GSH Levels Research Articles

Interleukin-17D accelerates atherosclerosis through promoting endothelial cells ferroptosis via CD93/miR-181a-5p/SLC7A11 signaling

IL-17D has been found to induce inflammatory cytokines in endothelial cells, but its exact role in atherosclerosis (AS) is unclear. This study aims to explore IL-17D’ function in AS development. The expression of IL-17D was examined in AS patients and mice, and its clinical significance was evaluated in patients with acute coronary syndrome (ACS). Apolipoprotein E and IL-17D deficient mice (ApoE−/−IL-17D−/−) were generated for this study. The inflammation response and ferroptosis status in vascular endothelial cells were assessed following IL-17D treatment. Flow cytometry was used to identify the functional receptor of IL-17D. Additionally, RNA-seq was utilized to analyze the miRNA expression profiles induced by IL-17D. Plasma levels of IL-17D were elevated in both AS patients and mice, and were correlated with an increased incidence of major adverse cardiovascular events (MACEs). ApoE−/−IL-17D−/− mice displayed reduced inflammation and fewer atherosclerotic lesions. Treatment with IL-17D resulted in elevated levels of IL-6, IL-8, and ROS, as well as impaired cell viability and GSH production in endothelial cells. Ferroptosis inhibitor (Fer-1) suppressed the proinflammatory effects by IL-17D. Furthermore, CD93 was identified as the functional receptor for IL-17D in endothelial cells. The inhibition of miR-181a-5p led to a significant increase in cell viability and GSH levels, alongside a reduction in ROS and IL-6/IL-8 levels, while the suppression of SLC7A11 abolished these effects. Our findings suggest that IL-17D promotes endothelial inflammation by causing ferroptosis via CD93/miR-181a-5p/SLC7A11 signaling pathway. These insights advance our understanding of the pathophysiology of AS and identify a potential target for therapeutic intervention.

β-cyclodextrin-modified carboxymethyl chitosan/hyaluronic acid-based crosslinked composite nanogels as a dual responsive carrier for targeting anti-tumor therapy.

Advanced nanosized drug delivery systems can significantly improve efficacy and safety of first-line chemotherapeutics by enhancing tumor targeting. Herein, one-pot covalent crosslinking approach was developed to generate biodegradable tumor-targeted composite Nanogels from carboxymethyl chitosan, hyaluronic acid, cystamine and 6-ethylene-diamine-6-deoxy-β-cyclodextrin loaded with doxorubicin (DOX) for controlled intracellular DOX release. The optimized synthetic procedures generated Nanogels of about 190 nm in size and 28.3 % drug loading capability. DOX-loaded Nanogels was effectively internalized into tumor cells mainly by CD44 receptor-mediated endocytosis and rapidly released DOX in response to the high level of GSH in cytoplasm and acidic intracellular environments. DOX-loaded Nanogels significantly inhibited the tumor growth especially without appreciable side toxicities in 4 T1 tumor-bearing mice model owing to CD44 receptor-mediated active targeting and the passive targeting of Nanogels by enhanced permeation and retention effect. Overall, our newly developed composite Nanogels might be employed as a potentially effective therapeutic strategy for tumor therapy.

NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination

AbstractThe oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what specific regulatory mechanism of xCT by ubiquitin ligases in human cancers. Here, we reported that NEDD4L, an E3 ubiquitin ligases, inhibited esophageal squamous cell carcinoma (ESCC) tumor growth and facilitated ferroptosis by ubiquitination of xCT. NEDD4L expression was declined in ESCC and was associated with tumor invasion, lymph node metastasis and distant metastasis. Silencing NEDD4L triggered ESCC tumor growth. Meanwhile, knock down of NEDD4L prevented the accumulation of ROS, elevated the level of GSH, reduced the content of MDA in ESCC cells, thereby inhibiting ferroptosis. Mechanistically, NEDD4L directly bound to the ∆CT domain of xCT through its WW and HECT domain. More importantly, NEDD4L promoted xCT degradation by facilitating its polyubiquitination in ESCC cells. Collectively, these findings suggest that NEDD4L is crucial in governing the stability of xCT and mediating ferroptosis in ESCC.

Neuroprotective Effects of Thymol and p-Cymene in Immobilized Male rats through Alterations in Molecular, Biochemical, Histological, and Behavioral Parameters.

The research was conducted to examine the neuroprotective effect of thymol and its precursor p-cymene on chronic immobility stress in adult male Wistar rats. The rats were subjected to 2.5h of stress every day for 14 consecutive days by placing them inside a restrainer. Thymol (10mg/kg) and p-cymene (50mg/kg) were given to the rats during the same period. The results showed that thymol and p-cymene prevented the increase of MDA level, decline of GSH level, and decrease of SOD and GPx activity in the hippocampus of rats exposed to stress. These monoterpenes also prevented the increase in the expression of Tnfa, Il1b, Tlr4, and Nfkb, and the decrease in the expression of Nrf2, Ho1, and Bdnf. In addition, thymol and p-cymene inhibited the increase in the expression and activity of acetylcholinesterase in the hippocampus of animals exposed to immobility and enhanced the expression of A7nachr. They also reduced neuronal death in the CA1 region of stressed animals and improved their performance in the Morris water maze and elevated plus maze tests. Based on these findings, thymol and p-cymene may be effective in preventing neurodegenerative diseases as they reduce oxidative stress and neuroinflammation, strengthen ACh signaling, and stimulate Bdnf expression.

Rational Design of a Tandem Activatable Fluorescent Probe for Differential Diagnosis and Therapeutic Assessment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a formidable disease, distinguished by its high aggressiveness and dismal outcomes. Although leucine aminopeptidase (LAP) has been widely employed as a biomarker in biological imaging of HCC, it is still susceptible to interference from false-positive signals activated in injured liver tissues. In this study, based on the significant difference of GSH levels in alcohol-damaged liver tissues and tumor tissues, a dual-tandem activatable probe (PCLT) was designed for differential diagnosis and treatment guidance of HCC by near-infrared fluorescence (NIRF) imaging. This probe comprised a dual-locked hemicyanine dye decorated with a tetraethylene glycol chain and dual-recognition unit of glutathione (GSH) and LAP, which could be sequentially cleaved by GSH and LAP to restore its NIRF signal. PCLT excellently discriminated orthotopic HCC from ALI far earlier (7 days) than histological analysis (28 days) and exhibited higher specificity toward early orthotopic HCC than the single-locked probe (PCL). In addition, PCLT is capable of accurately delineating the tumor contour, assisting in surgical resection of HCC tumors under fluorescence visualization, and noninvasively assessing the antitumor effect of HCC chemotherapy during ferroptosis, thereby presenting promising clinical implications for clinical diagnosis and therapy of HCC.

Effects of Kalimeris indica on alcohol-induced liver injury through storing Nrf2/HO-1 pathway and gut microbiota

BackgroundKalimeris indica (L.) Sch. Bip., (K. indica) is a plant classified under the genus Kalimeris within the Asteraceae family. The herb of K. indica has been historically utilized as a traditional medicine. The consumption of excessive amounts of alcohol represents a lifestyle choice that can induce tissue damage and contribute to the development of various health conditions.MethodThe HPLC-MS method was used to reveal the chemical composition of K. indica extract. HepG2 cells were used to test the in vitro oxidative stress. C57BL/6 mice were used to construct the in vivo alcohol-induced liver injury. H/E staining and serum ALT and AST levels were tested to assess the in vivo protective effect of ML (50 and 200 mg/kg). GSH, SOD, and CAT levels along with byproduct MDA levels were used to evaluate the in vivo oxidative stress. Immunohistochemical experiments were used to examine the in vivo Nrf2 and HO-1 levels. 16S rRNA gene-based profiling method was used to test the alteration in gut microbiota.Results16 compounds were identified from K. indica extract. K. indica treatment reduced oxidative stress in HepG2 cells treated with 5% alcohol. H/E staining results showed that K. indica (50 and 200 mg/kg) alleviated liver injury caused by alcohol administration, eliciting a similar protective effect to the positive drug silymarin. Serum ALT and AST examination gave a consistent result, showing that ML could restore serum ALT and AST levels in mice treated with alcohol. Furthermore, K. indica could also restore GSH, SOD, CAT, and MDA levels in alcohol-treated mice, showing a potent effect on oxidative stress alleviation. Immunohistochemical experiments indicated that K. indica showed the liver protective effect through Nrf2/HO-1 pathway. 16S rRNA gene-based profiling revealed that alcohol treatment caused the alteration in gut microbiota, while K. indica treatment could result in a significantly richer variety of microbial communities compared to the alcohol group.ConclusionK. indica (ML) has a protective effect on liver injury caused by alcohol administration. The Nrf2/HO-1 pathway and gut microbiota regulation were involved in the ML-induced liver protection. All the results indicate that K. indica has a potential in the treatment of alcohol-induced liver injury.

Salidroside ameliorates cerebral ischemic injury and regulates the glutamate metabolism pathway in astrocytes

Background and AimSalidroside (SA) is the main active component of Rhodiola rosea L., with potential in treating cardiovascular and cerebrovascular diseases and cerebral ischemia. However, its efficacy and mechanism in cerebral ischemia remain unclear, particularly regarding its effect on glutamate (Glu) metabolism. In this paper, we aimed to investigate the efficacy of SA in treating cerebral ischemia and its pharmacological mechanism.Experimental procedureWe studied the effects of SA on SD rats with cerebral ischemia, evaluating neurobehavior, cerebral water content, infarct size, and brain microstructure. We also assessed its impact on glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and glutamate transporter 1 (GLT-1) proteins using immunohistochemistry and Western blot. Additionally, we used SVGp12 cells to simulate cerebral ischemia and measured Glu levels and used Western blot to observe the level of GS and GLT-1.ResultsSA improved neural function, reduced infarct size, and regulated GSH and Glu levels in rats. In cell experiments, SA increased cell viability and decreased Glu concentration after ischemia induction. It also regulated the expression of GFAP, GS, and GLT-1.ConclusionSA alleviates cerebral ischemia-induced injury by acting on astrocytes, possibly through regulating the glutamate metabolic pathway.

Cicer arietinum phytosome ameliorates hepatosteatosis via downregulation of fatty acid synthase and stearoyl-CoA desaturase 1 in rats

Abstract Background Hepatosteatosis is considered a universal problematic health due to bad lifestyle. Thereby, the current study evaluates the influence of the Cicer arietinum polyunsaturated fatty acids (CAP) and newly synthesized C. arietinum polyunsaturated fatty acids phytosome (CAPP) against non-alcoholic fatty liver disease (NAFLD) persuaded through a high-fat diet (HFD) in addition to tamoxifen (TAM) in male albino rats. Forty-eight rats were separated into eight groups (6 rats/group). Rats of the control group were administered distilled water for 45 consecutive days, while phosphatidyl choline (PC), CAP, and CAPP groups administered distilled water (15 days), afterward administered PC, CAP, and CAPP, respectively (500 mg/kg b.wt), orally for 30 days. All the previous groups fed normal diet for the 45 days, while NAFLD rats feed HFD for 45 days and receive TAM (200 mg/kg b.wt, i.p) daily for 15 days, followed by administration of vehicle, PC, CAP, and CAPP orally for another 30 days. Results Hepatosteatosis was appraised biochemically by significant increase in the concentrations of serum AST, ALT, γGT, LDH, ALP, total bilirubin, total lipid, triglycerides, fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD-1), and LDL-cholesterol, as well as hepatic total lipids and triglycerides. In addition, a significant decline in serum total protein, albumin, and HDL-cholesterol concentrations was observed in comparison with the control group. NAFLD induces oxidative stress by noteworthy increase in hepatic MDA, H2O2, and meaningful reduction in hepatic GSH, SOD, GST, GRD, and CAT levels as compared with the corresponding control group. Liver histological changes were noted in the NAFLD group as compared to the control. Interestingly, CAP and CAPP treatments modulate the abnormal effects of NAFLD in all the previous parameters. For the histological changes caused by NAFLD, the liver tissue appeared nearly normal after the treatment with CAP and CAPP. Conclusion CAP and CAPP administration may have a potential role in alleviating hepatosteatosis. This may relate to its downregulation against FAS, SCD-1, and oxidative stress.

Effects of quercetin-immobilized albumin cerium oxide nanoparticles on glutamate toxicity: in vitro study.

One aspect of glutamate (Glut) toxicity may be the opening of the blood-brain barrier to albumin (Al), which in itself can cause nerve cell death. Quercetin (Q) is a polyphenolic substance and has a neuroprotective effect. Cerium oxide nanoparticles (Ce2O3NPs) are highly interested in biological applications due to their antioxidant properties. The current study aimed to investigate the impact of Q-immobilized Al+Ce2O3NPs in Glut-induced neurotoxicity, mainly focusing on cell viability and neurobiochemical changes. Hydrothermal synthesis and characterization of Q-immobilized Al+Ce2O3NPs were performed. After preparing the primary neuron culture, it was exposed to Glut to induce neurotoxicity. Then, various doses of Ce2O3NP, Al+Ce2O3NP, and Q+Al+Ce2O3NPs (1, 5, 10, and 25 µg/ml) were applied to the wells and incubated for 24 h. Then, cell viability was determined by MTT analysis. Additionally, oxidative stress parameters were measured. When the obtained data were examined, it was shown that cell viability decreased with Glut concentration but significantly increased with Q+Al+Ce2O3NPs treatment. When oxidative stress markers were considered, Glut treatment increased LDH, AChE, and TOS levels, while TAC and GSH levels decreased. However, the trend changed after Q+Al+Ce2O3NPs treatment, suggesting that damaged neurons were protected against oxidative stress. The results of this study indicate that Q+Al+Ce2O3NP can ameliorate Glut-induced neurotoxicity, especially when used at a dose of 25 µg/ml.

Toxicity of polystyrene nanoplastic and copper oxide nanoparticle in Artemiasalina: Single and combined effects on stress responses

Nanoparticles, such as copper oxide nanoparticle (CuO NP) and polystyrene nanoplastic (PSNP), are increasingly released into aquatic environments, and pose potential risks to aquatic animals such as brine shrimps. Understanding the toxicity of these nanoparticles, especially when combined, is very important to assess their environmental effects. Therefore, this work describes the toxicity of polystyrene nanoplastic (PSNP) and CuO nanoparticles (CuO NPs) for brine shrimp (Artemiasalina). The body length and stress biomarkers, including the activity of SOD, CAT, GST, Acid phosphatase, AChE, level of MDA and GSH, and expression of the hsp70 gene were quantified. The 48h-EC50 values for PSNP, CuO NPs, and their combination were determined as 1.024 and 5.089, and 0.512 mg L−1, respectively. The combined exposure groups showed the highest growth inhibition. This was associated with increased activity of SOD and GST, decreased activity of CAT, a significant decrease in the level of GSH, a significant increase in the MDA level, and expression of the hsp70 gene (P < 0.05). Moreover, an increased ACP and reduced AChE activity were observed in exposure groups. This study indicated that PSNP and CuO NPs have synergistic toxicity for A.salina, underscoring the importance of further investigation into their combined effect on aquatic animals.

Protective effects of berberine against diabetes-associated cognitive decline in mice.

Diabetes associated cognitive decline (DACD) is a common CNS-related consequence of diabetes. The primary clinical manifestation of DACD includes learning and memory impairment. Unfortunately, there is no cure to delay the cognitive symptoms of diabetes. Although berberine (BBR) has shown promising effect in the treating diabetes and cognitive dysfunction, more research is needed to understand the mechanism of its therapeutic effect. For better understanding, we investigated the functions of BBR involved in anti-inflammation, anti-oxidant and neuroprotection in the hippocampus of diabetic mice. Diabetes was induced in mice using STZ. BBR was administered for 4 weeks before (pre-treatment), and after (post-treatment) STZ administration. The effect of BBR on cognitive functions in diabetic mice was determined using neurobehavioural test. Moreover, how BBR affected neuroinflammation, oxidative stress, and acetylcholine levels in the hippocampus and BBB permeability were analyzed using standard biochemical assays. Lastly, we evaluated the mRNA expression of neuroprotective genes in the hippocampus to uncover the mechanism of BBR. Treatment with BBR improved cognition in diabetic mice. It significantly reduced the levels of IL-6, iNOS, TNF-α, IL-1β, ROS and MDA and increased the levels of TAC, GSH, SOD and Catalase. Moreover, levels of acetylcholine and BBB permeability were reduced in the diabetic mice which was reversed by BBR treatment and increased the expression of IGF and BDNF in the hippocampus of diabetic mice. Our results suggest that BBR might be a potential therapeutic candidate for the treatment of DACD. Our study might serve as a basis for developing novel drugs for treating DACD.

Tetrahedral framework nucleic acids inhibit Aβ-mediated ferroptosis and ameliorate cognitive and synaptic impairments in Alzheimer’s disease

BackgroundFerroptosis represents a nonapoptotic type of programmed cell death induced by excessive intracellular iron accumulation. Ferroptosis is an essential driver of the pathogenesis of Alzheimer’s disease (AD). Tetrahedral framework nucleic acids (tFNAs) are a novel type of nanoparticle with superior antiapoptotic capacity and excellent biocompatibility. However, the effect of tFNAs on Aβ triggered ferroptosis, cognitive and synaptic impairments in AD remains unknown.MethodsN2a cells were treated with Aβ combined with/without tFNAs. Cell viability and levels of Fe2+, lipid peroxidation, MDA, LDH, and GSH were examined. RNA sequencing was applied to explore dysregulated ferroptosis related genes. Seven-month-old APP/PS1 mice were intranasally administrated with tFNAs for two weeks. Fluorescence imaging was used to detect the tFNAs distribution in the brain. Novel object recognition (NOR) test followed by Morris water maze (MWM) was used to test the learning and memory performance of mice. Golgi staining, Western blot, and immunofluorescence staining were used to examine synaptic plasticity.ResultstFNAs promoted cell viability and GSH levels, reduced the levels of Fe2+, lipid peroxidation, MDA, and LDH in N2a cells treated with Aβ. RNA sequencing revealed that tFNAs reversed the promotive effect of Aβ on ferroptosis driver Atf3 gene and suppressive effect on ferroptosis suppressors Rrm2 and Furin genes. Fluorescence imaging confirmed the brain infiltration of tFNAs. tFNAs rescued synaptic and memory impairments, and ferroptosis in seven-month-old APP/PS1 mice.ConclusionsCollectively, tFNAs inhibited Aβ-mediated ferroptosis and ameliorated cognitive and synaptic impairments in AD mice. tFNAs may serve as novel option to deal with AD.Graphical abstract

Gastroprotective Effect of Quercetin and Misoprostol in Ethanol-Induced Gastric Ulcer in Rats.

This study aimed to evaluate the possible synergistic gastroprotective activity of quercetin and misoprostol in gastric ulcers induced by ethanol in rats. Male Wister albino rats were allocated into 6 groups: Negative control, positive control, esomeprazole, quercetin, misoprostol, and a combination of quercetin and misoprostol. All the treatment groups except for the negative control were challenged with a single dose of ethanol (90%) after 14 days of treatment. The animals were euthanized 1 hour after ethanol administration, and the blood samples were collected and used for the measurement of catalase, GSH, LDH, and IL-6. The stomachs were immediately removed and used for the measurement of gastric ulcer index, lesion area, gastric volume, and pH. Finally, gastric tissue was sent for histopathological examination. The combination of quercetin with misoprostol resulted in a comparable effect to esomeprazole regarding the inhibitory effect on gastric lesions, ulcer index, and free and total acidity. Moreover, this combination significantly decreased the level of LDH with a nonsignificant decrease in the IL-6 level. Esomeprazole and the combination group restored the level of catalase and quercetin alone and in the combination group elevated the level of GSH. Additionally, remarkable protection appeared in the pathological findings, especially in the group treated with quercetin and misoprostol. This study clearly revealed the gastroprotective effect produced by combining quercetin with misoprostol by decreasing ulcer area and index, restoring antioxidant enzyme levels, and ameliorating inflammation. These findings suggest the use of this combination in a clinical setting.

Fucoidan improves intestinal peristaltic function in rats with postoperative ileus.

The effect of fucoidan on postoperative ileus (POI) has not been studied. In this study, how fucoidan ameliorates POI in a rat POI model was investigated. The results showed that in the model animals, when the first defecation time was prolonged, the amount of food consumed decreased, the small intestinal propulsion rate dramatically slowed, and the motility index (MI%) of the small intestine decreased. In vitro experiments revealed that the contractile response of small intestinal smooth muscle strips to carbachol (CCh) was reduced. Immunohistochemistry revealed evident macrophage infiltration in the intestinal muscularis. However, after oral pretreatment with fucoidan, the time to first defecation decreased, and food intake, the small intestinal propulsion rate, and MI% of the small intestine increased. Additionally, the contractile response of the intestinal strips to CCh became stronger, and macrophage infiltration decreased. Mechanistically, fucoidan alleviated POI by exerting anti-inflammatory and antioxidant effects as well as likely through the TrkB/ERK1/2/Akt signalling pathways. When POI occurred, the expression levels of inflammatory factors in the intestines significantly increased while the phosphorylation of TrkB, ERK1/2, and Akt significantly decreased; malondialdehyde (MDA) levels in the intestines increased but the levels of superoxide dismutase (SOD) and glutathione (GSH) decreased. In contrast, after pretreatment with fucoidan, the expression levels of inflammatory factors decreased; the phosphorylation levels of TrkB, ERK1/2, and Akt increased; the MDA level decreased; and SOD and GSH levels increased. Thus, fucoidan alleviated POI-induced impairment of rat intestinal motility through anti-inflammatory and antioxidant effects possibly associated with the TrkB/ERK1/2 and Akt signalling pathways.

Effects of calcium lactate on in vitro fertilization and embryonic development in cattle.

Growing demand for embryo transfer is steadily expanding and further studies on in vitro fertilization of cattle. To assess the effect of calcium lactate by replacing Tyrode's Albumin Lactate Pyruvate (TALP) medium composition during fertilization and embryonic development. Sodium lactate and CaCl2 were replaced with 2.0, 3.0, 4.5 mM calcium lactate for TALP medium during fertilization in Experiment 1. In Experiment 2, the concentrations of sodium lactate and CaCl2 were re-modified as control, in comparison with the same concentration of calcium lactate at 4.5 mM. Zygotes were moved to sequential media to match early-and late-stage environments. Embryonic development was examined on day 8 after insemination. 4.5 mM calcium lactate enhanced the rate of fertilization and blastocyst formation (p<0.0001, p<0.01, respectively). It represented differences in the ROS (p<0.01) and GSH levels (p<0.05) and increased blastocyst diameter and total cell number (p<0.05). In Experiment 2, fertilization (p<0.05) and blastocyst formation rates (p<0.01) were increased in 4.5mM calcium lactate under same concentration effect of sodium lactate and CaCl2. Additionally, it reduced the ROS (p<0.01) and increased the GSH levels (p<0.05), leading increase embryo quality. The replacement of calcium lactate in TALP medium enhances fertilization and embryonic development while also improving oxidative stress. Specifically, it has been determined that a concentration of 4.5 mM calcium lactate is the most effective, irrespective of the varying concentrations of sodium lactate and CaCl2. This study presents a novel formulation of a modified TALP medium intended for implantation withing the bovine embryo industry. The current implications of the study are discussed in relation to previously stated objectives and hypotheses.

Switchable ROS generator and scavenger to prevent the cisplatin induced acute kidney injury and improve efficacy via synergistic chemodynamic/immune therapy

Acute kidney injury (AKI) induced by cisplatin (DDP), which is accompanied with the generation of reactive oxygen species (ROS), is a severe side effect during treatment and restricts the application of DDP. In this study, we develop ultrasmall Mn3O4 nanozyme (UMON) with tumor microenvironment (TME) responsive ROS scavenging and generating as adjuvant to alleviate DDP induced AKI with improved efficacy. In kidney, UMON with superoxide dismutase and catalase activity acts as ROS scavenger to eliminate ROS generated by DDP, successfully protecting the renal cells/tissue and alleviating AKI during DDP treatment. Alternatively, UMON rapidly responses to the high GSH level in TME and release Mn2+ in tumor. This unique feature endows it to generate hydroxyl radicals (∙OH) through a Fenton-like reaction and deplete GSH in tumor cell and tissue, achieving high efficient chemodynamic therapy (CDT). More importantly, the Mn2+ successfully activates the cGAS-STING pathway, initiating the immune response and effectively inhibiting the tumor metastases. The synergistic CDT and immune therapy effectively improve the anti-tumor efficacy of DDP in vitro and in vivo. This study demonstrates that TME responsive ROS scavenger/generator shows the potential to reduce side effects of DDP while improve its therapeutic efficacy, providing a new avenue to achieve efficient chemotherapy and promoting the progress of clinical chemotherapy.

Design, Synthesis, and Molecular Docking of Quinazolines Bearing Caffeoyl Moiety for Targeting of PGK1/PKM2/STAT3 Signaling Pathway in the Human Breast Cancer.

PGK1 and PKM2 are glycolytic enzymes, and their expression is upregulated in cancer cells. STAT3 is a transcription factor implicated in breast cancer progression and chemoresistance. Researchers worldwide continue to explore how targeting genes might lead to more effective anti-breast cancer therapies. The present study aims to synthesize quinazolines containing caffeoyl moiety for developing innovative anticancer agents against the human breast cancer cell line (MCF-7). A new quinazoline 2 was synthesized by reacting caffeic acid with 5-amino-phenylpyrazole carboxylate 1 in the presence of PCl3. Compound 2 reacted with NH2NH2.H2O to produce compound 3 through cyclo-condensation. Apoptosis and necrosis as well as inhibition activity compounds 2 and 3 against PGK1, and PKM2 were evaluated. The effect of compounds 2 and 3 on the levels of GSH, GR, SOD, GPx, CAT, MDA, Bax, Bcl-2, caspase-3, P53 and VEGF levels as well as PGK1, PKM2 and STAT3 gene expression were estimated in MCF-7 tumor cells. The viability of MCF-7 cells was reduced to 22.42% and 45.86% after incubation with compounds 2 and 3 for 48 hours, respectively. The IC50 values for compounds 2 and 3 are 62.05 μg/mL and 16.73 μg/mL. Furthermore, compound 3 exhibited more significant apoptosis and necrosis than compound 2. IC50 values of compound 2 against PGK1, and PKM2 at interval concentration equals 1.04, and 0.32 μM/mL, respectively, after 210 minutes of incubation. Moreover, compound 3 were revealed strong inhibition of PGK1, and PKM2 with IC50 values equals 0.55 and 0.21 μg/mL, respectively after 210 minutes of incubation. Our results proved that the incubation of compounds 2 and 3 with MCF-7 cells increased the levels of apoptotic proteins, elevated MDA, Bax, caspase-3 and P53 levels, depleted GSH, GR, SOD, GPx, CAT, Bcl-2 levels and downregulated the levels of STAT3, PGK1, and PKM2 gene expression significantly. Our In-silico results proved that compound 2 showed a stronger estimated binding affinity with a ΔG of -7.2, -7.5, and - 7.9 kcal/mol., respectively towards PGK1, PKM2 and STAT3 proteins. Also, compound 3 exhibits a strong binding affinity with ΔG of -7.9, -8.5, and - 8.7 kcal/mol., towards PGK1, PKM2 and STAT3 proteins. The results show that compounds 2 and 3 induce apoptotic activity by blocking the PGK1- PKM2-STAT3 signaling pathway. The present investigation opens exciting possibilities for developing innovative new anticancer quinazolines bearing caffeoyl moiety.

Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Engineered nanoplatform mediated gas therapy enhanced ferroptosis for tumor therapy in vivo

The high glutathione (GSH) environment poses a significant challenge for inducing ferroptosis in tumor cells, necessitating the development of nanoplatforms that can deplete intracellular GSH. In this study, we developed an engineered nanoplatform (MIL-100@Era/L-Arg-HA) that enhances ferroptosis through gas therapy. First, we confirmed that the Fe element in the nanoplatform undergoes valence changes under the influence of high GSH and H2O2 in tumor cells. Meanwhile, L-Arg generates NO gas in the presence of intracellular H2O2, which reacts with GSH. Additionally, Erastin depletes GSH by inhibiting the cystine/glutamate antiporter system, reducing cystine uptake and impairing GPX4, while also increasing intracellular H2O2 levels by activating NOX4 protein expression. Through these combined GSH-depletion mechanisms, we demonstrated that MIL-100@Era/L-Arg-HA effectively depletes GSH levels, disrupts GPX4 function, and increases intracellular lipid ROS levels in vitro. Furthermore, this nanoplatform significantly inhibited tumor cell growth and extended the survival time of tumor-bearing mice in vivo. This engineered nanoplatform, which enhances ferroptosis through gas therapy, shows significant promise for ferroptosis-based cancer therapy and offers potential strategies for clinical tumor treatment.

Tanacetum parthenium and parthenolide increase defensive agents and promote antisecretory activity supporting their gastroprotective actions in rodents

Tanacetum parthenium is popularly used to treat gastric disorders. However, the gastroprotective activity has not yet been tested. This study evaluated the anti-ulcer gastric effects of hydroalcoholic extract from T. parthenium (HETp) and parthenolide (PTL), its bioactive compound. Our findings revealed a significant reduction in HETp (10, 30, or 100 mg/Kg) and PTL (5 and 50 mg/Kg) in ethanol and piroxicam-induced ulcers, and this evidence was corroborated histologically. In addition, we explored the acid antisecretory activity by the pylorus ligation. Moreover, in mice pre-treated with the inhibitors indomethacin, L-NAME, and yohimbine, the antiulcerogenic effects of HETp and PTL were abolished, suggesting the involvement of nitric oxide, adrenergic receptors and prostaglandins in gastroprotective effects. Additionally, HETp and PTL prevented the depletion of SOD and CAT and decreased the activity of MPO and the levels of GSH and LPO. The results suggest that gastroprotection of HETp and PTL involves different pharmacological pathways.