Elevated GSH Research Articles

Regulation of FOXO3 on neuronal ferroptosis after intracerebral hemorrhage via modulating NOX4 transcription.

Intracerebral hemorrhage (ICH) is known to trigger neuronal ferroptosis while forkhead box O3 (FOXO3) is implicated in ICH. This study aimed to determine the specific effect of FOXO3 on neuronal ferroptosis after ICH. The ICH mouse model was established through the injection of bacterial collagenase type IV and the cell model was established in Hemin-induced HT-22 cells. Subsequently, neurological functions, brain water content, and histopathological changes in mice were assessed. HT-22 cell activity was examined via cell counting kit-8 (CCK-8) method, and the levels of FOXO3, NADPH oxidase 4 (NOX4), and glutathione peroxidase 4 (GPX4) in brain tissues and HT-22 cells were measured. Fe2+ concentration and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) in the tissues and cells were examined. The binding relationship between FOXO3 and the NOX4 promoter region was determined via chromatin-immunoprecipitation (Ch-IP). Rescue experiments were designed to probe the role of NOX4 in the regulation of FOXO3 on neuronal ferroptosis. FOXO3 was highly-expressed in ICH models while silencing FOXO3 alleviated brain damage, edema, and inflammatory infiltration in ICH mice. Meanwhile, silencing FOXO3 enhanced cell activity, diminished ROS and MDA activities and Fe2+ concentration, and elevated GSH and GPX4 levels in the tissues or cells. FOXO3 could bind to the NOX4 promoter and upregulate NOX4 transcription. NOX4 overexpression partially neutralized the repressive role of silencing FOXO3 in neuronal ferroptosis. Silencing FOXO3 attenuated ICH-induced neuronal ferroptosis via down-regulating NOX4 transcription levels, thus ameliorating post-ICH brain damage.

Glucose Metabolism-Derived Nicotinamide Adenine Dinucleotide Phosphate in Late-Onset Preeclampsia Placenta Tissue and Its Correlation with Oxidative Stress

To study the changes in the expression of nicotinamide adenine dinucleotide phosphate (NADPH), a glucose metabolism-derived antioxidant, in late-onset preeclampsia (LOPE) placenta tissue and the correlation with oxidative stress. A total of 13 normal pregnant women and 13 pregnant women with LOPE who were hospitalized in the Obstetrics Department, the First Affiliated Hospital of Chongqing Medical University and who underwent elective cesarean section between November 2020 and October 2021 were included in the study. Placenta tissues were collected from the subjects. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was done to determine the ROS levels in the placenta tissues of the LOPE group and the normal control group. Spectrophotometric analysis was conducted to determine the levels of NADPH, glutathione (GSH), and glucose, and the expressions and activities of glucose-6-phosphate dehydrogenase (G6PD) and phospho-gluconate dehydrogenase (PGD), key rate-limiting enzymes of the pentose phosphate pathway (PPP), in the placenta tissues of the LOPE group and the normal control group. Western blot was done to determine changes in the protein expressions of phosphofructokinase 1 (PFK1), a key rate-limiting enzyme of the glycolytic pathway, G6PD, and PGD in the placenta tissues from the two groups. ROS levels in the placenta tissue of the LOPE group were significantly higher than those of the control group ( P<0.05). The levels of NADPH and GSH, two antioxidants, and glucose in the LOPE placenta were significantly higher than those of the control group ( P<0.05). The expression of PFK1 was significantly elevated in the LOPE group ( P<0.05). However, there were no significant differences in the activities and protein expression of G6PD and PGD between the two groups. Glucose metabolism reprogramming takes place in LOPE placenta tissue, which may be one of the causes of the abnormal elevation of NADPH and GSH.

Antioxidant activity of 2-Thioxo Imidazolidin-4-ones in male rats exposed to oxidative stress by hydrogen peroxide in drinking water

In the present study, a new Thioxoimidazolidine derivative had been preparedasligand, L=(3{(E)[(4bromophenyl) methyldenamino2sulfanylideneimidazolidin-4-one. This ligand was synthesized by the reaction of 4-bromobenzaldehyde with thiosemicarbazide, then, the product was reacted with chloroethylacetate in an ethanol medium. The final product was isolated and characterized by suitable physical measurements, FT-IR, UV-Vis spectrophotometer, GC-mass spectrophotometer, and 1H-NMR spectroscopy as well as elemental analysis (CHNS). for assessment of the antioxidant activity of this new ligand in vivo we used twenty-four mature albino male rats divided into three equal groups, the first group served as control and received a normal diet and drank from tap water, while the other groups received a normal diet and drinking of 0.5%hydrogen peroxide, third group dosage by 50mg/kg of Thioxoimidazolidine daily. The results showed a decrease in GSH Catalase and total antioxidant concentrations of animals of selected groups when treated with 0.5% v/v of hydrogen peroxide, while a significant elevation in serum GSH, Catalase, and total antioxidant concentrations in another group after treatment with Thioxoimidazolidine of ligand.

Antioxidant activity of 2-Thioxo Imidazolidin-4-Ones in male rats exposed to oxidative stress by hydrogen peroxide in drinking water

In the present study, a new Thioxoimidazolidine derivative had been preparedasligand, L=(3{(E)[(4bromophenyl) methyldenamino2sulfanylideneimidazolidin-4-one. This ligand was synthesized by the reaction of 4-bromobenzaldehyde with thiosemicarbazide, then, the product was reacted with chloroethylacetate in an ethanol medium. The final product was isolated and characterized by suitable physical measurements, FT-IR, UV-Vis spectrophotometer, GC-mass spectrophotometer, and 1H-NMR spectroscopy as well as elemental analysis (CHNS). for assessment of the antioxidant activity of this new ligand in vivo we used twenty-four mature albino male rats divided into three equal groups, the first group served as control and received a normal diet and drank from tap water, while the other groups received a normal diet and drinking of 0.5%hydrogen peroxide, third group dosage by 50mg/kg of Thioxoimidazolidine daily. The results showed a decrease in GSH Catalase and total antioxidant concentrations of animals of selected groups when treated with 0.5% v/v of hydrogen peroxide, while a significant elevation in serum GSH, Catalase, and total antioxidant concentrations in another group after treatment with Thioxoimidazolidine of ligand.

The protective effects of rutin on the liver, kidneys, and heart by counteracting organ toxicity caused by synthetic and natural compounds.

Rutin is a flavonoid present in many plant species. Because of its antioxidant, anti-inflammatory, and antiapoptotic properties, rutin is of interest for its potential protective effects against toxic agents. The hepatoprotective, renoprotective, and cardioprotective effects of rutin are reviewed. The antioxidant effects of rutin are elicited by enhancing antioxidant enzymes such as GST, GGT, CAT, GPx, SOD, and GR, activating the Nrf2/HO-1 pathway, elevating GSH content, and the reduction in MDA. The anti-inflammatory effects of rutin are mediated by the inhibition of IL-1β, IL-6, TGF-β1, COX-2, iNOS, TLR4, and XO. Rutin exerted its antiapoptotic effects by inhibition of free radicals, caspase-3/-7/-9, hsp70, HMGB1, and p53, and the elevation of the antiapoptotic protein Bcl-2. Rutin has potential therapeutic effectiveness against several toxicants, and its beneficial effects are more than likely mediated by its antioxidant, anti-inflammatory, and/or antiapoptotic property.

Immunomodulatory effect of protocatechuic acid on cyclophosphamide induced brain injury in rat: Modulation of inflammosomes NLRP3 and SIRT1

Modulation of the inflammasome NLRP3 and SIRT1 are new combat strategy for brain injury protection. The inflammasome activates proinflammatory cytokines releasing interleukin-1β and interleukin-18 which in turn affect the toxins release from immune cells. In addition, SIRT1 controls many biological functions, such as immune response and oxidative stress. Protocatechuic has versatile biological activities and possesses antioxidant, anti-inflammatory and neuroprotective effects. So this work aims to study immunomodulatory effect of protocatechuic acid on cyclophosphamide chemotherapy drug-induced brain injury via modulation of inflammosomes NLRP3 and SIRT1. Rats were randomly assigned to four experimental groups. Normal control group was injected with a single i.p injection of saline. Cyclophosphamide group was injected with a single i.p injection of cyclophosphamide (200 mg/kg). Protocatechuic acid groups were orally administered (50 &100 mg/kg) once daily for 10 consecutive days after cyclophosphamide injection. Protocatechuic acid administration exhibited improvements of the cognition function and memory, a reduction in brain contents of MDA, NLRP3, IL-1 β, NF-κB, IKBKB and Galectin 3 and an elevation of GSH and SIRT1 compared to cyclophosphamide group. In addition, protocatechuic acid administration ameliorated the elevation of caspase 3 and iNOS gene expression and alleviated the neuron degeneration caused by cyclophosphamide. In conclusion, the therapeutic action of protocatechuic acid and its cellular and molecular mechanisms are new insights against various human ailments, especially, neurodegenerative disease as brain injury induced by cyclophosphamide chemotherapy drug in rats through modulation of inflammosomes NLRP3 and SIRT1.

SB332235, a CXCR2 antagonist, ameliorates thioacetamide-induced hepatic encephalopathy through modulation of the PI3K/AKT pathways in rats

RationaleHepatic encephalopathy (HE) is a neuropsychiatric disorder that results from either acute or chronic liver failure. CXCR2 plays an essential role in the pathophysiology of liver and brain diseases. In the present study, the potential beneficial effects of SB332235, a selective inhibitor of CXCR2, against HE were evaluated. MethodsHE was induced in male rats by thioacetamide injection (200 mg/kg, i.p.) at three alternative days. SB332235 was injected in rats 1 h before TAA at a dose of 1 and 3 mg/kg i.p. ResultsSB332235 alleviated oxidative stress as shown by the decreased serum NO and reduced MDA, elevated GSH and SOD levels, and reduced TNF-α and NF-κB levels in both brain and liver tissues of rats. Additionally, SB332235 suppressed brain ASK-1, JNK, IL-8, and caspase-3 expression, and activated PI3K/AKT expression in brain tissues. Markers of brain dysfunction, such as ammonia, and markers of hepatic injury, such as LDH, albumin, bilirubin, γGT, AST, ALT, and ALP, were significantly ameliorated. Also, the protective effect of SB332235 was confirmed by histological examination of both brain and liver tissues. ConclusionsBoth doses (1 and 3 mg/kg) of SB332235 revealed significant hepatic/neuroprotective effects due to their anti-inflammatory, antioxidant, and antiapoptotic activities via activation of the PI3K/AKT pathway. Between the two, the 1 mg/kg dose provided significantly improved outcomes.

Mitigating effects of methanolic leaf extract of Duranta erecta against X-ray induced oxidative stress in Wistar albino rats

Carcinogenic effects and other harmful effects associated with low dose-rate and low dose radiation have recently been reported. Therefore, it is important to identify effective and safe radioprotectors or radiation mitigators that can counter the effects of ionizing radiation damage. Therefore, the aim of the study was to evaluate the mitigating potential of methanolic leaves extract of Duranta erecta (DE) against acute whole-body X-ray irradiation-induced oxidative stress in Wistar albino rats. Rats in groups B, C and D, were exposed to double X-rays radiation at a source to skin distance (SSD) of 70 cm to deliver a total radiation dose of 18.4mGy at the rate of 9.2mGy/exposure using 100kVp and 30mAs exposure factors and quality factor of the X-ray machine (P) of 15. Rats in group A (control) were neither irradiated nor administered with DE extract. In contrast, group B rats were irradiated but not treated. DE extract at doses of 500 and 1000 mg/kg body weight was administered to groups C and D rats for 15 consecutive days. On post-irradiation days 1, 7, 14 and 21, the antioxidant status of the rats was evaluated and compared with control. Parameters assessed were catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA). Mean serum levels of GSH, SOD, CAT and MDA in the irradiated and treated groups did not vary significantly (P &gt; 0.05) from the un-irradiated control group. In conclusion, methanolic extract of DE mitigated against radiation-induced decline in serum GSH, SOD, CAT, and radiation-induced MDA elevation. Results obtained indicated that methanolic extract of DE can be used potentially as a natural radiation mitigating agent.

Ginsenoside Rg1 ameliorates sepsis-induced acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells.

Acute kidney injury (AKI) represents a prevailing complication of sepsis, and its onset involves ferroptosis. Ginsenoside Rg1 exerts a positive effect on kidney diseases. This study explored the action of ginsenoside Rg1 in sepsis-induced AKI (SI-AKI) by regulating ferroptosis in renal tubular epithelial cells (TECs). Sepsis rat models were established using cecal ligation and puncture (CLP) and cell models were established by treating human renal TECs (HK-2) with LPS to induce ferroptosis. Serum creatinine (SCr) and blood urea nitrogen (BUN) and urine KIM1 contents in rats were determined by ELISA kits. Kidney tissues were subjected to immunohistochemical and H&E stainings. Iron concentration, malondialdehyde (MDA), glutathione (GSH), and ferroptosis-related protein (ferritin light chain [FTL], ferritin heavy chain [FTH], GSH peroxidase 4 [GPX4], and Ferroptosis suppressor protein 1 [FSP1]) levels in kidney tissues and HK-2 cells were measured using ELISA kits and Western blotting. HK-2 cell viability was detected by cell counting kit-8, and cell death was observed via propidium iodide staining. Reactive oxygen species accumulation in cells was detected using C11 BODIPY 581/591 as a molecular probe. In CLP rats, ginsenoside Rg1 reduced SCr, BUN, KIM1, and NGAL levels, thus palliating SI-AKI. Additionally, ginsenoside Rg1 decreased iron content, FTL, FTH, and MDA levels, and elevated GPX4, FSP1, and GSH levels, thereby inhibiting lipid peroxidation and ferroptosis. Moreover, FSP1 knockdown annulled the inhibition of ginsenoside Rg1 on ferroptosis. In vitro experiments, ginsenoside Rg1 raised HK-2 cell viability and lowered iron accumulation and lipid peroxidation during ferroptosis, and its antiferroptosis activity was dependent on FSP1. Ginsenoside Rg1 alleviates SI-AKI, possibly resulting from inhibition of ferroptosis in renal TECs through FSP1.

LncRNA NEAT1 promoted MPP+‑induced ferroptosis via regulating miR‑150‑5p/BAP1 pathway in SK‑N‑SH cells.

As widely reported, dysregulated ferroptosis is closely associated with Parkinson's disease (PD) progression. The goal of the present study was to probe the roles of long non‑coding RNA (lncRNA) nuclear enriched assembly transcript 1 (NEAT1) in regulating ferroptosis in PD. PD cell model was constructed by subjecting SK‑N‑SH cells to 1‑methyl‑4‑phenylpyridinium (MPP+) for 24 h. The RNA levels of NEAT1, miRNA (miR)‑150‑5p, and BRCA1‑associated protein 1 (BAP1) were evaluated using qRT‑PCR. The protein levels of glutathione peroxidase 4 (GPX4), BAP1, and solute carrier family 7 member 11 (SLC7A11) were determined using western blot. Cell viability was assessed using 3‑(4,5‑dimethylthiazolyl2)‑2, 5‑diphenyltetrazolium bromide (MTT) assay. In addition, fluorescent probe 2,7‑dichlorodihydrofluorescein diacetate (DCFH‑DA) was employed to determine the ROS level. Moreover, the levels of GSH, MDA, and Fe2+ were also measured. Finally, the interactions among NEAT1, miR‑150‑5p, and BAP1 were identified by dual luciferase reporter gene assay, and/or RIP assay. Upregulated NEAT1 was observed in PD cell model. Knockdown of NEAT1 elevated viability and GSH level in PD cell model and reduced ROS, MDA, and Fe2+ levels. Moreover, NEAT1 functioned as a sponge to suppress miR‑150‑5p expression. Moreover, miR‑150‑5p overexpression suppressed ferroptosis in PD cell model. We subsequently found that miR‑150‑5p regulated SLC7A11 expression by directly binding to BAP1. miR‑150‑5p inhibition or BAP1 overexpression mitigated the anti‑ferroptosis effect meditated by sh‑NEAT1. Taken together, knockdown of NEAT1 mitigated MPP+‑induced ferroptosis through regulating BAP1/SLC7A11 axis by sponging miR‑150‑5p, indicating the potential of NEAT1 as a promising therapeutic target for PD.

Isolation and Quantification of the Hepatoprotective Flavonoids From Scleromitron diffusum (Willd.) R. J. Wang With Bio-Enzymatic Method Against NAFLD by UPLC-MS/MS.

Flavonoids were the major phytochemicals against hepatic peroxidative injury in Scleromitron diffusum (Willd.) R. J. Wang with an inventive bio-enzymatic method by our group (LU500041). Firstly, the total flavonoids from Scleromitron diffusum (Willd.) R. J. Wang were extracted by reflux, ultrasonic, ultrasound-assisted enzymatic methods (TFH), and the bio-enzymatic method (Ey-TFH). Then 24 flavonoid compounds were isolated and quantified in the extracts by UPLC-MS/MS. Next, six representative differential compounds in Ey-TFH were further screened out by multivariate statistical analysis compared with those in TFH. In a further step, Ey-TFH presented a higher protective rate (59.30 ± 0.81%) against H2O2-damaged HL-02 hepatocytes than TFH. And six representative differential compounds at 8 and 16 μmol/L all exerted significant hepatoprotective effects (p < 0.05 or p < 0.01). Finally, the therapeutic action of Ey-TFH for nonalcoholic fatty liver disease (NAFLD) was processed by a rat’s model induced with a high-fat diet. Ey-TFH (90, 120 mg/kg) significantly ameliorated the lipid accumulation in the rat model (p < 0.05). Meanwhile, Ey-TFH relieved liver damage. The levels of ALT, ALP, AST, LDH, and γ-GT in rats’ serum were also significantly reduced (p < 0.05 or p < 0.01). In addition to this, the body’s antioxidant capacity was improved with elevated SOD and GSH levels (p < 0.05) and down-regulated MDA content (p < 0.01) after Ey-TFH administration. Histopathological observations of staining confirmed the hepatic-protective effect of Ey-TFH.

Effects of dietary restriction on hepatic sulfur-containing amino acid metabolism and its significance in acetaminophen-induced liver injury

Dietary restriction (DR) has been revealed to have health benefits as it induces reduction in oxidative stress. Glutathione (GSH), an important cellular antioxidant, is increased in rodent livers owing to DR; however, the exact mechanism and clinical relevance of DR are yet to be fully understood. In this study, male C57BL/6 mice were administered a 50% restricted diet for 7 d, and the hepatic sulfur-containing amino acid (SAA) metabolism was determined to assess the biosynthesis of GSH. The hepatic methionine level was found to decrease, while the homocysteine, cysteine, and GSH levels were increased owing to decreased betaine-homocysteine methyltransferase (BHMT) and increased CβS, CγL, and glutamate cysteine ligase catalytic subunit (GCLC) proteins in the livers of mice subjected to DR. To determine the effects of DR on drug-induced oxidative liver injury, mice subjected to DR were injected with a toxic dose (300 mg/kg) of acetaminophen (APAP). DR significantly alleviated APAP-induced liver damage and oxidative stress, which might be attributed to the higher levels of GSH and related antioxidant enzyme (GPx, GSTα, and GSTµ) in the livers. The decrease in the levels of hepatic CYP1A, 2E1, and 3A, which imply the inhibition of APAP metabolic activation, could contribute to the lower hepatotoxicity in mice subjected to DR. Overall, our findings revealed that DR stimulated the hepatic transsulfuration pathway and GSH synthesis. The consequent elevation of GSH could thus serve as an important mechanism of DR-mediated liver protection against APAP intoxication.

Maresin-2 alleviates allergic airway inflammation in mice by inhibiting the activation of NLRP3 inflammasome, Th2 type immune response and oxidative stress

Asthma is a chronic inflammatory disease of the respiratory system. Maresin-2 (MaR2) is biosynthesized from docosahexaenoic acid (DHA) by macrophages, display strong anti-inflammatory and pro-resolving activity. To investigate the therapeutic effect and mechanism of MaR2 on asthmatic mice induced by ovalbumin (OVA) in conjunction with the adjuvant aluminum hydroxide. Twenty four female BALB/c mice were randomly divided into control, OVA, OVA + MaR2, and OVA + dexamethasone (Dexa) groups. MaR2 or Dexa were given as a treatment for OVA-induced asthma. Serum, bronchoalveolar alveolar lavage fluid (BALF) and lung tissue were collected for further analysis. The Pathological changes of lung tissue, proportion of inflammatory cells in BALF, levels of inflammatory cytokines in BALF or serum, oxidative stress indices, and the protein concentration of ASC, MPO, Ly-6G, ICAM-1, NLRP3 and Caspase-1 in lung tissues were evaluated. Compared with the OVA group, both OVA + MaR2 and OVA + Dexa group had reduced inflammation and mucus secretion in lung tissue, number of inflammatory cells in BALF, levels of related inflammatory cytokines in serum or BALF, and expressions of ASC, MPO, Ly-6G, ICAM-1, NLRP3 and Caspase-1 proteins in lung tissue. In addition, the oxidative stress was alleviated as indicated by decreased MDA, and elevated SOD and GSH. MaR2 has an obvious protective effect on OVA-induced bronchial asthma in mice, in a similar manner as Dexa. The mechanism may be related to the inhibition of the Th2 type immune response, the NLRP3 inflammasome activation and oxidative stress.

Protective Effect of a Water-Soluble Carotenoid-Rich Extract of Cordyceps militaris against Light-Evoked Functional Vision Deterioration in Mice.

Light-evoked retinal photodamage is considered an important factor contributing to functional vision deterioration and can even lead to light maculopathy or dry age-related macular degeneration. Loss of visual acuity (VA) and visual contrast sensitivity function (VCSF) are the major symptoms of retinal degenerative diseases. Cordyceps militaris is a carotenoid-rich Chinese medicinal fungus with antioxidant, anti-inflammatory, and immunomodulatory functions. C. militaris extract is a natural substance, and its bioactive constituents have been shown to confer health benefits, but their application in retinal tissue and functional vision protection in vivo remain incompletely understood. In the present study, we evaluated the influence of water-soluble, carotenoid-rich C. militaris extracts on the visual performance of light-damaged mouse retinas in vivo, using adult female CD-1® (ICR) albino mice. We showed that oral administration of this C. militaris extract (10 mg/kg, twice daily) protected the neural retina tissue against light-evoked photoreceptor cell death, reduced Müller cell hypertrophic gliosis, and elevated GSH levels and promoted the recovery of VA- and VCSF-thresholds, especially for high spatial frequency-characterized vision. These results suggest that, probably because of its water-soluble carotenoids, C. militaris extract has the potential to prevent or treat light-induced visual dysfunction.

Paeonol regulates NLRP3 inflammasomes and pyroptosis to alleviate spinal cord injury of rat

BackgroundSpinal cord injury (SCI) is a life-threatening traumatic disorder. Paeonol has been confirmed to be involved in a variety of diseases. The purpose of this study is to investigate the role of paeonol on SCI progression.MethodsSprague Dawley (SD) rat was used for the establishment of SCI model to explore the anti-inflammation, anti-oxidation, and neuroprotective effects of paeonol (60 mg/kg) on SCI in vivo. For in vitro study, mouse primary microglial cells (BV-2) were induced by lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment. The effect of paeonol on the polarization of LPS/ATP-induced BV-2 cells was determined by detection the expression inducible nitric oxide synthase (iNOS), tumour necrosis factor alpha (TNF-α), arginase-1 (Arg-1), and interleukin (IL)-10 using qRT-PCR. ELISA was used to assess the levels of IL-1β, IL-18, TNF-α, malondialdehyde (MDA), and glutathione (GSH). Western blotting was conducted to determine the levels of NLRP3 inflammasomes and TLR4/MyD88/NF-κB (p65) pathway proteins.ResultsPaeonol promoted the recovery of locomotion function and spinal cord structure, and decreased spinal cord water content in rats following SCI. Meanwhile, paeonol reduced the levels of apoptosis-associated speck-like protein (ASC), NLRP3, active caspase 1 and N-gasdermin D (N-GSDMD), repressed the contents of IL-1β, IL-18, TNF-α and MDA, and elevated GSH level. In vitro, paeonol exerted similarly inhibiting effects on pyroptosis and inflammation. Meanwhile, paeonol promoted BV-2 cells M2 polarization. In addition, paeonol also inactivated the expression of TLR4/MyD88/NF-κB (p65) pathway.ConclusionPaeonol may regulate NLRP3 inflammasomes and pyroptosis to alleviate SCI, pointing out the potential for treating SCI in clinic.

Evaluation of metformin performance on alloxan-induced diabetic rabbits.

This study aimed to evaluate metformin as a widely used oral hypoglycemic agent and identify the effects on biochemical and antioxidant body systems of rabbits. Four groups of rabbits were randomly allocated as the control, the alloxan-induced diabetic, metformin-treated, and alloxan treated with metformin. The results revealed that alloxan leads to significant elevation in glucose (Glc) levels, malondialdehyde (MDA), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), triglycerides (TGs), and total cholesterol (TCH), and a significant decline in high-density lipoprotein (HDL) and glutathione (GSH) as compared with the control group. Metformin alone caused a significant decline in Glc and HDL with significant elevation in LDL and MDA without significant changes in TCH, TGs, VLDL, and GSH. When metformin was offered as a treatment for alloxan-induced diabetic animals, it caused a significant decline in Glc, TCH, TGs, LDL, and VLDL levels with significant elevation in GSH and without a significant change in HDL and MDA. Metformin causes a decline in glucose levels due to its ability to decrease the use of substances hepatic cells use to create glucose and its ability to induce the enzymes participating in glucose oxidation.

Construction of disulfide containing redox-responsive polymeric nanomedicine.

Disulfide bonds (S-S) are widely found in chemistry, biology, and materials science. Polymer nanomaterials containing disulfide bonds with a variety of excellent properties have great potential as drug and gene delivery carriers. The disulfide bond can exist stably in extracellular environment, but upon entering cancer cells, it will undergo a sulfhydryl-disulfide bond exchange reaction with glutathione (GSH) in the cytoplasm, causing the disulfide bond cleavage. Therefore, polymeric nanomaterials containing disulfide bonds are promising in cancer treatment due to the elevated GSH concentration inside cancer cells. This review highlights various synthetic approaches to prepare disulfide containing redox-responsive polymeric nanomedicine, including synthesis of disulfide bonds containing polymers, construction of polymeric nanoparticle with shell or core crosslinked disulfide bonds, preparation of polymer-drug conjugates via disulfide linkers, and disulfide linked responsive payloads.

Atractylenolide Ⅰ improves acetaminophen-induced acute liver injury in mice by inhibiting MAPK/NF-κB signaling pathway

This study explored the protective effect of atractylenolide Ⅰ(AO-Ⅰ) against acetaminophen(APAP)-induced acute liver injury(ALI) in mice and its underlying mechanism. C57 BL/6 J mice were randomly divided into a control group, an APAP group(500 mg·kg~(-1)), a low-dose combination group(500 mg·kg~(-1) APAP + 60 mg·kg~(-1) AO-Ⅰ), and a high-dose combination group(500 mg·kg~(-1) APAP + 120 mg·kg~(-1) AO-Ⅰ). ALI was induced by intraperitoneal injection of APAP(500 mg·kg~(-1)). AO-Ⅰ by intragastric administration was performed 2 hours before APAP treatment, and the control group received the same dose of solvent by intragastric administration or intraperitoneal injection. The protective effect of AO-Ⅰ against APAP-induced ALI was evaluated by detecting alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels in the plasma and H&amp;E staining in liver tissues of mice. The malondialdehyde(MDA) and glutathione(GSH) content and catalase(CAT) activity in mouse liver tissues were detected to evaluate the effect of AO-Ⅰ on APAP-induced oxidative stress in the liver. The proteins in the liver p38 mitogen-activated protein kinase(p38 MAPK), c-jun N-terminal kinase(JNK), and nuclear factor kappa-B p65(NF-κB p65) signaling pathways were measured by Western blot, and the liver inflammatory cytokines interleukin-1β(IL-1β) and interleukin-6(IL-6) were detected by real-time PCR. Compared with the APAP group, the combination groups showed reduced APAP-induced ALT level and liver MDA content, potentiated liver CAT activity, and elevated GSH content. Mechanistically, AO-Ⅰ treatment significantly inhibited APAP-up-regulated MAPK phosphorylation and NF-κB p65, and significantly reduced the transcriptional activities of IL-1β and IL-6, downstream targets of NF-κB p65. AO-Ⅰ can improve APAP-induced ALI and the underlying mechanism is related to the inhibition of the MAPK/NF-κB p65 signaling pathway in APAP-challenged mice.

Curcumin Attenuates the PERK-eIF2α Signaling to Relieve Acrylamide-Induced Neurotoxicity in SH‑SY5Y Neuroblastoma Cells.

Curcumin is a natural polyphenolic compound with neuroprotective and antioxidant properties. Acrylamide (ACR) is a by-product of food processing that produces neurotoxicity in humans and animals. The pancreatic endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor-2α (eIF2α) signaling is involved in the occurrence of neurotoxicities. This study is aimed to investigate the protective effect of curcumin on ACR-induced cytotoxicity and explore the role of PERK-eIF2α signaling in this process. ACR exposure at 2.5 mM for 24h caused oxidative stress as revealed by the distinct increase in cellular reactive oxygen species (ROS) and malondialdehyde (MDA) level, and a significant decrease in glutathione (GSH) content. ACR induced phosphorylated tau aggregation, phosphorylated cAMP response elements binding protein (CREB) reduction, and Bax/Bcl-2 ratio up-regulation in SH-SY5Y cells. ACR also activated the PERK-eIF2α signaling in SH-SY5Y cells and triggered the activation of glycogen synthase kinase-3β (GSK-3β), up-regulated activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Curcumin pretreatment significantly attenuated ACR-induced neuronal toxicity as revealed by the ameliorated cell viability, mitigated intracellular ROS and MDA level, and elevated GSH content. Moreover, curcumin pretreatment inhibited PERK-dependent eIF2α phosphorylation, further suppressed GSK-3β and ATF4 function, and abolished abnormal tau phosphorylation, P-CREB reduction, and CHOP-induced apoptosis in SH-SY5Y cells. These results provided empirical evidence between curcumin and PERK-eIF2α signaling in ACR-induced neurotoxicity.

Anti-proliferative effects of the combination of Sulfamethoxazole and Quercetin via caspase3 and NFkB gene regulation: an in vitro and in vivo study.

Combination therapy comprising natural polyphenols and anticancer drugs has been used to decrease the adverse effects and increase the effectiveness and antioxidant activities of the drugs. The antioxidant and anticancer effects of quercetin (Q), a nutritive polyphenol, have been observed both in vitro and in vivo. Likewise, the anticancer activity of sulfamethoxazole (S) has been demonstrated in vitro and in vivo. This study aimed to investigate the in vitro and in vivo anticancer effects of Q alone and in combination with S. The in vitro effects of S, Q, and S + Q on HCT-116, HepG2, MCF-7, and PC3 cell lines were examined. Additionally, the in vivo effects of these drugs were evaluated using Ehrlich ascites carcinoma (EAC) tumor-bearing mice. The in vitro data revealed the potent anticancer activity of S + Q through the induction of apoptosis and cell cycle arrest. The EAC-inoculated mice treated with S + Q presented with elevated SOD, GSH, CAT, and TAC levels and decreased malondialdehyde levels compared with the untreated EAC group, thus revealing the antioxidant and protective actions of S + Q against EAC cell invasion. Furthermore, the downregulation of NFkB and upregulation of the caspase3 gene in the EAC-inoculated mice treated with the S + Q indicated the induction of the apoptotic pathway and decrease in both cell proliferation and metastasis. In conclusion, the combination of S and Q might exert anticancer effects by inducing apoptosis and exhibiting selective toxicity against the cancer cells and thereby protecting the vital organs.