Berberine Improves Cancer-Derived Myocardial Impairment in Experimental Cachexia Models by Targeting High-Mobility Group Box-1.

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system.

Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene.

Patients with cancer die from cardiac dysfunction second only to the disease itself. Cardiotoxicity caused by anticancer drugs has been emphasized as a possible cause; however, the details remain unclear. To investigate this mechanism, we treated rat cardiomyoblast H9c2 cells with sunitinib, lapatinib, 5-fluorouracil, and cisplatin to examine their effects. All anticancer drugs increased ROS, lipid peroxide, and iron (II) levels in the mitochondria and decreased glutathione peroxidase-4 levels and the GSH/GSSG ratio. Against this background, mitochondrial iron (II) accumulates through the unregulated expression of haem oxygenase-1 and ferrochelatase. Anticancer-drug-induced cell death was suppressed by N-acetylcysteine, deferoxamine, and ferrostatin, indicating ferroptosis. Anticancer drug treatment impairs mitochondrial DNA and inhibits oxidative phosphorylation in H9c2 cells. Similar results were observed in the hearts of cancer-free rats treated with anticancer drugs in vitro. In contrast, treatment with pterostilbene inhibited the induction of ferroptosis and rescued the energy restriction induced by anticancer drugs both in vitro and in vivo. These findings suggest that induction of ferroptosis and inhibition of oxidative phosphorylation are mechanisms by which anticancer drugs cause myocardial damage. As pterostilbene ameliorates these mechanisms, it is expected to have significant clinical applications.

Pterostilbene Induces Apoptosis from Endoplasmic Reticulum Stress Synergistically with Anticancer Drugs That Deposit Iron in Mitochondria.

Anticancer agents are playing an increasing role in the treatment of gastric cancer (GC); however, novel anticancer agents have not been fully developed. Therefore, it is important to investigate compounds that improve sensitivity to the existing anticancer drugs. We have reported that pterostilbene (PTE), a plant stilbene, enhances the antitumor effect of low doses of sunitinib in gastric cancer cells accumulating mitochondrial iron (II) (mtFe) at low doses. In this study, we investigated the relationship between the mtFe deposition and the synergistic effect of PTE and different anticancer drugs. For this study, we used 5-fluorouracil (5FU), cisplatin (CPPD), and lapatinib (LAP), which are frequently used in the treatment of GC, and doxorubicin (DOX), which is known to deposit mtFe. A combination of low-dose PTE and these drugs suppressed the expression of PDZ domain-containing 8 (PDZD8) and increased mtFe accumulation and mitochondrial H2O2. Consequently, reactive oxygen species-associated hypoxia inducible factor-1α activation induced endoplasmic reticulum stress and led to apoptosis, but not ferroptosis. In contrast, 5FU and CDDP did not show the same changes as those observed with PTE and DOX or LAP, and there was no synergistic effect with PTE. These results indicate that the combination of PTE with iron-accumulating anticancer drugs exhibits a strong synergistic effect. These findings would help in developing novel therapeutic strategies for GC. However, further clinical investigations are required.

Glucose loading for heart failure protects the myocardium and improves physical function.

[Purpose] The purpose of this study was to investigate the effects of glucose intake on physical function in a heart failure rat model. [Materials and Methods] Five-week-old male Wistar rats were used for this study. Monocrotalin (40 mg/kg) was administered intraperitoneally to rats to induce heart failure. The rats were divided into two groups, control and MCT; the MCT group was further classified according to glucose concentration (0%, 10%, and 50%). [Results] Glucose intake during heart failure prevented the loss of body weight, skeletal muscle, and fat mass. Myocardial metabolism in heart failure was enhanced by hypoxia, which in turn, enhanced the glycolytic system. [Conclusion] Glucose loading suppressed cardiac hypertrophy and improved physical function in the heart failure rat model.

Effects of continuous rehabilitation on intensive care unit-acquired weakness after open-heart surgery: a case report.

[Purpose] To assess the effects of continuous rehabilitation on intensive care unit-acquired weakness in a patient who underwent open-heart surgery. [Participant and Methods] This case report describes a 78-year-old female patient who developed intensive care unit-acquired weakness after open-heart surgery. She underwent cardiac surgery, via a thoracotomy, for valvular disease and angina pectoris. Her Medical Research Council sum score at the time of rehabilitative intervention was 28 points, indicating intensive care unit-acquired weakness. Rehabilitation was continued, and the patient's physical function was evaluated over time. [Results] Continuous rehabilitation improved the patient's grip strength, knee extension muscle strength, 6-minute walk test performance, and Short Physical Performance Battery score. [Conclusion] Although few reports have been published on rehabilitation for patients with intensive care unit-acquired weakness, our case suggests that appropriate rehabilitative intervention according to the severity of the condition and continuous rehabilitation may improve the patients' activities of daily living and physical function.

5-Aminolevrinic Acid Exhibits Dual Effects on Stemness in Human Sarcoma Cell Lines under Dark Conditions.

5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a metabolite of HO-1, was administered to sarcoma cells via carbon-monoxide-releasing molecule 2 (CORM2), it enhanced sphere-forming ability. We also compared the concentration of biliverdin (BVD) (a co-product of HO-1 activity alongside CO) with sphere-forming ability when HO-1 activity was inhibited using ZnPPIX in the dark. Both cell types showed a peak in sphere-forming ability at 60-80 µM BVD. Furthermore, a cell death inhibitor assay revealed that the HO-1-induced suppression of sphere formation was rescued by apoptosis or ferroptosis inhibitors. These findings suggest that in the absence of excitation, ALA promotes HO-1 expression and enhances the stemness of sarcoma cells, although excessive HO-1 upregulation induces apoptosis and ferroptosis. Our data indicate that systemic ALA administration induces both enhanced stemness and cell death in malignant cells located in dark environments deep in the body and highlight the need to pay attention to drug delivery and ALA concentrations during phototherapy.

Development of CVD Silica Membranes Having High Hydrogen Permeance and Steam Durability and a Membrane Reactor for a Water Gas Shift Reaction.

Water gas shift reaction of carbon monoxide (CO) with membrane reactors should be a promising method for hydrogen mass-production because of its high CO conversion, high hydrogen purity and low carbon dioxide emission. For developing such membrane reactors, we need hydrogen permselective membranes with high hydrogen permeance with order of 10-6 mol m-2 s-1 Pa-1 at 573 K and high steam durability. In this study, we have optimized the kind of substrates, precursors, vapor concentration, and chemical vapor deposition (CVD) time using the counter-diffusion CVD method for developing such membranes. The developed membrane prepared from hexamethyldisiloxane has a hydrogen permeance of 1.29 × 10-6 mol m-2 s-1 Pa-1 at 573 K and high steam durability. We also conducted water gas shift reactions with membrane reactors installed the developed silica membranes. The results indicated that reactions proceed efficiently with the conversion around 95-97%, hydrogen purity around 94%, and hydrogen recovery around 60% at space velocity (SV) 7000.