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Simple Summary: Standard chemotherapy is still ineffective in metastatic colon cancer and does not target cancer stem cells (CSCs). The combination of standard cytostatic drugs with natural compounds is considered a promising approach to improving cancer cell sensitivity to treatment. Here, a combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic and CSCs of colon cancer was investigated in vitro. γH2AX+ and Fast-Halo assays were used to evaluate genotoxicity, an annexin-V assay was used to rate the level of apoptosis, and a scratch test was used to assess antimigratory capacity. All combinations improved the genotoxicity of CPT, achieving a better efficacy with CPT-CEL combination in LOVO and CPT-RSV in LOVO/DX cells. No improvement in the pro-apoptotic effect of CPT was observed. Furthermore, higher efficiency in inhibiting cancer cell migration was noted. Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells. Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity. Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration. Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases. [ABSTRACT FROM AUTHOR]

CD19-targeted CAR-T cell therapy has revolutionized the treatment of relapsed/refractory (r/r) pre-B acute lymphoblastic leukemia (ALL). However, it can be associated with acute toxicities related to immune activation, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokines released from activated immune cells play a key role in their pathophysiology. This study was a prospective analysis of proinflammatory proteins and cytokines in children treated with tisagenlecleucel. Serial measurements of C-reactive protein, fibrinogen, ferritin, IL-6, IL-8, IL-10, IFNγ, and TNFα were taken before treatment and on consecutive days after infusion. The incidence of CRS was 77.8%, and the incidence of ICANS was 11.1%. No CRS of grade ≥ 3 was observed. All complications occurred within 14 days following infusion. Higher biomarker concentrations were found in children with CRS grade ≥ 2. Their levels were correlated with disease burden and CAR-T cell dose. While cytokine release syndrome was common, most cases were mild, primarily due to low disease burden before lymphodepleting chemotherapy (LDC). ICANS occurred less frequently but exhibited various clinical courses. None of the toxicities were fatal. All of the analyzed biomarkers rose within 14 days after CAR-T infusion, with most reaching their maximum around the third day following the procedure. [ABSTRACT FROM AUTHOR]

Exposure to aluminum (Al) and its compounds is an environmental factor that induces neurotoxicity, partially through oxidative stress, potentially leading to the development of neurodegenerative diseases. Components of the diet, such as caffeinated coffee, may play a significant role in preventing these diseases. In the present study, an experimental model of PC12 cells (rat pheochromocytoma tumor cells) was developed to investigate the influence of caffeine and caffeinated coffee on neurotoxicity induced by Al compounds and/or oxidative stress. For the induction of neurotoxicity, aluminum maltolate (Almal) and H2O2 were used. The present study demonstrates that 100 μM Almal reduced cell survival, while caffeinated coffee with caffeine concentrations of 5 μg/mL and 80 μg/mL reversed this effect, resulting in a higher than fivefold increase in PC12 cell survival. However, despite the observed antioxidant properties typical for caffeine and caffeinated coffee, it is unlikely that they are the key factors contributing to cell protection against neurotoxicity induced by both oxidative stress and Al exposure. Moreover, the present study reveals that for coffee to exert its effects, it is possible that Al must first activate certain mechanisms within the cell. Therefore, various signaling pathways are discussed, and modifications of these pathways might significantly decrease the risk of Al-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Transplanted organs are subjected to harmful conditions through stopping blood flow, hypothermic storage of the graft, and subsequent reperfusion. In particular, kidneys donated from patients after cardiac arrest (DCD) are classified as more vulnerable to ischemia–reperfusion injury (IRI). Hypothermic machine perfusion is proposed as a solution for better kidney storage before transplantation, and it is a good platform for additional graft treatment. Antioxidants have gained interest in regenerative medicine due to their ability to scavenge reactive oxygen species (ROS), which play a key role in IRI. We evaluated the effect of Mitoquinone (MitoQ), a strong mitochondria-targeted antioxidant, administered directly to the perfusing buffer. Rat kidneys were isolated, randomly classified into one of the following groups, donation after brainstem death (DBD), DCD, and DCD with MitoQ, and perfused for 22 hours with a hypothermic machine perfusion system. Subsequently, we detected levels of kidney injury (KIM-1) and oxidative stress (ROS/RNS, cytochrome C oxidase, and mitochondrial integrity) markers. We compared the activation of the apoptosis pathway (caspase 3 and 9), the concentration of phosphorylated Akt (pAkt), and the pAkt/total Akt ratio. MitoQ reduces KIM-1 concentration, total ROS/RNS, and the level of caspases. We observed a decrease in pAkt and the pAkt/total Akt ratio after drug administration. The length of warm ischemia time negatively impacts the graft condition. However, MitoQ added to the perfusing system as an 'on pump' therapy mitigates injury to the kidney before transplantation by inhibiting apoptosis and reducing ROS/RNS levels. We propose MitoQ as a potential drug for DCD graft preconditioning. [ABSTRACT FROM AUTHOR]

Colorectal cancers are one of the leading cancers worldwide and are known for their high potential for metastasis and resistance to therapy. The aim of this study was to investigate the effect of various combination therapies of irinotecan with melatonin, wogonin, and celastrol on drug-sensitive colon cancer cells (LOVO cell line) and doxorubicin-resistant colon cancer stem-like cells (LOVO/DX cell subline). Melatonin is a hormone synthesized in the pineal gland and is responsible for circadian rhythm. Wogonin and celastrol are natural compounds previously used in traditional Chinese medicine. Selected substances have immunomodulatory properties and anti-cancer potential. First, MTT and flow cytometric annexin-V apoptosis assays were performed to determine the cytotoxic effect and the induction of apoptosis. Then, the potential to inhibit cell migration was evaluated using a scratch test, and spheroid growth was measured. The results showed important cytotoxic effects of the drug combinations on both LOVO and LOVO/DX cells. All tested substances caused an increase in the percentage of apoptotic cells in the LOVO cell line and necrotic cells in the LOVO/DX cell subline. The strongest effect on the induction of cancer cell death was observed for the combination of irinotecan with celastrol (1.25 µM) or wogonin (50 µM) and for the combination of melatonin (2000 µM) with celastrol (1.25 µM) or wogonin (50 µM). Statistically significant improvements in the effect of combined therapy were found for the irinotecan (20 µM) and celastrol (1.25 µM) combination and irinotecan (20 µM) with wogonin (25 µM) in LOVO/DX cells. Minor additive effects of combined therapy were observed in LOVO cells. Inhibition of cell migration was seen in LOVO cells for all tested compounds, while only irinotecan (20 µM) and celastrol (1.25 µM) were able to inhibit LOVO/DX cell migration. Compared with single-drug therapy, a statistically significant inhibitory effect on cell migration was found for combinations of melatonin (2000 µM) with wogonin (25 µM) in LOVO/DX cells and irinotecan (5 µM) or melatonin (2000 µM) with wogonin (25 µM) in LOVO cells. Our research shows that adding melatonin, wogonin, or celastrol to standard irinotecan therapy may potentiate the anti-cancer effects of irinotecan alone in colon cancer treatment. Celastrol seems to have the greatest supporting therapy effect, especially for the treatment of aggressive types of colon cancer, by targeting cancer stem-like cells. [ABSTRACT FROM AUTHOR]

Kidney transplantation is the standard procedure for the treatment of end-stage renal disease (ESRD). During kidney storage and before implantation, the organ is exposed to damaging factors which affect the decline in condition. The arrest of blood circulation results in oxygen and nutrient deficiency that lead to changes in the cell metabolism from aerobic to anaerobic, damaging organelles and cell structures. Currently, most kidney grafts are kept in a cold preservation solution to preserve low metabolism. However, there are numerous reports that machine perfusion is a better solution for organ preservation before surgery. The superiority of machine perfusion was proved in the case of marginal donor grafts, such as extended criteria donors (ECD) and donation after circulatory death (DCD). Different variant of kidney machine perfusions are evaluated. Investigators look for optimal conditions to protect kidneys from ischemia-reperfusion damage consequences by examining the best temperature conditions and comparing systems with constant or pulsatile flow. Moreover, machine perfusion brings additional advantages in clinical practice. Unlike cold static storage, machine perfusion allows the monitoring of the parameters of organ function, which gives a real possibility to make a decision prior to transplantation concerning whether the kidney is suitable for implantation. Moreover, new pharmacological therapies are sought to minimize organ damage. New components or cellular therapies can be applied, since perfusion solution flows through the organ. This review outlines the pros and cons of each machine perfusion technique and summarizes the latest achievements in the context of kidney transplantation using machine perfusion systems. [ABSTRACT FROM AUTHOR]

Worldwide, tumors are one of the most common causes of death. Every year 3.7 million new cases occur in Europe and more than 1.9 million patients die (WHO data). Most of the fields of research are focused on developing new therapeutic strategies that will be effective in eliminating the tumor, preventing its remission, and avoiding or reducing the side effects of therapy. In the past, generally classical 2D cell cultures or immunodeficient animal models had been used to cultivate and test drugs on human cancer cell lines. Nowadays, there are increasing interests in three-dimensional (3D) cell cultures, a method with significant differences from flat cultured cells, both considering gene expressions and cell-cell interactions. Various evidence suggests that high tumorigenic properties might be dependent on the occurrence of a small cell population, pointed out to be responsible for metastasis and recurrence. This population is called cancer stem cells (CSCs), hinted to have a lot of similarities with normal stem cells. CSCs are the main reason for chemotherapy failure as well as multi-drug resistance (MDR). CSCs can also interact through the cytokine network, with other cells like the macrophages of the inflammatory system. The big advantage of a 3D culture is the possibility to isolate and investigate the CSCs population surrounded by its environment. This article aims to sum up known 3D cell cultures, especially in the field of CSCs research due to the importance of the tumor's environment on stem cell's markers expression and their development., Competing Interests: None., (AJCR Copyright © 2021.)