EXCLI Journal最新文献

Hepatocellular Carcinoma (HCC) is one of the most common and fatal types of liver cancer worldwide; in this sense, Diethylnitrosamine (DEN) has been established as a potent carcinogen affecting the development and progression of this disease. The present work focused on determining whether phosphodiesterase (PDE) enzymes, especially PDE5, may serve as targets in the therapeutic treatment of DEN-induced HCC. PDE5 inhibitors, widely used as therapeutic drugs for cardiovascular diseases and erectile dysfunction, have recently been found to be promising in preclinical cancer models through the modulation of key signaling pathways implicated in the progression of tumors, such as the cGMP-PKG, JNK, and MAPK pathways. These pathways are very important for cell proliferation, apoptosis and metastasis, and their dysregulation contributes to the aggressive nature of HCC. This study assessed the potential of PDE5 inhibitors to suppress proliferation, induce apoptosis, and alter the tumor microenvironment, thus potentially improving standard chemotherapy and immunotherapy interventions. By inhibiting certain PDE isoforms with these drugs, an anticancer response might occur as part of a complex mechanism that acts on both cancer cells and the microenvironment favorable for tumor growth. A preliminary review indicated that PDE inhibitors may be a promising therapeutic approach for overcoming some of the shortcomings of current treatments, particularly the development of resistance and the toxic effects of these treatments. Additional clinical investigations are necessary to determine the safety profile, appropriate amount of Osage, and long-term efficacy of these agents in the treatment of HCC, particularly in DEN-induced animal models. This study contributes to the expanding body of evidence supporting the use of PDE inhibitors in cancer treatment.

p-Synephrine is a popular ingredient in dietary supplements. It is also found in trace amounts in living organisms. It is advertised as a weight loss supplement and it is supposed to improve performance in sports. It is contained in plants of the Citrus family, making it widespread in the human diet. Its pharmacological properties include effects on multiple receptors and signaling pathways. Its effects on the alpha and betanergic systems promote doubts about its safety. There are many studies describing a lack of concern when it comes to the potential harmful effects of this compound. On the other hand, several health incidents associated with p-synephrine use have been reported in the scientific literature, making the toxicity of this compound unclear. This review aims to organize the current knowledge about p-synephrine, including physicochemical characteristics, sources of occurrence, pharmacological effects and possible toxic effects. In addition, the presence of three substitution isomers of the hydroxyl group and one chiral carbon atom causes confusion in the literature. Studies conducted on the short-term use of p-synephrine do not indicate its toxicity at low doses for healthy people. Further studies are needed to determine its long-term safety and possible interactions with other chemical compounds. See also the graphical abstract(Fig. 1).

Cell death is a fundamental process that needs to be maintained to balance cellular functions and prevent disease. There are several cell death pathways; however, apoptosis and parthanatos are the most prominent and have important roles in cancer biology. As an extremely well-regulated process, apoptosis removes damaged or abnormal cells via caspase activation and mitochondrial involvement. Unlike in the healthy cells, the loss of ability to induce apoptosis in cancer permits tumor cells to survive and multiply out of control and contribute to tumor progression and therapy resistance. On the contrary, parthanatos is a caspase-independent metabolic collapse driven by poly (ADP-ribose) polymerase 1 (PARP1) overactivation, translocation of apoptosis-inducing factor (AIF), and complete DNA damage. Several cancer models are involved with parthanatos. Deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells by excessive ROS generation, PARP1 upregulation, and AIF nuclear translocation. Like in acute myeloid leukemia (AML), the cannabinoid derivative WIN-55 triggers parthanatos, and the effects can be reversed by PARP inhibitors such as olaparib. Developing cancer treatment strategies involving advanced cancer treatment strategies relies on the interplay between apoptosis and parthanatos. However, such apoptosis-based cancer therapies tend to develop resistance, so there is an urgent need to look into alternative pathways like parthanatos, which may not always trigger apoptosis. In overcoming apoptosis resistance, there is evidence that combining apoptosis-inducing agents, such as BH3 mimetics, with PARP inhibitors synergistically enhances cell death. Oxidative stress modulators have been found to promote the execution of parthanatic and apoptotic pathways and allow treatment. In this review, apoptosis and parthanatos are thoroughly compared at the molecular level, and their roles in cancer pathogenesis as related to cancer therapeutic potential are discussed. We incorporate recent findings to demonstrate that not only can parthanatos be used to manage therapy resistance and enhance cancer treatment via the combination of parthanatos and apoptosis but also that immunity and bone deposition can feasibly be employed against long-circulating cancer stem cells to treat diverse forms of metastatic cancers.

The increased sialin gene expression in the main tissues of diabetic rats is associated with decreased nitrate and nitrite levels, suggesting a counterregulatory response for reduced nitric oxide (NO) bioavailability. In this study, we hypothesized that long-term nitrate administration (6 months) would decrease sialin gene expression in rats with type 2 diabetes (T2D). Rats were assigned to two groups (n=10): T2D and T2D+nitrate, receiving nitrate in their drinking water at a concentration of 100 mg/L over 6 months. Samples from the main tissues were collected and used to measure the gene expression of sialin, as well as nitrate and nitrite levels. Nitrate-treated T2D rats had higher nitrate levels in the soleus muscle (SM) (163 %), stomach (83 %), lung (271 %), pancreas (90 %), aorta (61 %), adrenal gland (88 %), brain (145 %), liver (95 %), and heart (87 %). Nitrite levels were also higher in SM (136 %), lung (108 %), pancreas (86 %), kidney (88 %), aorta (33 %), brain (221 %), epididymal adipose tissue (eAT) (52 %), and heart (93 %), of nitrate treated T2D rats (all P<0.05). Nitrate decreased sialin gene expression in the SM (0.21-fold, P<0.001), stomach (0.37-fold, P=0.002), liver (0.21-fold, P<0.001), and eAT (0.47-fold, P=0.016) but it increased it in the intestine (1.99-fold, P<0.001), pancreas (2.01-fold, P=0.006), and the kidney (2.45-fold, P<0.001) of diabetic rats, with no effects in the lung, aorta, adrenal gland, brain, and heart. Nitrate administration restores the compensatory increase in sialin gene expression in tissues of T2D rats. However, this compensatory mechanism is not generalizable to all tissues.

Osteoarthritis (OA) is one of the most common forms of degenerative joint disease characterized by persistent pain, inflammation of the joints, and restricted range of motion among the elderly worldwide. Interleukin-1 beta (IL-1β) is increased in the injured joints and contributes to the OA pathobiology by inducing chondrocyte apoptosis and inflammation. Transient receptor potential (TRP) ion channels have recently been reported as potential players in the modulation of apoptosis and inflammation. Here, we aimed to understand the regulatory role and effect of TRPV3 on apoptosis and inflammation in osteoarthritis by using C28/I2 chondrocyte cells as a model. Chondrocytes were transfected with TRPV3-specific siRNA for 24 hours and then stimulated with IL-1β in vitro. Cell cycle progression and apoptosis were evaluated with flow cytometry. The levels of TRPV3, apoptotic (Bax, Caspase-3, and Bcl-2), and inflammatory (iNOS, COX-2) genes were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and confirmed with western blot. Treatment of the C28/I2 chondrocyte cells with IL-1β resulted in the over-expression of TRPV3, induction of apoptosis, and over-expression of inflammation indices. Knockdown of TRPV3 significantly reduced the expression of Bax and Caspase 3 proapoptotic factors while increasing the expression of the Bcl-2 antiapoptotic factor in the mRNA and protein levels in the IL-1β-stimulated cells. Its knockdown also decreased the expression of the inflammatory factors iNOS and COX-2 in mRNA and protein levels, confirming that TRPV3 knockdown hinders apoptosis and inflammation in IL-1β-stimulated chondrocytes. In conclusion, we demonstrated that si-TRPV3 treatment significantly mitigates IL-1β-related effects on the C28/I2 chondrocyte cells. These findings suggested that TRPV3 could be an effective target for the treatment of OA. See also the graphical abstract(Fig. 1).

Rhoifolin is a flavonoid found in various plant species, especially within the Rutaceae family, and is considered a dietary component due to its presence in edible plants. Its bioactive properties, such as cytotoxic and anticancer activities, have gained significant attention. This review aims to highlight the general properties and diverse bioactivities of rhoifolin, with a particular focus on its cytotoxic and anticancer effects. This is based on a comprehensive literature search, focusing on the presence of rhoifolin in different plant species and its biological activities, particularly its anticancer properties. Rhoifolin is widely distributed in the plant kingdom, especially in Citrus species. It exhibits a variety of bioactivities, including strong cytotoxic and anticancer effects. Recent studies have shown that rhoifolin can induce apoptosis and inhibit cancer cell proliferation, making it a promising candidate for anticancer therapies. Rhoifolin's diverse bioactivities, particularly its cytotoxic and anticancer properties, position it as a potential therapeutic agent. Further detailed investigations into its molecular mechanisms and well-designed clinical studies are needed to fully understand and utilize its therapeutic potential. See also the graphical abstract(Fig. 1).