Oxidative Stress Production Research Articles

Mechanism of Action of Natural Compounds in Peripheral Multiorgan Dysfunction and Hippocampal Neuroinflammation Induced by Sepsis.

Bacterial sepsis induces the production of excessive pro-inflammatory cytokines and oxidative stress, resulting in tissue injury and hyperinflammation. Patients recovering from sepsis have increased rates of central nervous system (CNS) morbidities, which are linked to long-term cognitive impairment, such as neurodegenerative pathologies. This paper focuses on the tissue injury and hyperinflammation observed in the acute phase of sepsis and on the development of long-term neuroinflammation associated with septicemia. Here we evaluate the effects of Coriolus versicolor administration as a novel approach to treat polymicrobial sepsis. Rats underwent cecal ligation and perforation (CLP), and Coriolus versicolor (200 mg/kg in saline) was administered daily by gavage. Survival was monitored, and tissues from vital organs that easily succumb to infection were harvested after 72 h to evaluate the histological changes. Twenty-eight days after CLP, behavioral analyses were performed, and serum and brain (hippocampus) samples were harvested at four weeks from surgery. Coriolus versicolor increased survival and reduced acute tissue injury. Indeed, it reduced the release of pro-inflammatory cytokines in the bloodstream, leading to a reduced chronic inflammation. In the hippocampus, Coriolus versicolor administration restored tight junction expressions, reduce cytokines accumulation and glia activation. It also reduced toll-like receptor 4 (TLR4) and neuronal nitric oxide synthase (nNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome components expression. Coriolus versicolor showed antioxidant activities, restoring glutathione (GSH) levels and catalase and superoxide dismutase (SOD) activities and reducing lipid peroxidation, nitrite and reactive oxygen species (ROS) levels. Importantly, Coriolus versicolor reduced amyloid precursor protein (APP), phosphorylated-Tau (p-Tau), pathologically phosphorylated tau (PHF1), phosphorylated tau (Ser202 and Thr205) (AT8), interferon-induced transmembrane protein 3 (IFITM3) expression, and β-amyloid accumulation induced by CLP. Indeed, Coriolus versicolor restored synaptic dysfunction and behavioral alterations. This research shows the effects of Coriolus versicolor administration on the long-term development of neuroinflammation and brain dysfunction induced by sepsis. Overall, our results demonstrated that Coriolus versicolor administration was able to counteract the degenerative process triggered by sepsis.

Effects of High-Fat Diet on Cardiovascular Protein Expression in Mice Based on Proteomics.

To investigate the effect of high-fat diet on protein expression in mouse heart and aorta using proteomic techniques. A high-fat diet was used to construct an obese mouse model, and body weight was checked regularly. After the experiment, serum lipid and oxidative stress levels were measured. Proteomic detection of cardiac and aortic protein expression. Cardiac and aortic common differentially expressed proteins (Co-DEPs) were screened based on proteomic results. Subsequently, functional enrichment analysis and screening of key proteins were performed. A high-fat diet significantly increased body weight in mice. Obese mice had considerably higher levels of TC, TG, LDL-C, ROS, and MDA. In the heart and aorta, 17 Co-DEPs were discovered. The results of functional analysis of these proteins indicated that they were mainly related to lipid metabolism. Ech1, Decr1, Hsd17b4, Hsdl2 and Acadvl were screened as key proteins. In mice, a high-fat diet causes lipid metabolism to become disrupted, resulting in higher levels of oxidative stress and lipid peroxidation products. Ech1, Decr1, Hsd17b4, Hsdl2 and Acadvl as cardiac and aortic Co-DEPs are closely related to lipid metabolism and may serve as potential diagnostic and therapeutic targets for obesity-induced cardiovascular disease.

Potent nanoreactor-mediated ferroptosis-based strategy for the reversal of cancer chemoresistance to Sorafenib.

The drug resistance of cancer cells is related to a variety of mechanisms, among which the destruction of redox homeostasis is one of the key factors. Ferroptosis, an intracellular iron-dependent form of cell death, is related to the production of oxidative stress. The accumulation of lipid peroxidation (LPO) during ferroptosis disrupts intracellular redox homeostasis, thereby affecting the sensitivity of tumor cells to drugs. In this work, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein and inactivated glutathione peroxidase 4 (GPX4) to reverse the chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO, but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG+Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'. The study proposed the mechanism and feasibility of ferroptosis to reverse drug resistance, providing a promising strategy for chemo-resistant cancer treatment. STATEMENT OF SIGNIFICANCE: Herein, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein, and inactivated glutathione peroxidase 4 (GPX4) to reverse chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG+Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'.

Polyphenols: Natural food grade biomolecules for treating neurodegenerative diseases from a multi-target perspective.

As natural functional bioactive ingredients found in foods and plants, polyphenols play various antioxidant and anti-inflammatory roles to prevent the development of disease and restore human health. The multi-target modulation of polyphenols provides a novel practical therapeutic strategy for neurodegenerative diseases that are difficult to treat with traditional drugs like glutathione and cholinesterase inhibitors. This review mainly focuses on the efficacy of polyphenols on ischemic stroke, Parkinson's disease and Alzheimer's disease, including in vivo and in vitro experimental studies. It is further emphasized that polyphenols exert neuroprotective effects primarily through inhibiting production of oxidative stress and inflammatory cytokines, which may be the underlying mechanism. However, polyphenols are still rarely used as medicines to treat neurodegenerative diseases. Due to the lack of clinical trials, the mechanism of polyphenols is still in the stage of insufficient exploration. Future large-scale multi-center randomized controlled trials and in-depth mechanism studies are still needed to fully assess the safety, efficacy and side effects of polyphenols.

Evaluation of oxidative stress biomarkers and liver enzyme activity in workers occupationally exposed to respirable free crystalline silica

Introduction: In various mining activities, workers are exposed to free Crystalline Silica (CS), which can cause the constant production of reactive oxygen species and silicosis. This research was conducted to evaluate oxidative stress biomarkers and liver tissue function in workers occupationally exposed to CS during their activities.
 Materials and methods: In this study, the biomarkers of oxidative stress were evaluated in 40 workers in silica mines of Azandarian region (Hamadan province, Iran) with occupational exposure to CS, as the case group and 40 workers without any silica-exposure as controls.
 Results: A significant higher serum levels of Malondialdehyde (MDA), Reactive Oxygen Species (ROS) and Alanine Transaminase (ALT) were observed in the silica-exposed group compared to the controls. Moreover, in the serum of the silica-exposed cases, the total antioxidant capacity was lower than that of the control group. Based on findings chronic exposure to CS can obviously affect the serum levels of oxidative stress biomarker and liver tissue function in the exposed workers.
 Conclusion: Therefore, the use of suitable face mask and different dietary antioxidants are recommended in the silica-exposed workers for the reduction of oxidative stress production and prevention of liver tissue disorders.

Polymerized human cord hemoglobin assisted with ascorbic acid as a red blood cell substitute alleviating oxidative stress for blood transfusion.

Introduction: Blood transfusion is widely used in clinical settings, where considerable efforts have been devoted to develop red blood cell substitutes to overcome blood shortage and safety concerns. Among the several kinds of artificial oxygen carriers, hemoglobin-based oxygen carriers are promising due to their inherent good oxygen-binding and -loading properties. However, difficulties in prone to oxidation, production of oxidative stress, and injury in organs limited their clinical utility. In this work, we report a red blood cell substitute composed of polymerized human cord hemoglobin (PolyCHb) assisted with ascorbic acid (AA) that alleviates oxidative stress for blood transfusion. Methods: In this study, the in vitro impacts of AA on the PolyCHb were evaluated by testing the circular dichroism, methemoglobin (MetHb) contents and oxygen binding affinity before and after the addition of AA. In the in vivo study, guinea pigs were subjected to a 50% exchange transfusion with PolyCHb and AA co-administration, followed by the collection of blood, urine, and kidney samples. The hemoglobin contents of the urine samples were analyzed, and histopathologic changes, lipid peroxidation, DNA peroxidation, and heme catabolic markers in the kidneys were evaluated. Results: After treating with AA, there was no effect on the secondary structure and oxygen binding affinity of the PolyCHb, while the MetHb content was kept at 55%, which was much lower than that without AA treating. Moreover, the reduction of PolyCHbFe3+ was significantly promoted, and the content of MetHb could be reduced from 100% to 51% within 3h. In vivo study results showed that PolyCHb assisted with AA inhibited the formation of hemoglobinuria, upgraded the total antioxidant capacity and downgraded the superoxide dismutase activity of kidney tissue, and lowered the expression of biomarkers for oxidative stress, e.g., malondialdehyde (ET vs ET+AA: 4.03±0.26μmol/mg vs 1.83±0.16μmol/mg), 4-hydroxy-2-nonenal (ET vs ET+AA: 0.98±0.07 vs 0.57±0.04), 8-hydroxy 2 deoxyguanosine(ET vs ET+AA: 14.81±1.58ng/ml vs 10.91±1.36ng/ml), heme oxygenase 1 (ET vs ET+AA: 1.51±0.08 vs 1.18±0.05) and ferritin (ET vs ET+AA: 1.75±0.09 vs 1.32±0.04). The kidney histopathology results also demonstrated that kidney tissue damage was effectively alleviated. Conclusion: In conclusion, these comprehensive results provide evidence for the potential role of AA in controlling oxidative stress and organ injury in the kidneys induced by PolyCHb, and suggest that PolyCHb assisted with AA has promising application for blood transfusion.

Single 30min treadmill exercise session suppresses the production of pro-inflammatory cytokines and oxidative stress in obese female adolescents.

Regular treadmill exercise may result in changes in pro-inflammatory cytokines and oxidative stress. However, the way acute treadmill exercise mechanisms affect the changes in pro-inflammatory cytokines and oxidative stress in obese has not been comprehensively exposed. This study aimed to analyze the pro-inflammatory cytokines and oxidative stress between 30min before treadmill exercise and 24h after treadmill exercise in obese adolescents. A total of 20 obese females aged 19-24years were recruited from female students and given one session of treadmill exercise with an intensity of 60-70% HRmax. Thiobarbituric acid reactive substance (TBARS) was used to analyze serum levels of MDA, while enzyme-linked immunosorbent assay (ELISA) was used to analyze serum levels of TNF-α and IL-6. Moreover, the independent samples t-test with a significance level of 5% was employed to have the statistical analysis. The results on 24h after treadmill exercise and delta (Δ) between CTRL and TREG showed a significant difference (p<0.001). This study found a decrease in pro-inflammatory cytokines and oxidative stress 24h after treadmill exercise in obese adolescents. Therefore, treadmill exercise can be a promising strategy for preventing adolescents from obesity as well as preventing disease risks associated with oxidative stress and chronic inflammation.

Pseudomonas aeruginosa Nonphosphorylated AlgR Induces Ribonucleotide Reductase Expression under Oxidative Stress Infectious Conditions.

Ribonucleotide reductases (RNRs) are key enzymes which catalyze the synthesis of deoxyribonucleotides, the monomers needed for DNA replication and repair. RNRs are classified into three classes (I, II, and III) depending on their overall structure and metal cofactors. Pseudomonas aeruginosa is an opportunistic pathogen which harbors all three RNR classes, increasing its metabolic versatility. During an infection, P. aeruginosa can form a biofilm to be protected from host immune defenses, such as the production of reactive oxygen species by macrophages. One of the essential transcription factors needed to regulate biofilm growth and other important metabolic pathways is AlgR. AlgR is part of a two-component system with FimS, a kinase that catalyzes its phosphorylation in response to external signals. Additionally, AlgR is part of the regulatory network of cell RNR regulation. In this study, we investigated the regulation of RNRs through AlgR under oxidative stress conditions. We determined that the nonphosphorylated form of AlgR is responsible for class I and II RNR induction after an H2O2 addition in planktonic culture and during flow biofilm growth. We observed similar RNR induction patterns upon comparing the P. aeruginosa laboratory strain PAO1 with different P. aeruginosa clinical isolates. Finally, we showed that during Galleria mellonella infection, when oxidative stress is high, AlgR is crucial for transcriptional induction of a class II RNR gene (nrdJ). Therefore, we show that the nonphosphorylated form of AlgR, in addition to being crucial for infection chronicity, regulates the RNR network in response to oxidative stress during infection and biofilm formation. IMPORTANCE The emergence of multidrug-resistant bacteria is a serious problem worldwide. Pseudomonas aeruginosa is a pathogen that causes severe infections because it can form a biofilm that protects it from immune system mechanisms such as the production of oxidative stress. Ribonucleotide reductases are essential enzymes which synthesize deoxyribonucleotides used in the replication of DNA. RNRs are classified into three classes (I, II, and III), and P. aeruginosa harbors all three of these classes, increasing its metabolic versatility. Transcription factors, such as AlgR, regulate the expression of RNRs. AlgR is involved in the RNR regulation network and regulates biofilm growth and other metabolic pathways. We determined that AlgR induces class I and II RNRs after an H2O2 addition in planktonic culture and biofilm growth. Additionally, we showed that a class II RNR is essential during Galleria mellonella infection and that AlgR regulates its induction. Class II RNRs could be considered excellent antibacterial targets to be explored to combat P. aeruginosa infections.

Nonalcoholic Fatty Liver Disease Severity Is Related to Plasma Pro-Oxidative Biomarkers Rather Than Liver Tissue-Measured Nitrogen Metabolism Biomarkers in Population with Obesity and Metabolic Syndrome.

Background: The metabolic syndrome (MS) is associated with an increased production of nitrogen metabolites and elevated oxidative stress, which favors progression of nonalcoholic fatty liver disease (NAFLD). Subjects with the phenotype known as metabolically unhealthy obese (MUO) meet most of the MS cardiometabolic risk criteria and show a higher risk of advanced NAFLD severity, compared with the so-widely known metabolically healthy obese (MHO). Obese individuals with MS are more susceptible to abnormal lipid accumulation in different tissues, whereas oxidative stress and nitrogen metabolites are increased in MS and/or obesity. This study aimed to explore whether plasma- or liver tissue-determined biomarkers of nitrogen metabolism and oxidative stress relate to NAFLD severity and/or metabolic phenotype. Methods: This cross-sectional study included candidates for bariatric surgery with biopsy-proven NAFLD diagnosis and staging. For comparison, the study population was divided according to NAFLD damage (steatohepatitis F0-F1 vs. steatohepatitis F2-F4) and metabolic phenotype (MHO vs MUO, based on the MS criteria). Hepatic and plasma concentrations of nitrogen metabolites and oxidative stress biomarkers were determined by enzymatic kinetics assays, enzyme-linked immunosorbent assay, and Greiss reaction. Results: The study population (N = 45) was constituted by patients with obesity and higher prevalence of dyslipidemia, diabetes mellitus, and hypertension. According to plasma biomarkers, MUO phenotype was related to higher cardiometabolic risk; meanwhile, advanced NAFLD damage was related to higher glycated hemoglobin (HbA1c) and triglycerides. Elevated hepatic concentrations of ammonium, nitrites, arginine, and citrulline were found in MUO phenotype, but only higher plasma concentration of malondialdehyde was found as specifically related to advanced NAFLD damage. Conclusions: Circulating biomarkers of redox state were selectively related to advanced NAFLD damage, suggesting prognostic and therapeutic targets. Hepatic concentrations of nitrogen metabolism biomarkers may be more related to cardiometabolic risk.

Increased Expression of the Mitochondrial Glucocorticoid Receptor Enhances Tumor Aggressiveness in a Mouse Xenograft Model

Mitochondria are important organelles for cellular physiology as they generate most of the energy requirements of the cell and orchestrate many biological functions. Dysregulation of mitochondrial function is associated with many pathological conditions, including cancer development. Mitochondrial glucocorticoid receptor (mtGR) is proposed as a crucial regulator of mitochondrial functions via its direct involvement in the regulation of mitochondrial transcription, oxidative phosphorylation (OXPHOS), enzymes biosynthesis, energy production, mitochondrial-dependent apoptosis, and regulation of oxidative stress. Moreover, recent observations revealed the interaction of mtGR with the pyruvate dehydrogenase (PDH), a key player in the metabolic switch observed in cancer, indicating direct involvement of mtGR in cancer development. In this study, by using a xenograft mouse model of mtGR-overexpressing hepatocarcinoma cells, we showed increased mtGR-associated tumor growth, which is accompanied by reduced OXPHOS biosynthesis, reduction in PDH activity, and alterations in the Krebs cycle and glucose metabolism, metabolic alterations similar to those observed in the Warburg effect. Moreover, autophagy activation is observed in mtGR-associated tumors, which further support tumor progression via increased precursors availability. Thus, we propose that increased mitochondrial localization of mtGR is associated with tumor progression possible via mtGR/PDH interaction, which could lead to suppression of PDH activity and modulation of mtGR-induced mitochondrial transcription that ends up in reduced OXPHOS biosynthesis and reduced oxidative phosphorylation versus glycolytic pathway energy production, in favor of cancer cells.

Impact of Preoperative Immunonutrition on Oxidative Stress and Gut Barrier Function in Surgical Patients with Crohn's Disease.

Several international guidelines recommend a peri-operative immunonutrition (IN) support for patients care in elective colorectal surgery, to reduce postoperative complications, particularly infections. In Crohn's patients, is also used to mitigate the severity of the disease. We performed a pilot study on 16 Crohn's patients undergoing intestinal surgery for active disease, not responsive to pharmacological treatment; half of them received an oral nutritional supplement enriched with immunonutrients (IN patients) for 7 days prior to surgery, in addition to normal food intake. Markers of oxidative stress (Advanced Glycated End-products (AGEs) and Advanced Oxidation Protein Products (AOPPs) were measured both in plasma and tissue samples wherein the Receptor for Advanced Glycation End products (RAGE) and Tight Junction Protein 1 (TJP1) gene expression were also determined. Plasma AGEs were significantly and positively correlated with tissue levels of AGEs (p = 0.0354) and AOPPs (p = 0.0043) while they were negatively correlated with TJP1 expression (p = 0.0159). The expression of RAGE was also negatively correlated with that of TJP1 gene (p = 0.0146). IN patients exhibited significantly lower AGEs plasma levels (p = 0.0321) and a higher mucosal TJP1 expression (p = 0.0182). No patient had postoperative complications and the length of hospital stay was similar in the two groups, but IN patients, showed a significantly shorter time to resume fluid and solid diet. These preliminary data suggest that IN might support patient's recovery by improving intestinal mucosa barrier function through the regulation of AGEs/RAGE signaling.

A NOVEL DRUG THERAPY INDUCES MITOCHONDRIAL BIOGENESIS AND ATTENUATES COLITIS

Abstract Mitochondrial dysfunction is a characteristic feature of intestinal epithelium cells (IEC) in IBD patients, associated with oxidative stress and impaired ATP production. We posit that disrupted mitochondrial bioenergetics impairs ulcer healing in IBD. In the current study, we tested a novel gold-based compound (AuPhos) that improves mitochondrial function by increasing mitochondrial biogenesis and antioxidant enzymes in IEC and human colonic biopsies. METHODS: Normal human colonic epithelial cells (NCM460) were used to evaluate the effect of AuPhos on mitochondrial proteins and anti-oxidant proteins by western blotting in the presence or absence of low-dose TNF (1ng/ml). To model mitochondrial deficiency, TFAM (mitochondrial transcriptional factor A) was silenced (shTFAM) in NCM460 cells. These cells were treated with low-dose TNF to mimic inflammatory conditions in the human intestine. The mitochondrial mass was assessed by flow cytometry using mito tracker green. The transcriptional activity of genes associated with mitochondrial biogenesis, mitochondrial complexes, and anti-oxidants was evaluated using RT-qPCR in AuPhos or vehicle-treated (overnight) cells with or without TNF. Human colonic biopsy samples were collected in Allprotect, treated ex-vivo with vehicle or AuPhos (3h, 4oC), and processed for RNA isolation followed by RT-qPCR. RESULTS: Biochemical and mass spectrometry analyses revealed that AuPhos localizes to the mitochondria. We show here that AuPhos increases mitochondrial mass and mRNA for mitochondrial complexes [complex IV (Cox6A1) and complex V (ATP5A1)] in NCM460 cells in TNF or vehicle-treated cells. Similarly, AuPhos increased protein levels of upstream regulators of mitochondrial biogenesis such as TFAM, PGC-1α, and Nrf2 compared to nontreated cells. Further protein analysis of AuPhos-treated cells showed that AuPhos increases downstream antioxidant markers such as manganese superoxide dismutase (MnSOD), peroxidane 3 (Prd3), glutathione peroxidase 4 (GPX4), thioredoxin reductase2 (Trx2), and catalase expression when compared to the TNF or control samples. Interestingly, expression of genes associated with mitochondria-specific (MnSOD) and cytoplasmic superoxide dismutase (CuZnSOD) were also significantly increased in AuPhos-treated shTFAM NCM cells compared to vehicle or TNF-treated cells. AuPhos substantially upregulates the expression of mtCO1, mtCO2, Cox6A1, ATP5A1, NRF1, MnSOD, GPX, PRDX-2,-4, and -6, in ex vivo treated human colonic biopsies compared to vehicle or TNF-treated samples. CONCLUSIONS: The current data suggest that the AuPhos compound improves mitochondrial function by promoting the expression of mitochondrial-associated proteins and antioxidant enzymes (Figure 1). We believe AuPhos can be used as a potential therapeutic in treating ulcerative colitis and Crohn’s disease by restoring mitochondrial biogenesis.

Mitochondrial Dysfunction and Increased DNA Damage in Vascular Smooth Muscle Cells of Abdominal Aortic Aneurysm (AAA-SMC).

There is increasing evidence for enhanced oxidative stress in the vascular wall of abdominal aortic aneurysms (AAA). Mitochondrial damage and dysfunction are hypothesized to be actors in altered production of reactive oxygen species (ROS) and oxidative stress. However, the role of mitochondria and oxidative stress in vascular remodelling and progression of AAA remains uncertain. We here addressed whether mitochondrial dysfunction is persistently increased in vascular smooth muscle cells (VSMCs) isolated from AAA compared to healthy VSMC. AAA-derived VSMC cultures (AAA-SMC, n = 10) and normal VSMC cultures derived from healthy donors (n = 7) were grown in vitro and analysed for four parameters, indicating mitochondrial dysfunction: (i) mitochondrial content and morphology, (ii) ROS production and antioxidative response, (iii) NADP+/NADPH content and ratio, and (iv) DNA damage, in the presence or absence of angiotensin II (AngII). AAA-SMC displayed increased mitochondrial circularity (rounded shape), reduced mitochondrial area, and reduced perimeter, indicating increased fragmentation and dysfunction compared to healthy controls. This was accompanied by significantly increased O2 - production, reduced NADP+/NADPH levels, a lower antioxidative response (indicated by antioxidative response element- (ARE-) driven luciferase reporter assays), more DNA damage (determined by percentage of γ-H2A.X-positive nuclei), and earlier growth arrest in AAA-SMC. Our data suggest that mitochondrial dysfunction and oxidative stress are persistently increased in AAA-SMC, emphasizing their implication in the pathophysiology of AAA.

S-Allylcysteine limits cardiac structural changes via antioxidant status in ovariectomized rats with induced myocardial injury

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Higher Education, Malaysia (Fundamental Research Grant Scheme) Background Cardiovascular disease is the primary cause of death in Malaysia. Past studies have shown the incidence of cardiovascular diseases among post-menopausal women increased where their estrogen level is deficient. Thus, there is growing interest in investigating alternative approach in which to limit cardiovascular injury for post-menopausal women. S-Allylcysteine (SAC) is one of the aged garlic extract compounds that has shown its cardioprotective effect through mitochondrial preservation and CSE/hydrogen sulfide pathway. Purpose Hence, this study was aimed to investigate the effect of SAC in ovariectomized rats with isoprenaline-induced myocardial injury. Methods Ovariectomy surgery (ovary removal) was done onto 32 female Wistar rats, whereas eight rats had the same surgery without ovary removal (Sham). After three weeks of recovery, all rats received subcutaneous administration of either normal saline (Sham, OVX) or isoprenaline 85 mg/kg (OVXIM, 2x) to induce myocardial injury. Then, oral gavage of either distilled water (Sham, OVX, OVXIM) or SAC 100 mg/kg (OVXS, OVXIMS) were given to the rats for one week. Finally, the rats were anesthetized before the hearts were cannulated on Langendorff isolated heart system for cardiac function measurement. Results The rat models were validated by decreased estrogen level, while cardiac injury was from the increased ST elevation on electrocardiogram and plasma Troponin T level. Systolic blood pressure in OVXS (142.45±5.17 mmHg vs 120.53±6.75 mmHg) showed significant decrease after receiving SAC. Although SAC did not reduce oxidative stress product TBARS in OVXIM, but it increased GSH (OVX: 0.0291±0.002 vs. OVXMIS: 0.0644±0.005 nmol/mg protein) and SOD (OVX: 0.7148±0.039 vs OVXMIS: 0.4991±0.068 E/mg protein/min) antioxidants in the treatment group. This is probably due to the allyl and cysteine group in the SAC molecule that has antioxidative property which protects vascular tissue, thus contributes to the lowering of blood pressure. Histological observation showed that SAC treatment was able to limit hypertrophy and collagen deposition in OVXIM group. This suggests that SAC antioxidant action may be able to limit the cell injury from oxidative stress, thus decreasing fibrosis effect (OVXIM: 5.41 ± 1.15 vs. OVXIMS: 2.31 ± 0.42%) and preserving cardiomyocyte size (OVXIM: 5.41 ± 1.15 vs. OVXIMS: 2.31 ± 0.42 µm2). Despite the histological alteration, the Langendorff-perfused hearts of the treated rats showed similar function as Sham. CSE enzyme activity and protein expression in OVXS tended to return to the same level as Sham. Conclusion In summary, this study showed SAC’s potential in preserving cardiac structure in estrogen-deficient condition, but in-depth study is warranted to further understand antioxidant and CSE enzyme signalling pathway.

Effects of Bioactive Composition in Oryza sativa L. cv. KDML105 Bran Extract on Gene Expression Related to Hair Cycle in Human Hair Follicle Dermal Papilla Cells

The aim of this study is to identify the effects of KDML105 bran extract on gene expression involving the hair cycle in HFDPCs and investigate its bioactive constituents, antioxidant, and anti-inflammatory activities. The content of tocopherols, γ-oryzanol, phytic acid, and phenolic compounds was quantified by liquid chromatography. Free fatty acids were determined using gas chromatography. Antioxidant capacities were estimated by DPPH, ABTS, and metal chelating assay. The nitric oxide (NO) production was determined by Griess reaction. Gene expression was measured by semi-quantitative RT-PCR. The major compounds in the extract were α- and γ-tocopherol, phytic acid, γ-oryzanol, chlorogenic acid, o-coumaric acid, palmitic acid, oleic acid, and linoleic acid, giving its antioxidant capacities. The nitrite level in lipopolysaccharide-induced macrophages (2.76 ± 0.13 μM) was significantly mitigated by the extract (0.81 ± 0.11 μM). Additionally, SRD5A2 and TGFB1 expressions in HFDPCs were downregulated, whereas CTNNB1 and VEGF genes were upregulated after treatment with the extract. KDML105 extract ameliorated oxidative stress and NO production. According to the gene expression study, KDML105 bran extract may be involved in the induction and maintenance of the anagen phase and angiogenesis in the hair growth pathway. Therefore, KDML105 bran extract might be a promising source of anti-hair loss substances.

Brief research report: Repurposing pentoxifylline to treat intense acute swimming-Induced delayed-onset muscle soreness in mice: Targeting peripheral and spinal cord nociceptive mechanisms.

In this study, we pursue determining the effect of pentoxifylline (Ptx) in delayed-onset muscle soreness (DOMS) triggered by exposing untrained mice to intense acute swimming exercise (120min), which, to our knowledge, has not been investigated. Ptx treatment (1.5, 4.5, and 13.5mg/kg; i.p., 30min before and 12h after the session) reduced intense acute swimming-induced mechanical hyperalgesia in a dose-dependent manner. The selected dose of Ptx (4.5mg/kg) inhibited recruitment of neutrophils to the muscle tissue, oxidative stress, and both pro- and anti-inflammatory cytokine production in the soleus muscle and spinal cord. Furthermore, Ptx treatment also reduced spinal cord glial cell activation. In conclusion, Ptx reduces pain by targeting peripheral and spinal cord mechanisms of DOMS.

The HL-60 human promyelocytic cell line constitutes an effective in vitro model for evaluating toxicity, oxidative stress and necrosis/apoptosis after exposure to black carbon particles and 2.45 GHz radio frequency

The cellular and molecular mechanisms by which atmospheric pollution from particulate matter and/or electromagnetic fields (EMFs) may prove harmful to human health have not been extensively researched. We analyzed whether the combined action of EMFs and black carbon (BC) particles induced cell damage and a pro-apoptotic response in the HL-60 promyelocytic cell line when exposed to 2.45 GHz radio frequency (RF) radiation in a gigahertz transverse electromagnetic (GTEM) chamber at sub-thermal specific absorption rate (SAR) levels. RF and BC induced moderately significant levels of cell damage in the first 8 or 24 h for all exposure times/doses and much greater damage after 48 h irradiation and the higher dose of BC. We observed a clear antiproliferative effect that increased with RF exposure time and BC dose. Oxidative stress or ROS production increased with time (24 or 48 h of radiation), BC dose and the combination of both. Significant differences between the proportion of damaged and healthy cells were observed in all groups. Both radiation and BC participated separately and jointly in triggering necrosis and apoptosis in a programmed way. Oxidative-antioxidant action activated mitochondrial anti-apoptotic BCL2a gene expression after 24 h irradiation and exposure to BC. After irradiation of the cells for 48 h, expression of FASR cell death receptors was activated, precipitating the onset of pro-apoptotic phenomena and expression and intracellular activity of caspase-3 in the mitochondrial pathways, all of which can lead to cell death. Our results indicate that the interaction between BC and RF modifies the immune response in the human promyelocytic cell line and that these cells had two fates mediated by different pathways: necrosis and mitochondria-caspase dependent apoptosis. The findings may be important in regard to antimicrobial, inflammatory and autoimmune responses in humans.

In vivo recognition of bioactive substances of Polygonum multiflorum for protecting mitochondria against metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a severe threat to human health. Polygonum multiflorum (PM) has been proven to remedy mitochondria and relieve MAFLD, but the main pharmacodynamic ingredients for mitigating MAFLD remain unclear. To research the active ingredients of PM adjusting mitochondria to relieve high-fat diet (HFD)-induced MAFLD in rats. Fat emulsion-induced L02 adipocyte model and HFD-induced MAFLD rat model were used to investigate the anti-MAFLD ability of PM and explore their action mechanisms. The adipocyte model was also applied to evaluate the activities of PM-derived constituents in liver mitochondria from HFD-fed rats (mitochondrial pharmacology). PM-derived constituents in liver mitochondria were confirmed by ultra-high-performance liquid chromatography/mass spectrometry (mitochondrial pharmacochemistry). The abilities of PM-derived monomer and monomer groups were evaluated by the adipocyte model and MAFLD mouse model, respectively. PM repaired mitochondrial ultrastructure and prevented oxidative stress and energy production disorder of liver mitochondria to mitigate fat emulsion-induced cellular steatosis and HFD-induced MAFLD. PM-derived constituents that entered the liver mitochondria inhibited oxidative stress damage and improved energy production against cellular steatosis. Eight chemicals were found in the liver mitochondria of PM-administrated rats. The anti-steatosis ability of one monomer and the anti-MAFLD activity of the monomer group were validated. PM restored mitochondrial structure and function and alleviated MAFLD, which may be associated with the remedy of oxidative stress and energy production. The identified eight chemicals may be the main bioactive ingredients in PM that adjusted mitochondria to prevent MAFLD. Thus, PM provides a new approach to prevent MAFLD-related mitochondrial dysfunction. Mitochondrial pharmacology and pharmacochemistry further showed efficient strategies for determining the bioactive ingredients of Chinese medicines that adjust mitochondria to prevent diseases.

Mst1 attenuates myocardial ischemia/reperfusion injury following heterotopic heart transplantation in mice through regulating Keap1/Nrf2 axis

Ischemia reperfusion (I/R) injury remains a frequent adverse event that accompanies heart transplantation. Oxidative stress and aberrant production of free radicals were regarded as the culprit of cell death and tissue damage in post-transplant IR injury. Mst1 has been identified as a mediator of oxidative stress and Nrf2 regulates anti-oxidative enzymes, however, the interaction between Mst1 and Nrf2 anti-oxidative stress pathway remains to be clarified in the event of cardiac IR injury. Herein, the model of ischemia-reperfusion injury in heterotopic heart transplantation mice was firstly established.. We observed that cardiac IR induced upregulation of Mst1 and activation of Nrf2/HO-1pathway in mice receiving heterotopic heart transplantation. Further Cobalt dichloride-induced oxidative stress model of RAW264.7 macrophage cells were then established to mimic cardiac I/R injury, results showed that exposure to CoCl2 induced the upregulation of Mst1 and activation of Keap1/Nrf2 pathway, and genetic ablation of Mst-1 and inhibition of Keap1/Nrf2 pathway aggravated oxidative damage in those cells. Additional in vivo study showed that transfection of Mst1 shRNA spurred ROS generation and worsened cardiac damage in IR mice. Meanwhile, Mst1-KD mice receiving heart transplantation showed markedly downregulation of Nrf2, HO-1 yet upregulation of Keap1, indicating diminished protective effect against tissue damage caused by IR probably owing to the frustration of Keap1/Nrf2 pathway. Taken together, our findings demonstrated the protective effect of Mst1 from cardiac IR injury via triggering Keap1/Nrf2 axis and suppressing ROS generation, which shed light on the promising role of Mst1 in transitional management of IR injury resulted from cardiac transplantation.

A correlation biomarker between BMI and lipid peroxidation in type 2 diabetes mellitus with and without other complications

Objectives: Body mass index (BMI) is a traditional measurement practice that divides a person’s weight by their height to find out whether they have a healthy range of weight. The objective of this study is to understand the relation between BMI and prevalence of diabetes mellitus, hypertension, and dyslipidemia. Material and Methods: BMI distribution among these patients was compared with and without hypertension and dyslipidemia. The improper of secretion of insulin leads to changes in metabolism of lipids, proteins, and carbohydrates also characterized hyperglycemia generally considered as diabetes mellitus (DM). Results: The excessive formation of free radicals induces oxidative stress, and the antioxidant defense system becomes weaken and hence arises diabetic disorder and overproduction of malondialdehyde (MDA). In cells, the polyunsaturated fatty acid peroxidation is considered as the final product and marker of oxidative stress. Conclusion: In this study, significantly increased BMI is observed in diabetic victims in comparison with control group. A significant positive correlation was noticed between glycated hemoglobin, cholesterol, and MDA. In conclusion, for the prevention and management of vascular complication in type 2 diabetes mellitus, maintaining normal levels of MDA and body weight are very important. Further large-scale studies are required to confirm it.