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It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy. We report that radiation-induced endothelial-to-mesenchymal transition (EndMT) leads to tumour vasculature with abnormal SMA + NG2 + pericyte recruitment during tumour regrowth after radiotherapy. Trp53 (but not Tgfbr2 ) deletion in endothelial cells (ECs) inhibited radiation-induced EndMT, reducing tumour regrowth and metastases with a high CD44v6 + cancer-stem-cell (CSC) content after radiotherapy. Osteopontin, an EndMT-related angiocrine factor suppressed by EC- Trp53 deletion, stimulated proliferation in dormant CD44v6 + cells in severely hypoxic regions after radiation. Radiation-induced EndMT significantly regulated tumour-associated macrophage (TAM) polarization. CXCR4 upregulation in radioresistant tumour ECs was highly associated with SDF-1 + TAM recruitment and M2 polarization of TAMs, which was suppressed by Trp53 deletion. These EndMT-related phenomena were also observed in irradiated human lung cancer tissues. Our findings suggest that targeting tumour EndMT might enhance radiotherapy efficacy by inhibiting the re-activation of dormant hypoxic CSCs and promoting anti-tumour immune responses. Radiotherapy is the main treatment for most cancer, but it is unclear if targeting tumour vasculature can enhance tumour radiosensitivity. Here, the authors show that tumour endothelial-mesenchymal transition after radiotherapy leads to proliferation of radioresistant CSCs and tumour associated macrophages polarization.

Endothelial-to-mesenchymal transition (EndMT) involves the phenotypic conversion of endothelial-to-mesenchymal cells, and was first discovered in association with embryonic heart development. EndMT can regulate various processes, such as tissue fibrosis and cancer. Recent findings have shown that EndMT is related to resistance to cancer therapy, such as chemotherapy, antiangiogenic therapy, and radiation therapy. Based on the known effects of EndMT on the cardiac toxicity of anticancer therapy and tissue damage of radiation therapy, we propose that EndMT can be targeted as a strategy for overcoming tumor resistance while reducing complications, such as tissue damage. In this review, we discuss EndMT and its roles in damaging cardiac and lung tissues, as well as EndMT-related effects on tumor vasculature and resistance in anticancer therapy. Modulating EndMT in radioresistant tumors and radiation-induced tissue fibrosis can especially increase the efficacy of radiation therapy. In addition, we review the role of hypoxia and reactive oxygen species as the main stimulating factors of tissue damage due to vascular damage and EndMT. We consider drugs that may be clinically useful for regulating EndMT in various diseases. Finally, we argue the importance of EndMT as a therapeutic target in anticancer therapy for reducing tissue damage.Cell biology: effect of changes in cell type on diseaseA process of cellular conversion known as endothelial-to-mesenchymal transition (EndMT) may offer a valuable target for treating cancer and other diseases. In EndMT, the cells lining blood vessels undergo a striking change in shape and physiology, acquiring features of cells called fibroblasts. Fibroblasts form the body’s connective tissue, but also produce scar tissue that impairs organ function. Researchers led by Yoon-Jin Lee of the Korea Institute of Radiological & Medical Sciences in Seoul, South Korea, have reviewed the impact of this transformation on human disease. EndMT is seen as a prelude to heart failure, in lung tissue affected by pulmonary fibrosis, and within tumors, where the process recruits cells that further stimulate cancer progression. The authors highlight the potential of using drugs that target EndMT to bolster the efficacy and safety of tumor therapy.

This study aimed to evaluate the regenerative effects of various microcurrent waveforms in cast-induced gastrocnemius muscle atrophy in rabbits, integrating both in vitro and in vivo analyses. After two weeks of enforced hindlimb immobilization via casting, twenty-four rabbits were divided into four groups and treated for two weeks: Group-1 (control) received sham microcurrent, Group-2 was treated with a square waveform microcurrent, Group-3 with a sine waveform, and Group-4 with a triangular waveform. Treatments were administered daily for one hour. Calf circumference, muscle thickness (via ultrasound), tibial nerve CMAP, muscle fiber CSA, and protein expression (via Western blot analysis) were assessed. Among the groups, the sine waveform microcurrent resulted in significantly enhanced recovery across all measured parameters (p < 0.05), showing superior improvements in muscle thickness, CMAP amplitude, and fiber CSA. Immunohistochemical analysis revealed increased expression of proliferation and angiogenesis markers, including BrdU, PCNA, VEGF, and PECAM-1, while Western blotting demonstrated robust upregulation of myogenic regulatory factors such as MyoD and myogenin. Furthermore, levels of inflammatory and apoptotic markers, including TNF-α, NF-κB, and cleaved caspase-3, and stress response proteins, including p-CHK1 and p-CHK2, were markedly reduced. Collectively, these findings indicate that sine waveform microcurrent stimulation most effectively promotes muscle regeneration in both dexamethasone-induced C2C12 myoblasts and cast-induced muscle atrophy, underscoring its therapeutic potential and warranting further studies to optimize clinical application parameters.

Objective. Curcumin, a major bioactive curcuminoid derived from the rhizome of Curcuma longa, is known to have anticancer potential and is still under investigation. In this study, we investigated the cytotoxic mechanism(s) of curcumin against acidity-tolerant prostate cancer PC-3AcT cells in lactic acid-containing medium. Methods. Using 2D-monolyer and 3D spheroid culture models, MTT assay, annexin V-PE binding assay, flow cytometric analysis, measurement of ATP content, and Western blot analysis were used for this study. Results. At nontoxic concentrations in normal prostate epithelial RWPE-1 and HPrEC cells, curcumin led to strong cytotoxicity in PC-3AcT cells, including increases in sub-G0/G1 peak, annexin V-PE-positive cells, and ROS levels; loss of mitochondrial membrane potential; reduction of cellular ATP content; DNA damage; and concurrent induction of apoptosis and necroptosis. A series of changes induced by curcumin were effectively reversed by reducing ROS levels or replenishing ATP. Pretreatment with apoptosis inhibitor Q-VD-Oph-1 or necroptosis inhibitor necrostatin-1 restored cell viability inhibited by curcumin. Treatment of 3D spheroids with curcumin decreased cell viability, accompanied by an increase in mediators of apoptosis and necroptosis, including cleaved caspase-3 and cleaved PARP, phospho (p)-RIP3, and p-MLKL proteins. Conclusion. This study shows that curcumin simultaneously induces apoptosis and necroptosis by oxidative mitochondrial dysfunction and subsequent ATP depletion, providing a mechanistic basis for understanding the novel role of curcumin for prostate carcinoma cells.

The value of image based texture features as a powerful method to predict prognosis and assist clinical management in cancer patients has been established recently. However, texture analysis using histograms and grey-level co-occurrence matrix in pancreas cancer patients has rarely been reported. We aimed to analyze the association of survival outcomes with texture features in pancreas head cancer patients. Eighty-eight pancreas head cancer patients who underwent preoperative CT images followed by curative resection were included. Texture features using different filter values were obtained. The texture features of average, contrast, correlation, and standard deviation with no filter, and fine to medium filter values as well as the presence of nodal metastasis were significantly different between the recurred (n = 70, 79.5%) and non-recurred group (n = 18, 20.5%). In the multivariate Cox regression analysis, lower standard deviation and contrast and higher correlation with lower average value representing homogenous texture were significantly associated with poorer DFS (disease free survival), along with the presence of lymph node metastasis. Texture parameters from routinely performed pre-operative CT images could be used as an independent imaging tool for predicting the prognosis in pancreas head cancer patients who underwent curative resection.

This study primarily aimed to investigate the combined effects of polydeoxyribonucleotide (PDRN) and extracorporeal shock wave therapy (ESWT) sequences on the regenerative processes in atrophied animal muscles. Thirty male New Zealand rabbits, aged 12 weeks, were divided into five groups: normal saline (Group 1), PDRN (Group 2), ESWT (Group 3), PDRN injection before ESWT (Group 4), and PDRN injection after ESWT (Group 5). After 2 weeks of cast immobilization, the respective treatments were administered to the atrophied calf muscles. Radial ESWT was performed twice weekly. Calf circumference, tibial nerve compound muscle action potential (CMAP), and gastrocnemius (GCM) muscle thickness after 2 weeks of treatment were evaluated. Histological and immunohistochemical staining, as well as Western blot analysis, were conducted 2 weeks post-treatment. Staining intensity and extent were assessed using semi-quantitative scores. Groups 4 and 5 demonstrated significantly greater calf muscle circumference, GCM muscle thickness, tibial nerve CMAP, and GCM muscle fiber cross-sectional area (type I, type II, and total) than the remaining three groups (p < 0.05), while they did not differ significantly in these parameters. Groups 2 and 3 showed higher values for all the mentioned parameters than Group 1 (p < 0.05). Group 4 had the greatest ratio of vascular endothelial growth factor (VEGF) to platelet endothelial cell adhesion molecule-1 (PECAM-1) in the GCM muscle fibers compared to the other four groups (p < 0.05). Western blot analysis revealed significantly higher expression of angiogenesis cytokines in Groups 4 and 5 than in the other groups (p < 0.05). The combination of ESWT and PDRN injection demonstrated superior regenerative efficacy for atrophied calf muscle tissue in rabbit models compared to these techniques alone or saline. In particular, administering ESWT after PDRN injection yielded the most favorable outcomes in specific parameters.

BackgroundInactivation of TP53, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the correlation between the overexpression of p53 and survival in different Lauren-type GCs.MethodsFrom May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression.ResultsAmong 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (P = 0.026) and Early gastric cancer (P = 0.044) in intestinal-type GC, and with advanced TNM stage (P < 0.001) and Advanced gastric cancer (P < 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio [aHR] = 1.423, P = 0.022; OS in diffuse-type: aHR = 1.401 P = 0.035; cancer recurrence in diffuse-type: aHR = 1.502, P = 0.039).Conclusionp53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC.

Alzheimer's disease (AD) is a neurodegenerative disorder due to Aβ plaque accumulation, followed by loss of synapses and decline in cognitive abilities. Donepezil is currently one of the standard pharmacological treatments for Alzheimer's disease. Recently, microcurrent (MC) therapy has emerged as a non-pharmacological adjunct for AD management. Recently, microcurrent therapy emerged as a non-pharmacological alternative to treat AD. The study investigates the therapeutic outcomes of the MC as an adjuvant to donepezil in mitigating cognitive dysfunction in the transgenic mouse model (5XFAD). Transgenic 5xFAD mice were assigned to the control, donepezil, MC, or MC + donepezil (combination) groups. Behavioral performance was assessed using the novel object recognition (NOR) and radial arm maze (RAM) tests. Amyloid burden, glial activation, cytokine expression, apoptotic signaling, and intracellular pathways (PI3K-AKT, AMPK, and JAK2/3) were analyzed by immunohistochemistry and Western blotting. Combined treatment with donepezil and microcurrent showed a trend toward improved cognitive performance and reduced pathology compared to donepezil alone, although these differences were not statistically significant. Aβ plaque burden in the cortex and the hippocampus was reduced by approximately 68%, thereby exceeding reductions observed with either treatment alone. Microglial and astroglial activation (Iba1, GFAP, and CD68) and pro-inflammatory cytokines (TNF- and IL-1β) were reduced in both the donepezil and combination groups compared with untreated 5xFAD mice, with no significant difference between 5xD and 5xD + MC. Apoptotic markers (cleaved caspase-3 and cleaved PARP) were significantly reduced in both treatment groups compared with untreated controls but not significantly different between donepezil and combination therapy. At the molecular level, both donepezil and combination therapy activated PI3K-AKT and AMPK signaling and increased inhibitory phosphorylation of GSK-3β compared with untreated 5xFAD mice; no significant difference was observed between the two treatment groups. Donepezil combined with microcurrent therapy showed comparable efficacy to donepezil alone, with numerical trends toward further improvement in cognitive function and pathology, but without statistically significant differences. Both treatments reduced Aβ burden, attenuated glial activation, and modulated survival-related pathways to a similar extent. These findings support a multi-target therapeutic strategy and highlight the translational potential of integrating microcurrent therapy with standard pharmacological treatment for AD.

Arctigenin, a mitochondrial complex I inhibitor, has been identified as a potential anti-tumor agent, but the involved mechanism still remains elusive. Herein, we studied the underlying mechanism(s) of action of arctigenin on acidity-tolerant prostate cancer PC-3AcT cells in the lactic acid-containing medium. At concentration showing no toxicity on normal prostate epithelial RWPE-1 and HPrEC cells, arctigenin alone or in combination with docetaxel induced significant cytotoxicity in PC-3AcT cells compared to parental PC-3 cells. With arctigenin treatment, reactive oxygen species (ROS) levels, annexin V-PE positive fractions, sub-G0/G1 peak in cell cycle analysis, mitochondrial membrane depolarization, and cell communication network factor 1 (CCN1) levels were increased, while cellular ATP content and phospho (p)-Akt level were decreased. Pretreatment with ROS scavenger N-acetylcysteine effectively reversed the series of phenomena caused by arctigenin, suggesting that ROS served as upstream molecules of arctigenin-driven cytotoxicity. Meanwhile, arctigenin increased the levels of p-receptor-interacting serine/threonine-protein kinase 3 (p-RIP3) and p-mixed lineage kinase domain-like pseudokinase (p-MLKL) as necroptosis mediators, and pretreatment with necroptosis inhibitor necrostatin-1 restored their levels and cell viability. Treatment of spheroids with arctigenin resulted in necroptotic cell death, which was prevented by N-acetylcysteine. The siRNA-based knockdown of CCN1 suppressed the levels of MLKL, B-cell lymphoma 2 (Bcl-2), and induced myeloid leukemia cell differentiation (Mcl-1) with increased cleavage of Bcl-2-associated X (Bax) and caspase-3. Collectively, these results provide new insights into the molecular mechanisms underlying arctigenin-induced cytotoxicity, and support arctigenin as a potential therapeutic agent for targeting non-Warburg phenotype through induction of necroptosis via ROS-mediated mitochondrial damage and CCN1 upregulation.

Object. Extracellular acidosis of the tumor microenvironment plays an important role in cancer progression. In the 2D monolayer and 3D spheroid cultures of prostate cancer cells, we investigated the efficacy of curcumin in targeting glycolysis and the role of ERK1/2 as an upstream signaling molecule in this process. Methods. Cell viability, glycolytic activity, Annexin V-PE binding activity, reactive oxygen species levels, mitochondrial membrane potential, ATP content, Western blot analysis, and spheroid viability were measured for this study. Results. Acidic pH-tolerant prostate cancer cells, PC-3AcT and DU145AcT, increased cytotoxicity with ERK1/2 inhibition in a curcumin concentration-dependent manner at concentrations that resulted in >90% cell viability in normal prostate epithelial HPrEC cells. ERK1/2 inhibition by curcumin and/or PD98059 suppressed cell growth, reduced glucose consumption, and downregulated the expression of key regulatory enzymes in glucose metabolism including hexokinases, phosphofructokinase, and pyruvate dehydrogenase. In addition, these compounds caused loss of mitochondrial membrane potential with increased intracellular ROS levels, decreased levels of complexes I, III, and IV in the mitochondrial electron transport chain, and cellular ATP depletion, leading to upregulation of marker proteins in apoptosis (cleaved caspase-3 and cleaved PARP) and necroptosis (p-MLKL and p-RIP3). The results of curcumin and/or PD98059 treatment in 3D cultures showed similar trends to those in 2D cultures. Conclusion. Taken together, the results provide mechanistic evidence for the antiglycolytic and cytotoxic roles of curcumin through inhibition of the MEK/ERK signaling pathway in prostate carcinoma cells preadapted to acidic conditions.