Stress Damage Research Articles

The preventive effects of natural plant compound carvacrol against combined UVA and UVB-induced endoplasmic reticulum stress in skin damage of rats.

The skin is constantly exposed to a variety of environmental stressors, including ultraviolet (UV) radiation. Exposure of the skin to UV radiation causes a number of detrimental biological damages such as endoplasmic reticulum (ER) stress. The ER stress response is a cytoprotective mechanism that maintains homeostasis of the ER by increasing the capacity of the ER against the accumulation of unfolded proteins in the ER. Carvacrol (CRV) is a monoterpenoid phenol found in essential oils with antimicrobial and anti-inflammatory activities. We investigated for the first time in the literature the potential protective role of CRV against combined UVA and UVB-induced skin damage by targeting the ER stress pathway in a rat model. For this purpose, expressions of Grp78, Perk, Atf6, Ire-1, Chop, Xbp1, Casp12, elF2α, and Traf2 genes related to ER stress were analyzed by RT-PCR and protein expression levels of GRP78, ATF6, CHOP, and XBP1 were determined by ELISA assay in tissue sections taken from the back of the rats. As a result of analysis, it was seen that the expression levels of aforementioned ER stress genes increased significantly in the UVA + UVB irradiated group compared to the control group, while their expression levels decreased markedly by supplementation of CRV in UVA + UVB + CRV group. With regard to expressions of foregoing proteins, their levels escalated notably with UVA + UVB application and decreased markedly by CRV supplementation. In conclusion, present study revealed that CRV ameliorates UVA + UVB-induced ER stress via reducing the expression of mRNA as well as proteins involved in the unfolded protein response (UPR) pathway and inducing apoptosis as evidenced from high Caspase12 level.

Mild hypothermia therapy alleviates neuronal damage and repairs cerebral ischemia-reperfusion injury through the SIRT1/AMPK pathway.

Cerebrovascular disease, one of the high-risk diseases worldwide, is high in morbidity, disability, mortality, and recurrence rates, which brings many harms to human beings such as physical and mental harm, economic losses, and impairment of social relations. Cerebral ischemia-reperfusion injury (CIRI) is one of the most common pathological manifestations, with mild hypothermia therapy being the most commonly used treatment in clinical practice. In this study, the research team established a CIRI animal model and found that the neuronal apoptosis rate was significantly increased, accompanied by significant ferroptosis, increased inflammation and oxidative stress damage in brain tissue, and obviously inhibited SIRT1/AMPK pathway. However, after mild hypothermia treatment, the pathological changes of CIRI rats were significantly reversed, and the SIRT1/AMPK pathway was reactivated. Therefore, mild hypothermia may achieve the purpose of CIRI repair by activating the SIRT1/AMPK signaling pathway, and targeted regulation of the SIRT1/AMPK signaling pathway may be a research direction for optimizing mild hypothermia therapy or developing new treatment plans for CIRI.

Grain-based coupled thermo-mechanical modeling for stressed heterogeneous granite under thermal shock

Microscopic damage and macroscopic mechanical properties of granite under the coupling effect of thermal load and initial stress are crucial considerations for the safe construction of underground geo-energy engineering. However, visualizing real-time micro-crack processes in rocks under high-temperature and high-pressure conditions using the current experimental techniques remains challenging. In this study, a numerical method is developed to analyze the thermally induced damage in heterogeneous granite under the coupled influence of initial stress and thermal loading. A biaxial thermo-mechanical grain-based model considering real mineral distribution is established based on digital image processing technology, the grain-based modeling method, and heat conduction theory. The microscopic parameters are calibrated and the effectiveness of the model is verified based on thermal shock and uniaxial compression experiments. The thermal destruction mechanism of granite under initial stress from a microscopic perspective was unveiled for the first time. During the thermal shock process, the stress within the rock does not remain constant at the initial stress value. Instead, it changes continuously with the progression of heat conduction. The impact of the initial stress on the thermally induced cracks is relatively minor. Cooling causes more damage to the rock than heating during thermal shock. The intragranular cracks of quartz consistently outnumber other intragranular or intergranular cracks during thermal shock. The initial stress and thermal shock damage enhance and weaken the biaxial peak strength of granite, respectively. The weakening effect of thermal shock on the peak strength becomes more pronounced at a higher initial stress. These research findings and proposed research techniques contribute to the management and optimization of underground geo-energy engineering.

Influence of initial stresses and stress paths on the deformation and failure mechanism of sandy slate

Rocks exhibit various mechanical properties under different stress conditions, with changes during unloading having significant implications for geological engineering safety. This study carried out triaxial loading and unloading mechanical tests on sandy slate to investigate its mechanical properties, deformation characteristics, and failure mechanisms at different initial stress levels and stress paths. The results showed that during the unloading process, the deformation modulus (E) of the sandy slate decreased, and the Poisson's ratio (μ) gradually increased. This indicates that significant volume expansion of the rock is the dominant factor in its deformation and failure. The exponential function can be used to describe the evolution of E and μ with confining pressure during unloading. The damage stress of the rock under unloading conditions was lower than that under loading conditions, suggesting that unloading led to an earlier onset of volumetric expansion in the sandy slate. Under conditions where the initial axial stress level approached the damage stress, the mechanical properties were most significantly affected by unloading. Compared to loading conditions, when the initial axial stress level was at 70% of the peak strength, the cohesion (c) decreased by 15.77 to 29.37%, while the internal friction angle (φ) increased by 1.88 to 5.14%. The rock's failure process can be divided into four stages based on the development of microcracks. Unloading during the stages of microcrack initiation and propagation can lead to tensile cracks of varying degrees, resulting in different mechanical properties and failure characteristics under loading and unloading conditions.

Corilagin alleviated intestinal ischemia-reperfusion injury by modulating endoplasmic reticulum stress via bonding with Bip

BackgroundIntestinal ischemia-reperfusion (II/R) injury is a common clinical emergency with high morbidity and mortality. Given the absence of efficacious prophylactic and therapeutic interventions and specific drugs, sustained efforts are essential to develop new targeted drugs. Corilagin, a naturally polyphenolic tannic acid widespread in longan, rambutan and many other edible economic crops with medicinal properties in China, is of interest due to its multiple bioactivities, including the potential to mitigate II/R injuries. Nevertheless, a clear understanding of its molecular targets and the intricate mechanisms against II/R injury remains obscure and requires further elucidation. ObjectiveThis study aimed to investigate corilagin's pharmacological impact and molecular mechanism for II/R injury. MethodsAn animal II/R model was established by clamping superior mesenteric artery (SMA), and the therapeutic efficacy of corilagin against II/R was evaluated by biochemical and pathological analysis. Next, integrated transcriptomic and proteomic analyses was performed to identify key targets. Moreover, endoplasmic reticulum stress (ERS) damage was respectively observed by transmission electron microscope (TEM), immunohistochemistry, TUNEL, flow cytometry and western blotting (WB). Finally, molecular docking, molecular dynamics (MD) simulation, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays were utilized to assess the interaction between corilagin and binding immunoglobulin protein (Bip, Grp78 or Hspa5), and co-IP assay was conducted to investigate the interaction between Bip and its substrate proteins. ResultsCorilagin exhibited robust protection against II/R injuries, effectively alleviating intestinal tissue damage and oxidative stress induced by II/R. The modulation of ERS as a potential regulatory mechanism was investigated through an integrated transcriptomic and proteomic analysis, identifying Bip as a key target contributing to corilagin's protective effects. Further experimental evidence using molecular docking, MD simulation, CETSA, and DARTS assays confirmed the potentially direct interaction of corilagin with Bip. This interaction promoted the ubiquitin-dependent degradation of the Bip-substrate complex, thereby suppressing ERS-related signalling pathways, including the IRE1 branch, PERK branch, and ATF6 branch, to alleviate tissue damage. ConclusionThis study confirmed that corilagin could selectively bind to Bip, facilitating its ubiquitin-dependent recognition and degradation, thereby inhibiting severe endoplasmic reticulum stress signalling and alleviating II/R injury. A detailed mechanistic insight into the action mode of corilagin had been proposed, supporting its potential usage as an ERS inhibitor.

Microbial Biocontrol Agents and Natural Products Act as Salt Stress Mitigators in Lactuca sativa L.

One of the major problems related to climate change is the increase in land area affected by higher salt concentrations and desertification. Finding economically and environmentally friendly sustainable solutions that effectively mitigate salt stress damage to plants is of great importance. In our work, some natural products and microbial biocontrol agents were evaluated for their long-term effectiveness in reducing salt stress in lettuce (Lactuca sativa L. var. romana) plants. Fourteen different treatments applied to soil pots, with and without salt stress, were analyzed using biometric (leaf and root length and width), physiological (chlorophyll and proline content), and morphological (microscopic preparations) techniques and NGS to study the microbial communities in the soil of plants subjected to different treatments. Under our long-term experimental conditions (90 days), the results showed that salt stress negatively affected plant growth. The statistical analysis showed a high variability in the responses of the different biostimulant treatments. Notably, the biocontrol agents Papiliotrema terrestris (strain PT22AV), Bacillus amyloliquefaciens (strain B07), and Rahnella aquatilis (strain 36) can act as salt stress mitigators in L. sativa. These findings suggest that both microbial biocontrol agents and certain natural products hold promise for reducing the adverse effects of salt stress on plants.

Loss of Diphthamide Increases DNA Replication Stress in Mammalian Cells by Modulating the Translation of RRM1.

Diphthamide (DPH) is a highly conserved post-translational modification exclusively present in eukaryotic translation elongation factor 2 (eEF2), with its loss leading to embryonic lethality in mice and developmental disorders in humans. In this study, we unveil the role of diphthamide in mammalian cell DNA damage stress, with a particular emphasis on DNA replication stress. We developed a systematic strategy to identify human proteins affected by diphthamide with a combination of computational profiling and quantitative proteomics. Through this approach, we determine that the translation of RRM1 is modulated by diphthamide via -1 frameshifting. Importantly, our results reveal that the dysregulation of RRM1 translation in DPH-deficient cells is causally linked to elevated DNA replication stress. These findings provide a potential explanation for how diphthamide deficiency leads to cancer and developmental defects in humans.

ATM phosphorylation of CD98HC increases antiporter membrane localization and prevents chronic toxic glutamate accumulation in Ataxia telangiectasia.

Ataxia telangiectasia (A-T) is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in A-T, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of A-T is not understood. CD98HC chaperones cystine/glutamate (x c - ) and cationic/neutral amino acid (y + L) antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on SLC family antiporters relevant to A-T phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes) with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance both in ATM-deficient cells and mouse models. These findings provide new insight into the long-known benefits of N-acetyl cysteine to A-T cells beyond oxidative stress through removing excess glutamate by production of glutathione.

Quercetin ameliorates oxidative stress-induced apoptosis of granulosa cells in dairy cow follicular cysts by activating autophagy via the SIRT1/ROS/AMPK signaling pathway

BackgroundFollicular cysts contribute significantly to reproductive loss in high-yield dairy cows. This results from the death of follicular granulosa cells (GCs) caused by oxidative stress. Quercetin is known to have significant antioxidant and anti-apoptotic effects. However, the effect of quercetin on follicular cysts has yet been elucidated. Therefore, this study aimed to explore the anti-oxidant and anti-apoptosis effects and potential molecular mechanisms of quercetin in H2O2-induced primary cow GCs and 3-nitropropionic acid (3-NPA)-induced mouse model of oxidative stress and thus treat ovarian cysts in dairy cows.ResultsIn this study, compared with estrus cows, cows with follicular cysts showed heightened levels of oxidative stress and increased follicular cell apoptosis, while autophagy levels were reduced. A model of oxidative stress was induced in vitro by H2O2 and showed significant increases in apoptosis together with reduced autophagy. These effects were significantly ameliorated by quercetin. Effects similar to those of quercetin were observed after treatment of cells with the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC). Further investigations using chloroquine (autophagy inhibitor), rapamycin (autophagy activator), selisistat (SIRT1 inhibitor), and compound C (AMPK inhibitor) showed that chloroquine counteracted the effects of quercetin on oxidative stress-induced apoptosis, while rapamycin had the same effect as quercetin. In addition, the SIRT1/AMPK pathway inhibitors antagonized quercetin-mediated mitigation of the effects of oxidative stress on increased apoptosis and reduced autophagy. Consistent with the results in vitro, in mouse ovarian oxidative stress model induced by 3-NPA, quercetin activated autophagy through the SIRT1/AMPK signaling pathway, while alleviating oxidative stress damage and inhibiting apoptosis in mouse ovaries.ConclusionsThese findings indicate that quercetin can inhibit apoptosis in GCs and restore ovarian function by activating autophagy through the SIRT1/ROS/AMPK signaling pathway, suggesting a new direction for the treatment of ovarian follicular cysts in high-yield dairy cows.

Hyperoxia in Sepsis and Septic Shock: A Comprehensive Review of Clinical Evidence and Therapeutic Implications.

Sepsis and septic shock are leading causes of mortality in intensive care units, characterized by a dysregulated immune response to infection, leading to severe organ dysfunction. Oxygen therapy is a cornerstone of supportive care in sepsis management, aimed at correcting hypoxemia and improving tissue oxygenation. However, the administration of supplemental oxygen must be carefully managed to avoid hyperoxia, which can lead to oxidative stress and additional tissue damage. This review aims to comprehensively analyze the clinical evidence regarding hyperoxia in the context of sepsis and septic shock, evaluating its potential therapeutic benefits and risks and discussing the implications for clinical practice. A thorough literature review included observational studies, randomized controlled trials (RCTs), meta-analyses, and clinical guidelines. The review focuses on the pathophysiology of sepsis, the mechanisms of hyperoxia-induced injury, and the clinical outcomes associated with different oxygenation strategies. The evidence suggests that while oxygen is crucial in managing sepsis, the risk of hyperoxia-related complications is significant. Hyperoxia has been associated with increased mortality and adverse outcomes in septic patients due to mechanisms such as oxidative stress, impaired microcirculation, and potential worsening of organ dysfunction. RCTs and meta-analyses indicate that conservative oxygen therapy may be beneficial in reducing these risks, though optimal oxygenation targets remain under investigation. This review highlights the importance of careful oxygen management in sepsis and septic shock, emphasizing the need for individualized oxygen therapy to avoid the dangers of hyperoxia. Further research is required to refine oxygenation strategies, establish clear clinical guidelines, and optimize outcomes for sepsis and septic shock patients. Balancing adequate oxygenation with the prevention of hyperoxia-induced injury is crucial in improving the prognosis of these critically ill patients.

Intestinal and hepatic benefits of BBR-EVO on DSS-induced experimental colitis in mice.

Ulcerative colitis (UC), characterized by disrupted intestinal barrier integrity and chronic inflammation, was modeled in mice via dextran sulfate sodium (DSS) induction. This study explored the therapeutic potential of berberine-evodiamine (BBR-EVO), bioactive components of the traditional Chinese medicine Yulian decoction, in DSS colitis. BBR-EVO intervention ameliorated weight loss, diarrhea, colonic shortening, and histopathological damage in colitic mice. The substance increased antioxidant activity while reducing high levels of pro-inflammatory cytokines in the colon, including as TNF-α, IL-1β, and IL-6. BBR-EVO inhibited the DSS-induced decrease in the tight junction proteins ZO-1 and occludin, according to immunohistochemistry. 16S rRNA sequencing demonstrated BBR-EVO partially attenuated DSS-elicited intestinal dysbiosis, reducing opportunistic pathogens and restoring diminished beneficial taxa. Critically, BBR-EVO alleviated secondary hepatic injury in colitic mice, mitigating immune cell infiltration, oxidative stress, cytokine production, and ultrastructural damage, likely by beneficially modulating gut-liver crosstalk. This study reveals BBR-EVO, derived from a traditional Chinese medicine, confers multi-target protective effects in experimental colitis and associated hepatic pathology, warranting further evaluation as a potential therapy for inflammatory bowel diseases like UC. The mechanisms may involve simultaneous augmentation of intestinal barrier integrity, inhibition of inflammation, microbiota regulation, and gut-liver axis optimization.

A carbon dot nanozyme hydrogel enhances pulp regeneration activity by regulating oxidative stress in dental pulpitis

Preserving pulp viability and promoting pulp regeneration in pulpitis have attracted widespread attention. Restricted by the oxidative stress microenvironment of dental pulpitis, excessive reactive oxygen and nitrogen species (RONS) trigger uncontrolled inflammation and exacerbate pulp tissue destruction. However, modulating redox homeostasis in inflamed pulp tissue to promote pulp regeneration remains a great challenge. Herein, this work proposes an effective antioxidative system (C-NZ/GelMA) consisting of carbon dot nanozymes (C-NZ) with gelatin methacryloyl (GelMA) to modulate the pulpitis microenvironment for dental pulp regeneration by utilizing the antioxidant properties of C-NZ and the mechanical support of an injectable GelMA hydrogel. This system effectively scavenges RONS to normalize intracellular redox homeostasis, relieving oxidative stress damage. Impressively, it can dramatically enhance the polarization of regenerative M2 macrophages. This study revealed that the C-NZ/GelMA hydrogel promoted pulp regeneration and dentin repair through its outstanding antioxidant, antiapoptotic, and anti-inflammatory effects, suggesting that the C-NZ/GelMA hydrogel is highly valuable for pulpitis treatment.

JuA alleviates liver ischemia-reperfusion injury by activating AKT/NRF2/HO-1 pathways

Liver ischemia-reperfusion (I/R) injury is a detrimental complication of organ transplantation, shock, and sepsis. However, the available drugs to mitigate I/R injury remain limited. Jujuboside A (JuA) is renowned for its antioxidant, anti-inflammatory, and anti-apoptotic properties; nevertheless, its potential in liver I/R injury remains unknown. Thus, this study aimed to explore the role and underlying mechanisms of JuA in liver I/R injury. Mouse models of I/R and AML12 cell models of hypoxia/reoxygenation (H/R) were constructed. Haematoxylin and eosin staining, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) detection, and cell viability analysis were used to assess liver injury. To evaluate oxidative stress, inflammation, apoptosis, and mitochondrial damage, immunofluorescence staining, transmission electron microscopy analysis, enzyme-linked immunosorbent assay, and flow cytometry were conducted. Moreover, molecular docking techniques and western blot were employed to identify downstream target molecules and pathways affected by JuA. The results showed that JuA pretreatment effectively attenuated liver necrosis and ALT and AST level elevations induced by I/R while enhancing AML12 cell viability following H/R. Furthermore, JuA pretreatment suppressed oxidative stress triggered by I/R and H/R, thereby inhibiting the level of pro-inflammatory factors and NLRP3 inflammasome activation. Notably, JuA pretreatment alleviated mitochondrial damage and apoptosis. Mechanistically, JuA pretreatment resulted in the activation of the AKT/NRF2/HO-1 signalling pathways, whereas MK2206, the inhibitor of AKT, partially reversed the hepatoprotective effects of JuA during liver I/R. Collectively, our findings illustrated that JuA mitigated oxidative stress, inflammation, apoptosis, and mitochondrial damage by facilitating the AKT/NRF2/HO-1 signalling pathway, thereby alleviating liver I/R injury.

Oxidative lipid damage by naringenin selectively sensitizes chronic myeloid leukemia cell lines and patient samples to Bcr-Abl tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) treatment with Bcr-Abl tyrosine kinase inhibitors (TKIs) has significantly improved patient outcomes, yet challenges such as drug resistance and persistence of leukemic stem cells persist. This study explores the potential of naringenin, a natural flavonoid, to enhance the efficacy of Bcr-Abl TKIs in CML therapy. We showed that naringenin reduces viability of a panel of CML cell lines regardless of varying cellular origin and genetic mutations, and acts synergistically with dasatinib and ponatinib. Importantly, naringenin is effective in targeting blast crisis CML CD34+ cells by decreasing their colony formation, self-renewal and viability. Compared to CML, naringenin is significantly less effective against normal bone marrow (NBM) counterparts. In addition, naringenin significantly enhances the inhibitory effects of dasatinib in CML but not NBM CD34+ cells. Mechanism studies showed that naringenin's inhibitory effects were associated with the induction of oxidative stress and lipid damage, as evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Notably, naringenin upregulated genes related to mitochondrial biogenesis while downregulating antioxidant defense genes. Pretreatment with α-tocopherol, which inhibits lipid-mediated ROS production, completely abolished the ROS increase and restored cell viability, indicating that lysosomal lipid peroxidation plays a crucial role in naringenin's mechanism of action. In a CML xenograft mouse model, the combination of naringenin and dasatinib resulted in remarkably more tumor growth suppression compared to single drug alone. Importantly, this combination was well-tolerated, with no adverse effects on body weight observed. These findings suggest that naringenin, by inducing oxidative lipid damage, enhances the anti-leukemic effects of Bcr-Abl TKIs, offering a promising therapeutic strategy for CML.

α-Lipoic Acid Mitigates Heat Stress and Oxidative Damage in Broiler Chickens

Introduction: Heat stress has become a significant concern for the global poultry industry as a result of climate change. This condition can adversely affect growth, gut health, immune function, production levels, and reproductive performance, and can lead to lipid peroxidation in poultry. Therefore, this study aimed to evaluate Interleukin 6 and 10 immune responses, anti-oxidant indices, serum biochemistry, and hepatic and splenic histopathology of heat-stressed broiler chickens supplemented with α-lipoic acid (α-LA) in their diet. Materials and methods: A total of two hundred and four unsexed day-old Arbor acre broiler chicks were randomly divided into four treatment groups and replicated three times to receive α-LA at 0, 50, 100, and 200 mg/kg, respectively in a completely randomized design for 42 days after a one-week adjustment period. The average temperature in the morning and afternoon was 27.9℃ and 35.1℃, respectively, while the morning and afternoon humidity was 73.1% and 44.1% respectively. Feed and water were provided ad libitum. At the end of the feeding trial, samples were taken for cytokines (interleukin-6 and 10), anti-oxidant, serum biochemistry, and hepatic and splenic histopathology analyses. Results: An inverse relationship was observed between pro-inflammatory (IL-6) and anti-inflammatory (IL-10) cytokines whereby, IL-6 levels decreased while IL-10 levels increased relative to increasing α-LA levels in treatment groups. The treatment groups also indicated an increasing trend with rising levels of α-LA for superoxide dismutase, catalase, glutathione, and total antioxidant capacity. The α-LA significantly influenced malondialdehyde production, showing its reduction with rising levels of α-LA. A decrease in serum glucose and low-density lipoproteins was observed with increasing levels of α-LA, while high-density lipoproteins increased with increasing levels of α-LA. Cholesterol, triglycerides, very low-density lipoproteins, aspartate transaminase, alanine transaminase, and alkaline phosphate remained unchanged across the treatment groups. Conclusion: α-LA supplementation at 200mg/kg in diet had the highest effects on immune responses of interleukin 6 and 10, antioxidant, serum biochemical indices, and histopathology of heat-stressed broiler chickens.

Hypoglycemic, hypolipidemic and antioxidant potential of Myrcia pubipetala in an animal model of type 1 diabetes

Myrcia genus plants, like Myrcia pubipetala, traditionally used as hypoglycemic agents, hold promise for Type 1 Diabetes Mellitus (DM1) research but need more comprehensive chemical and pharmacological investigation. This is an experimental study involving controlled administration of treatments to a group of rats to assess their effects compared with a control group, investigating the effects of M. pubipetala on alloxan-induced Type 1 Diabetes Mellitus in rats. After the induction of diabetes, the rats received the hydroalcoholic extract (HAE) or aqueous fraction (AF) (25, 50, 100, or 150 mg kg-1) of M. pubipetala, or water. The results showed that diabetic rats presented cell damage in kidneys, oxidative stress, and high levels of glucose and triglycerides in their plasma and erythrocytes. The HAE (150 mg kg-1), per se, reduced lipid and protein oxidation, and the AF (150 mg kg-1) decreased lipoperoxidation. AF (150 mg kg-1), per se, decreased triglyceride levels. Conclusion: treatment with HAE and AF reduced oxidative damage, positively modulated antioxidant defenses, and exerted hypoglycemic and hypolipidemic effects, representing a potential adjuvant treatment for diabetes.

The Protective Effects of Mcl-1 on Mitochondrial Damage and Oxidative Stress in Imiquimod-Induced Cancer Cell Death.

Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development.

HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis

BackgroundClear cell renal cell carcinoma (ccRCC) is a serious threat to human life. It is very important to clarify the pathogenesis of ccRCC. In this study we evaluated the clinical value of HADH and explored its role and mechanism in the malignant progression of ccRCC. MethodsHADH expression and its relationship with prognosis were analyzed using bioinformatics database. RT-PCR, Western blot and immunohistochemistry were used to examine the expression of HADH in ccRCC tissues and tissue microarrays. To examine the cell proliferation, apoptosis, migration and invasion ability, ccRCC cells with HADH overexpressed were constructed. Xenograft experiments were performed to determine the role of HADH. Non-target metabolomics was applied to explore the potential metabolic pathway by which HADH inhibited ccRCC progression. Plasmid pcDNA3.1-NRF2 was used to confirm whether HADH inhibited the process of ccRCC cells through NRF2-related glutathione (GSH) synthesis. ResultsBioinformatics database analysis showed that HADH expression was significantly decreased in ccRCC tissues, and its low expression predicted a poor prognosis. Both ccRCC tissues and tissue microarrays exhibited a significantly decreased HADH level compared with adjacent normal renal tissues. HADH overexpression inhibited the malignant behaviors of ccRCC cells. Furthermore, HADH overexpression attenuated GSH synthesis and induced oxidative stress damage. Exogenously increased NRF2 effectively attenuated the inhibitive effect of HADH overexpression on ccRCC cells. ConclusionOur data revealed that HADH suppressed the malignant behaviors of ccRCC cells by attenuating GSH synthesis through inhibition of NRF2 nuclear translocation, and HADH might be a novel therapeutic target for ccRCC treatment.

Hepatoprotective Effect of Ethanolic Pomegranate Peel Extract Against Levofloxacin via Suppression of Oxidative Stress, Proinflammation, and Apoptosis in Male Rats.

One of the fluoroquinolone antibiotics, levofloxacin (LEV), is used to treat a variety of illnesses leading to oxidative stress and cellular damage. Peel from Punica granatum is a waste product abundant in phytochemicals with various biological activities. This study aimed to evaluate P. granatum peel extract's (PGPE) potential to mitigate oxidative stress, inflammation, apoptosis, and liver damage caused by LEV. There were four groups of rats: control, PGPE, LEV, and PGPE + LEV, respectively, and they were orally administered their daily treatments for 2 weeks. Results revealed that PGPE has a large number of phytochemical components with high antioxidant activity. PGPE intake alone enhanced the antioxidant status and decreased oxidative stress. On the other hand, pretreatment of the LEV group with PGPE restored oxidative stress, antioxidant enzymes, glutathione content, liver function biomarkers, and hematological parameters. Also, normalization of gene expressions (cyclooxygenase-2, transforming growth factor-beta1, caspase-3, heme oxygenase-1, B cell lymphoma-2, interleukin [IL]-10, and IL-1) and improvement in liver architecture, and immunohistochemical alpha-smooth muscle actin, were seen in comparison to the LEV group. Conclusively, PGPE exhibits strong anti-inflammatory, antiapoptotic, and antioxidant properties that shield rat liver from the damaging effects of LEV and offer a fresh viewpoint on the application of fruit waste products.

Abstract P203: Nicotine Exposure: A Catalyst for Nitrosative and Oxidative Stress in Glomerular Podocytes and Renal Impairment

Introduction: Nicotine consumption through vaping, cigarettes, or nicotine replacement therapy poses major risks for renal health, especially in individuals with hypertension or kidney disease. Nicotine induces oxidative stress and nitric oxide synthase (NOS) remodeling in endothelial cells, but a gap in knowledge persists regarding its impact on glomerular epithelial cells, particularly podocytes. We hypothesize that nicotine promotes nitrosative stress in podocytes, generating peroxynitrite (ONOO - ), causing mitochondrial damage, and glomerular impairment. Methods: We performed confocal imaging on human cultured podocytes to detect ONOO - , Ca 2+ , and nitric oxide (NO) in response to nicotine. We used Seahorse assay (Agilent XFe24) to test mitochondrial respiration. Nicotine was then chronically infused in Dahl SS rats (0.2 mg/kg/day s.c., 0.4% NaCl diet) for 21 days, and recorded blood pressure with telemetry. Glomerular damage was evaluated, and electron microscopy was employed to assess mitochondrial ultrastructure. Electron paramagnetic resonance (EPR) spectroscopy was used to access the NO levels in cultured podocytes and in vivo . OriginPro was used for statistical analysis. Results: Acute application of nicotine promoted intracellular Ca 2+ and ONOO - transients in podocytes. The ONOO - response was blocked in the presence of SOD, indicating that ONOO - production requires superoxide. The application of specific α7, α4β2, α2β4, α4β4, and α3β4 nicotinic acetylcholine receptor (nAChR) agonists elicited Ca 2+ transients but did not produce ONOO - , suggesting that nitrosative stress occurs independently from nAChR activation. Incubation with nicotine (12 hrs) resulted in a decrease in podocytes’ mitochondrial respiration (two-sample t-test, p<0.05). In vivo , nicotine infusion did not affect blood pressure but promoted mitochondrial damage in podocytes, which exhibited swelling, loss of cristae, and mitophagy (t-test, p<0.05). Histopathological assessment showed higher glomerular damage in nicotine-exposed rats (t-test, p<0.05). Both EPR and confocal approaches demonstrated nicotine-mediated changes in NO bioavailability and an increase in NOS2 activity (t-test, p<0.05). Conclusion: Nicotine products promote NOS uncoupling in podocytes, leading to ONOO - formation, redox stress, mitochondrial impairment, and glomerular damage. Understanding nicotine's impact on podocytes is crucial for preventing or developing therapies against smoking and vaping-related pathologies.