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Shikonin, an herbal naphthoquinone, demonstrates a broad spectrum of pharmacological properties. Owing to increasingly adverse environmental conditions, human skin is vulnerable to harmful influences from dust particles. This study explored the antioxidant capabilities of shikonin and its ability to protect human keratinocytes from oxidative stress induced by fine particulate matter (PM2.5). We found that shikonin at a concentration of 3 µM was nontoxic to human keratinocytes and effectively scavenged reactive oxygen species (ROS) while increasing the production of reduced glutathione (GSH). Furthermore, shikonin enhanced GSH level by upregulating glutamate‐cysteine ligase catalytic subunit and glutathione synthetase mediated by nuclear factor‐erythroid 2‐related factor. Shikonin reduced ROS levels induced by PM2.5, leading to recovering PM2.5‐impaired cellular biomolecules and cell viability. Shikonin restored the GSH level in PM2.5‐exposed keratinocytes via enhancing the expression of GSH‐synthesizing enzymes. Notably, buthionine sulphoximine, an inhibitor of GSH synthesis, diminished effect of shikonin against PM2.5‐induced cell damage, confirming the role of GSH in shikonin‐induced cytoprotection. Collectively, these findings indicated that shikonin could provide substantial cytoprotection against the adverse effects of PM2.5 through direct ROS scavenging and modulation of cellular antioxidant system. [ABSTRACT FROM AUTHOR]

It is still unclear whether or how quercetin influences the toxic events induced by acetaldehyde in hepatocytes, though quercetin has been reported to mitigate alcohol-induced mouse liver injury. In this study, we evaluated the modulating effect of quercetin on the cytotoxicity induced by acetaldehyde in mouse hepatoma Hepa1c1c7 cells, the frequently used cellular hepatocyte model. The pretreatment with quercetin significantly inhibited the cytotoxicity induced by acetaldehyde. The treatment with quercetin itself had an ability to enhance the total ALDH activity, as well as the ALDH1A1 and ALDH3A1 gene expressions. The acetaldehyde treatment significantly enhanced the intracellular reactive oxygen species (ROS) level, whereas the quercetin pretreatment dose-dependently inhibited it. Accordingly, the treatment with quercetin itself significantly up-regulated the representative intracellular antioxidant-related gene expressions, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase, catalytic subunit (GCLC), and cystine/glutamate exchanger (xCT), that coincided with the enhancement of the total intracellular glutathione (GSH) level. Tin protoporphyrin IX (SNPP), a typical HO-1 inhibitor, restored the quercetin-induced reduction in the intracellular ROS level, whereas buthionine sulphoximine, a representative GSH biosynthesis inhibitor, did not. SNPP also cancelled the quercetin-induced cytoprotection against acetaldehyde. These results suggest that the low-molecular-weight antioxidants produced by the HO-1 enzymatic reaction are mainly attributable to quercetin-induced cytoprotection. [ABSTRACT FROM AUTHOR]

Background and Purpose: IL‐11 is a member of the IL‐6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL‐11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow‐derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL‐11 on fibrocytes is unknown. We investigated the role of IL‐11 system on fibrocyte activation in different in vitro and in vivo models of lung fibrosis associated with pulmonary hypertension. Experimental Approach: Human fibrocytes were isolated from peripheral blood of six healthy donors. Recombinant human (rh)‐IL‐11 and soluble rh‐IL‐11 receptor, α subunit (IL‐11Rα) were used to stimulated fibrocytes in vitro to measure:‐ cell migration in a chemotactic migration chamber, fibrocyte to endothelial cell adhesion in a microscope‐flow chamber and fibrocyte to myofibroblast transition. Mouse lung fibrosis and pulmonary hypertension was induced using either IL‐11 (s.c.) or bleomycin (intra‐tracheal), while in the rat monocrotaline (intra‐tracheal) was used. In vivo siRNA‐IL‐11 was administered to suppress IL‐11 in vivo. Key Results: RhIL‐11 and soluble rhIL‐11Rα promote fibrocyte migration, endothelial cell adhesion and myofibroblast transition. Subcutaneous (s.c.) IL‐11 infusion elevates blood, bronchoalveolar and lung tissue fibrocytes. SiRNA‐IL‐11 transfection in bleomycin and monocrotaline animal models reduces blood and lung tissue fibrocytes and reduces serum CXCL12 and CXCL12/CXCR4 lung expression. Conclusion and Implications: Targeting IL‐11 reduces fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension‐associated lung fibrosis. [ABSTRACT FROM AUTHOR]

The therapeutic potential of autologous stem cell transplantation for heart repair diminishes in the elderly due to stem cell aging. Rejuvenating aged stem cells to enhance their protective effects on injured cardiomyocytes is crucial for aging patients with heart failure. In this study, we aimed to investigate whether neuron-derived neurotrophic factor (NDNF) over-expression improves the protective effect of aged stem cells for injured cardiomyocytes and explore the underlying mechanism. Human bone marrow was collected from both young and old patients, and bone marrow mesenchymal stem cells (BMSCs) were cultured. Lentivirus expression vectors carrying NDNF genes were used to transfect aged BMSCs. Fatal hypoxia-induced injury in H9C2 cells served as an in vitro ischemia model. The conditioned medium from different BMSC groups was applied to assess the beneficial effects on hypoxia-induced damage in myocardial H9C2 cells. Results revealed that the conditioned medium of NDNF over-expressed old BMSCs increased H9C2 cell viability and reduced oxidative stress and apoptosis levels under fatal hypoxia. NDNF over-expressed old BMSCs exhibited an antiapoptotic role by upregulating the antiapoptotic gene Bcl-2 and downregulating the proapoptotic genes Bax. Additionally, the protective effects were mediated through the elevation of phosphorylated AKT. Our data support the promise of NDNF as a potential target to enhance the protective effects of autologous aged BMSCs on ischemic cardiomyocytes and then improve the curative effects of stem cell for ischemic heart injury in aged patients. [ABSTRACT FROM AUTHOR]

Background: Preservation of organ function and viability is a crucial factor for survival in cardiogenic shock (CS) patients. There is not information enough on cytoprotective substances that may delay organs damage in CS. We hypothesize that cytidine-5-diphosphocholine (CDP-choline) can act as a cytoprotective pharmacological measure that diminishes the target organ damage. So, we aimed to perform a review of works carried out in our institution to evaluate the effect of therapeutic cytoprotection of the CDP-choline. Summary: CDP-choline is an intermediate metabolite in the synthesis of phosphatidylcholine. It is also a useful drug for the treatment of acute ischaemic stroke, traumatic brain injury, and neurodegenerative diseases and has shown an excellent pharmacological safety profile as well. We review our institution's work and described the cytoprotective effects of CDP-choline in experimental models of heart, liver, and kidney acute damage, where this compound was shown to diminish reperfusion-induced ventricular arrhythmias, oxidative stress, apoptotic cell death, inflammation, lactic acid levels and to preserve mitochondrial function. Key Messages: We propose that additional research is needed to evaluate the impact of cytoprotective therapy adjuvant to mitigate target organ damage in patients with CS. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

In this study, antioxidant peptides derived from sheep hemoglobin were prepared from fresh sheep blood. Sephadex G-25 chromatography, DEAE Sephadex A-50 chromatography, reverse phase high performance liquid chromatography (RP-HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to separate, purify, and identify peptides from the hydrolysate of sheep hemoglobin. The antioxidant activity of the obtained peptides was evaluated by their free radical scavenging capacity, stability against simulated gastrointestinal digestion and protective effect on H2O2-induced oxidative injury in Caco-2 cells. The results indicated that three novel antioxidant peptides, Ala-Tyr-Glu-Val-Asp (AYEVD), Phe-His-Thr-Met-Glu (FHTME) and Ser-Phe-Met-Tyr-Glu-Lys (SFMYEK), were purified and identified from the hydrolysate, with molecular masses of 595.60, 663.74 and 803.92 Da, respectively. Among them, AYEVD had the strongest scavenging capacity to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, and AYEVD showed stronger antioxidant activity after simulated gastrointestinal digestion. In addition, AYEVD inhibited H2O2-induced oxidative injury in Caco-2 cells, significantly reduced the accumulation of reactive oxygen species (ROS), suppressed early cell apoptosis and the formation of malondialdehyde (MDA), and increased the activity of intracellular antioxidant enzymes. Therefore, this study could provide a theoretical basis for the application of novel antioxidant peptides from sheep hemoglobin in functional foods.

Magnoliae Flos (MF) is a medicinal herb widely employed in traditional medicine for relieving sinusitis, allergic rhinitis, headaches, and toothaches. Here, we investigated the potential preventive effects of MF extract (MFE) against 4-vinylcyclohexene diepoxide (VCD)-induced ovotoxicity in ovarian cells and a mouse model of premature ovarian insufficiency (POI). The cytoprotective effects of MFE were assessed using CHO-K1 or COV434 cells. In vivo, B6C3F1 female mice were intraperitoneally injected with VCD for two weeks to induce POI, while MFE was orally administered for four weeks, beginning one week before VCD administration. VCD led to a significant decline in the viabilities of CHO-K1 and COV434 cells and triggered excessive reactive oxygen species (ROS) production and apoptosis specifically in CHO-K1 cells. However, pretreatment with MFE effectively prevented VCD-induced cell death and ROS generation, while also activating the Akt signaling pathway. In vivo, MFE increased relative ovary weights, follicle numbers, and serum estradiol and anti-Müllerian hormone levels versus controls under conditions of ovary failure. Collectively, our results demonstrate that MFE has a preventive effect on VCD-induced ovotoxicity through Akt activation. These results suggest that MFE may have the potential to prevent and manage conditions such as POI and diminished ovarian reserve. [ABSTRACT FROM AUTHOR]

The silencing regulatory factor 2-like protein 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent deacetylase located primarily in the mitochondria. This protein plays an important role in oxidative stress, energy metabolism, and autophagy in multicellular organisms. Autophagy (macroautophagy) is primarily a cytoprotective mechanism necessary for intracellular homeostasis and the synthesis, degradation, and recycling of cellular products. Autophagy can influence the progression of several neural, cardiac, hepatic, and renal diseases and can also contribute to the development of fibrosis, diabetes, and many types of cancer. Recent studies have shown that SIRT3 has an important role in regulating autophagy. Therefore in this study, we aimed to perform a literature review to summarize the role of SIRT3 in the regulation of cellular autophagy. The findings of this study could be used to identify new drug targets for SIRT3-related diseases. Methods: A comprehensive literature review of the mechanism involved behind SIRT3 and autophagy-related diseases was performed. Relevant literature published in Pubmed and Web of Science up to July 2023 was identified using the keywords "silencing regulatory factor 2-like protein 3", "SIRT3" and "autophagy". [ABSTRACT FROM AUTHOR]

The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-actylglucosamine (O-GlcNAc) is an essential posttranslational modification that is common in metozoans. O-GlcNAc is cycled on and off proteins in response to environmental and physiological stimuli impacting protein function, which, in turn, tunes pathways that include transcription, translation, proteostasis, signal transduction, and metabolism. One class of stimulus that induces rapid and dynamic changes to O-GlcNAc is cellular injury, resulting from environmental stress (for instance, heat shock), hypoxia/reoxygenation injury, ischemia reperfusion injury (heart attack, stroke, trauma hemorrhage), and sepsis. Acute elevation of O-GlcNAc before or after injury reduces apoptosis and necrosis, suggesting that injury-induced changes in O-GlcNAcylation regulate cell fate decisions. However, prolonged elevation or reduction in O-GlcNAc leads to a maladaptive response and is associated with pathologies such as hypertrophy and heart failure. In this review, we discuss the impact of O-GlcNAc in both acute and prolonged models of injury with a focus on the heart and biological mechanisms that underpin cell survival. [ABSTRACT FROM AUTHOR]

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There is a worrying scarcity of drug options for patients with severe COVID-19. Glycine possesses anti-inflammatory, cytoprotective, endothelium-protective, and platelet-antiaggregant properties, so its use in these patients seems promising. In this open label, controlled clinical trial, inpatients with severe COVID-19 requiring mechanical ventilation randomly received usual care (control group) or usual care plus 0.5 g/kg/day glycine by the enteral route (experimental group). Major outcomes included mortality, time to weaning from mechanical ventilation, total time on mechanical ventilation, and time from study recruitment to death. Secondary outcomes included laboratory tests and serum cytokines. Patients from experimental (n = 33) and control groups (n = 23) did not differ in basal characteristics. There were no differences in mortality (glycine group, 63.6% vs control group, 52.2%, p = 0.60) nor in any other major outcome. Glycine intake was associated with lower fibrinogen levels, either evaluated per week of follow-up (p < 0.05 at weeks 1, 2, and 4) or as weighted mean during the whole hospitalization (608.7 ± 17.7 mg/dl vs control 712.2 ± 25.0 mg/dl, p = 0.001), but did not modify any other laboratory test or cytokine concentration. In summary, in severe COVID-19 glycine was unable to modify major clinical outcomes, serum cytokines or most laboratory tests, but was associated with lower serum fibrinogen concentration. Registration: ClinicalTrials.gov NCT04443673, 23/06/2020. [ABSTRACT FROM AUTHOR]

Nowadays, the unique features of nanoparticles (NPs) have encouraged new applications in different areas including biology, medicine, agriculture, and electronics. Their quick joining into daily life not only enhances the uses of NPs in a wide range of modern technologies but also their release into the aquatic environment causes inevitable environmental concerns. On the other hand boron exhibits key physiological effects on biological systems. This research was designed for evaluating the toxicity of magnetite nanoparticles (Fe3O4-MNPs) on aquatic organisms and obtaining data for the information gap in this area. In this study, Rainbow trout (Oncorhynchus mykiss) was considered as an aquatic indicator, and trials were designed as Ulexite (a boron mineral, UX) treatment against exposure to Fe3O4-MNPs. Synthesized and characterized Fe3O4-MNPs were exposed to rainbow trouts in wide spectrum concentrations (0.005–0.08 mL/L) to analyze its lethal dose (LC50) and cytoprotective properties by UX treatment were assessed against Fe3O4-MNPs applications for 96 h. For the initial toxicity analysis, hematological parameters (blood cell counts) were examined in experimental groups and micronucleus (MN) assay was performed to monitor nuclear abnormalities after exposure to NPs. Biochemical analyzes in both blood and liver samples were utilized to assess antioxidant/oxidative stress and inflammatory parameters. Also, 8-hydroxy-2'-deoxyguanosine (8-OHdG) assay was used to investigate oxidative DNA lesions and Caspase-3 analysis was performed on both blood and liver tissues to monitor apoptotic cell death occurrence. When antioxidant enzymes in blood and liver tissue were examined, time-dependent decreases in activity were determined in SOD, CAT, GPx, and GSH enzymes, while increased levels of MDA and MPO parameters were observed in respect to Fe3O4-MNPs exposure. It was found that TNF-α, Il-6 levels were enhanced against Fe3O4-MNPs treatment, but Nrf-2 levels were decreased at the 46th and 96th h. In the 96th application results, all parameters were statistically significant (p < 0.05) in blood and liver tissue, except for the IL-6 results. It was determined that the frequency of MN, the level of 8-OHdG and caspase-3 activity increased in respect to Fe3O4-MNPs exposure over time. Treatment with UX alleviated Fe3O4-MNPs-induced hematotoxic and hepatotoxic alterations as well as oxidative and genetic damages. Our findings offer strong evidence for the use of UX as promising, safe and natural protective agents against environmental toxicity of magnetite nanoparticles. [ABSTRACT FROM AUTHOR]

Though crucial for natural bone healing, local calcium ion (Ca2+) and phosphate ion (Pi) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H2S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca2+/Pi concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H2S donor, were applied to assess the influence of H2S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca2+ (32 mM) and/or Pi (16 mM). To controllably deliver H2S over time, a novel donor molecule (thioglutamic acid—GluSH) was synthesized and evaluated for its H2S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H2S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca2+/Pi concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H2S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications. [ABSTRACT FROM AUTHOR]

Oxidovanadium(V) complexes, [(+)VOL1-5] and [(–)VOL1-5], with chiral tetradentate Schiff bases, which are products of monocondensation of S(‒)-3-amino-1,2-propanediol or R(+)-3-amino-1,2-propanediol with salicylaldehyde derivatives, have been synthesized. Different spectroscopic methods, viz. 1H and 51V NMR, IR, UV-Vis, and circular dichroism, as well as elemental analysis, have been used for their detailed characterization. Furthermore, the epoxidation of styrene, cyclohexene, and two monoterpenes, S(‒)-limonene and (‒)-α-pinene, using two oxidants, aqueous 30% H2O2 or tert-butyl hydroperoxide (TBHP) in decane, has been studied with catalytic amounts of all complexes. Finally, biological cytotoxicity studies have also been performed with these oxidovanadium(V) compounds for comparison with cis-dioxidomolybdenum(VI) Schiff base complexes with the same chiral ligands, as well as to determine the cytoprotection against the oxidative damage caused by 30% H2O2 in the HT-22 hippocampal neuronal cells in the range of their 10–100 μM concentration. [ABSTRACT FROM AUTHOR]

Background: Cellular stress caused by noise-induced hearing loss can be observed through the damage of cochlear hair cells, mechanically and metabolically. SNR value on the DPOAE examination assesses the sensory function of cochlear outer hair cells. HSP70 as marker of cellular stress can be identified from its levels in blood and its expression in the cochlea. Methods: Three groups of rats were used for the noise intervention: Group 1 was the control group, Group 2 had a noise exposure of 100 dB, and Group 3 received a noise exposure of 110 dB. DPOAE examination was then conducted, blood samples from rats' tail were collected after a noise treatment, followed by the measurement of HSP70 levels by ELISA readings. Rats were terminated afterwards and immunohistochemical examination of the cochlear organ of Corti was performed to calculate the expression of HSP70. The data obtained were analyzed using SPSS. Results: A decrease occurred in the values of SNR and an increase occurred in HSP70 levels in blood along with its expression in the cochlea of noise model Rattus norvegicus, and there is a correlation between the three. Conclusion: The decrease in SNR values, increase in HSP70 levels in blood, and increase in HSP70 expression in the cochlear organ of Corti of Rattus norvegicus, proves that noise-induced hearing loss triggers the production of HSP70 as a cytoprotective agent in preventing inner ear damage. [ABSTRACT FROM AUTHOR]

Despite the significant progress in the fields of biology, physiology, molecular medicine, and pharmacology; the designation of the properties of nitrogen monoxide in the regulation of life-supporting functions of the organism; and numerous works devoted to this molecule, there are still many open questions in this field. It is widely accepted that nitric oxide (•NO) is a unique molecule that, despite its extremely simple structure, has a wide range of functions in the body, including the cardiovascular system, the central nervous system (CNS), reproduction, the endocrine system, respiration, digestion, etc. Here, we systematize the properties of •NO, contributing in conditions of physiological norms, as well as in various pathological processes, to the mechanisms of cytoprotection and cytodestruction. Current experimental and clinical studies are contradictory in describing the role of •NO in the pathogenesis of many diseases of the cardiovascular system and CNS. We describe the mechanisms of cytoprotective action of •NO associated with the regulation of the expression of antiapoptotic and chaperone proteins and the regulation of mitochondrial function. The most prominent mechanisms of cytodestruction—the initiation of nitrosative and oxidative stresses, the production of reactive oxygen and nitrogen species, and participation in apoptosis and mitosis. The role of •NO in the formation of endothelial and mitochondrial dysfunction is also considered. Moreover, we focus on the various ways of pharmacological modulation in the nitroxidergic system that allow for a decrease in the cytodestructive mechanisms of •NO and increase cytoprotective ones. [ABSTRACT FROM AUTHOR]

Increased oxidative stress is one of the critical pathologies inducing age-related macular degeneration (AMD), characterized by retinal pigment epithelial (RPE) cell damage and death. The unbalanced acetylation and deacetylation of histones have been implicated in AMD pathogenesis or hydrogen peroxide (H2O2)-induced cell damage. Therefore, strategies aimed at controlling the balance between acetylation and deacetylation may effectively protect RPE cells from oxidative damage. Artemisinin is an antimalarial lactone drug derived from Artemisia annua, with antioxidant activity known to modulate histone acetylation in the brain, but its effect on the retina is unknown. In this study, we aimed to investigate whether Artemisinin exerts a cytoprotective effect on oxidative stress-induced apoptosis in RPE cells by regulating histone acetylation. We hypothesized that Artemisinin confers cytoprotection toward H2O2-induced apoptosis in RPE cells through this mechanism. In the present study, we found that Artemisinin at a sub-clinic dosage of 20 μM inhibited the H2O2-induced cell viability decrease and B-cell lymphoma 2 (Bcl-2) protein level decrease and attenuated the H2O2-induced decrease in the histone H4 lysine (Lys) 8 acetylation [Acetyl-H4 (Lys 8)] level in the retinal RPE cell line D407. As expected, histone deacetylase inhibitor Trichostatin A at the concentration of 250 nM increased the Acetyl-H4 (Lys 8) level in D407 cells and attenuated the H2O2-induced cell viability decrease and apoptosis. Similar findings were obtained using adult RPE (ARPE)19 cells, another human RPE cell line, and primary human RPE cell cultures. In conclusion, these results confirmed our hypothesis and indicated that Artemisinin attenuated H2O2-induced apoptosis in apparent correlation with the increase in the Acetyl-H4 (Lys 8) level, which is associated with gene transcription and cell survival. By modulating histone acetylation, Artemisinin may restore the balance between acetylation and deacetylation and enhance the resistance and survival of RPE cells under oxidative stress. Our study provides novel mechanistic insights into the effect of Artemisinin on histone acetylation and apoptosis in RPE cells and supports the potential application of Artemisinin in the prevention and/or treatment of AMD. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are implicated in various pathological conditions due to their ability to induce oxidative damage to cellular components. In this study, we investigated the antioxidant properties of a peptide isolated from the hydrolysate of Manila clam (Ruditapes philippinarum) muscle. Purification steps yielded RPTE2-2-4, exhibiting potent scavenging activities against DPPH•, HO•, and O2•−, akin to Vitamin C. Structural analysis showed that the isolated peptide, LFKKNLLTL, exhibited characteristics associated with antioxidant activity, including a short peptide length and the presence of aromatic and hydrophobic amino acid residues. Moreover, our study demonstrated the cytoprotective effects of the peptide against H2O2-induced oxidative stress in HepG2 cells. Pretreatment with the peptide resulted in a dose-dependent reduction in intracellular ROS levels and elevation of glutathione (GSH) levels, indicating its ability to modulate cellular defense mechanisms against oxidative damage. Furthermore, the peptide stimulated the expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), further reinforcing its antioxidant properties. Overall, our findings highlight the potential of the Manila clam-derived peptide as a natural antioxidant agent with therapeutic implications for oxidative stress-related diseases. Further investigation into its mechanisms of action and in vivo efficacy is warranted to validate its therapeutic potential. [ABSTRACT FROM AUTHOR]

We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application. [ABSTRACT FROM AUTHOR]

Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS. [ABSTRACT FROM AUTHOR]

Introduction Diabetes mellitus is a chronic metabolic disease that affects a large fraction of the world’s population. In addition to the many complications associated with it, the lack of effectiveness and insufficiency of current treatments have driven the WHO to return to traditional medicine, which generally involves the use of plant materials as remedies. Purpose This study investigates the protective effects of Dioscorea alata and D. rotundata extracts on the liver, pancreas, and kidney in alloxan-induced diabetic guinea pigs. Methods Diabetes was induced by a single intraperitoneal injection of alloxan (150 mg/kg). Post-induction, guinea pigs (Cavia porcellus L.) were treated orally with Dioscorea alata and D. rotundata extracts (200 mg/kg and 400 mg/kg, respectively) for 21 days. The liver, pancreas, and kidneys were assessed for histopathological changes. Two standard synthetic antidiabetics (insulin 5 IU/100g and glibenclamide 5 mg/kg) were used as positive controls. Results Histopathological examination revealed marked improvement in the tissue morphology of the liver, pancreas, and kidneys in the treated groups compared to the untreated group. The renal parenchyma showed a fairly normal structure, with the Malpighian glomerulus clearly visible, exhibiting hyperplastic cell nuclei in full regeneration. Conclusion Tuber extracts from these two yam species have shown potential to repair and regenerate tissue damaged by the deleterious effects of alloxan-induced free radicals and permanent hyperglycemia during diabetes. The evident antidiabetic and cytoprotective potential of these plant species could be utilized for the development of biologically active natural molecules for the treatment of diabetes mellitus and its complications. The study is limited by its short duration, and further long-term studies with varied dosage regimens are recommended to better understand the effects of these extracts. Additional research should explore the specific bioactive compounds responsible for the observed protective effects and their mechanisms of action.

Neurodegenerative disorders are difficult to treat because of natural barrier in the brain. Moreover, neurovascular units seem to be essential targets/mediators of the nervous system cytoprotective effects. Functionalized nanomaterials have gained significant prominence in the medical domain due to their extensive utilization in targeted drug delivery and therapeutics within the neurovascular system. Their remarkable potential in neurovascular therapy has been demonstrated, highlighting their effectiveness in this field. A systematic summary of the specific applications and limitations of functionalized nanomaterials in the targeted delivery system is essential for developing smart therapies to overcome the gaps in neurovascular therapy for the treatment of neurological disorders. The objective of present article was to highlight the advancements in recent therapies support the potential role of functionalized nanomaterials to tackle the difficulties in targeted delivery systems for neurodegenerative disorders. We review the role of functionalized nanomaterials as therapeutics within the neurovascular units and their potential to lead to more sophisticated and smart treatment techniques despite some obstacles, given to the patients of neurological disorders, particularly when paired with multimodal drugs who are likely to benefit from cytoprotection. This review also addresses the current understanding, gaps, and issues to be resolved.

Cisplatin is a prominent chemotherapeutic agent that can induce significant damage to normal cells. Therefore, it is important to develop agents that protect normal cells without influencing the chemotherapeutic effect of cisplatin. The present study was conducted to explore the protective effects of Annona muricata leaf polysaccharides (ALPS) against cisplatin‑induced toxicity in macrophages. Apoptosis was assessed in macrophages and lung cancer cells to investigate the cytoprotective effect of ALPS, their effect on the production of cisplatin‑induced reactive oxygen species (ROS) and the loss of the mitochondrial transmembrane potential (MTP). Cisplatin, when used alone or in combination with ALPS, showed significant toxicity against A549 and H460 lung cancer cells. However, cisplatin‑induced cytotoxicity was suppressed by cotreatment of RAW 264.7 macrophages with ALPS. ALPS significantly inhibited the upregulation of Bax, cytosolic cytochrome c and caspases‑3, ‑8 and ‑9. Moreover, ALPS resulted in the cleavage of PARP and downregulation of Bcl‑2 levels in a concentration‑dependent manner, which ultimately led to a reduction in the apoptotic and necrotic populations of cisplatin‑treated RAW 264.7 macrophages. The suppression of the apoptotic signaling pathways was mediated through the reduction of ROS and MTP loss in cisplatin‑treated RAW 264.7 macrophages. In addition, ALPS alleviated cell damage by suppressing the mitochondrial apoptotic pathways in cisplatin‑treated bone marrow‑derived macrophages. Together, these findings suggested that ALPS may alleviate the toxic side effects of chemotherapeutic agents and act as a potential candidate for use as an effective adjuvant therapy.

Introduction: Dysfunction of the endothelium impairs its' protective role and promotes inflammation and progression of vascular diseases. Activated Protein C (APC) elicits endothelial cytoprotective responses including barrier stabilization, anti-inflammatory and anti-apoptotic responses through the activation of the G protein-coupled receptor (GPCR) protease-activated receptor-1 (PAR1) and is a promising therapeutic. Despite recent advancements in developing new Activated protein C variants with clinical potential, the mechanism by which APC/PAR1 promotes different cytoprotective responses remains unclear and is important to understand to advance Activated protein C and new targets as future therapeutics. Here we examined the mechanisms by which APC/PAR1 attenuates cytokine-induced pro-inflammatory vascular cell adhesion molecule (VCAM-1) expression, a key mediator of endothelial inflammatory responses. Methods: Quantitative multiplexed mass spectrometry analysis of Activated protein C treated endothelial cells, endothelial cell transcriptomics database (EndoDB) online repository queries, biochemical measurements of protein expression, quantitative real-time polymerase chain reaction (RT-qPCR) measurement of mRNA transcript abundance, pharmacological inhibitors and siRNA transfections of human cultured endothelial cells. Results: Here we report that Activated Protein C modulates phosphorylation of tumor necrosis factor (TNF)-α signaling pathway components and attenuates of TNF-α induced VCAM-1 expression independent of mRNA stability. Unexpectedly, we found a critical role for the G protein-coupled receptor co-receptor sphingosine-1 phosphate receptor-1 (S1PR1) and the G protein receptor kinase-2 (GRK2) in mediating APC/PAR1 anti-inflammatory responses in endothelial cells. Discussion: This study provides new knowledge of the mechanisms by which different APC/PAR1 cytoprotective responses are mediated through discrete β-arrestin-2-driven signaling pathways modulated by specific G protein-coupled receptor co-receptors and GRKs.

Abstract Background Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of chemotherapy, with an estimated incidence of 65% and limited treatment options. Cyclophosphamide (CYP) is a common alopecia-inducing chemotherapy agent. Human dental pulp stem cells (DPSCs) secrete several paracrine factors that up-regulate hair growth. Conditioned medium (CM) collected from DPSCs (DPSC-CM) promotes hair growth; culturing mesenchymal stem cells under hypoxic conditions can enhance this effect. Methods The effect of DPSC-CM cultured under normoxic (N-) and hypoxic (H-) conditions against CYP-mediated cytotoxicity in keratinocytes was examined using cell viability assay, lactate dehydrogenase (LDH) cytotoxicity assay, and apoptosis detection. The damage-response pathway was determined in a well-established CIA mouse model by analyzing macroscopic effects, histology, and apoptosis. Reverse transcription-quantitative PCR and Caspase-3/7 activity assay were used to investigate the impact of DPSC-CM on the molecular damage-response pathways in CYP-treated mice. The effect of post-CIA DPSC-CM application on post-CIA hair regrowth was analyzed by macroscopic effects and microstructure observation of the hair surface. Furthermore, to investigate the safety of DPSC-CM as a viable treatment option, the effect of DPSC-CM on carcinoma cell lines was examined by cell viability assay and a subcutaneous tumor model. Results In the cell viability assay, DPSC-CM was observed to increase the number of keratinocytes over varying CYP concentrations. Furthermore, it reduced the LDH activity level and suppressed apoptosis in CYP-treated keratinocytes. DPSC-CM exhibited the cytoprotective role in vivo via the dystrophic anagen damage-response pathway. While both N-CM and H-CM downregulated the Caspase-3/7 activity level, H-CM downregulated Caspase-3 mRNA expression. The proportion of post-CIA H-CM-treated mice with > 90% normal hair was nearly twice that of vehicle- or N-CM-treated mice between days 50 and 59 post-depilation, suggesting that post-CIA H-CM application may accelerate hair regrowth and improve hair quality. Furthermore, DPSC-CM suppressed proliferation in vitro in certain carcinoma cell lines and did not promote the squamous cell carcinoma (SCC-VII) tumor growth rate in mice. Conclusions The potentiality of DPSC-CM and H-CM as a promising cytoprotective agent and hair regrowth stimulant, respectively, for CIA needs in-depth exploration.

Background: Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of chemotherapy, with an estimated incidence of 65% and limited treatment options. Cyclophosphamide (CYP) is a common alopecia-inducing chemotherapy agent. Human dental pulp stem cells (DPSCs) secrete several paracrine factors that up-regulate hair growth. Conditioned medium (CM) collected from DPSCs (DPSC-CM) promotes hair growth; culturing mesenchymal stem cells under hypoxic conditions can enhance this effect. Methods: The effect of DPSC-CM cultured under normoxic (N-) and hypoxic (H-) conditions against CYP-mediated cytotoxicity in keratinocytes was examined using cell viability assay, lactate dehydrogenase (LDH) cytotoxicity assay, and apoptosis detection. The damage-response pathway was determined in a well-established CIA mouse model by analyzing macroscopic effects, histology, and apoptosis. Reverse transcription-quantitative PCR and Caspase-3/7 activity assay were used to investigate the impact of DPSC-CM on the molecular damage-response pathways in CYP-treated mice. The effect of post-CIA DPSC-CM application on post-CIA hair regrowth was analyzed by macroscopic effects and microstructure observation of the hair surface. Furthermore, to investigate the safety of DPSC-CM as a viable treatment option, the effect of DPSC-CM on carcinoma cell lines was examined by cell viability assay and a subcutaneous tumor model. Results: In the cell viability assay, DPSC-CM was observed to increase the number of keratinocytes over varying CYP concentrations. Furthermore, it reduced the LDH activity level and suppressed apoptosis in CYP-treated keratinocytes. DPSC-CM exhibited the cytoprotective role in vivo via the dystrophic anagen damage-response pathway. While both N-CM and H-CM downregulated the Caspase-3/7 activity level, H-CM downregulated Caspase-3 mRNA expression. The proportion of post-CIA H-CM-treated mice with > 90% normal hair was nearly twice that of vehicle- or N-CM-treated mice between days 50 and 59 post-depilation, suggesting that post-CIA H-CM application may accelerate hair regrowth and improve hair quality. Furthermore, DPSC-CM suppressed proliferation in vitro in certain carcinoma cell lines and did not promote the squamous cell carcinoma (SCC-VII) tumor growth rate in mice. Conclusions: The potentiality of DPSC-CM and H-CM as a promising cytoprotective agent and hair regrowth stimulant, respectively, for CIA needs in-depth exploration. [ABSTRACT FROM AUTHOR]

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S), traditionally recognized as a noxious gas with a pungent odor, has emerged as a fascinating metabolite originating from proteinaceous foods. This review provides a comprehensive examination of H 2 S regulatory metabolism in cell. Dysregulation of cellular processes plays a pivotal role in the pathogenesis of numerous diseases. Recent development explores the chemistry of biosynthesis and degradation of H 2 S in cells. The consequences of dysregulation causing diseases and the emerging role of hydrogen sulfide (H 2 S) modulation as a promising therapeutic platform has not been explored much. These disturbances can manifest as oxidative stress, inflammation, and aberrant cellular signaling pathways, contributing to the development and progression of diseases such as cancer, cardiovascular disorders, neurodegenerative diseases, and diabetes. Hydrogen sulfide has gained recognition as a key player in cellular regulation. H 2 S is involved in numerous physiological processes, including vasodilation, inflammation control, and cytoprotection. Recent advances in research have focused on modulating H 2 S levels to restore cellular balance and mitigate disease progression. This approach involves both exogenous H 2 S donors and inhibitors of H 2 S -producing enzymes. By harnessing the versatile properties of H 2 S, researchers and clinicians may develop innovative therapies that address the root causes of dysregulation-induced diseases. As our understanding of H 2 S biology deepens, the potential for precision medicine approaches tailored to specific diseases becomes increasingly exciting, holding the promise of improved patient outcomes and a new era in therapeutics. [Display omitted] • Cellular Regulators of H2S Metabolism. • Investigate the multifaceted roles of hydrogen sulfide in maintaining cellular homeostasis. • Unravel the molecular mechanisms through which dysregulation of H2S metabolism contributes to the pathogenesis of specific diseases. • Discuss emerging precision medicine strategies. • Highlights promising therapeutic interventions harnessing the unique properties of hydrogen sulfide. [ABSTRACT FROM AUTHOR]

Anthracycline antibiotics, namely, doxorubicin (DOX) and daunorubicin, are among the most widely used anticancer therapies, yet are notoriously associated with severe myocardial damage due to oxidative stress and mitochondrial damage. Studies have indicated the strong pharmacological properties of Berberine (Brb) alkaloid, predominantly mediated via mitochondrial functions and nuclear networks. Despite the recent emphasis on Brb in clinical cardioprotective studies, pharmaceutical limitations hamper its clinical use. A nanoformulation for Brb was developed (mMic), incorporating a cationic lipid, oleylamine (OA), into the TPGS-mixed corona of PEGylated-phosphatidylethanolamine (PEG-PE) micelles. Cationic TPGS/PEG-PE mMic with superior Brb loading and stability markedly enhanced both intracellular and mitochondria-tropic Brb activities in cardiovascular muscle cells. Sub-lethal doses of Brb via cationic OA/TPGS mMic, as a DOX co-treatment, resulted in significant mitochondrial apoptosis suppression. In combination with an intense DOX challenge (up to ~50 µM), mitochondria-protective Brb-OA/TPGS mMic showed a significant 24 h recovery of cell viability (p ≤ 0.05–0.01). Mechanistically, the significant relative reduction in apoptotic caspase-9 and elevation of antiapoptotic Bcl-2 seem to mediate the cardioprotective role of Brb-OA/TPGS mMic against DOX. Our report aims to demonstrate the great potential of cationic OA/TPGS-mMic to selectively enhance the protective mitohormetic effect of Brb to mitigate DOX cardiotoxicity. [ABSTRACT FROM AUTHOR]

Glucose oxidase (GOx)-based enzyme therapeutics are potential alternatives for colorectal cancer (CRC) treatment via glucose consumption and accumulation of hydrogen peroxide (H 2 O 2). Given that H 2 O 2 can be eliminated by cytoprotective autophagy, autophagy inhibitors that can interrupt autolysosome-induced H 2 O 2 elimination are promising combination drugs of GOx. Here, we developed a multifunctional biomimetic nanocarrier for effective co-delivery of an autophagy inhibitor-chloroquine phosphate (CQP) and GOx to exert their synergistic effect by irreversibly upregulating intracellular reactive oxygen species (ROS) levels. Poly (D, l -lactide- co -glycolide) (PLGA) nanoparticles (NPs) were used to encapsulate both GOx and CQP using a W/O/W multi-emulsion method. Calcium phosphate (CaP) was used to "fix" CQP to GOx in the internal water phase, where it served as a pH-sensitive unit to facilitate intracellular drug release. Folic acid-modified red blood cell membranes (FR) were used to camouflage the GOx/CQP/CaP encapsulated PLGA NPs (referred to as PLGA/GCC@FR). In an AOM/DSS-induced CRC mouse model, PLGA/GCC@FR exhibited improved antitumor effects, in which the number of tumor nodes were only a quarter of that in the free drug combination group. The enhanced therapeutic effects of PLGA/GCC@FR were attributed to the prolonged tumor retention which was verified by both dynamic in vivo imaging and drug biodistribution. This multifunctional biomimetic nanocarrier facilitated combined enzyme therapeutics by depleting glucose and augmenting intracellular ROS levels in tumor cells, which exerted a synergistic inhibitory effect on tumor growth. Therefore, this study proposed a novel strategy for the enhancement of combined enzyme therapeutics, which provided a promising method for effective CRC treatment. [Display omitted] • CQP was fixed to GOx via CaP formation to facilitate co-encapsulation by PLGA NPs. • PBA-PEG-FA was inserted on RBCm to realize "right-side-out" coating and CRC targeting. • Glucose consumption and ROS accumulation mediated CRC tumor regression. [ABSTRACT FROM AUTHOR]

Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by the healthier neighbors. The precise connection between proteotoxic stress and competitive cell survival remains largely elusive. Here, we reveal the function of an endoplasmic reticulum (ER) and Golgi localized protein Rer1 in the regulation of protein homeostasis in the developing Drosophila wing epithelium. Our results show that loss of Rer1 leads to proteotoxic stress and PERK-mediated phosphorylation of eukaryotic initiation factor 2α. Clonal analysis showed that rer1 mutant cells are identified as losers and eliminated through cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc-overexpression that causes overgrowth, albeit under high proteotoxic stress. Our results suggest that increased levels of Rer1 provide cytoprotection to Myc-overexpressing cells by alleviating the proteotoxic stress and thereby supporting Myc-driven overgrowth. In summary, these observations demonstrate that Rer1 acts as a novel regulator of proteostasis in Drosophila and reveal its role in competitive cell survival. Author summary: In developing tissues, cells can stochastically acquire defects that can reduce their fitness. To maintain the overall health of tissues, these unfit cells are identified by the healthier neighboring cells and eliminated via a juxtacrine-acting cellular fitness sensing mechanism called cell competition. An example of such physiological regulation of cellular fitness is the maintenance of proteostasis. Defects in maintaining proteostasis cause proteotoxic stress. Interestingly, proteotoxic stress is observed not only in the unfit loser cells but also in the overgrowing super-competitor cells, for instance, cells with higher levels of Myc. How cell competition is linked to the maintenance of proteostasis is poorly understood. In this study, we have characterized for the first time the function of Drosophila Rer1 protein in development. We demonstrate that Rer1 is essential for maintaining protein homeostasis and loss of Rer1 activates stress-induced unfolded protein responses. Cells lacking Rer1 are identified as unfit cells and become losers when juxtaposed to the normal neighboring cells. Moreover, we show that Myc-overexpressing cells upregulate Rer1 levels, which allows them to maintain a higher demand for stress regulation, caused by increased protein translation. In this work, we propose that Rer1 functions as a stress regulator and that modulating its levels could provide cytoprotection under stress conditions. [ABSTRACT FROM AUTHOR]

Insulin and insulin-like growth factor 1 (IGF-1) are metabolic hormones with known effects on CD4+ T cells through insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling. Here, we describe specific and distinct roles for these hormones and receptors. We have found that IGF-1R, but not IR, expression is increased following CD4+ T cell activation or following differentiation toward Th17 cells. Although both insulin and IGF-1 increase the metabolism of CD4+ T cells, insulin has a more potent effect. However, IGF-1 has a unique role and acts specifically on Th17 cells to increase IL-17 production and Th17 cell metabolism. Furthermore, IGF-1 decreases mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS) in Th17 cells, providing a cytoprotective effect. Interestingly, both IR and IGF-1R are required for this effect of IGF-1 on mitochondria, which suggests that the hybrid IR/IGF-1R may be required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production. [ABSTRACT FROM AUTHOR]

Considering that Sorbus aucuparia fruits have been underutilized despite their tremendous potential, this study aimed to correlate the in vitro antioxidant, antibacterial and cell-protective abilities of fruit extracts derived from Sorbus aucuparia Romanian cultivars with their phytochemical composition. Therefore, following the preparation of ethanolic and carotenoid extracts, phytochemical screening was performed using UV–Vis and HPLC-DAD-ESI-MS methods. The antioxidant activity was analyzed using DPPH and FRAP tests. As the results revealed high contents of bioactive compounds (polyphenols 1.11 mg GAE/g DM, flavonoids 430.06 µg QE/g DM and carotenoids 95.68 µg/g DM) and an important antiradical action (DPPH 24.51 mg/mL and FRAP 0.016 µM TE/mL), we chose to further examine the fruits' biological properties. The antibacterial capacity was assessed employing agar well diffusion and broth microdilution techniques, with fruits displaying an intense activity against MSSA, MRSA and Enterococcus faecalis, but also E. coli and Pseudomonas aeruginosa. The cell-protective activity was analyzed on gentamicin-stressed renal cells, through MTT and Annexin V-FITC assays. Importantly, a significant increase in viability was registered on stressed cells following extract administration in low doses; nevertheless, viability was noticed to decline when exposed to elevated concentrations, potentially due to the cumulative actions of the extract and gentamicin. These findings offer novel light on the antibacterial activity of Sorbus aucuparia Romanian cultivars, as well as their cell-protective ability in renal cell injury. [ABSTRACT FROM AUTHOR]

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCellsTM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI. [ABSTRACT FROM AUTHOR]

Using duodenocolic fistula in rats, this study attempts to highlight the particular cytoprotection aspects of the healing of fistulas and therapy potential of the stable gastric pentadecapeptide BPC 157, a cytoprotection mediator (i.e. upgrading minor vessels to induce healing at both fistula's sides). Upon duodenocolic fistula creation (two 'perforated' lesions put together) (assessed at 3, 6, 9, 12, and 15 min), BPC 157, given locally at the fistula, or intragastrically (10 µg/kg, 10 ng/kg), rapidly induces vessel 'recruitment', 'running' toward the defect, simultaneously at duodenum and colon, providing numerous collaterals and branching. The mRNA expression studies done at that time provided strongly elevated (nitric oxide synthase 2) and decreased (cyclooxygenase-2, vascular endothelial growth factor A, nitric oxide synthase (NOS)-1, NOS-3, nuclear factor-kappa-B-activating protein) gene expression. As therapy, rats with duodenocolic fistulas, received BPC 157 10 µg/kg, 10 ng/kg, per-orally, in drinking water till sacrifice, or alternatively, intraperitoneally, first application at 30 min after surgery, last at 24 h before sacrifice, at day 1, 3, 7, 14, 21, and 28. Controls exhibited both defects persisting, continuous fistula leakage, diarrhea, continuous weight loss, advanced adhesion formation and intestinal obstruction. Contrary, all BPC 157-treated rats have closed both defects, duodenal and colonic, no fistula leakage (finally, maximal instilled volume corresponds to healthy rats), no cachexia, the same weight as before surgery, no diarrhea, markedly less adhesion formation and intestinal passage obstruction. Thus, BPC 157 regimens resolve the duodenal/colon lesions and duodenocolic fistulas in rats, and rapid vessels recovery appears as the essential point in the implementation of the cytoprotection concept in the fistula therapy. [ABSTRACT FROM AUTHOR]

Nanoencapsulation of living cells within artificial shells is a powerful approach for augmenting the inherent capacity of cells and enabling the acquisition of extrinsic functions. However, the current state of the field requires the development of nanoshells that can dynamically sense and adapt to environmental changes by undergoing transformations in form and composition. This paper reports the compositional transformation of an enzyme‐embedded nanoshell of Fe3+‐trimesic acid complex to an iron phosphate shell in phosphate‐containing media. The cytocompatible transformation allows the nanoshells to release functional molecules without loss of activities and biorecognition, while preserving the initial shell properties, such as cytoprotection. Demonstrations include the lysis and killing of Escherichia coli by lysozyme, and the secretion of interleukin‐2 by Jurkat T cells in response to paracrine stimulation by antibodies. This work on micrometric Transformers will benefit the creation of cell‐in‐shell nanobiohybrids that can interact with their surroundings in active and adaptive ways. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, and energy formation. H2Sn, which have additional sulfur atoms to H2S, and other S-sulfurated molecules such as cysteine persulfide and S-sulfurated cysteine residues of proteins, are produced by enzymes including 3-mercaptopyruvate sulfurtransferase (3MST). H2Sn are also generated by the chemical interaction of H2S with NO, or to a lesser extent with H2O2. S-sulfuration (S-sulfhydration) has been proposed as a mode of action of H2S and H2Sn to regulate the activity of target molecules. Recently, we found that H2S/H2S2 regulate the release of neurotransmitters, such as GABA, glutamate, and D-serine, a co-agonist of N-methyl-D-aspartate (NMDA) receptors. H2S facilitates the induction of hippocampal long-term potentiation, a synaptic model of memory formation, by enhancing the activity of NMDA receptors, while H2S2 achieves this by activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading to the activation of nearby neurons. The recent findings show the other aspects of TRPA1 channels—that is, the regulation of the levels of sulfur-containing molecules and their metabolizing enzymes. Disturbance of the signalling by H2S/H2Sn has been demonstrated to be involved in various diseases, including cognitive and psychiatric diseases. The physiological and pathophysiological roles of these molecules will be discussed. [ABSTRACT FROM AUTHOR]

Nanoarmor strengthens the structure and function of single cells by coating and encapsulating nanomaterials on single cells. It has tremendous potential for environmental, energy, and medical applications. Nanoarmor can isolate cells from their environment, endowing them with catalytic functions and photoelectric properties, and protecting the patient when used for medical applications. Nanoarmor can endow cells with self-driving capability, which has good prospects for applications in disease treatments. Nanoarmor can form heterojunctions on cells to facilitate electron transfer. Nanoarmor can be formed through biomineralization or biomimetic mineralization, with different involvements of the cell. Single cell modification or hybridization technology has become a popular direction in bioengineering in recent years, with applications in clean energy, environmental stewardship, and sustainable human development. Here, we draw attention to nanoarmor, a representative achievement of cytoprotection and functionalization technology. The fundamental principles of nanoarmor need to be studied with input from multiple disciplines, including biology, chemistry, and material science. In this review, we explain the role of nanoarmor and review progress in its applications. We also discuss three main challenges associated with its development: self-driving ability, heterojunction characteristics, and mineralization formation. Finally, we propose a preliminary classification system for nanoarmor. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway and oxidative stress is one of the main mechanisms that lead to neuronal death in this disease. Previous studies have shown antioxidant activity from the leaves of Byrsonima sericea, a plant of the Malpighiaceae family. This study aimed to evaluate the cytoprotective activity of the B. sericea ethanolic extract (BSEE) against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) in PC12 cells, an in vitro model of parkinsonism. The identification of phenolic compounds in the extract by HPLC-DAD revealed the presence of geraniin, rutin, isoquercetin, kaempferol 3-O-β-rutinoside, and quercetin. The BSEE (75–300 µg/mL) protected PC12 cells from toxicity induced by 6-OHDA (25 µg/mL), protected cell membrane integrity and showed antioxidant activity. BSEE was able to decrease nitrite levels, glutathione depletion, and protect cells from 6-OHDA-induced apoptosis. Thus, we suggest that the BSEE can be explored as a possible cytoprotective agent for Parkinson's disease due to its high antioxidant capacity and anti-apoptotic action. [ABSTRACT FROM AUTHOR]

In this work, for the first time, a gruyt beer and the same one after the addition of Citrus aurantium essential oil (AEO), were investigated to determine the composition of the volatile fraction. The applied analytical techniques, such as Head Space/Solid Phase Microextraction-Gas Chromatography-Mass Spectrometry (HS/SPME-GC-MS) and Proton Transfer Reaction-Time of Flight-Mass Spectrometer (PTR-ToF-MS), allowed us to identify the content of volatile organic compounds (VOCs). From the comparison between the two beer samples, it showed that the one after the addition of AEO was particularly richened in limonene and a series of minor terpene compounds. AEO was also characterized by GC/MS analysis and the results showed that limonene reached 95%. Confocal microscopy was used to look at riboflavin autofluorescence in yeast cells. It was found that beer with AEO had twice as much fluorescence intensity as the control. A spectrophotometric analysis of total polyphenols, tannins, and flavonoids, and a bioactivity screening, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-Azinobis-(3-Ethylbenzthiazolin-6-Sulfonic Acid) (ABTS) radical scavenger, chelating, reducing, antiglycative ones, were also carried out. Moreover, the tolerability of the tested samples in human H69 cholangiocytes and the cytoprotection towards the tert-butyl hydroperoxide (tBOOH)-induced oxidative damage were evaluated. Under our experimental conditions, the beers were found to be able to scavenge DPPH and ABTS radicals and chelate iron ions, despite weak antiglycative and reducing properties. The tested samples did not affect the viability of H69 cholangiocytes up to the highest concentrations; moreover, no signs of cytoprotection against the damage induced by tBOOH were highlighted. Adding AEO to beer resulted in a moderate enhancement of its DPPH scavenging and chelating abilities, without improvements in the other assays. Conversely, AEO and its major compound limonene were ineffective when assessed at the concentrations added to beer. This evidence suggests that the addition of AEO may enhance the organoleptic features of the beer and slightly potentiate some of its bioactivities. [ABSTRACT FROM AUTHOR]

Mitochondrial investigations have extended beyond their traditional functions, covering areas such as ATP synthesis and metabolism. Mitochondria are now implicated in new functional areas such as cytoprotection, cellular senescence, tumor function and inflammation. The basis of these new areas still relies on fundamental biochemical/biophysical mitochondrial functions such as synthesis of reactive oxygen species, mitochondrial membrane potential, and the integrity of the inner mitochondrial membrane i.e., the passage of various molecules through the mitochondrial membranes. In this view transport of potassium cations, known as the potassium cycle, plays an important role. It is believed that K+ influx is mediated by various potassium channels present in the inner mitochondrial membrane. In this article, we present an overview of the key findings and characteristics of mitochondrial potassium channels derived from research of many groups conducted over the past 33 years. We propose a list of six fundamental observations and most important ideas dealing with mitochondrial potassium channels. We also discuss the contemporary challenges and future prospects associated with research on mitochondrial potassium channels.

Abstract The Nastaran plant, with the scientific name of Rosa canina, has been used since ancient times as a plant with medicinal properties. In the present study, human umbilical vein endothelial cells (HUVECs) were used to examine the protective effects of R. canina fruit extract (RCFE) and its flavonoid ingredient (quercetin) against H2O2‐induced cell injury. RCFE (1.25–20 μg/mL) and quercetin (1.25–20 μM) were exposed to H2O2‐oxidizing agent (1 and 2 mM) and the protective effect was examined on HUVEC cells by Alamar Blue test. The amount of intracellular reactive oxygen species (ROS) was measured by using DCFDA reagent by fluorimetric method. The effects of RCFE and quercetin on cell apoptosis were studied by staining with hypotonic PI solution and flow cytometry. The amount of PARP and survivin involved in the apoptotic process was measured using the western blot analysis. The results of the Alamar Blue test showed that RCFE and quercetin could reduce the toxicity of H2O2. RCFE and quercetin were able to significantly increase cell viability against H2O2. Also, it was found that RCFE and quercetin reduced the production of ROS by H2O2. It was found that RCFE and quercetin reduced the apoptosis and sub‐G1 peak area in flow histogram after exposure of cells to H2O2. Based on western blot results, pretreatment with RCFE and quercetin could significantly increase survivin protein after exposure of cells to H2O2. Also, RCFE and quercetin could significantly reduce the amount of cleaved PARP after exposure of cells to H2O2. RCFE and its ingredient (quercetin) can be considered a promising source of phytochemicals in the prevention of cardiovascular diseases.

Antioxidant cytoprotective properties of mexidol have been studied under the influence of argon and helium gas-discharge cold plasma of atmospheric pressure on Paramecium caudatum cell culture. It has been shown that mexidol exhibits strong antioxidant properties and practically completely eliminates the negative effects of oxidative stress, retaining almost 100% of the initial number of cells. The data obtained demonstrate a wide range of behavioral responses of cells of Paramecium caudatum, which confirms their practical value as model objects for pharmacological and toxicological studies, and the use of gas-discharge cold plasma makes it possible to exclude the direct oxidative effect of hydrogen peroxide (the standard model of oxidative stress) on the studied drugs and to increase the reliability of toxicological studies. [ABSTRACT FROM AUTHOR]

The Nastaran plant, with the scientific name of Rosa canina, has been used since ancient times as a plant with medicinal properties. In the present study, human umbilical vein endothelial cells (HUVECs) were used to examine the protective effects of R. canina fruit extract (RCFE) and its flavonoid ingredient (quercetin) against H2O2‐induced cell injury. RCFE (1.25–20 μg/mL) and quercetin (1.25–20 μM) were exposed to H2O2‐oxidizing agent (1 and 2 mM) and the protective effect was examined on HUVEC cells by Alamar Blue test. The amount of intracellular reactive oxygen species (ROS) was measured by using DCFDA reagent by fluorimetric method. The effects of RCFE and quercetin on cell apoptosis were studied by staining with hypotonic PI solution and flow cytometry. The amount of PARP and survivin involved in the apoptotic process was measured using the western blot analysis. The results of the Alamar Blue test showed that RCFE and quercetin could reduce the toxicity of H2O2. RCFE and quercetin were able to significantly increase cell viability against H2O2. Also, it was found that RCFE and quercetin reduced the production of ROS by H2O2. It was found that RCFE and quercetin reduced the apoptosis and sub‐G1 peak area in flow histogram after exposure of cells to H2O2. Based on western blot results, pretreatment with RCFE and quercetin could significantly increase survivin protein after exposure of cells to H2O2. Also, RCFE and quercetin could significantly reduce the amount of cleaved PARP after exposure of cells to H2O2. RCFE and its ingredient (quercetin) can be considered a promising source of phytochemicals in the prevention of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Introduction: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells that have been examined for their potential role in cell therapy. BM-MSCs displayed repairing and cytoprotective functions against many injured tissues. Furthermore, they exerted trophic effects mediated by different growth factors and cytokines. For severe spleen-associated diseases, stem cell therapy could be considered for its possible use in targeting and repairing damaged tissues and organs. Therefore, the aim of the present study is to investigate, on molecular basis, the cytoprotective and healing capacity of BMMSCs in cyclophosphamide (CP)-induced spleen damage in rats. Materials and Methods: A total number of Forty Sprague Dawley adult female rats were divided into two groups: the normal control group (NC) and CP-treated group. Normal control (NC) group that was treated once daily with sterile saline, and a CP-treated group that was injected intraperitoneally by CP at the concentration of 70 mg/kg for three successive days. The latter group was further subdivided into three subgroups: - the (CP-treated group) was sacrificed one week after CP treatment, the (BM-MSCs treated group), in which BM-MSCs were injected by a single dose of Male BM-MSCs 5x106/Kg BW via intraperitoneal injection on the tenth day after CP treatment, and the (CP auto-healing group ) was left without treatment. Spleen was dissected from all animals and prepared for histological examination. The expression of genes and proteins was estimated by real-time qPCR and immunohistochemistry. Results: BM-MSCs restored the normal architecture of the damaged spleen. They regained the mRNA levels of p53, caspase3, bcl2 more/less similar to the normal control group. The expression of VEGF was upregulated after BM-MSCs injection. Also, BM-MSCs relatively retained the normal expression of CD14, CD21, Akt and PI3K proteins after CP-induced toxicity. Conclusion: This study revealed the potential therapeutic role of BM-MSCs in severe damaged spleen and explained the underlying mechanism on molecular basis. [ABSTRACT FROM AUTHOR]

Molecular homeostats play essential roles across all levels of biological organization to ensure a return to normal function after responding to abnormal internal and environmental events. SKN-1 is an evolutionarily conserved cytoprotective transcription factor that is integral for the maintenance of cellular homeostasis upon exposure to a variety of stress conditions. Despite the essentiality of turning on SKN-1/NRF2 in response to exogenous and endogenous stress, animals with chronic activation of SKN-1 display premature loss of health with age, and ultimately, diminished lifespan. Previous genetic models of constitutive SKN-1 activation include gain-of-function alleles of skn-1 and loss-of-function alleles of wdr-23 that impede the turnover of SKN-1 by the ubiquitin proteasome. Here, we define a novel gain-of-function mutation in the xrep-4 locus that results in constitutive activation of SKN-1 in the absence of stress. Although each of these genetic mutations results in continuously unregulated transcriptional output from SKN-1, the physiological consequences of each model on development, stress resistance, reproduction, lipid homeostasis, and lifespan are distinct. Here, we provide a comprehensive assessment of the differential healthspan impacts across multiple models of constitutive SKN-1 activation. Although our results reveal the universal need to reign in the uncontrolled activity of cytoprotective transcription factors, we also define the unique signatures of each model of constitutive SKN-1 activation, which provides innovative solutions for the design of molecular "off-switches" of unregulated transcriptional homeostats. [ABSTRACT FROM AUTHOR]