Short-term autophagy inhibition by autophinib or SAR405 does not alter the effect of cisplatin on ATP production in prostate cancer cells.

OBJECTIVES: Cisplatin is a widely used anticancer drug for the treatment of many solid cancers. DNA damage is thought to be the key mechanism of cisplatin's anticancer activity. However, cisplatin may also affect cellular metabolism. The aim of this study was to determine the effect of cisplatin on the types of ATP production (OXPHOS versus glycolysis) and their rate in prostate cancer cells and to determine the potentially protective effect of autophagy and amino acids during cisplatin treatment. We also wanted to investigate the potential synergy between the metabolic effects of cisplatin on ATP production and the inhibition of autophagy. METHODS: Cisplatin treatment can significantly affect the metabolism of cancer cells. Important metabolic pathways can be altered, leading to changes in energy production and nutrient utilization. Autophagy and amino acid pool modulations can serve as protective mechanisms significantly affecting tumor cell survival under metabolic stress caused by anticancer treatment. By enabling the recycling of amino acids, autophagy helps cancer cells maintain cellular homeostasis and overcome nutrient limitations. Thus, inhibition of autophagy could have a supportive effect on the metabolic effects of cisplatin. RESULTS: After cisplatin treatment, ATP production by way of OXPHOS was significantly decreased in 22Rv1 and PC-3 cells. On the other hand, ATP production by glycolysis was not significantly affected in 22Rv1 cells. DU145 cells with dysfunctional autophagy were the most sensitive to cisplatin treatment and showed the lowest ATP production. However, short-term autophagy inhibition (24h) by autophinib or SAR405 in 22Rv1 and PC-3 cells did not alter the effect of cisplatin on ATP production. Levels of some amino acids (arginine, methionine) significantly affected the fitness of cancer cells. CONCLUSION: Persistent defects of autophagy can affect the metabolic sensitivity of cancer cells due to interference with arginine metabolism. Amino acids contained in the culture medium had an impact on the overall effect of cisplatin (Fig. 3, Ref. 38).

TGF-ß induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids.

Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-ß signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-ß signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-ß-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-to-mesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-ß signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination.

Possibilities of Interpreting the Night-to-Day Ratio Specified by 24-Hour Blood Pressure Monitoring.

Aim: Specify the risk rate of incorrect patient classification based on the night-to-day ratio specification from singular 24-h ABPM in comparison to the results of 7-day ABPM monitoring. Materials and Methods: 1197 24 h cycles were enrolled in 171 subjects in the study and divided into 4 groups: group 1 (40 healthy men and women without exercise), group 2 (40 healthy exercise-training men and women), group 3 (40 patients with ischemic coronary artery disease without exercise), and group 4 (51 patients with ischemic coronary artery disease following cardiovascular rehabilitation). The subject of the evaluation was the percentage rate of incorrect subject classification (dipper, nondipper, extreme dipper, and riser) based on the mean blood pressure values for 7 days and from seven independent 24-hour cycles (the mean value mode). Results: In the case of the individuals included in the monitored groups, the mean night-to-day ratio-based (mode for the 7 days versus the individual days of 24-hour monitoring) classification accordance ranged between 59% and 62%. Only in singular cases did the accordance reach 0% or 100%. The accordance size was not dependent on the health or cardiovascular disease (p < 0.594; 56% vs. 54%) or physical activity (p < 0.833; 55% vs. 54%) of the monitored individuals. Conclusion: The specification of the night-to-day ratio of each individual for each day of the 7-day ABPM monitoring would be the most convenient option. In many patients, diagnosing could thus be based on the most frequently occurring values (mode specification).

Inverted Takotsubo Cardiomyopathy as an Early Complication After Liver Transplantation.

BACKGROUND Takotsubo cardiomyopathy (TTC) is a cardiac syndrome characterized by transient left ventricle (LV) dysfunction, typically showing apical ballooning due to apical akinesis with preserved basal segment contractility. The inverted form is very uncommon and is characterized by basal segment hypokinesis or akinesis and normal LV apical segment contractility. CASE REPORT We describe the case of a 49-year-old woman who developed inverted TTC after orthotopic liver transplantation. On day 1 (D1), dyspnea and oliguria suddenly appeared. A chest X-ray showed pulmonary edema, and echocardiography showed severe systolic LV dysfunction with an estimated ejection fraction of approximately 25% and akinesis of basal and midventricular LV segments, normal apical segment contractility, and mild mitral regurgitation. Elevated troponin T, creatine kinase-MB, and N-terminal pro B-type natriuretic peptide were found in the blood sample. Suspected inverted takotsubo cardiomyopathy was confirmed by left ventriculography, with normal apical part motion, akinesis in the other LV parts, and negative coronary angiography. The echocardiographic findings returned to normal on D14, and the patient was discharged from the hospital on D19 with normal LV motion and an ejection fraction of 65%. The transplanted liver function was excellent. CONCLUSIONS Organ transplantation is connected with a great emotional stress because the patient's life depends on the death of another person. Therefore, we have to think about the possibility of stress cardiomyopathy even after liver transplantation, because early diagnosis and treatment can be life-saving for the patient. To our knowledge, this is the first described case of inverted takotsubo cardiomyopathy after liver transplantation.

Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond.

Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.

Novel Mitochondria-targeted Drugs for Cancer Therapy.

The search for mitochondria-targeted drugs has dramatically risen over the last decade. Mitochondria are essential organelles serving not only as a powerhouse of the cell but also as a key player in cell proliferation and cell death. Their central role in the energetic metabolism, calcium homeostasis and apoptosis makes them an intriguing field of interest for cancer pharmacology. In cancer cells, many mitochondrial signaling and metabolic pathways are altered. These changes contribute to cancer development and progression. Due to changes in mitochondrial metabolism and changes in membrane potential, cancer cells are more susceptible to mitochondria-targeted therapy. The loss of functional mitochondria leads to the arrest of cancer progression and/or a cancer cell death. Identification of mitochondrial changes specific for tumor growth and progression, rational development of new mitochondria-targeted drugs and research on delivery agents led to the advance of this promising area. This review will highlight the current findings in mitochondrial biology, which are important for cancer initiation, progression and resistance, and discuss approaches of cancer pharmacology with a special focus on the anti-cancer drugs referred to as 'mitocans'.

Tumor in 3D: In Vitro Complex Cellular Models to Improve Nanodrugs Cancer Therapy.

Nanodrugs represent novel solutions to reshuffle repurposed drugs for cancer therapy. They might offer different therapeutic options by combining targeted drug delivery and imaging in unique platforms. Such nanomaterials are deemed to overcome the limitations of currently available treatments, ultimately improving patients' life quality. However, despite these promises being made for over three decades, the poor clinical translation of nanoparticle- based therapies calls for deeper in vit.. and in vivo investigations. Translational issues arise very early during the development of nanodrugs, where complex and more reliable cell models are often replaced by easily accessible and convenient 2D monocultures. This is particularly true in the field of cancer therapy. In fact, 2D monocultures provide poor information about the real impact of the nanodrugs in a complex living organism, especially given the poor mimicry of the solid Tumors Microenvironment (TME). The dense and complex extracellular matrix (ECM) of solid tumors dramatically restricts nanoparticles efficacy, impairing the successful implementation of nanodrugs in medical applications. Herein, we propose a comprehensive guideline of the 3D cell culture models currently available, including their potential and limitations for the evaluation of nanodrugs activity. Advanced culture techniques, more closely resembling the physiological conditions of the TME, might give a better prediction of the reciprocal interactions between cells and nanoparticles and eventually help reconsider the use of old drugs for new applications.

Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading.

The mechanoregulated proteins YAP/TAZ are involved in the adipogenic/osteogenic switch of mesenchymal stem cells (MSCs). MSC fate decision can be unbalanced by controlling substrate mechanics, in turn altering the transmission of tension through cell cytoskeleton. MSCs have been proposed for orthopedic and reconstructive surgery applications. Thus, a tight control of their adipogenic potential is required in order to avoid their drifting towards fat tissue. Substrate mechanics has been shown to drive MSC commitment and to regulate YAP/TAZ protein shuttling and turnover. The mechanism by which YAP/TAZ co-transcriptional activity is mechanically regulated during MSC fate acquisition is still debated. Here, we design few bioengineering tools suited to disentangle the contribution of mechanical from biological stimuli to MSC adipogenesis. We demonstrate that the mechanical repression of YAP happens through its phosphorylation, is purely mediated by cell spreading downstream of substrate mechanics as dictated by dimensionality. YAP repression is sufficient to prompt MSC adipogenesis, regardless of a permissive biological environment, TEAD nuclear presence or focal adhesion stabilization. Finally, by harnessing the potential of YAP mechanical regulation, we propose a practical example of the exploitation of adipogenic transdifferentiation in tumors.