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Dual involvement of ROS/RNS in physiology and disease. ROS, such as H2O2 and O 2 , are important factors involved in the process of signal transduction in cells, especially in the β-cells and skeletal muscle, both involved in insulin synthesis and action, respectively. In the immune system cells, ROS/RNS are important to generate HOCL through MPO, contributing to the destruction of pathogens. ROS play a functional role in pregnancy and is required for implantation, labour and proper placenta–foetal development processes, including vascularisation, extracellular matrix remodelling and appropriate cell signalling with concomitant apoptosis. However, an imbalance between ROS/RNS removal production and the biological system’s ability to readily detoxify reactive species and its intermediates, or even repair the resulting damage, is considered detrimental and may result in oxidative stress. Oxidative stress has been strongly involved in insulin resistance and insulin secretion exhaustion in β-cell, autoimmune diabetes, GDM, chronic inflammation, obesity, non-alcoholic fatty liver disease (NAFLD), among others. GSIS, glucose-stimulated insulin secretion; MPO, myeloperoxidase; HOCL, hypochlorous acid; TNF-α, tumour necrosis factor α; IL-1β, interleukin-1β; H2O2, hydrogen peroxide; NO·, nitric oxide; ONOO−, peroxynitrite ion; 1O2*, singlet oxygen; ·OOH, peroxyl radical; ·OH, hydroxyl; R+, free radicals in general; O 2 , superoxide anion; LOOH, lipid hydroperoxides.
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Oxidative stress and chronic inflammation are known to be associated with the development of metabolic diseases, including diabetes. Oxidative stress, an imbalance between oxidative and antioxidative systems of cells and tissues, is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). One outcome of e...
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... regulation of tissue inflammation, ROS generation and pathways of intracellular signalling are required for homeostasis and survival. However, excess nutrient consumption and low levels of physical activity lead to an imbalance in redox regulation, insulin secretion and insulin action resulting in DM progression and severe consequences for whole body metabolism and health outcomes, as detailed in Figure 2. Indeed, oxidative stress and inflammation provoked by excessive nutrient availability and obesity are key factors associated with meta- bolic diseases and DM progression both for the peripheral tissues and for β-cells within the islets. ...
Citations
... ROS and RNS play biologically significant roles in several normal bodily functions, including adaptation to hypoxia, signal transduction, as well as control of autophagy, immunity, differentiation, and lifespan (Sena and Chandel, 2012;Di Meo et al., 2016). However, when the body fails to counteract the overproduction of these species through antioxidant networks present in cells, the excessive levels of ROS, RNS, and associated free radicals can result in oxidative stress, which can subsequently lead to cellular dysfunction, excessive inflammation, and chronic conditions such as cancer, diabetes, cataracts, and many cardiovascular, inflammatory, and neurodegenerative diseases (Newsholme et al., 2016;Hernández-Rodríguez et al., 2019). ...
The Rubiaceae family, comprising 550 species in the Philippines, is a significant source of bioactive components with ethnopharmacological uses. This study assessed the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity of six Rubiaceae species, collected in Ilocos Norte, Philippines: Guettardella microphylla (Bartl. ex DC.) Merr., Timonius ternifolius (Bartl. ex DC.) Fern.-Vill., Kanapia monstrosa (A. Rich.) Arriola & Alejandro, Pyrostria triflora Arriola, Calaramo & Alejandro, Pyrostria subsessilifolia (Merr.) Arriola & Alejandro, and Psychotria luzoniensis (Cham. & Schltdl.) Fern.-Vill. Identification of the plant species was done using morphological characterization. The TFC results ranged between 1.86-3.81 mg quercetin equivalent/g dry weight (GAE/g DW), while TPC indicated 5.47-17.17 mg gallic acid equivalent/g dry weight (QE/g DW). G. microphylla showed the highest TFC (3.81±0.20 mg QE/g DW) while P. triflora exhibited the highest TPC (17.17±0.83 mg GAE/g DW). Antioxidant profiling showed P. luzoniensis exhibiting the highest activity in the NOS, ABTS, DPPH, and FRAP assays. G. microphylla showed the highest hydrogen peroxide scavenging activity, while T. ternifolius demonstrated the highest hydroxyl radical scavenging activity. Findings suggest that the crude methanolic extracts of the Rubiaceae species have relatively high TPC and TFC values and exhibit promising antioxidant capacities.
... H2O2 can easily cross the cell membrane to damage cells [17,18]. To investigate whether MLF can protect cells from H2O2-mediated oxidative damage, first, the effect of different concentrations of MLF on the survival rate of HepG2 cells was investigated. ...
Oxidative stress significantly contributes to ageing and disease, with antioxidants holding promise in mitigating its effects. Functional foods rich in flavonoids offer a potential strategy to mitigate oxidative damage by free radicals. We investigated the protective effects of mulberry leaf flavonoids (MLF) against H2O2-induced oxidative damage in HepG2 cells. It assessed the inhibitory effect of MLF (62.5-500 μg/mL) on H2O2-induced oxidative damage by analyzing cellular morphology and oxidative stress markers, including ROS production, mitochondrial membrane potential, antioxidant enzyme levels, MDA, and apoptosis-related proteins. The results demonstrated that MLF prevented spiny cell formation triggered by 750 μM H2O2 and significantly reduced ROS levels, restored mitochondrial membrane potential, decreased lactate dehydrogenase and alanine transaminase leakage, and reduced MDA content induced by H2O2. MLF also modulated antioxidant enzymes and attenuated oxidative damage to HepG2 cell DNA, as confirmed by staining techniques. These findings indicate the potential of MLF as a hepatoprotective agent against oxidative damage in HepG2 cells.
... Under typical conditions, the body maintains a balanced and gradual oxidation equilibrium. However, certain stimuli can disrupt the antioxidant system of the body, leading to oxidative stress reactions triggered by factors such as ROS, resulting in localized or systemic damage (94). Currently, abnormal number and function of T lymphocyte subpopulations, the activation of inflammatory cytokines and the pathological loss of cell histology in the pathogenesis of gouty arthritis are closely linked to the extensive release of free radicals following oxidative stress. ...
The present review expounds the advancements in the application and mechanisms of flavonoids in gouty arthritis, highlighting their significance in managing the disease. Gouty arthritis is among the most common and severe inflammatory diseases, caused by hyperuricemia and the deposition of sodium urate crystals in the joints and surrounding tissues, posing a serious threat to human life and health. Flavonoids, extracted from various herbs, have attracted significant attention due to their efficacy in improving gouty arthritis. The present study systematically reviews the in vivo studies and in vitro animal studies on flavonoids from herbal medicines for the treatment of gouty arthritis that have been previously published in the PubMed, ScienceDirect, Google Scholar and China National Knowledge Infrastructure databases between 2000 and 2023. The review of the literature indicated that flavonoids can improve gouty arthritis through multiple mechanisms. These include lowering xanthine oxidase activity, inhibiting uric acid (UA) synthesis, regulating UA transporters to promote UA excretion, reducing the inflammatory response and improving oxidative stress. These mechanisms predominantly involve regulating the NOD‑like receptor 3 inflammasome, the Toll‑like receptor 4/myeloid differentiation factor 88/nuclear factor‑κB signaling pathway, and the levels of UA transporter proteins, namely recombinant urate transporter 1, glucose transporter 9, organic anion transporter (OAT)1 and OAT3. Various flavonoids used in traditional Chinese medicine hold therapeutic promise for gouty arthritis and are anticipated to pave the way for novel pharmaceuticals and clinical applications.
... TNF-α, leptin, FFAs, and resistin are the components of adipose tissue remodeling in obesity that can contribute to oxidative stress-induced insulin resistance [16]. In addition, the accumulation of lipid peroxidation products in cells, such as 4HNE and oxysterols, can activate NF-κB signaling and result in inflammation and insulin resistance [47]. Leptin, visfatin, and FFAs are other activators of NF-κB signaling [8,16]. ...
... The importance of these cells is due to their role in insulin production. Furthermore, the increased sensitivity of these cells to oxidative stress is related to their lower levels of antioxidants such as SOD, GPx, CAT, and thioredoxin (TR) [16,36,47]. Mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage are significant consequences of oxidative stress in β-cells. ...
... The activation of AMP-activated protein kinase (AMPK) and JNK and down-regulation of the mammalian target of rapamycin (mTOR), as a result of increased oxidative stress, can lead to decreases in the mass, proliferation, apoptosis, and dedifferentiation of β-cells [48]. The damaging and dysfunction of these cells indicate excessive ROS generation, a reduction in ATP production, and insulin secretion [47]. It should be noted that appropriate levels of H 2 O 2 up-regulate insulin secretion; however, the excessive generation of this molecule, and the ability of β-cells to detoxify them, result in inhibited insulin secretion [38]. ...
In people with obesity, diabetes, and hypertension, lipid and glucose metabolism and oxidative stress generation interact. This condition, known as a “metabolic syndrome” (MetS), presents a global challenge and appears to be the underlying mechanism for the development of cardiovascular diseases (CVDs). This review is designed based on evidence indicating the pathogenic mechanisms of MetS. In detail, we will look at the mechanisms of oxidative stress induction in MetS, the effects of elevated oxidative stress levels on the condition’s pathophysiology, and matters related to endothelial function. According to different components of the MetS pathophysiological network, the effects of antioxidants and endothelial dysfunction are reviewed. After considering the strategic role of oxidative stress in the pathophysiology of MetS and its associated CVDs, oxidative stress management by antioxidant supplementation seems an appropriate therapeutic approach.
... ROS and RNS play biologically significant roles in several normal bodily functions, including adaptation to hypoxia, signal transduction, as well as control of autophagy, immunity, differentiation, and lifespan (Sena and Chandel, 2012;Di Meo et al., 2016). However, when the body fails to counteract the overproduction of these species through antioxidant networks present in cells, the excessive levels of ROS, RNS, and associated free radicals can result in oxidative stress, which can subsequently lead to cellular dysfunction, excessive inflammation, and chronic conditions such as cancer, diabetes, cataracts, and many cardiovascular, inflammatory, and neurodegenerative diseases (Newsholme et al., 2016;Hernández-Rodríguez et al., 2019). ...
The Rubiaceae family, comprising 550 species in the Philippines, is a significant source of bioactive components with ethnopharmacological uses. This study assessed the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity of six Rubiaceae species, collected in Ilocos Norte, Philippines: Guettardella microphylla (Bartl. ex DC.) Merr., Timonius ternifolius (Bartl. ex DC.) Fern.-Vill., Kanapia monstrosa (A. Rich.) Arriola & Alejandro, Pyrostria triflora Arriola, Calaramo & Alejandro, Pyrostria subsessilifolia (Merr.) Arriola & Alejandro, and Psychotria luzoniensis (Cham. & Schltdl.) Fern.-Vill. Identification of the plant species was done using morphological characterization. The TFC results ranged between 1.86-3.81 mg quercetin equivalent/g dry weight (GAE/g DW), while TPC indicated 5.47-17.17 mg gallic acid equivalent/g dry weight (QE/g DW). G. microphylla showed the highest TFC (3.81±0.20 mg QE/g DW) while P. triflora exhibited the highest TPC (17.17±0.83 mg GAE/g DW). Antioxidant profiling showed P. luzoniensis exhibiting the highest activity in the NOS, ABTS, DPPH, and FRAP assays. G. microphylla showed the highest hydrogen peroxide scavenging activity, while T. ternifolius demonstrated the highest hydroxyl radical scavenging activity. Findings suggest that the crude methanolic extracts of the Rubiaceae species have relatively high TPC and TFC values and exhibit promising antioxidant capacities.
... It also causes decreased testosterone levels, ejaculation disorders, and low libido. The oxidative stress induced by diabetes is the main cause of its chronic harmful effects on tissues such as the testis in streptozotocin-induced animal models of diabetes [8][9][10][11][12]. ...
... However, the antioxidant effects of harmine on testicular tissue observed in this study may explain its beneficial impact on sperm [33]. Considering the role of oxidative stress in the progression of diabetes, it seems that the development of oxidative stress conditions in these patients is due to increased production of reactive oxygen species in the blood plasma and a weakened antioxidant defense system [11]. Thus, we suggest that the mechanism of diabetes-related injury is linked to the depletion of the antioxidant support system. ...
... Therefore, the generation of free radicals and the subsequent oxidative stress may be one of the primary causes of tissue apoptosis, reflecting the pervasive impact of oxidative stress [36]. Numerous studies support the conclusion that free radical generation and oxidative stress are key factors in the onset of diabetes [11,26,31]. This stress triggers apoptosis not only in the pancreas [37] but also in distant organs such as the testes, as demonstrated in our study. ...
Objective: Diabetes mellitus induces fertility problems in men, mainly because of increased free radicals. Natural resources are effective for male infertility treatment. This study investigated the effects of harmine, an alkaloid available in Peganum harmala L., on the male reproductive system of diabetic rats. Methods: We divided 32 rats into four groups, and eight were randomly placed in each group. For diabetes induction, the animals received 50 mg/kg of streptozotocin intraperitoneally. After 1 week, animals received 15 mg/kg of harmine (28 days; intraperitoneal). Histopathological examinations, serum levels of male hormones, levels of nitric oxide (NO) and malondialdehyde (MDA) in the testes, total antioxidant capacity (TAC), insulin serum levels, fasting blood glucose levels, the apoptotic index, and semen analysis were assessed. Results: The diabetes group exhibited morphological changes in testicular tissue, significant decreases in the diameter of the seminiferous tubule, the Johnsen score, testosterone, luteinizing hormone, follicle-stimulating hormone, insulin serum levels, and TAC in testicular tissue (p<0.01). Harmine treatment ameliorated the morphological changes in the testes and improved sperm parameters relative to the diabetes group (p<0.05). The NO and MDA levels in the testes, fasting blood glucose serum levels, and apoptotic index parameters were significantly elevated in the diabetes group, while in the diabetes+harmine group, these parameters were reduced (p<0.01). Conclusion: Harmine protects testicular tissue and sperm against diabetes-induced damage. This effect of harmine is associated with a rebalancing of the antioxidant capacity that subsequently decreases apoptosis in the testes.
... Consuming excessive high-fat and/or carbohydrate diets has been shown to promote oxidative stress, as evidenced by higher levels of lipid peroxidation products, and reduced antioxidant status. In the context of obesity, chronic oxidative stress and the resulting inflammation are key factors contributing to the development of various pathologies, including insulin resistance, disrupted metabolic pathways, and diabetes mellitus (DM) (Newsholme et al., 2016). ...
Chemical investigation of Carthamus tinctorius L. flowers resulted in isolation of seven metabolites that were identified as; p-Hydroxybenzoic acid (1), trans hydroxy cinnamic acid (2), kaempferol-6-C-glucoside (3), astragalin (4), cartormin (5), kaempferol-3-O-rutinoside (6), and kaempferol–3-O-sophoroside (7). Virtual screening of the isolated compounds against human intestinal α-glucosidase, acetylcholinesterase, and butyrylcholinesterase was carried out. Additionally, the antioxidant activity of the bioactive compounds was assessed. Compounds 1 and 5 exhibited moderate binding affinities to acetylcholinesterase (binding energy −5.33 and −4.18 kcal/mol, respectively), compared to donepezil (-83.33kcal/mol). Compounds 1–7 demonstrated weak affinity to butyrylcholinesterase. Compounds 2 and 4 displayed moderate binding affinity to human intestinal α-glucosidase,compared to Acarbose (reference compound), meanwhile compound 2 exhibited lower affinity. Molecular dynamic studies revealed that compound 4 formed a stable complex with the binding site throughout a 100 ns simulation period. The in-vitro results were consistent with the virtual experimental results, as compounds 1 and 5 showed mild inhibitory effects on acetylcholinesterase (IC50s 150.6 and 168.7 µM, respectively). Compound 4 exhibited moderate α-glucosidase inhibition with an IC50 of 93.71 µM. The bioactive compounds also demonstrated notable antioxidant activity in ABTS [2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)], ORAC (oxygen radical-absorbance capacity), and metal chelation assays, suggesting their potential in improving dementia in Alzheimer’s disease (AD) and mitigating hyperglycemia.
... They are involved in physiological functions like phagocytosis , necrosis, apoptosis, signaling , immunity , inflammation and tissue injury [1,2]. Further, they are highly toxic to cells and damage cellular lipids, proteins, and DNA leading to cardiovascular diseases [3] , neurological diseases [4], auto immune diseases like rheumatoid arthritis [5], inflammatory bowel disease [6], reproductive disorders [7], diabetes mellitus [ 8] , hypertension [9], liver diseases [10] ,cataract [11],cancer [12] and aging [13] etc . ...
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced by oxygen linked enzymes. Antioxidant enzymes super oxide dismutase, glutathione peroxidase, catalase, peroxidase, peroxy redoxins and antioxidants vit. E, vit C, vit. A, flavanoids, carotenoids, lycopene, curcummin, piperine, hydroxy cinnamic acid, allicin, uric acid, glutathione, carnitine and Co Q10 protect cells from ROS and RNS mediated diseases. Traditional medicine based anti oxidant rich diet, calorie restriction , exercise, yoga and meditation decreases ROS mediated oxidative damage and prolongs disease free life.
... 51 Previous studies reported that hyperglycemia evokes the production of ROS and the change in local microenvironment in the spinal cord, triggering the activation of microglia. 3,52 It is well documented that activated microglia synthesize and release a variety of pro-inflammatory factors that activate neighboring neurons. 19,37 Therewith, our results showed that the proinflammation factors expression in spinal cord was also reduced after MOTS-c treatment both in vivo and in vitro. ...
Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.
... GSH is a major cellular antioxidant. The de novo synthesis of GSH is dependent on the utilization of L-glutamine, but L-glutamine levels have been reported to be reduced in patients with type 2 diabetes mellitus (T2DM) (Calabrese et al., 2012;Cruzat et al., 2014;Menge et al., 2010;Newsholme et al., 2016). Depletion of antioxidants such as GSH increases the susceptibility of the CNS to oxidative changes in DM and untreated DM results in lower GSH levels in several brain regions (Ates et al., 2007). ...
Evidence suggests that insulin resistance plays an important role in developing diabetes complications. The association between insulin resistance and pain perception is less well understood. This study aimed to investigate the effects of peripheral insulin deficiency on pain pathways in the brain. Diabetes was induced in 60 male rats with streptozotocin (STZ). Insulin was injected into the left ventricle of the brain by intracerebroventricular (ICV) injection, then pain was induced by subcutaneous injection of 2.5% formalin. Samples were collected at 4 weeks after STZ injection. Dopamine (DA), serotonin, reactive oxygen species (ROS), and mitochondrial glutathione (mGSH) were measured by ELISA, and gene factors were assessed by RT‐qPCR. In diabetic rats, the levels of DA, serotonin, and mGSH decreased in the nuclei of the thalamus, raphe magnus, and periaqueductal gray, and the levels of ROS increased. In addition, the levels of expression of the neuron‐specific enolase and receptor for advanced glycation end genes increased, but the expression of glial fibrillary acidic protein expression was reduced. These results support the findings that insulin has an analgesic effect in non‐diabetic rats, as demonstrated by the formalin test. ICV injection of insulin reduces pain sensation, but this was not observed in diabetic rats, which may be due to cell damage ameliorated by insulin.
