Oxidative DNA Damage Research Articles

Role of oxidative stress in the occurrence of periodontitis in the background of metabolically associated diseases

Oxidative stress is an important component of slow pathological inflammation in metabolic diseases and chronic periodontitis. Periodontal diseases are interrelated with somatic pathology. This results in both local and systemic inflammatory reactions, which increases the risk of the onset and progression of somatic diseases. Psychological stress associated with oxidative stress with increased production of oxidants and oxidative damage is an important factor in the etiology of both periodontitis and metabolic disorders. Objective — to analyze the possible bond between chronic periodontitis, 8‑hydroxydeoxyguanosine (8‑OHdG), as a biomarker of oxidative stress, and cortisol in persons with metabolic‑associated diseases. Materials and methods. 68 people were surveyed, of which 47 had metabolically ‑associated diseases that were diagnosed according to domestic and international criteria. The control group consisted of systematically healthy people, representative by age and article that did not receive dental therapeutic and preventive measures for the last 6 months. The diagnosis of «chronic periodontitis» was carried out in accordance with existing recommendations provided at World Workshop on the Classification of Periodontal and Peri­Implant Diseases and Conditions (2017). The concentration of 8‑OHdG in plasma and the level of saliva cortisol were measured by the immunoenzyme method according to the manufacturer’s instructions. The arithmetic mean, standard error, and Student’s t‑test were calculated to compare the characteristics. Pearson’s correlation test was used to identify the relationship between the indicators. Results. Each of the groups had patients who had a healthy periodontium and those who had chronic periodontitis. The 8‑OHdG level in the main group was much higher (p<0.001) than in the control group, and the difference in the concentration of 8‑OHdG was also observed between those patients who had periodontal disease and those who had a healthy periodontium. The level of salivary cortisol in patients with chronic periodontitis was much higher compared to patients with clinically healthy periodontium (p=0.00). A correlation was found between cortisol levels and the presence of periodontal disease (r=0.619; p=0.00), between plasma 8OHdG levels and the epithelial attachment loss index (r=0.537; p=0.00), the hygiene index (r=0.599; p=0.00), and between 8OHdG levels and salivary cortisol concentrations (r=0.292; p=0.036). Conclusions. Oxidative stress plays an important role in delayed pathological inflammation in both metabolic diseases and chronic periodontitis. 8‑OHdG is a key and universal biomarker for the evaluation of DNA oxidative damage. There is a positive relationship between the oxidative marker, periodontitis and cortisol.

The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells

Background/ObjectiveActive vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells. MethodsBone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/−) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups. ResultsABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins. ConclusionABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency. The translational potential of this articleThis study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

DNA-Protective, Antioxidant and Anti-Carcinogenic Potential of Meadowsweet (Filipendula ulmaria) Dry Tincture.

Nowadays, interest in natural antioxidants (especially phenolics) for the prevention of oxidative stress-related diseases is increasing due to their fewer side effects and more potent activity than some of their synthetic analogues. New chemical and pharmacological studies of well-known herbal substances are among the current trends in medicinal plant research. Meadowsweet (Filipendula ulmaria) is a popular herb used in traditional medicine to treat various diseases (including rheumatic-, inflammatory- and tumor-related disease, etc.). The dry tincture of Filipendulae ulmariae herba, collected from the Bulgarian flora, was analyzed using the HPLC method and bioassayed for antioxidant, antiproliferative and DNA-protective activities against oxidative damage. The HPLC phenolic profile showed 12 phenolics, of which salicylic acid (18.84 mg/g dry extract), rutin (9.97 mg/g de), p-coumaric acid (6.80 mg/g de), quercetin (4.47 mg/g de), rosmarinic acid (4.01 mg/g de) and vanillic acid (3.82 mg/g de) were the major components. The high antioxidant potential of the species was confirmed by using four methods, best expressed by the results of the CUPRAC assay (10,605.91 μM TE/g de). The present study reports for the first time the highly protective activities of meadowsweet dry tincture against oxidative DNA damage and its antiproliferative effect against hepatocellular carcinoma (HepG2 cell line). Meadowsweet dry tincture possesses great potential to prevent diseases caused by oxidative stress.

Sea cucumber-derived extract can protect skin cells from oxidative DNA damage and mitochondrial degradation, and promote wound healing

Our skin serves as the primary barrier against external environmental insults, the latter of which can cause oxidative stress within cells, while various bioactive peptides sourced from natural resources hold promise in protecting cells against such oxidative stress. In this study, we investigate the efficacy of a low molecular weight extract from the sea cucumber Apostichopus japonicus, denoted as Sample-P, in facilitating cell migration and wound healing under oxidative stress conditions in skin cells. The naturally derived compound is a highly complex mix of peptides exhibiting antioxidative properties, as highlighted through liquid chromatography-mass spectrometry peptide screening and an in vitro antioxidant assay. Our results demonstrate that Sample-P is capable of promoting cell migration while preventing severe stress responses such as visible through mTOR expression. To further identify the molecular pathways underpinning the overall protective mechanism of Sample-P, we have utilised a proteomics approach. Our data reveal that Sample-P regulates protein expression associated with ribosomal pathways, glycolysis/gluconeogenesis and protein processing in the endoplasmic reticulum (ER), which help in preserving DNA integrity and safeguarding cellular organelles, such as mitochondria and the ER, under oxidative stress conditions in skin cells. In summary, in the presence of H2O2, Sample-P exhibits antioxidative properties at both molecular and cellular levels, rendering it a promising candidate for topical skin treatment to wound healing and to address age-related skin conditions.

Resveratrol inhibited colorectal cancer progression by reducing oxidative DNA damage by targeting the JNK signaling pathway

Recent evidence has proved that resveratrol as a natural polyphenol has great anti-cancer and anti-proliferative effects in cancer cells. In this study, we aimed to examine the protective effects of resveratrol in rats with 1,2-dimethylhydrazine (DMH)-induced colorectal cancer and investigate the potential underlying molecular mechanisms. Male Wistar rats were classified into different groups, including Group 1 without any intervention, group 2 as resveratrol-received rats (8 mg/kg), Group 3 as DMH-received rats, and Group 4, as DMH and resveratrol-received rats. DNA damage, DNA repair, the expression levels and activities of antioxidants, and JNK signaling were evaluated in colon tissues. We found that DNA damage and DNA repair were significantly suppressed and induced, respectively, in DMH + resveratrol groups. The expression levels and activities of antioxidants were increased in DMH + resveratrol groups. Lipid and protein peroxidation were significantly suppressed in DMH + resveratrol groups. In addition, resveratrol also modulated JNK signaling in DMH + resveratrol groups. Our findings demonstrated that resveratrol effectively reversed DMH-mediated oxidative stress and DNA damage by targeting the JNK signaling pathway.

Role of iron homeostasis in the mutagenicity of disinfection by-products in mammalian cells

Disinfection by-products (DBPs) generated from water treatment have serious adverse effects on human health and natural ecosystems. However, research on the mutagenicity of DBPs with different chemical structures is still limited. In the present study, we compared the mutagenicity of 8 typical DBPs in human-hamster hybrid (AL) cells and clarified the mechanisms involved. Our data displayed that the rank order for mutagenicity was as follows: iodoacetamide (IAcAm) > iodoacetonitrile (IAN) > iodoacetic acid (IAA) > bromoacetamide (BAcAm) ≈ bromoacetonitrile (BAN) > bromoacetic acid (BAA), which was confirmed by DNA double strand breaks and oxidative DNA damage. In contrast, bromoform (TBM) and iodoform (TIM) had minimal mutagenicity. The mutation spectrum analysis further revealed that IAN, IAcAm, and IAA could induce multilocus deletions in mammalian cells. Interestingly, nitrogenous DBPs (N-DBPs) and IAA were found to cause varying degrees of iron overload and lipid peroxidation, which was mediated by the activation of the Nrf2/HO-1 signaling pathway. Moreover, the presence of deferoxamine (DFO), an iron ion inhibitor, effectively reduced γ-H2AX and 8-OHdG induced by N-DBPs and IAA. These results indicated that the variations in genotoxicity among DBPs with different structures were associated with their ability to disrupt iron homeostasis. This study provided new insights into the mechanisms underlying the structure-dependent toxicity of DBPs and established a foundation for a more comprehensive understanding and intervention of the health risks associated with DBPs.

Silicon dioxide particles induce DNA oxidative damage activating the AIM2-mediated PANoptosis in mice cerebellum

Silicon dioxide (SiO2) particles are novel materials with wide-ranging applications across various fields, posing potential neurotoxic effects. This study investigates the toxicological mechanisms of SiO2 particles of different sizes on murine cerebellar tissue and cells. Six-week-old C57BL/6 mice were orally administered SiO2 particles of three sizes (1 μm, 300 nm, 50 nm) for 21 days to establish an in vivo model, and mice cerebellar astrocytes (C8-D1A cells) were cultured in vitro. Indicators of oxidative stress, DNA damage, and the PANoptosis pathway were detected using methods such as immunofluorescence staining, comet assay, western blotting, and qRT-PCR. The results show that SiO2 particles induce oxidative stress leading to DNA oxidative damage. The aberrant DNA is recognized by AIM2 (absent in melanoma 2), which activates the assembly of the PANoptosome complex, subsequently triggering PANoptosis. Furthermore, the extent of damage is inversely correlated with the size of SiO2 particles. This study elucidates the toxicological mechanism of SiO2 particles causing cerebellar damage via PANoptosis, extending research on PANoptosis in neurotoxicology, and aiding in the formulation of stricter safety standards and protective measures to reduce the potential toxic risk of SiO2 particles to humans.

HUC-MSC-derived exosomes repaired the damage induced by hydroquinone to 16HBE cells via miR-221/PTEN pathway

Mesenchymal stem cell - originated exosomes (MSC-exo) are promising non-cellular treatment agents for various diseases. The present study aimed to explore whether human umbilical cord MSC - originated exosomes (HUC-MSC-exo) have the function of protecting human cells (16HBE) against the damage caused by HQ and the related mechanism. HUC-MSC-exo was isolated with differential gradient ultracentrifugation method and characterized by using transmission electron microscope (TEM). 16HBE cells were used as the tool cells and co-cultured with HUC-MSC-exo. Confocal laser scanning microscope was employed to confirm the ingestion of HUC-MSC-exo by 16HBE. Cell proliferation, migration, oxidative stress, DNA and chromosome damages of 16HBE were analyzed under HQ stress, and the role of miR-221/PTEN axis was investigated. Our data showed that under HQ stress, different groups of cells exhibited significantly decreased proliferation and migration abilities, and significant oxidative stress, DNA and chromosome damage effects. HUC-MSC-exo could alleviate the cytotoxic, oxidative stress and genotoxic damage effects of HQ on 16HBE cells. Mechanistically, HQ exposure up-regulated the level of miR-221 and down-regulated PTEN, while HUC-MSC-exo could significantly reduce the level of miR-221 and promote PTEN expression, which was involved in alleviating the toxic effects of HQ on 16HBE cells. Our data indicates that HUC-MSC-exo can alleviate the oxidative stress, cytotoxic and genotoxic effects of HQ on 16HBE cells via miR-221/PTEN pathway, and it may be a promising agent for protecting against the toxicity of HQ.

AKR7A5 knockout promote acute liver injury by inducing inflammatory response, oxidative stress and apoptosis in mice.

Alcohol liver disease has become a worldwide critical health problem. The ingested alcohol could be converted into acetaldehyde or combined with free fatty acids to induce the endoplasmic reticulum oxidative stress in the liver. Coincidentally, AKR7A5 has both aldehyde detoxification and antioxidant effects. Therefore, we discuss the possible role and mechanism of AKR7A5 in the acute alcohol injury of mice liver. There were four experiment groups, the C57BL/6 mice of wild-type mice (WT) or AKR7A5-/- mice (KO) were intragastrically administrated with saline or 50% ethanol at 14 mL/kg, respectively. Compared to the WT + alcohol group, abnormal liver function, disordered hepatic cord, severe congestion in the hepatic sinus and the space of the hepatic cord, occurrence of oxidative stress, DNA damage and different expressions of apoptosis-related proteins were detected in the KO + alcohol group. Meanwhile, the biological process enrichment analysis showed that the down-regulated proteins were related to the metabolism of fatty acid, the up-regulated proteins positive regulation of reactive oxygen species metabolic process, negative regulation of coagulation and haemostasis. In conclusion, single ethanol binge combined with the absence of AKR7A5 caused more severe inflammatory response, oxidative stress, apoptosis of endogenous pathways, abnormal lipids metabolism and disordered coagulation in mice liver.

DNA Probing of Peroxidase‐Mimetic Activities of Selected Manganese‐Based Nanozymes and Measurement of Antioxidant Activity for DNA Protection

AbstractThree different Mn‐based peroxidase‐mimetic nanoparticles (NPs) were synthesized as nanozymes: (i) manganese (II)‐ferrite (MnFe2O4) fabricated by co‐precipitating MnCl2.4H2O and FeCl3.6H2O; (ii) MnO2 synthesized from precipitation of MnSO4 in basic medium; (iii) manganese oxide obtained by reducing KMnO4 with tris(2‐hydroxyethyl) amine, all characterized using STEM, EDXS, FTIR and XPS techniques. These NPs acted as peroxidases, revealed by using a DNA probe, on which the damage generated by peroxidase mimetic NPs was monitored spectrophotometrically by CUPRAC and 3,3′,5,5′‐tetramethylbenzidine (TMB) methods. Results were confirmed by RP‐HPLC and voltammetry, the latter involving an AuNPs‐modified glassy carbon electrode (GCE), multi‐walled carbon nanotubes (MWCNT) and Nafion combination. Colorimetric assay with CUPRAC rather than TMB better agreed with chromatographic/voltammetric findings in detecting both peroxidase activity and DNA hazard. Mn(III)‐containing manganese oxide from permanganate reduction had stronger peroxidase activity. The proposed method demonstrated protective effects of antioxidants (morin, catechin and quercetin) against oxidative DNA damage for the first time.

Regeneration of zebrafish retina following toxic injury

The structure of the zebrafish retina appears to be very similar to that of mammals, that is why it is used as a model for studying the eye. Indeed, the zebrafish retina can regenerate itself through mechanisms of Müller cell reprogramming. In this research, adult zebrafish were exposed to aluminum to cause damage in the retina and thus evaluate the regenerative capacity of the damaged tissue. Histological and histochemical analyses assessed the retinal structure and the neurodegenerative process, respectively. An expression analysis of PARPs was carried out to verify whether a potential oxidative DNA damage happens. In addition, some genes involved in the regeneration process (pax6a, pax2a, ngn1, and notch1a) were analyzed. The data confirmed the toxicity of aluminum which caused retinal neurodegeneration, but also highlighted the ability of zebrafish to regenerate the retinal structure, repairing the damage and confirming its use as a good model for translational studies.

PRDM16 Controls Cellular Senescence and Organ Aging by Promoting Oxidative DNA Damage

PRDM16 Controls Cellular Senescence and Organ Aging by Promoting Oxidative DNA Damage

Testicular oxidative DNA damage induced by cyclophosphamide and the impact role of pumpkin seed extract: Descriptive histopathological, ultrastructural, and immunohistochemical analysis

Testicular oxidative DNA damage induced by cyclophosphamide and the impact role of pumpkin seed extract: Descriptive histopathological, ultrastructural, and immunohistochemical analysis

Evaluation of Oxidative Stress activity, DNA Damage and Global DNA Methylation among Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is a serious threat to global medicine as more than two million get CKD yearly. However, the understanding of DNA damage, DNA methylation in chronic kidney disease (CKD) remains elusive. The study goal was to establish whether homocysteine (Hcy), oxidative DNA damage (ODD), glutathione peroxidase (GPX3) and 5-methylcytosine (5mC) could be used as a potential marker of CKD. Measurements of Hcy, ODD, and GPX3 levels were done by commercial enzyme linked immunosorbent assay (ELISA) kits of 60 patients with chronic kidney disease (age range 20-87 years) and 30 age-matched healthy controls. DNA extracted from blood of patients was used to evaluate the global 5-methylcytosine (5mC) levels by the MethylFlashTM methylated DNA quantification Kit (Epigentek, USA). Results indicated a highly significant rise in Hcy and ODD in CKD patients in contrast to the healthy controls group. Although GPX3 level reduced in CKD patients, there was no significant difference between the patients and healthy controls. This research results also revealed significant rise in global 5mC level in CKD patients in comparison to the healthy controls. There is a potential role of homocysteine, oxidative DNA damage and global 5mC to be used as a biomarker for the progression of CKD.

Antioxidative properties of baicalin on methylparaben-induced testicular oxidative stress and oxidative DNA damage in a rat experimental model

Antioxidative properties of baicalin on methylparaben-induced testicular oxidative stress and oxidative DNA damage in a rat experimental model

Metal-organic framework-edaravone nanoparticles for radiotherapy-induced brain injury treatment

Cranial radiotherapy may cause damage to normal brain tissues and induce cognitive dysfunction, so developing an effective strategy to prevent radiotherapy-induced brain injury is essential. Metal-organic frameworks (MOFs) can be used as vectors for the delivery of neuroprotective drugs due to their high drug loading capacity and low toxicity. In this study, we synthesized MIL-53(Cr) nanoparticles, which were used to deliver edaravone, and modified the surface of the nanoparticles with polyethylene glycol and Angiopep-2 (EDA@MIL-53(Cr)–P/A) to improve their oral bioavailability and ability to cross the blood–brain barrier (BBB). We confirmed that MIL-53(Cr)–P/A nanoparticles could achieve the sustained release of edaravone and enhance its ability to cross the BBB. The results of in vitro experiments showed that EDA@MIL-53(Cr)–P/A could exert radioprotective effects on HT22 and BV2 cells. We also demonstrated that EDA@MIL-53(Cr)–P/A could alleviate brain injury and cognitive dysfunction in mice receiving whole-brain irradiation. Mechanistically, EDA@MIL-53(Cr)–P/A alleviated irradiation-induced brain damage by inhibiting oxidative stress, DNA damage, apoptosis and inflammatory reactions. This study provides a new strategy for the protection against radiotherapy-induced brain injury.

Caenorhabditis elegans as a Model to Study Aging and Photoaging.

Caenorhabditis elegans (C. elegans) has emerged as an outstanding model organism for investigating the aging process due to its shortened lifespan, well-defined genome, and accessibility of potent genetic tools. This review presents the current findings on chronological aging and photoaging in C. elegans, exploring the elaborate molecular pathways that control these processes. The progression of chronological aging is characterized by a gradual deterioration of physiological functions and is influenced by an interaction of genetic and environmental factors, including the insulin/insulin-like signaling (IIS) pathway. In contrast, photoaging is characterized by increased oxidative stress, DNA damage, and activation of stress response pathways induced by UV exposure. Although the genetic mechanisms of chronological aging in C. elegans have been characterized by extensive research, the pathways regulating photoaging are comparatively less well-studied. Here, we provide an overview of the current understanding of aging research, including the crucial genes and genetic pathways involved in the aging and photoaging processes of C. elegans. Understanding the complex interactions between these factors will provide invaluable insights into the molecular mechanisms underlying chronological aging and photoaging and may lead to novel therapeutic approaches and further studies for promoting healthy aging in humans.

Ecotoxicological risk of co-exposure to fosthiazate and microplastics on earthworms (Eisenia fetida): Integrating biochemical and transcriptomic analyses

Fosthiazate (FOS) is a widely used organophosphorus insecticide effective against soil root-knot nematodes. However, its ecotoxicity to non-target soil organisms, particularly in combination with microplastics (MPs), is unclear. This study explores the toxic-effects and molecular mechanisms of co-exposure to FOS and MPs on earthworms (Eisenia fetida) using multilevel toxicity endpoints and transcriptomics. Results showed that both FOS and MPs elevated the intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OHdG) in earthworms’ cells. The superoxide dismutase (SOD) and catalase (CAT) activities followed a similar trend in all treatments, with changes observed at 14 and 28 days, indicating that co-exposure to FOS and MPs increased DNA oxidative damage. Notably, the co-exposure more significantly inhibited Ca2+-ATPase activity and exacerbated neurotoxicity compared to individual treatments, closely associated with changes in intracellular ROS levels that mediate neuroinhibition and lead to neurotoxicity. KEGG enrichment analysis revealed that MPs and FOS disrupted pathways related to metabolism, immunity, and apoptosis, while co-exposure primarily impaired endocrine and receptor pathways, showing higher toxicity. Our study offers novel insights into the ecotoxicological effects and mechanisms of pesticides and microplastics on earthworms, providing valuable data for evaluating the soil environmental health risks associated with compound pollution.

Therapeutic potential of astrocyte-derived extracellular vesicles in mitigating cytotoxicity and transcriptome changes in human brain endothelial cells

This study investigates the therapeutic effect of astrocyte-derived extracellular vesicles (EVs) in mitigating neurotoxicity-induced transcriptome changes, mitochondrial function, and base excision repair mechanisms in human brain endothelial cells (HBECs). Neurodegenerative disorders are marked by inflammatory processes impacting the blood–brain barrier (BBB) that involve its main components- HBECs and astrocytes. Astrocytes maintain homeostasis through various mechanisms, including EV release. The effect of these EVs on mitigating neurotoxicity in HBECs has not been investigated. This study assesses the impact of astrocyte-derived EVs on global transcriptome changes, cell proliferation, cytotoxicity, oxidative DNA damage, and mitochondrial morphology in HBECs exposed to the neurotoxic reagent Na2Cr2O7. Exposure to Na2Cr2O7 for 5 and 16 h induced oxidative DNA damage, measured by an increase in genomic 8OHdG, while the EVs reduced the accumulation of the adduct. A neurotoxic environment caused a non-statistically significant upregulation of the DNA repair enzyme OGG1 while the addition of astrocyte-derived EVs was associated with the same level of expression. EVs caused increased cell proliferation and reduced cytotoxicity in Na2Cr2O7-treated cells. Mitochondrial dysfunction associated with a reduced copy number and circular morphology induced by neurotoxic exposure was not reversed by astrocyte-derived EVs. High-throughput RNA sequencing revealed that exposure to Na2Cr2O7 suppressed immune response genes. The addition of astrocyte-derived EVs resulted in the dysregulation of long noncoding RNAs impacting genes associated with brain development and angiogenesis. These findings reveal the positive impact of astrocytes-derived EVs in mitigating neurotoxicity and as potential therapeutic avenues for neurodegenerative diseases.

Synergistic modulation of endoplasmic reticulum stress pathway, oxidative DNA damage and apoptosis by β-amyrin and metformin in mitigating hyperglycemia-induced renal damage using adult zebrafish model

Diabetic nephropathy (DN) can be prevented with early therapeutic intervention in diabetic patients. Recent investigations suggest that β-amyrin, a pentacyclic triterpenoid, could offer significant benefits with its potential antihyperglycemic and nephroprotective effects. We investigated the protective effects of β-amyrin alone and combined it with metformin, the cornerstone therapy for diabetes, using a hyperglycemic adult Zebrafish (ZF) model. The ZF were subjected to hyperglycemia by immersing them in 111 mM glucose solutions. Treatment efficacy was assessed by measuring serum glucose and insulin levels and antioxidant, ER stress, apoptosis, and proinflammatory markers. ZF kidneys were also studied for immunohistochemistry and histopathology. Results revealed that the combined treatment of β-amyrin and metformin resulted in a significant decrease (p ≤ 0.05) in blood glucose levels to 104.54 ± 1.63 mg/dL, in comparison to 388.75 ± 4.32 mg/dL in the untreated diseased control group. The reduction in hyperglycemia was more pronounced than treatment with either compound alone. Moreover, treatment with the combination restored renal function in diseased ZF, leading to significantly lower (p ≤ 0.05) serum urea (SU: 19.57 ± 1.61 mg/dL) and serum creatinine (SC: 0.56 ± 0.02 mg/dL) values compared to treatment with β-amyrin (SU:27.02 ± 0.96 mg/dL; SC: 0.7 ± 0.01 mg/dL) or metformin (SU: 24.53 ± 1.29 mg/dL; SC: 0.6 ± 0.02 mg/dL) alone. The treatment also reduced oxidative stress markers, apoptosis and ER stress markers, and proinflammatory cytokines. Histopathological analysis showed improved renal architecture with significantly lower (p ≤ 0.05) renal tubular injury scores with the combination than with individual treatment. This study provides novel insights into the combined therapeutic effects of β-amyrin and metformin in mitigating hyperglycemia-induced renal damage through key molecular pathways, highlighting a potentially effective therapeutic strategy for diabetic nephropathy. The findings hold promising translational relevance for developing combination therapies aimed at improving clinical outcomes in diabetic nephropathy patients.