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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Most of the works aimed at studying the cytoprotective properties of nanocerium are usually focused on the mechanisms of regulation of the redox status in cells while the complex effects of nanocerium on calcium homeostasis, the expression of pro-apoptotic and protective proteins are generally overlooked. There is a problem of a strong dependence of the effects of cerium oxide nanoparticles on their size, method of preparation and origin, which significantly limits their use in medicine. In this study, using the methods of molecular biology, immunocytochemistry, fluorescence microscopy and inhibitory analysis, the cytoprotective effect of cerium oxide nanoparticles obtained by laser ablation on cultured astrocytes of the cerebral cortex under oxygen–glucose deprivation (OGD) and reoxygenation (ischemia-like conditions) are shown. The concentration effects of cerium oxide nanoparticles on ROS production by astrocytes in an acute experiment and the effects of cell pre-incubation with nanocerium on ROS production under OGD conditions were studied. The dose dependence for nanocerium protection of cortical astrocytes from a global increase in calcium ions during oxygen–glucose deprivation and cell death were demonstrated. The concentration range of cerium oxide nanoparticles at which they have a pro-oxidant effect on cells has been identified. The effect of nanocerium concentrations on astrocyte preconditioning, accompanied by increased expression of protective proteins and limited ROS production induced by oxygen–glucose deprivation, has been investigated. In particular, a correlation was found between an increase in the concentration of cytosolic calcium under the action of nanocerium and the suppression of cell death. As a result, the positive and negative effects of nanocerium under oxygen–glucose deprivation and reoxygenation in astrocytes were revealed at the molecular level. Nanocerium was found to act as a "double-edged sword" and to have a strictly defined concentration therapeutic "window". [ABSTRACT FROM AUTHOR]

Plant secondary metabolites are important sources of biologically active compounds with wide pharmacological potentials. Among the different classes, the chalcones form integral pharmacologically active agents. Natural chalcones and bis-chalcones exhibit high antioxidant and anti-inflammatory properties in various experiments. Studies are also underway to explore more biologically active bis-chalcones by chemical synthesis of these compounds. In this study, the effects of six synthetic bis-chalcones were evaluated in intestinal epithelial cells (IEC-6); further, the anti-inflammatory potentials were studied in lipopolysaccharide-induced cytokine production in macrophages. The synthesized bis-chalcones differ from each other first of all by the nature of the aromatic cores (functional group substitution, and their position) and by the size of a central alicycle. The exposure of IEC-6 cells to peroxide radicals reduced the cell viability; however, pre-treatment with the bis-chalcones improved the cell viability in these cells. The mechanism of action was observed to be the increased levels of glutathione and antioxidant enzyme activities. Further, these bis-chalcones also inhibited the LPS-stimulation-induced inflammatory cytokine production in RAW 264.7 macrophages. Overall, the present study indicated the cytoprotective and anti-inflammatory abilities of synthetic bis-chalcones. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA. [ABSTRACT FROM AUTHOR]

L -asparaginase (L -ASNase) is a life-saving medication used in the treatment of Acute Lymphoblastic Leukemia (ALL) which affects over 60,000 people yearly. However, L -ASNase still requires improvement since up to 60% of the patients develop hypersensitivity due to its immunogenicity. To address this issue, this work describes the downstream process of an L -ASNase from Erwinia chrysanthemi expressed extracellularly by Pichia pastoris with human-like glycosylation pattern and its further impact on leukemic cells co-cultured with bone marrow (BM) cytoprotective stromal cells. After size exclusion chromathography, a final yield of 54.93% was achieved and the proteomics analyses confirmed the attainment of an extremely pure enzyme. Glycosylated L -ASNase induced the complete inhibition of the proliferation of ALL and Acute Myeloid Leukemia (AML) cell lines tested, independently of the presence of BM stromal cells. However, the cytotoxic efficacy (induction of apoptosis) of glycosylated L -ASNase varied across cell lines, with ALL cell lines showing the most sensitivity. Additionally, the pro-apoptotic effect of glycosylated L -ASNase was partially inhibited by BM stromal cells. Taken together, our data warrant further investigations for the use of glycosylated L -ASNase against ALL and AML that should take into consideration the mechanisms of resistance mediated by the BM stroma for improved efficacy. [Display omitted] • Detailed method for isolation of glycosylated L -ASNase with high yield and purity. • Glycosylated L -ASNase blocks the proliferation of leukemic cells. • Bone marrow stromal niches provide cytoprotection to leukemic cells. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the functional role of hypoxic preconditioning (HPC) in human neuroblastoma cells. BNIP3 small-interfering RNA (BNIP3-siRNA) sequence was synthesized and used to transfect human neuroblastoma SH-SY5Y cell lines. Thereafter, BNIP3 expression at mRNA and protein levels and its effects on the cell proliferation were analyzed. The most effective pair of siRNA was selected to knockdown the expression level of BNIP3. Moreover, the effects of HPC on oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis and autophagy in SH-SY5Y cells were explored to further reveal the possible mechanisms underlying HPC. BNIP3-siRNA attenuated the protective effects of HPC by decreasing the cell viability, increasing the enzymatic activity of caspase-3 and 9, increasing the rate of apoptosis, and increasing the protein expression level of activated caspase-3. Additionally, BNIP3-siRNA had no significant influence on the expression level of HIF-1α induced by HPC, while it substantially inhibited HPC-induced BNIP3/Beclin1 and autophagy. HPC promoted autophagy through regulating BNIP3 to reduce OGD/R. [ABSTRACT FROM AUTHOR]

Radio protective effects of metformin and its ability to alter the spontaneous and induced genotoxic and cytotoxic levels effects on human peripheral blood lymphocytes were investigated in this study. Metformin, a hypoglycemic oral drug, is a biguanide derived from Galega officinalis that is widely utilized in controlling type 2 diabetes mellitus. Whole blood samples from 10 healthy donors (5 males and 5 females) were exposed to two doses of gamma-rays (1 and 2 Gray). Lymphocytes in cultures were treated with metformin (10 and 50µM) before gamma-irradiation. Cytokinesis-block micronucleus test was used to evaluate the protective effects of metformin on radiation induced genomic damage, cytostasis and cytotoxicity, via scoring micronuclei and nucleoplasmic bridges in once divided binucleated cells as well as counting nuclear division index. The results of the current study revealed that the increase in micronuclei and nucleoplasmic bridges rate is associated with the decrease of nuclear division index in human lymphocytes exposed to gamma radiation in a dose dependent manner. Metformin effectively decreased the rate of spontaneous micronuclei and nucleoplasmic bridges paralleled with the control as well as increased nuclear division index. Moreover, treatment of whole blood samples with metformin (10 and 50 µM), 2 h preceding to irradiation, remarkably reduced rate of micronuclei and nucleoplasmic bridges accompanied with an increase in nuclear division index rate. The results introduced metformin to be an effective radio protector against DNA damage induced by gamma radiation in human lymphocytes and that it can be used to develop radio protective materials for protection cells of cancer patients from the genomic damage prompted via radiotherapy. [ABSTRACT FROM AUTHOR]

Inhibitors of human poly(ADP-ribose) polymerase (PARP) are considered as promising agents for treatment of cardiovascular, neurological, and other diseases accompanied by inflammation and oxidative stress. Previously, the ability of natural compounds 7-methylguanine (7mGua) and 8-hydroxy-7-methylguanine (8h7mGua) to suppress activity of the recombinant PARP protein was demonstrated. In the present work, we have investigated the possibility of PARP-inhibitory and cytoprotective action of 7mGua and 8h7mGua against the rat cardiomyoblast cultures (undifferentiated and differentiated H9c2). It was found that 7mGua and 8h7mGua rapidly penetrate into the cells and effectively suppress the H2O2-stimulated PARP activation (IC50 = 270 and 55 μM, respectively). The pronounced cytoprotective effects of 7mGua and 8h7mGua were shown in a cellular model of oxidative stress, and effectiveness of 8h7mGua exceeded the classic PARP inhibitor 3-aminobenzamide. The obtained data indicate promise for the development of PARP inhibitors based on guanine derivatives and their testing using the models of ischemia–reperfusion tissue damage. [ABSTRACT FROM AUTHOR]

Biocompatible nanoparticles have attracted considerable attention as cellular antioxidant agents for the improvement of new therapeutics for several and diverse oxidative stress related disorders. Here, it is shown that the biocompatible cell membrane@gold nanoparticle displays catalase‐mimic behavior by decomposing H2O2. This interesting behavior can be used for cell protection against induced oxidative injury by reactive oxygen species (ROS). So, after characterizing this novel biocompatible nanostructure, the protective effect of cell membrane@AuNPs pretreatment in front of a well‐defined oxidative stress‐inducing chemotherapy drug, doxorubicin (Dox) is assessed. Doxorubicin pretreatment significantly reduces the intracellular ROS production. Similarly, a reduction in the levels of DNA oxidative damage, as measured with the AO/EB staining, is also observed. Obtained results would support that this novel nanostructure can show how a pharmacological agent can be used against oxidative stress‐mediated diseases. [ABSTRACT FROM AUTHOR]

In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to scavenge peroxides and free radicals in cell-free systems, their ability to exhibit these properties in vivo, upon pharmacological supplementation, has not been confirmed so far. Their cytoprotective activity is explained mainly by the ability not to suppress, but to activate multiple redox pathways, which causes biphasic hormetic responses and highly pleiotropic effects in cells. N-acetylcysteine, polyphenols, and vitamin C affect redox homeostasis by generating low-molecular-weight redox-active compounds (H2O2 or H2S), known for their ability to stimulate cellular endogenous antioxidant defense and promote cytoprotection at low concentrations but exert deleterious effects at high concentrations. Moreover, the activity of antioxidants strongly depends on the biological context and mode of their application. We show here that considering the biphasic and context-dependent response of cells on the pleiotropic action of antioxidants can help explain many of the conflicting results obtained in basic and applied research and build a more logical strategy for their use. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is the most common type of stroke and the second leading cause of death overall. Neural stem cells play protective roles in IS, but the underlying mechanism remains to be determined. Neural stem cells (NSC) were obtained from the fetal brain tissue of C57BL/6J mice. NSC-derived exosomes (NSC-Exos) were identified in the conditioned medium. Internalization of NSC-Exos was analyzed by fluorescence microscopy. In vitro microglia ischemic stroke injury model was induced using oxygen glucose deprivation/re-oxygenation (OGD/R) method. Cell viability and inflammation were analyzed by MTT, qPCR, ELISA and Western blotting assay. Interaction between ZEB1 and the promoter of GPR30 was verified by luciferase assay and chromatin immunoprecipitation. NSC-Exos prevented OGD/R-mediated inhibition of cell survival and the production of inflammatory cytokines in microglia cells. NSC-Exos increased ZEB1 expression in OGD/R-treated microglia. Down-regulation of ZEB1 expression in NSC-Exos abolished NSC-Exos' protective effects on OGD/R-treated microglia. ZEB1 bound to the promoter region of GPR30 and promoted its expression. Inhibiting GPR30 reversed NSC-Exos effects on cell viability and inflammation injury in OGD/R-treated microglia. Our study demonstrated that NSC exerted cytoprotective roles through release of exosomal ZEB1,which transcriptionally upregulated GPR30 expression, resulting in a reduction in TLR4/NF-κB pathway-induced inflammation. These findings shed light on NSC-Exos' cytoprotective mechanism and highlighted its potential application in the treatment of IS. [ABSTRACT FROM AUTHOR]

As a progressive neurological disorder, Parkinson's disease (PD) is characterized by tremors and slow movement. Mitochondrial dysfunction and amino acid (AA) metabolism are essential mechanisms of PD. Previous work has confirmed that the changes in amino acid contents in SH-SY5Y cells are earlier than the changes in cell viability. In the present study, we aimed to investigate whether Taohong Siwu dispensing granules (THSWDG) could alleviate rotenone-induced SH-SY5Y cytotoxicity by improving mitochondrial dysfunction and amino acid metabolism disorder. MTT assay was used to analyze the cell viability. JC-1 dye assay was used to measure mitochondrial membrane potential (MMP). HPLC was used to determine the content of amino acids (AAs) in SH-SY5Y cells. Principal component analysis was used to analyze the changes in the content of AAs. In order to further explore the PD-related biological functions involved in amino acid regulation, bioinformatics analysis tools were used to assess the biological processes involved in these protective effects. This study showed that the changes in AA contents in SH-SY5Y cells were earlier than the changes in cell activity. THSWDG dramatically increased cell viability and improved the rotenone-induced repression of MMP and abnormal metabolism of AAs. The results of the bioinformatic analysis suggested that the effects of THSWDG involved nine biological processes, including five AA metabolism regulations related to PD and four biological processes related to oxidative damage. The cellular AA process is a common biological process involved in the regulation of AA metabolism and oxidative damage. These results suggested that THSWDG exerted a cytoprotective effect on SH-SY5Y cells by rescuing mitochondrial dysfunction and AA metabolism disarrangements. [ABSTRACT FROM AUTHOR]

Objective To study the protective effect of Shexiang Baoxin Pill (SBP) on hypoxia-reoxygenation cardiomyocytes and its effect on apoptosis. Methods The model of hypoxia and reoxygenation of cardiomyocytes was established. The active components of SBP were extracted by water extraction. According to whether different concentrations of SBP active components were given, cells were divided into the control group, the model group, the 0.5 g/L SBP group, the 1 g/L SBP group, the 2 g/L SBP group and the 5 g/L SBP group. The highest survival rate in the SBP intervention group was selected as the group for the follow-up experiments. The cell survival rate of each group was detected by CCK-8. The apoptosis rate of each group was detected by Anexxin-VFITC/PI double staining. Western bolt assay was used to detect the relative expression levels of B cell lymphoma factor 2 (Bcl-2), Bcl-2 associated X protein (Bax) and cysteine protease 3 (Caspase-3) in each group. Results Compared with the model group, survival rates of cardiomyocytes were increased in the 0.5 g/L, 1 g/L, 2 g/L and 5 g/L SBP groups (P＜0.01), and the survival rate of cardiomyocytes was the highest in the 2 g/L SBP group. Compared with the control group, the apoptosis rate, relative expression levels of Bax and Caspase-3 were increased in the model group and the 2 g/L SBP group (P＜0.05), but there was no significant difference in Bcl-2 between the groups. Compared with the model group, the apoptosis rate, relative expression levels of Bax and Caspase-3 were decreased in the 2 g/L SBP group (P＜0.05), while relative expression levels of Bcl-2 and Bcl-2/Bax ratio were increased (P＜0.05). Conclusion Shexiang Baoxin Pill has a protective effect on hypoxia-reoxygenation cardiomyocytes, and the inhibition of apoptosis is one of its protective mechanisms. [ABSTRACT FROM AUTHOR]

Unlike plant and microbial cells having cell walls, the outermost layer of mammalian cell is a delicate, two‐layered structure of phospholipids with proteins embedded, which is susceptible to environmental changes. It is necessary to create an "armor" on cell surface to protect cell integrity. Here, we propose an Auto‐assembled Resilient bioMimetic calcified ORnaments (ARMOR) strategy driven by dual‐aptamer‐based hybridization chain reaction (HCR) and Ca2+ assisted calcification for selective cell protection. This co‐recognition design enhances the selectivity and leverages robust in situ signal amplification by HCR to improve the sensitivity. The calcified shell is cogenerated by crosslinking the alginate‐HCR product with Ca2+ ion. ARMOR has high efficiency for shielding cells from environmental assaults, which can be applied to circulating tumor cell (CTC) protection, isolation, and identification, maintaining the native state and intact genetic information for downstream analysis. [ABSTRACT FROM AUTHOR]

Unlike plant and microbial cells having cell walls, the outermost layer of mammalian cell is a delicate, two‐layered structure of phospholipids with proteins embedded, which is susceptible to environmental changes. It is necessary to create an "armor" on cell surface to protect cell integrity. Here, we propose an Auto‐assembled Resilient bioMimetic calcified ORnaments (ARMOR) strategy driven by dual‐aptamer‐based hybridization chain reaction (HCR) and Ca2+ assisted calcification for selective cell protection. This co‐recognition design enhances the selectivity and leverages robust in situ signal amplification by HCR to improve the sensitivity. The calcified shell is cogenerated by crosslinking the alginate‐HCR product with Ca2+ ion. ARMOR has high efficiency for shielding cells from environmental assaults, which can be applied to circulating tumor cell (CTC) protection, isolation, and identification, maintaining the native state and intact genetic information for downstream analysis. [ABSTRACT FROM AUTHOR]

Cardiovascular, rheumatic, kidney, and neurodegenerative diseases and mental disorders are a common cause of deterioration in the quality of life up to severe disability and death worldwide. Many pathological conditions, including this group of diseases, are based on increased cell death through apoptosis. It is known that this process is associated with signaling pathways controlled by a group of gaseous signaling molecules called gasotransmitters. They are unique messengers that can control the process of apoptosis at different stages of its implementation. However, their role in the regulation of apoptotic signaling in these pathological conditions is often controversial and not completely clear. This review analyzes the role of nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), and sulfur dioxide (SO2) in apoptotic cell death in cardiovascular, rheumatic, kidney, and neurodegenerative diseases. The signaling processes involved in apoptosis in schizophrenia, bipolar, depressive, and anxiety disorders are also considered. The role of gasotransmitters in apoptosis in these diseases is largely determined by cell specificity and concentration. NO has the greatest dualism; scales are more prone to apoptosis. At the same time, CO, H2S, and SO2 are more involved in cytoprotective processes. [ABSTRACT FROM AUTHOR]

The high incidence of oxidative stress in sows during late gestation and lactation affects mammary gland health, milk yield, and milk quality. Recently, we found that supplementing maternal diets with 1% taurine improved antioxidant capability and enhanced growth performance in offspring; however, the mechanisms underlying these are unknown. This study aimed to investigate the cytoprotective effects and the mechanism of taurine in mitigating oxidative stress in porcine mammary epithelial cells (PMECs). PMECs were pretreated with 0–2.0 mM taurine for 12 h and then subjected to oxidative injury with 500 μM hydrogen peroxide (H2O2). Pretreatment with taurine attenuated decreased cell viability, enhanced superoxide dismutase, and reduced the intracellular reactive oxygen species accumulation after H2O2 exposure. Taurine also prevented H2O2‐induced endoplasmic reticulum stress. Nuclear factor erythroid 2‐related factor 2 (Nrf2) was essential to the cytoprotective effects of taurine on PMECs, as Nrf2 knockdown significantly inhibited taurine‐induced cytoprotection against oxidative stress. Moreover, we confirmed that Nrf2 induction by taurine was mediated through the inactivation of the p38/MAPK pathway. Overall, taurine supplementation has beneficial effects on redox balance regulation and may protect against oxidative stress in lactating animals. [ABSTRACT FROM AUTHOR]

Recent findings have suggested that the natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated the anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and the sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage. Exposure of human brain endothelial cells to 7KC led to a loss of cell viability, together with an increase in intracellular free calcium levels, increased cellular and mitochondrial reactive oxygen species, a decrease in mitochondrial membrane potential, reductions in ATP levels, and increases in mRNA expression of TFAM, Nrf2, IL-1β, IL-6 and IL-8. These effects were significantly decreased by ET. Protective effects of ET were diminished when endothelial cells were coincubated with verapamil hydrochloride (VHCL), a nonspecific inhibitor of the ET transporter OCTN1 (SLC22A4). This outcome demonstrates that ET-mediated protection against 7KC-induced mitochondrial damage occurred intracellularly and not through direct interaction with 7KC. OCTN1 mRNA expression itself was significantly increased in endothelial cells after 7KC treatment, consistent with the notion that stress and injury may increase ET uptake. Our results indicate that ET can protect against 7KC-induced mitochondrial injury in brain endothelial cells. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, and autophagy dysregulation. BGP-15 has a wide range of cytoprotective effects, including mitochondrial protection, but up to now, there is no information about any of its beneficial effects on DOX-induced cardiotoxicity. In this study, we investigated whether the protective effects of BGP-15 pretreatment are predominantly via preserving mitochondrial function, reducing mitochondrial ROS production, and if it has an influence on autophagy processes. H9c2 cardiomyocytes were pretreated with 50 μM of BGP-15 prior to different concentrations (0.1; 1; 3 μM) of DOX exposure. We found that BGP-15 pretreatment significantly improved the cell viability after 12 and 24 h DOX exposure. BGP-15 ameliorated lactate dehydrogenase (LDH) release and cell apoptosis induced by DOX. Additionally, BGP-15 pretreatment attenuated the level of mitochondrial oxidative stress and the loss of mitochondrial membrane potential. Moreover, BGP-15 further slightly modulated the autophagic flux, which was measurably decreased by DOX treatment. Hence, our findings clearly revealed that BGP-15 might be a promising agent for alleviating the cardiotoxicity of DOX. This critical mechanism appears to be given by the protective effect of BGP-15 on mitochondria. [ABSTRACT FROM AUTHOR]

One-step fabrication method for thin films and shells is developed with nature-derived eggshell membrane hydrolysates (ESMHs) and coffee melanoidins (CMs) that have been discarded as food waste. The nature-derived polymeric materials, ESMHs and CMs, prove highly biocompatible with living cells, and the one-step method enables cytocompatible construction of cell-in-shell nanobiohybrid structures. Nanometric ESMH-CM shells are formed on individual probiotic Lactobacillus acidophilus, without any noticeable decrease in viability, and the ESMH-CM shells effectively protected L. acidophilus in the simulated gastric fluid (SGF). The cytoprotection power is further enhanced by Fe3+-mediated shell augmentation. For example, after 2 h of incubation in SGF, the viability of native L. acidophilus is 30%, whereas nanoencapsulated L. acidophilus, armed with the Fe3+-fortified ESMH-CM shells, show 79% in viability. The simple, time-efficient, and easy-to-process method developed in this work would contribute to many technological developments, including microbial biotherapeutics, as well as waste upcycling. [ABSTRACT FROM AUTHOR]

Gut injury is a severe and unpredictable illness related to the increased cell death of intestinal epithelial cells (IECs). Excessive IEC apoptotic cell death during the pathophysiological state entails chronic inflammatory diseases. This investigation was undertaken to assess the cytoprotective action and underlying mechanisms of polysaccharides from Tunisian red alga, Gelidium spinosum (PSGS), on H2O2-induced toxicity in IEC-6 cells. The cell viability test was initially carried out to screen out convenient concentrations of H2O2 and PSGS. Subsequently, cells were exposed to 40 µM H2O2 over 4 h in the presence or absence of PSGS. Findings revealed that H2O2 caused oxidative stress manifested by over 70% cell mortality, disturbed the antioxidant defense, and increased the apoptotic rate in IEC-6 cells (32% than normal cells). Pretreatment of PSGS restored cell viability, especially when used at 150 µg/mL and normal cell morphology in H2O2-callenged cells. PSGS also equally sustained superoxide dismutase and catalase activities and hindered the apoptosis induced by H2O2. This protection mechanism of PSGS may be associated with its structural composition. The ultraviolet visible spectrum, Fourier-transformed infrared (FT-IR), X-ray diffraction (XRD), and high-performance liquid chromatography (HPLC) demonstrated that PSGS is mainly sulfated polysaccharides. Eventually, this research work provides a deeper insight into the protective functions and enhances the investment of natural resources in handling intestinal diseases. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), accumulation of amyloid β-protein (Aβ) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aβ has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aβ-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aβ oligomers (Aβo), which include high-molecular-weight (HMW) Aβo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 μM) on Aβo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the Aβo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aβo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aβo exposure. [ABSTRACT FROM AUTHOR]

In a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work confirmed the anti-proliferation and pro-apoptosis effects of YZT in NSCLC cells. Furthermore, YZT promotes autophagy and provokes complete autophagic flux in NSCLC cells. Notably, compared with YZT alone, the combination of YZT with the autophagy inhibitor chloroquine (CQ) or 3-methyladenine (3-MA) markedly strengthened the anti-proliferative and pro-apoptotic actions, suggesting that YZT-induced autophagy is cytoprotective. We further found that YZT-induced autophagy may exert a cytoprotective function by preserving the integrity of mitochondria and decreasing mitochondrial apoptosis. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that PDK1 is an upstream protein of the Akt/mTOR axis and western blotting verified that YZT induces autophagy by the PDK1/Akt/mTOR signaling axis. Finally, YZT plus CQ significantly enhanced the anticancer activities compared to YZT alone in an animal study and immunohistochemistry showed that the level of LC3 was increased by YZT, which is in line with the in vitro results. In short, our study provides reliable experimental basis for developing Compound YZT as a new chemotherapeutic drug candidate and suggests that combined administration of YZT with CQ is a potential therapy against NSCLC. [ABSTRACT FROM AUTHOR]

New structurally diverse groups of C8-substituted caffeine derivatives were synthesized and evaluated for their chemical and biological properties. Mass spectrometry, FT-IR, and NMR characterizations of these derivatives were performed. The cytotoxic activity of the derivatives was estimated in vitro using human red blood cells (RBC) and in silico pharmacokinetic studies. The antioxidant capacity of the compounds was analyzed using a ferrous ion chelating activity assay. The ability of the derivatives to protect RBC from oxidative damage, including the oxidation of hemoglobin to methemoglobin, was assessed using a water-soluble 2,2′-azobis(2-methyl-propionamidine) dihydrochloride (AAPH) as a standard inducer of peroxyl radicals. The level of intracellular oxidative stress was assessed using the fluorescent redox probe 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA). The results indicate that all derivatives are biocompatible compounds with significant antioxidant and cytoprotective potential dependent on their chemical structure. In order to explain the antioxidant and cytoprotective activity of the derivatives, a mechanism of hydrogen atom transfer (HAT), radical adduct formation (RAF), or single electron transfer (SET), as well as the specific interactions of the derivatives with the lipid bilayer of RBC membrane, have been proposed. The results show that selected modifications of the caffeine molecule enhance its antioxidant properties, which expands our knowledge of the structure–activity relationship of caffeine-based cytoprotective compounds. [ABSTRACT FROM AUTHOR]

The Nrf2 gene encodes a transcription factor best known for regulating the expression of antioxidant and detoxification genes. A long list of small molecules has been reported to induce Nrf2 protein via Keap1 oxidation or alkylation. Many of these Nrf2 inducers exhibit off-target or toxic effects due to their nature as electrophiles. In searching for non-toxic Nrf2 inducers, we found that a culture medium change to fresh DMEM is capable of inducing Nrf2 protein in HeLa, HEK293, AC16 and MCF7 cells. Testing the components of DMEM led to the discovery of L-Cystine as an effective Nrf2 inducer. L-Cystine induces a dose-dependent increase of Nrf2 protein, from 0.1 to 1.6 mM. RNA-seq analyses and RT-PCR revealed an induction of multiple Nrf2 downstream genes, including NQO1, HMOX1, GCLC, GCLM, SRXN1, TXNRD1, AKR1C and OSGIN1 by 0.8 mM L-Cystine. The induction of Nrf2 protein was dependent on L-Cystine entering cells via the cystine/glutamate antiporter and the presence of Keap1. The half-life of Nrf2 protein increased from 19.4 min to 30.9 min with 0.8 mM L-Cystine treatment. L-Cystine was capable of eliciting cytoprotection by reducing ROS generation and protecting against oxidant- or doxorubicin-induced apoptosis. As an amino acid derivative, L-Cystine is considered a non-toxic Nrf2 inducer that exhibits the potential for protection against oxidative stress and tissue injury. [ABSTRACT FROM AUTHOR]

Metal-nitrogen-doped carbon single-atom nanozymes (M − NC SAzymes) have tremendous prospects to replace natural enzymes for the treatment of reactive oxygen species (ROS)-related diseases. However, developing a pyrolysis-free and universal synthesis of M − NC SAzymes with robust enzyme-mimicking activity still remains a challenge. Herein, a promising cytoprotective agent (Fe-NC SAzymes) with multiple enzyme-mimicking activities was fabricated based on the reaction of Schiff bases with Fe ions via one-pot solvothermal method. In Fe-NC SAzymes, Fe-N x moieties served as the main catalytic sites to mimick oxidase, peroxidase, and catalase; meanwhile, the co-catalytic sites of the π-conjugated nitrogen-doped carbon structure mimicked superoxide dismutase to achieve the multiple enzyme-mimicking catalysis. Owing to the dual catalytic sites and pyrolysis-free synthesis strategy, Fe-NC SAzymes showed enhanced catalytic performance and excellent biocompatibility, which could scavenge excessive intracellular ROS to alleviate oxidative stress. The viability of cells subjected to oxidative stress recovered from 1.4% to 80.3% after Fe-NC SAzymes treatment, demonstrating an outstanding cytoprotective performance. Remarkably, this synthetic strategy can be expanded to other metal-NC SAzymes (Cu, Mn, Co, Zn, and Ni), which provides a feasible route to design specific functional SAzymes for ROS-related diseases therapy. [Display omitted] • A non-pyrolytic method was proposed to get Fe-NC SAzymes via Schiff base reaction. • Fe-NC has dual sites of π-conjugated structure and Fe-N x to mimick natural enzyme. • Fe-NC showed robust ROS scavenging ability to alleviate oxidative stress of cells. • This strategy is universal to prepare various metal-NC SAzymes. [ABSTRACT FROM AUTHOR]

Heme oxygenase-1 (HO-1) is a protective protein in oxidative stress response. LXA4 is an "inflammatory braking signal" that is widely studied at present. The purpose of this study was to elucidate that LXA4 can protect cells by inducing HO-1 in human pulmonary microvascular endothelial cells (HPMECs) as in vitro model to explain acute lung injury after severe acute pancreatitis. This study was performed in two parts: (1) To investigate the mechanisms of lipoxin A4-induced HO-1 expression in vitro , the study subjects were divided into four groups: a control group, LXA4 group (50 ng/mL LXA4), inhibitor group (50 ng/mL LXA4 + 20 μM LY294002 or 50 ng/mL LXA4 + 2 nmol/mL Bis II), and agonist group (50 ng/mL insulin-like growth factor 1, PMA). Western blotting was used to detect the expression of p-Akt, Akt, protein kinase C (PKC), p-Nrf2, Nrf2, and Keap1, and the location of Nrf2 was detected using immunofluorescence. The activation of antioxidant responsive element induced by Nrf2 was detected using Electrophoretic Mobility Shift Assay and (2) to investigate the cytoprotection of HO-1 induced by LXA4 in vitro , the subjects were divided into four groups: a control group, tumor necrosis factor α (TNF-α) group (50 ng/mL), LXA4 group (50 ng/mL TNF-α + 50 ng/mL LXA4), and Zinc protoporphyrin IX group (pretreated with 0.5 μM Zinc protoporphyrin IXfor 12 h, followed by 50 ng/mL TNF-α + 50 ng/mL LXA4). BCECF/AM-labeled THP-1 cells were used to analyze the adhesion of HPMECs, and a mitochondrial membrane potential assay kit with JC-1 was used to analyze the apoptosis of HPMECs. In part one, (1) LXA4 upregulated the expression of HO-1 in a dose-dependent manner and (2) LXA4 activated the PI3K/Akt and PKC pathways and modulated the phosphorylation and subsequent depolymerization of Nrf2 from Keap1, promoting the translocation of Nrf2 to the nucleus. In part two, (1) LXA4 reversed the changes in mitochondrial membrane potential to alleviate apoptosis in HPMECs and (2) LXA4 attenuated the adhesion of HPMECs induced by TNF-α. LXA4 can activate the PI3K/Akt and PKC pathways and induce the phosphorylation of Nrf2, resulting in the upregulation of HO-1. In addition, LXA4 alleviates adhesion and protects mitochondrial function by upregulating the expression of HO-1, which exerts cytoprotection in severe acute pancreatitis–induced lung injury. [ABSTRACT FROM AUTHOR]

Antioxidants are being explored as novel therapeutics for the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) through strategies such as chemically linking antioxidants to synthesize novel co-drugs. The main objective of this study was to assess the cytoprotective effects of the novel antioxidant compound VANL-100 in a cellular model of beta-amyloid (Aβ)-induced toxicity. The cytotoxic effects of Aβ in the presence and absence of all antioxidant compounds were measured using the 3-(4,5-dimethylthiazol-2-yl)2-5-diphenyl-2H-tetrazolium bromide (MTT) assay in SH-SY5Y cells in both pre-treatment and co-treatment experiments. In pre-treatment experiments, VANL-100, or one of its parent compounds, naringenin (NAR), alpha-lipoic acid (ALA), or naringenin + alpha-lipoic acid (NAR + ALA), was administrated 24 h prior to an additional 24-h incubation with 20 μM non-fibril or fibril Aβ25–35. Co-treatment experiments consisted of simultaneous treatment with Aβ and antioxidants. Pre-treatment and co-treatment with VANL-100 significantly attenuated Aβ-induced cell death. There were no significant differences between the protective effects of VANL-100, NAR, ALA, and NAR + ALA with either form of Aβ, or in the effect of VANL-100 between 24-h pre-treatment and co-treatment. These results demonstrate that the novel co-drug VANL-100 is capable of eliciting cytoprotective effects against Aβ-induced toxicity. [ABSTRACT FROM AUTHOR]