phosphorylated expression levels of PI3K, AKT, and mTOR. Conclusion. This study shows that LCH ameliorates the kidney damage in kidney stone rats and HK-2 cells. The mechanism of LCH in treating kidney stones is related to the activation of the Nrf2/HO-1 axis and the inhibition of the PI3K/Akt/mTOR pathway.
Open Access
The role of GIP in carbohydrate metabolism: Implications in the development of therapies for T2DM, a narrative review
(2026) Alfredo Díaz-Gómez; Francisco Visiedo; José-Carlos García-Ortiz; Alonso Camacho-Ramírez; Antonio Ribelles-García; José-Arturo Prada-Oliveira; Gonzalo-Martín Pérez-Arana; David Almorza-Gomar; Biología Celular e Histología
Introduction. For the last three decades, bariatric/metabolic surgeries have highlighted the relevance of certain gastrointestinal hormones in controlling and regulating glucose metabolism. The incretins have been a significant focus in developing therapies against Type 2 Diabetes Mellitus (T2DM). Glucagon-like peptide-1 (GLP-1) has been a primary focus in this field, leading to the development of analogues with high therapeutic potential and efficiency, such as semaglutide. However, recently another incretin, glucose-dependent insulinotropic polypeptide (GIP), has become a key target in T2DM drug development due to its complex pleiotropic effects, which include modulating insulin/glucagon secretion, acting on adipose tissue, and regulating appetite. The description of GIP properties as dual can be ambiguous, as this may refer either to its capacity to regulate both insulin and glucagon or to its distinct actions at the central versus peripheral level. Connecting this multifaceted activity was the rationale for developing combined GIP/GLP-1 analogues, like tirzepatide, and has culminated in triple receptor agonists such as retratutide, which also engages the glucagon receptor (LY3437943). These multi agonists potentially enhance the therapeutic potential of GLP-1 analogues. Commentaries. This review covers GIP physiology, its role within the context of T2DM, and the properties of GIP analogues, which represent a new line of drugs against T2DM. This field includes not only GIP analogues, since some are dual or triple agonists that also target GLP-1. We aim to elucidate the future perspectives offered by the use of these drugs.
Open Access
Morphological changes in microglia in the mouse brain during postnatal development and obesity
(2026) Chu Zhang; Ge Gao; Xiaonan Shao; YJing Kang; Xin Yan; Juntang Lin; Liang Qiao; Yang Li1; Biología Celular e Histología
Microglia are innate immune cells in the central nervous system (CNS) and play critical roles in proper brain development and function. During postnatal development, microglia have a highly plastic morphology and change rapidly in response to the temporal brain environment. However, their dynamics and phenotypes during this period are still not fully elucidated. Here, we systematically elucidated microglial density and morphological changes during postnatal development as well as in pathological obese conditions. Our results demonstrated a spatiotemporal distribution of microglia in different brain regions associated with gradually increased microglial complexity during postnatal development. Moreover, microglia become reactive in most brain regions of obese mice, but their morphological diversity has a region-specific manner, with an obvious alteration in the hypothalamus. Overall, our data emphasized the morphological dynamics of microglia following developing time windows and provided the basic information for future investigations.
Open Access
CD63 is a diagnostic marker of prostate cancer and a prognostic marker of biochemical progression following radical prostatectomy
(2026) Marit Bernhardt1; Isabella Federica Bollen; Tobias Kreft; Anna Katrin Scherping; Xiaolin Zhou; Manuel Ritter; Jörg Ellinger; Carsten Stephan; Glen Kristiansen; Elisabeth Dingendorf; Biología Celular e Histología
Aims. We aimed to analyze CD63, a cell surface protein that has been associated with tumor aggressiveness in several cancers, including breast, colorectal, and lung cancer, as well as melanoma, in prostate cancer. Methods. CD63 expression was analyzed immuno histochemically in a cohort of primary prostate cancers from 281 patients. The results were correlated with clinico-pathologic parameters, including biochemical recurrence. In addition, CD63 expression in 251 of the 281 patients with prostate cancer was compared with CD63 expression in matched benign tissue samples (490 tissue samples). The analysis was performed automatically using the open-source software QuPath© and tested for statistical significance. For comparison with the diagnostic markers AMACR and GOLPH2, CD63 was analyzed in an additional cohort of 198 prostate cancers. Results. CD63 expression was found in 100% of prostate cancer cases and benign tissue spots. Increased CD63 expression was significantly associated with higher tumor stage (pT), tumor grade (ISUP), as well as shorter progression-free survival (PFS). Compared with the CD63 intensity of benign tissue, expression in tumor tissue was higher in >80% of cases. In addition, combining the expression of CD63 and AMACR, positivity reached 97.2%, making CD63 a promising diagnostic biomarker in challenging cases. Conclusions. CD63 is commonly overexpressed in prostate cancer, and higher levels are associated with earlier biochemical tumor progression; hence, CD63 is a promising diagnostic and prognostic biomarker in primary prostate cancer.
Open Access
Oncocytic salivary gland carcinomas
(2026) Anne Champagnac; Nazim Benzerdjeb; Ziyad Alsugair; Biología Celular e Histología
Oncocytic carcinomas of the salivary glands represent a rare and diverse group of malignancies characterised by granular eosinophilic cytoplasm due to abundant mitochondria. This review provides a comprehensive overview of oncocytic salivary gland carcinomas, categorised by their morphological patterns: monophasic, biphasic, and complex. Monophasic entities include oncocytic intraductal carcinoma (OIDC), oncocytic salivary duct carcinoma (OSDC), acinic cell carcinoma (ACC), and secretory carcinoma (SC). These tumours vary significantly in histological architecture, immunohistochemical profiles, and genetic alterations, ranging from TRIM33::RET fusions and BRAF V600E mutations in OIDC to NR4A3 rearrangements in ACC and ETV6::NTRK3 fusions in SC. Biphasic tumours, such as oncocytic epithelial-myoepithelial carcinoma (OEMC) and oncocytic adenocarcinoma not otherwise specified (OANOS), further complicate diagnosis due to dual cellular composition and overlapping features with other neoplasms. Complex-pattern tumours, particularly oncocytic mucoepidermoid carcinoma (OMEC), highlight diagnostic challenges and underscore the need for advanced molecular diagnostics. This article emphasises the critical role of integrated histo pathological examination, immunohistochemical staining, and molecular profiling in the accurate classification of these neoplasms. Despite diagnostic advancements, some entities, like OANOS, remain provisional, pending widespread access to transcriptomic tools. Recognising the molecular heterogeneity and clinicopathologic nuances of oncocytic carcinomas is essential for improving diagnostic precision, prognostication, and guiding targeted therapy.
Open Access
Mechanism of the protective effect of 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-D-glucoside on MPTP-induced Parkinson's disease mice
(2026) Xiaolin Dong; Qingyun Li; Yanping Li; Furong Jin; Jingting Lu; Chengda Han; Lianbing Lin; Gang Wu1; Biología Celular e Histología
Background and purpose. Parkinson's disease (PD) is a common neurodegenerative disorder with a complex pathogenesis. 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-D-glucoside (TSG) is one of the main active components of Polygonum multiflorum Thunb., which has therapeutic effects in various neurodegenerative diseases. The aim of this study was to explore the influence of TSG on the PD process. Methods. The PD mouse model was constructed via the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The PD process was evaluated via behavioral tests, HE staining, immunohistochemistry, and immunofluorescence. The levels of related proteins and inflammatory factors were detected via western blotting and ELISA. The effect of TSG on the intestinal flora of MPTP-induced PD mice was evaluated through 16S rDNA sequencing. Results. TSG intervention can significantly alleviate motor dysfunction in PD mice, increase the number of TH-positive neurons in the substantia nigra, inhibit the accumulation of α-syn and glial cell activation, reduce the expression of the tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, iNOS, and COX2 proteins in the substantia nigra and colon, inhibit neuroinflamma-tion and intestinal inflammation, decrease the levels of LPS, LBP, TNF-α, IL-1β, and IL-6 in the serum, suppress systemic inflammation, reduce damage to the blood-brain barrier (BBB) and intestinal barrier in PD mice, and restore species diversity and abundance of the intestinal flora in PD mice to a certain extent. Conclusion. TSG can improve motor coordination ability, systemic and neuroinflammatory levels, BBB injury, intestinal barrier injury, and the intestinal flora composition of PD mice, suggesting that TSG has a protective effect on MPTP-induced PD mice.
Open Access
Gastric neoplasm with foveolar-cell differentiation in Helicobacter pylori-naïve patients
(2026) Kotaro Shibagaki; Ryoji Kushima; Tsuyoshi Mishiro; Kenichi Kishimoto; Yusuke Takahashi; Norihisa Ishimura; Asuka Araki; Mamiko Nagase; Daisuke Niino; Shunji Ishihara; Satoshi Kotani; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
The incidence of Helicobacter pylori (Hp) naïve gastric neoplasms (HpNGNs) is increasing due to a growing Hp-naïve population and improved recognition. Among these, HpNGNs that predominantly exhibit foveolar-cell differentiation include foveolar-type gastric adenomas (FGA) and fundic gland polyps with dysplasia (FGPD). Traditionally, FGAs have been considered large, whitish, flat lesions (flat-type FGA), primarily associated with syndromic conditions, such as familial adenomatous polyposis (FAP) and gastric adeno carcinoma and proximal polyposis of the stomach (GAPPS), while sporadic cases are rare. This type exhibits a gastric immunophenotype with diverse differentiation, mainly toward foveolar cells, and harbors APC and KRAS mutations in all sporadic and most syndromic cases. A distinct subset of FGAs, termed foveolar-type gastric adenoma with a raspberry-like appearance (FGA RA), has been identified. It presents as small, reddish polyps with unique macroscopic and microscopic features and only occurs sporadically. FGA-RA often mimics gastric hyperplastic polyps macroscopically and typically exhibits low-grade dysplasia, making biopsy based diagnosis challenging and leading to its historical underrecognition. It shows pure foveolar differentiation and consistently harbors Krüppel-like factor 4 (KLF4) mutations. FGPD primarily develops sporadically in Hp-naïve individuals with long-term proton pump inhibitor use. A syndromic form, resembling flat-type FGAs, is also associated with FAP and GAPPS. Histologically, FGPD features dysplasia confined to the superficial foveolar epithelium and mucus neck cells overlying fundic gland polyps, with APC mutations detected in approximately 50% of cases. This review explores the clinicopathological and molecular characteristics of HpNGNs with predominant foveolar cell differentiation, emphasizing the need for an updated histological diagnostic framework
Open Access
Resveratrol attenuates hepatic inflammation and oxidative stress in collagen-induced arthritis (CIA) mice via the Nrf2/Keap1 pathway
(2026) Suhuan Chen; Haomiao Liu; Mengyan Zhang; Mengmeng Chen; Wuqi Chen; Guangyi Chen; Weilu Gao; Tao Yao; Xiaoyu Chen; Xuefei Fan1; Biología Celular e Histología
Background. Rheumatoid arthritis can affect extra-articular organs such as the liver, and the problem of drug-induced liver injury caused by traditional antirheumatic drugs for improving the condition cannot be ignored. This study aims to investigate the therapeutic effects of resveratrol (Res) on hepatic inflammation and oxidative stress in mice with collagen-induced arthritis (CIA) and to elucidate the relationship between the regulatory mechanisms of the nuclear factor erythroid 2 related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway. Methods. In this study, we used chicken type II collagen in combination with complete Freund's adjuvant to induce arthritis in a mouse model, and Res was administered by tube feeding to detect the serum biochemical liver function and inflammation levels, oxidative stress, and apoptosis in the livers of mice. An in vitro cellular model of liver inflammation and oxidative stress was established by treating mouse primary hepatocytes (MPHs) with tumor necrosis factor α (TNF-α) and H2O2. The intrinsic mechanism of Res in attenuating hepatic inflammation and oxidative stress in CIA mice was explored by treating MPHs with an Nrf2 inhibitor and Keap1 overexpression plasmid. Results. Res significantly reduced the levels of inflammation and oxidative stress in liver tissues of CIA mice as well as in MPHs treated with TNF-α and H2O2 and activated the Nrf2/Keap1 signaling pathway. Inflammation and oxidative stress levels in MPHs were exacerbated by the use of Nrf2 inhibitors and Keap1 overexpression, which promoted apoptosis. Conclusion. This study demonstrated the intrinsic mechanism of Res of attenuating hepatic inflammation and oxidative stress in CIA mice through the Nrf2/Keap1 pathway, which provides a new idea for finding hepatoprotective treatments for rheumatoid arthritis.
Open Access
SLMO2 inhibits apoptosis in ovarian cancer cells by modulating mitochondrial function via TRIAP1
(2026) Yuesong Wang; Zixuan Li; Tianmei Zhang; Yaqi Wang; Biología Celular e Histología
Objective. This study aimed to investigate the role of SLMO2 in regulating mitochondrial function and its interaction with TRIAP1, which inhibited apoptosis in ovarian cancer cells. The findings provided valuable insights into potential therapeutic targets for ovarian cancer. Methods. Lentiviral infection models were developed using SKOV3 and OVCAR3 ovarian cancer cell lines. Techniques such as flow cytometry, western blotting, immunofluorescence, and transmission electron microscopy were employed to systematically assess the regulatory effects of SLMO2 and TRIAP1 on cell proliferation, apoptosis, mitochondrial function, and autophagy. Additionally, a subcutaneous mouse tumor xenograft model was utilized to further investigate the combined effects of SLMO2 and TRIAP1 on ovarian cancer cells, with the aim of elucidating the specific mechanisms underlying tumor growth and apoptosis. Results. SLMO2 enhanced mitochondrial function by increasing membrane potential and reducing reactive oxygen species (ROS) levels. Furthermore, through its interaction with TRIAP1, SLMO2 inhibited autophagy, which further suppressed apoptosis in ovarian cancer cells and regulated mitochondrial function. In vivo experiments showed decreased ROS levels and reduced expression of autophagy-related proteins, further supporting the roles of SLMO2 and TRIAP1 in the regulation of mitochondrial function. Conclusions. SLMO2 regulated mitochondrial function and inhibited apoptosis in ovarian cancer cells by interacting with TRIAP1. The combination of SLMO2 and TRIAP1 promoted tumor cell growth and induced oxidative stress, suggesting potential therapeutic targets for ovarian cancer.
Open Access
Betulinic acid isolated from Betula platyphylla induces apoptosis and reduces the mTOR/PI3K/AKT signaling pathway in endometrial cancer cells
(2026) Ceren Oy; Mücahit Secme; Duygu Gok Yurtseven; Sema Serter Koçoğlu; Gözde Korkusuz Akçal; Biología Celular e Histología
Endometrial cancer is one of the most common gynecological cancers worldwide, and an average of 42,000 women die each year. Chemotherapy, radiotherapy, and surgery are among the treatments available for endometrial cancer. Currently, drugs used for chemotherapy have had limited success in increasing the cure rate. Betulinic acid, a lupane-type triterpene widely found in the plant kingdom, has attracted attention for cancer treatment in recent years due to its ability to inhibit tumor growth and induce cell apoptosis. The aim of this study is to investigate the mTOR pathway-mediated anticancer effects of betulinic acid in human endometrial cancer cells. The effect of betulinic acid on Ishikawa cell viability was determined by the CCK-8 method. Its effect on the expression of genes involved in apoptosis and the mTOR pathway was assessed by real-time PCR. The effect on protein expression in the mTOR pathway was evaluated with immunohistochemistry and western blot, and the effects on apoptosis via Annexin V. Betulinic acid reduced Ishikawa endometrial cancer cell proliferation. Betulinic acid administration caused a significant decrease in Bcl2 (p=0.008) expression and increased caspase-8 (p=0.001) expression in Ishikawa cells. The results of Annexin V supported the idea that betulinic acid administration triggered apoptosis in Ishikawa cells. The mean rate of apoptotic cells in the betulinic acid group was 22±3.23%, while it was 2.31±0.2% in the control group (p=0.02). Betulinic acid caused a significant decrease in the expression of AKT1 (p=0.0001) and a significant increase in the expression of RAPTOR (p=0.00002). Betulinic acid administration also significantly percentage of p-PI3K, p-AKT, and p-mTOR-positive cells in Ishikawa cells was 89.39±5.19%, 74.84%±5.07, and 82.02%±6.14, respectively, in the control group. In the betulinic acid group, these values were 49.12± 19.12% (p=0.002), 44.46±7.39% (p<0.001), and 53.70±8.94% (p<0.001), respectively. This study showed that betulinic acid decreased Ishikawa cell proliferation, triggered apoptosis, and decreased mTOR signaling; thus, betulinic acid may be a potential anticancer agent for the treatment of endometrial cancer. decreased protein expression in the mTOR pathway. The
Open Access
Suppressing SMURF1 to preserve GSTM2: An approach to reducing gastric cancer aggressiveness in vitro and in vivo
(2026) Jingwu Li; Yuanting Liu; Weiwei Zuo; Guoming Ma; Biología Celular e Histología
Background. Smad Ubiquitination Regulatory Factor-1 (SMURF1) is implicated in promoting gastric cancer progression by enhancing cell proliferation, migration, and invasion. This study aims to elucidate how SMURF1 drives gastric cancer aggressiveness, with a focus on its interaction with Glutathione S-transferase mu 2 (GSTM2). Methods. Bioinformatics analysis identified dysregulated SMURF1 and GSTM2 expression in stomach adenocarcinoma (STAD). The relation between GSTM2 and SMURF1 was predicted using Unibrowser. Functional assays, including cell counting kit-8, wound healing, and Transwell invasion, were conducted on gastric cancer cells to explore the effects of GSTM2 and/or SMURF1. The ubiquitination level of GSTM2 was measured using western blot and immuno-precipitation. In vivo tumorigenicity was assessed in a xenograft mouse model, alongside analysis of tumor growth and molecular markers of epithelial-mesenchymal transition (EMT). Results. SMURF1 was highly expressed and the GSTM2 level was significantly downregulated in STAD. GSTM2 silencing activated the viability, migration, and invasion of gastric cancer cells, and these cell functions were inhibited by GSTM2 overexpression, which was reversed by SMURF1 overexpression. SMURF1 was predicted to be an E3 ubiquitin ligase for GSTM2. SMURF1 overexpression or Cyclohexanecarboxamide (CHX) addition suppressed GSTM2 levels in gastric cancer cells. Silencing of SMURF1 restrained GSTM2 ubiquitination. In vivo, GSTM2 overexpression suppressed tumor growth and EMT markers, such as Vimentin, while elevating E-cadherin, which was offset by SMURF1 upregulation. Conclusion. This study reveals a novel oncogenic axis, where SMURF1 promotes gastric cancer progression by targeting GSTM2 for degradation. Inhibiting SMURF1 stabilizes GSTM2, leading to reduced cell proliferation, migration, and invasion both in vitro and in vivo.

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