Cadmium (Cd) toxicity poses a significant threat to cellular health, leading to oxidative stress and cell damage. Antioxidant agents, particularly those of natural origin, have been studied as a potential alternative for mitigating heavy metal toxicity. This study aimed to evaluate the cytoprotective effects of the antioxidant melatonin (MLT) in comparison with Vitamin E (VitE) and Trolox against Cd2+-induced cellular toxicity. The MTT assay was employed to assess cell viability in neuronal SH-SY5Y, colorectal HCT 116, and hepatic HepG2 cell lines. The results showed that all three antioxidants offered some level of protection against Cd toxicity, with Vitamin E proving to be the most effective. MLT also demonstrated a substantial cytoprotective effect, especially at the highest Cd concentration of 30 µM. These findings suggest that MLT, alongside Vit E and Trolox, could be valuable in mitigating the detrimental effects of Cd exposure by reducing the oxidative stress in these cellular models.

Excessive reactive oxygen species (ROS) can lead to the imbalance of antioxidant system in the body and cause oxidative damage to cells. It is imperative to rationally design nanomaterials with high catalytic activity and multiple antioxidant activities. Here, line peppers-derived carbon dots (CDs) is encapsulated into zeolitic imidazolate framework-8 (CDs@ZIF-8) to achieve enhanced antioxidant activities for improved protective effect on cells. This nanosystem has a broad spectrum of antioxidant properties, which can effectively remove a variety of intracellular ROS and protect cells from ROS-induced death and cytoskeleton damage. In addition, CDs@ZIF-8 can reduce malondialdehyde (MDA) level and increase the enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), as well as the level of glutathione (GSH) in human kidney proximal tubular epithelial cells (HK-2) cells. Mechanism studies demonstrated that CDs@ZIF-8 can up-regulate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), allowing the regulation of antioxidant enzymes to further achieve antioxidant effect. Besides, CDs@ZIF-8 inhibited the secretion of proinflammatory cytokines. This work demonstrates that the constructed CDs@ZIF-8 with multi-antioxidant activity can act as a highly efficient intracellular ROS scavenger and provide potential for the application in related oxidative stress-induced diseases.

All living organisms - from single-celled prokaryotes through to invertebrates and humans - are frequently exposed to numerous challenges during their lifetime, which could damage their molecular and cellular contents and threaten their survival. Nevertheless, these diverse organisms are, on the whole, remarkably resilient to potential threats. Recent years have seen rapid advances in our mechanistic understanding of this emerging phenomenon of biological resilience, which enables cells, tissues and whole organisms to bounce back from challenges or stress. In this At a Glance article, I discuss current knowledge on the diverse molecular mechanisms driving biological resilience across scales, with particular focus on its dynamic and adaptive nature. I highlight emerging evidence that loss of biological resilience could underly numerous pathologies, including age-related frailty and degenerative disease. Finally, I present the multi-disciplinary experimental approaches that are helping to unravel the causal mechanisms of resilience and how this emerging knowledge could be harnessed therapeutically in the clinic.

BACKGROUND: Despite substantial improvement of acute ischemic stroke (AIS) care with the advent of extended time windows for intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), a substantial portion of patients still suffer poor outcomes. Additional adjuvant therapies are needed but pharmacologic interactions among therapies may dictate how they could be used. We conducted a survey to determine physician decision-making regarding the use of cytoprotective agents in patients presenting with AIS.
METHODS: The survey was structured, web-based, anonymous, and invite-only among physicians across the world treating patients presenting with AIS. Respondents were asked about the use of a hypothetical cytoprotective agent (that provided an added 10% benefit) in the context of a treatment interaction with IVT or its timing in relation to IVT.
RESULTS: A total of 282 stroke physicians (74.9% males, mean age 46 years) participated in the survey. When the respondent could give both the cytoprotective agent and IVT with no treatment interaction, 177 (78.0%) chose to administer both. In the presence of treatment interaction, 88 (38.3%) would withhold IVT, 83 (36.1%) would withhold the cytoprotective agent and 56 (24.4%) were uncertain. Lastly, 111 (48.9%) were willing to administer the cytoprotective agent if it meant a necessary 10-minute delay in IVT administration.
CONCLUSIONS: Pharmacologic interactions result in major uncertainty about cytoprotective treatment choices.

Protective effect of quercetin against acetaldehyde was evaluated using the cultured hepatocyte models with aldehyde dehydrogenase (ALDH) isozyme deficiency (aldh2-kd and aldh1a1-kd). The quercetin-induced cytoprotection against acetaldehyde in the ALDH1A1-deficient mutant (aldh1a1-kd) was weaker than that in wild type. Furthermore, quercetin did not enhance the ALDH activity in aldh1a1-kd cells, suggesting that ALDH1A1 is involved in the quercetin-induced cytoprotection.

Since the early 1990s, when Robert\'s and Szabo\'s cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain-gut and gut-brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.

The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism of resistance is the promotion of autophagy, which is a direct consequence of the inhibition of the mTOR signaling pathway. Autophagy is primarily considered to be a cytoprotective survival mechanism, whereby cytoplasmic components are recycled to generate energy and metabolic intermediates. The autophagy induced by everolimus and temsirolimus appears to play a largely protective function, whereas a cytotoxic function appears to predominate in the case of rapamycin. In this review we provide an overview of the autophagy induced in response to mTOR inhibitors in different tumor models in an effort to determine whether autophagy targeting could be of clinical utility as adjuvant therapy in association with mTOR inhibition.

The serotonin type 6 receptor (5-HT6R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT6R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT6R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT6R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT6R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT6R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT6R and provide insight into the glioprotective properties of 5-HT6R neutral antagonists at Gs signaling.

Cell death-inducing p53-target protein 1 (CDIP1) is a proapoptotic protein that is normally expressed at low levels and is upregulated by genotoxic and endoplasmic reticulum stresses. CDIP1 has been reported to be localized to endosomes and to interact with several proteins, including B-cell receptor-associated protein 31 (BAP31) and apoptosis-linked gene 2 (ALG-2). However, the cellular and molecular mechanisms underlying CDIP1 expression-induced apoptosis remain unclear. In this study, we first demonstrated that CDIP1 was upregulated after treatment with the anticancer drug adriamycin in human breast cancer MCF-7 cells but was degraded rapidly in the lysosomal pathway. We also demonstrated that treatment with the cyclin-dependent kinase 5 (CDK5) inhibitor roscovitine led to an increase in the electrophoretic mobility of CDIP1. In addition, a phosphomimetic mutation at Ser-32 in CDIP1 resulted in an increase in CDIP1 expression-induced apoptosis. We also found that CDIP1 expression led to the induction of autophagy prior to apoptosis. Treatment of cells expressing CDIP1 with SAR405, an inhibitor of the class III phosphatidylinositol 3-kinase VPS34, caused a reduction in autophagy and promoted apoptosis. Therefore, autophagy is thought to be a defense mechanism against CDIP1 expression-induced apoptosis.

Doxorubicin (DOX) is an effective anticancer agent, yet its clinical utility is hampered by dose-dependent cardiotoxicity. This study explores the cardioprotective potential of Marein (Mar) against DOX-induced cardiac injury and elucidates underlying molecular mechanisms. Neonatal rat cardiomyocytes (NRCMs) and murine models were employed to assess the impact of Mar on DOX-induced cardiotoxicity (DIC). In vitro, cell viability, oxidative stress were evaluated. In vivo, a chronic injection method was employed to induce a DIC mouse model, followed by eight weeks of Mar treatment. Cardiac function, histopathology, and markers of cardiotoxicity were assessed. In vitro, Mar treatment demonstrated significant cardioprotective effects in vivo, as evidenced by improved cardiac function and reduced indicators of cardiac damage. Mechanistically, Mar reduced inflammation, oxidative stress, and apoptosis in cardiomyocytes, potentially via activation of the Focal Adhesion Kinase (FAK)/AKT pathway. Mar also exhibited an anti-ferroptosis effect. Interestingly, Mar did not compromise DOX\'s efficacy in cancer cells, suggesting a dual benefit in onco-cardiology. Molecular docking studies suggested a potential interaction between Mar and FAK. This study demonstrates Mar\'s potential as a mitigator of DOX-induced cardiotoxicity, offering a translational perspective on its clinical application. By activating the FAK/AKT pathway, Mar exerts protective effects against DOX-induced cardiomyocyte damage, highlighting its promise in onco-cardiology. Further research is warranted to validate these findings and advance Mar as a potential adjunctive therapy in cancer treatment.