Oxidative Stress Signaling Pathways Research Articles

Effect of 2-methoxyestradiol nanoparticles combined with propofol on hippocampal nerve cells and metabolism after cerebral ischemia-reperfusion

Short-term or permanent reduction in cerebral blood flow can lead to cerebral ischemia, and if it persists, it can lead to necrosis and cell death. Reperfusion is restoration of blood supply, but it may further aggravate the damage of ischemic brain tissue. Propofol has characteristics such as rapid recovery, continuous infusion, and no accumulation. 2-Methoxyestradiol (2ME2) is a HIF-1-α inhibitor and reduces cell apoptosis. The brain ischemia-reperfusion hippocampal nerve cell model was in this study prepared in vitro. Samples were randomly assigned into control group (control), cerebral ischemia-reperfusion (CIR) group, propofol group (Propofol), 2ME2 nanoparticle group (2ME2-NPs), and combination group (Propofol+2ME2-NPs). The changes of cell proliferation and apoptosis activities were analyzed in each group, which included changes of Survivin expression, changes of intracellular Adenosine monophosphate, diphosphate, and triphosphate (AMP, ADP, and ATP, respectively) changes of malondialdehyde (MDA) and superoxide dismutase (SOD) Analysis also included secretion of IL-6 and TNF-α, and detection of HIF-1α and NF-κB expression. Results revealed that, CIR hippocampal nerve cell proliferation decreased, apoptosis activity increased, while Survivin expression increased. Moreover, ATP, ADP and AMP contents decreased, while secretion of inflammatory factors IL-6 and TNF-α increased, MDA increased, and SOD decreased. HIF-1α and NF-κB expressions increased. Propofol and 2ME2 nanoparticles promoted hippocampal neurons proliferation after CIR brain injury, inhibit the apoptotic activity, and reduce the expression of apoptotic protein Survivin. ATP, ADP and AMP content increased, IL-6 and TNF-α decreased, MDA decreased, SOD activity increased, HIF-1α and NF-κB decreased. The and combined group had a more significant effect. 2ME2 nanoparticles combined with propofol can inhibit HIF-1α and secretion of inflammatory factors by regulating oxidative stress and NF-κB signaling pathways, promoting the proliferation of hippocampal neurons, inhibiting apoptosis, and restoring cell energy and helping to restore nerve cell function.

Role of Licochalcone A in Potential Pharmacological Therapy: A Review.

Licochalcone A (LA), a useful and valuable flavonoid, is isolated from Glycyrrhiza uralensis Fisch. ex DC. and widely used clinically in traditional Chinese medicine. We systematically updated the latest information on the pharmacology of LA over the past decade from several authoritative internet databases, including Web of Science, Elsevier, Europe PMC, Wiley Online Library, and PubMed. A combination of keywords containing “Licochalcone A,” “Flavonoid,” and “Pharmacological Therapy” was used to help ensure a comprehensive review. Collected information demonstrates a wide range of pharmacological properties for LA, including anticancer, anti-inflammatory, antioxidant, antibacterial, anti-parasitic, bone protection, blood glucose and lipid regulation, neuroprotection, and skin protection. LA activity is mediated through several signaling pathways, such as PI3K/Akt/mTOR, P53, NF-κB, and P38. Caspase-3 apoptosis, MAPK inflammatory, and Nrf2 oxidative stress signaling pathways are also involved with multiple therapeutic targets, such as TNF-α, VEGF, Fas, FasL, PI3K, AKT, and caspases. Recent studies mainly focus on the anticancer properties of LA, which suggests that the pharmacology of other aspects of LA will need additional study. At the end of this review, current challenges and future research directions on LA are discussed. This review is divided into three parts based on the pharmacological effects of LA for the convenience of readers. We anticipate that this review will inspire further research.

Evaluating the Immune Response in Treatment-Naive Hospitalised Patients With Influenza and COVID-19.

The worldwide COVID-19 pandemic has claimed millions of lives and has had a profound effect on global life. Understanding the body’s immune response to SARS-CoV-2 infection is crucial in improving patient management and prognosis. In this study we compared influenza and SARS-CoV-2 infected patient cohorts to identify distinct blood transcript abundances and cellular composition to better understand the natural immune response associated with COVID-19, compared to another viral infection being influenza, and identify a prognostic signature of COVID-19 patient outcome. Clinical characteristics and peripheral blood were acquired upon hospital admission from two well characterised cohorts, a cohort of 88 patients infected with influenza and a cohort of 80 patients infected with SARS-CoV-2 during the first wave of the pandemic and prior to availability of COVID-19 treatments and vaccines. Gene transcript abundances, enriched pathways and cellular composition were compared between cohorts using RNA-seq. A genetic signature between COVID-19 survivors and non-survivors was assessed as a prognostic predictor of COVID-19 outcome. Contrasting immune responses were detected with an innate response elevated in influenza and an adaptive response elevated in COVID-19. Additionally ribosomal, mitochondrial oxidative stress and interferon signalling pathways differentiated the cohorts. An adaptive immune response was associated with COVID-19 survival, while an inflammatory response predicted death. A prognostic transcript signature, associated with circulating immunoglobulins, nucleosome assembly, cytokine production and T cell activation, was able to stratify COVID-19 patients likely to survive or die. This study provides a unique insight into the immune responses of treatment naïve patients with influenza or COVID-19. The comparison of immune response between COVID-19 survivors and non-survivors enables prognostication of COVID-19 patients and may suggest potential therapeutic strategies to improve survival.

The Combination of a Novel GLUT1 Inhibitor and Cisplatin Synergistically Inhibits Breast Cancer Cell Growth By Enhancing the DNA Damaging Effect and Modulating the Akt/mTOR and MAPK Signaling Pathways.

Breast cancer is the most prevalent cancer and the second leading cause of cancer death in women. Cisplatin is a commonly used chemotherapeutic drug for breast cancer treatment. Owing to serious side effects, the combination of cisplatin with other drugs is an effective strategy to simultaneously reduce side effects and increase the anticancer efficacy. GLUT1 is an emerging target for cancer treatment since cancer cells usually consume more glucose, a phenomenon called the Warburg effect. In this study, we found that the combination of cisplatin and a novel GLUT1 inhibitor #43 identified from our previous high-throughput screening exerted a synergistic anticancer effect in MCF-7 and MDA-MB-231 breast cancer cells. Mechanism studies in MCF-7 cells revealed that combination of cisplatin and #43 significantly induced apoptosis, intracellular reactive oxygen species, and loss of mitochondrial membrane potential. Furthermore, #43 enhanced the DNA damaging effect of cisplatin. Akt/mTOR downstream signaling and the ERK signaling pathway usually involved in cell growth and survival were inhibited by the combination treatment. On the other hand, phosphorylation of p38 and JNK, which may be associated with apoptosis, was induced by the combination treatment. Altogether, our data indicate that oxidative stress, DNA damage, the Akt/mTOR and MAPK signaling pathways, and apoptosis may be involved in the synergism of cisplatin and #43 in breast cancer cells.

Mechanism of Cadmium Exposure Induced Hepatotoxicity in the Mud Crab (Scylla paramamosain): Activation of Oxidative Stress and Nrf2 Signaling Pathway.

Cadmium, one of the most toxic heavy metals, can cause severe oxidative damage to aquatic animals. However, the mechanism whereby the mud crabs respond to cadmium exposure remains unclear. This study investigated the effects of cadmium exposure on oxidative stress and histopathology changes and evaluated the role of the Nrf2 signaling pathway in regulating responses to cadmium-induced hepatotoxicity were investigated in mud crabs. Mud crabs were exposed to 0, 0.01, 0.05, and 0.125 mg/L cadmium for 21 d. The present results indicated that cadmium exposure increased hydrogen peroxide (H2O2) production, lipid peroxidation and tissue damage, but decreased the activity of superoxide dismutase (SOD) and catalase (CAT), and caused lipid peroxidation and tissue damage. The results of an integrated biomarker index analysis suggested that the toxicity of cadmium was positively related to cadmium concentration. The expression levels of the Nrf2 signaling pathway (Nrf2, metallothionein, and cytochrome P450 enzymes) were up-regulated after cadmium exposure. Silencing of Nrf2 in vivo decreased antioxidant gene (SOD, CAT, and glutathione S-transferase) expression, suggesting that Nrf2 can regulate antioxidant genes. Knocking down Nrf2 in vivo also significantly decreased the activity of SOD and CAT after cadmium exposure. Moreover, silencing of Nrf2 in vivo enhanced H2O2 production and the mortality rates of mud crabs after cadmium exposure. The present study indicated that cadmium exposure induced hepatotoxicity in the mud crab by increasing H2O2 content, which decreased the antioxidant capacity, leading to cell injury. In addition, the Nrf2 is activated to bound with antioxidant response element, initiating the expression of antioxidant enzyme genes during cadmium induced hepatotoxicity in the mud crabs.

Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway.

This study investigated whether artemisinin (ART) exerts a neuroprotective effect against cerebral ischemia/reperfusion (I/R) injury. Hypoxia-glucose deprivation and reoxygenation (OGD/R) of SH-SY5Y cells were used as the I/R injury model in vitro. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and lactate dehydrogenase (LDH) release was measured. Cell apoptosis and apoptosis-associated protein expression were determined via flow cytometry and western blotting, respectively. The levels of glutathione peroxidase, superoxide dismutase, catalase, and malondialdehyde were determined. The secretion of tumor necrosis factor-α and interleukin-1β was measured using ELISA. The activation of the nuclear factor kappa B (NF-κB) pathway was also determined. The indicated ART concentrations (0, 25, 50, 75, and 100 μM) had no significant effect on SH-SY5Y cell viability and LDH activity. ART promoted cell viability, reduced cell apoptosis, repressed cellular inflammation, and inhibited cellular oxidative stress and NF-κB signaling pathway in OGD/R-induced SH-SY5Y cells. In addition, all the protective effects of ART on OGD/R-induced SH-SY5Y cell injury were significantly reversed by an NF-κB agonist. In conclusion, ART protects neurons from OGD/R-induced damage in vitro by inhibiting the NF-κB signaling pathway. These results suggest that ART may be a potential agent for the treatment of cerebral I/R injury.

Investigation of nickel sulfate-induced cytotoxicity and underlying toxicological mechanisms in human umbilical vein endothelial cells through oxidative stress, inflammation, apoptosis, and MAPK signaling pathways.

Growing evidence indicates that nickle and its compounds have adverse effects on the cardiovascular system. In this study, the cytotoxic insults caused by nickel sulfate (NiSO4 ) in human umbilical vein endothelial cells (HUVECs) were explored by examining cell viability, oxidative stress, inflammation, apoptosis, and MAPK signaling pathway activity. Cultured HUVECs were treated with varying concentrations of NiSO4 (0, 62.5, 250, and 1000 μM) for 24 h. Subsequently, markers of oxidative stress, inflammation, apoptosis, and MAPK signaling pathways were analyzed using biochemical assays, real-time quantitative polymerase chain reaction, and western blot. Rates of apoptosis were evaluated using flow cytometry. The results showed that NiSO4 exerted dose- and time-dependent inhibitory effects on cell growth. It induced oxidative stress and lipid peroxidation by increasing the generation of reactive oxygen species, the oxidized glutathione to reduced glutathione ratio (GSSG/GSH ratio), and malondialdehyde levels. Further, it inhibited superoxide dismutase activity in HUVECs. Flow cytometry analysis results revealed that NiSO4 (62.5-1000 μM) could induce apoptosis in HUVECs. The protein and gene expressions of cleaved Caspase 3 and Bax were elevated, and those of Bcl-2 and Bcl-XL were reduced after NiSO4 treatment. Additionally, NiSO4 triggered inflammation in HUVECs, increasing the protein and mRNA levels of IL-6 and TNF-α and reducing those of TGF-β. Furthermore, western blot findings revealed that NiSO4 could activate MAPK signaling pathways, upregulating p38, JNK, and ERK1/2 in HUVECs by increasing the levels of p-P38，p-JNK, and p-ERK1/2 in a dose-dependent manner. MAPK pathway inhibitors (10μM SB203580 and 10μM SP600125) could attenuate the NiSO4 -induced increase in apoptosis and inflammation in HUVECs. They could also attenuate the dysregulation of inflammatory factors and related proteins caused by high-dose NiSO4 exposure. Interestingly, while the MEK inhibitor U0126 (10μM) enhanced NiSO4 -induced apoptosis in HUVECs, it reduced cell inflammation. Taken together, these experimental results suggest that NiSO4 can inhibit cell growth, induce oxidative stress, and trigger subsequent inflammatory responses and apoptosis in HUVECs. These effects may be mediated by the P38 and JNK MAPK stress response pathways.

Analysis of Therapeutic Targets of A Novel Peptide Athycaltide-1 in the Treatment of Isoproterenol-Induced Pathological Myocardial Hypertrophy

Myocardial hypertrophy is a pathological feature of many heart diseases. This is a complex process involving all types of cells in the heart and interactions with circulating cells. This study is aimed at identifying the differentially expressed proteins (DEPs) in myocardial hypertrophy rats induced by isoprenaline (ISO) and treated with novel peptide Athycaltide-1 (ATH-1) and exploring the mechanism of its improvement. ITRAQ was performed to compare the three different heart states in control group, ISO group, and ATH-1 group. Pairwise comparison showed that there were 121 DEPs in ISO/control (96 upregulated and 25 downregulated), 47 DEPs in ATH-1/ISO (27 upregulated and 20 downregulated), and 116 DEPs in ATH-1/control (77 upregulated and 39 downregulated). Protein network analysis was then performed using the STRING software. Functional analysis revealed that Hspa1 protein, oxidative stress, and MAPK signaling pathway were significantly involved in the occurrence and development of myocardial hypertrophy, which was further validated by vivo model. It is proved that ATH-1 can reduce the expression of Hspa1 protein and the level of oxidative stress in hypertrophic myocardium and further inhibit the phosphorylation of p38 MAPK, JNK, and ERK1/2.

Berberine as a Potential Agent for the Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignancies worldwide. The incidence of CRC has been increasing, especially in young people. Although great advances have been made in managing CRC, the prognosis is unfavorable. Numerous studies have shown that berberine (BBR) is a safe and effective agent presenting significant antitumor effects. Nevertheless, the detailed underlying mechanism in treating CRC remains indistinct. In this review, we herein offer beneficial evidence for the utilization of BBR in the management and treatment of CRC, and describe the underlying mechanism(s). The review emphasizes several therapeutic effects of BBR and confirms that BBR could suppress CRC by modulating gene expression, the cell cycle, the inflammatory response, oxidative stress, and several signaling pathways. In addition, BBR also displays antitumor effects in CRC by regulating the gut microbiota and mucosal barrier function. This review emphasizes BBR as a potentially effective and safe drug for CRC therapy.

Mitochondrial Dysfunction Pathway Alterations Offer Potential Biomarkers and Therapeutic Targets for Ovarian Cancer

The mitochondrion is a very versatile organelle that participates in some important cancer-associated biological processes, including energy metabolism, oxidative stress, mitochondrial DNA (mtDNA) mutation, cell apoptosis, mitochondria-nuclear communication, dynamics, autophagy, calcium overload, immunity, and drug resistance in ovarian cancer. Multiomics studies have found that mitochondrial dysfunction, oxidative stress, and apoptosis signaling pathways act in human ovarian cancer, which demonstrates that mitochondria play critical roles in ovarian cancer. Many molecular targeted drugs have been developed against mitochondrial dysfunction pathways in ovarian cancer, including olive leaf extract, nilotinib, salinomycin, Sambucus nigra agglutinin, tigecycline, and eupatilin. This review article focuses on the underlying biological roles of mitochondrial dysfunction in ovarian cancer progression based on omics data, potential molecular relationship between mitochondrial dysfunction and oxidative stress, and future perspectives of promising biomarkers and therapeutic targets based on the mitochondrial dysfunction pathway for ovarian cancer.

Diesel exhaust particles distort lung epithelial progenitors and their fibroblast niche

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by inflammation and impaired tissue regeneration, and is reported as the fourth leading cause of death worldwide by the Centers for Disease Control and Prevention (CDC). Environmental pollution and specifically motor vehicle emissions are known to play a role in the pathogenesis of COPD, but little is still known about the molecular mechanisms that are altered following diesel exhaust particles (DEP) exposure. Here we used lung organoids derived from co-culture of alveolar epithelial progenitors and fibroblasts to investigate the effect of DEP on the epithelial-mesenchymal signaling niche in the distal lung, which is essential for tissue repair. We found that DEP treatment impaired the number as well as the average diameter of both airway and alveolar type of lung organoids. Bulk RNA-sequencing of re-sorted epithelial cells and fibroblasts following organoid co-culture shows that the Nrf2 pathway, which regulates antioxidants' activity, was upregulated in both cell populations in response to DEP; and WNT/β-catenin signaling, which is essential to promote epithelial repair, was downregulated in DEP-exposed epithelial cells. We show that pharmacological treatment with anti-oxidant agents such as N-acetyl cysteine (NAC) or Mitoquinone mesylate (MitoQ) reversed the effect of DEP on organoids growth. Additionally, a WNT/β-catenin activator (CHIR99021) successfully restored WNT signaling and promoted organoid growth upon DEP exposure. We propose that targeting oxidative stress and specific signaling pathways affected by DEP in the distal lung may represent a strategy to restore tissue repair in COPD.

The Polysaccharides from the Aerial Parts of Bupleurum chinense DC Attenuate Epilepsy-Like Behavior through Oxidative Stress Signaling Pathways.

Bupleurum chinense DC. is a traditional Chinese medicine with a long medicinal history and is often used as the main ingredient in prescription drugs for epilepsy. The aerial parts of B. chinense DC. have similar efficacy and composition to B. chinense DC. Therefore, we speculated that the aerial parts of B. chinense DC. could be used in the treatment of epilepsy. Polysaccharides from the aerial parts of B. chinense DC. were selected to explore their therapeutic effects on epilepsy and their potential mechanism of action. The study is aimed at clarifying the antiepileptic effects of the polysaccharides from the aerial parts of B. chinense DC. and their potential underlying mechanisms. The chemical profile of the aerial parts of B. chinense DC. polysaccharides (ABP) was characterized by FT-IR spectrum and HPLC chromatogram. To determine the therapeutic effects of ABPs on epilepsy, we established a kainic acid- (KA-) induced rat model of epilepsy, and through H&E staining, Nissl staining, immunohistochemistry, biochemical analysis, ELISA, and Western blot analysis, we explored the mechanisms underlying the therapeutic effects of ABPs on epilepsy. The monosaccharide content of ABP included galacturonic acid (45.19%), galactose (36.63%), arabinose rhamnose (12.13%), and mannose (6.05%). Moreover, the average molecular weight of ABP was 1.38 × 103 kDa. ABP could improve hippocampal injuries and neuronal function in the KA-induced epilepsy rat model. ABP significantly inhibited oxidative stress in the hippocampus of KA-induced rats. More importantly, ABP could regulate TREM2 activation in the PI3K/Akt/GSK-3β pathway to inhibit neuronal apoptosis, including increasing the expression of superoxide dismutase and lactate dehydrogenase and decreasing the expression of malondialdehyde. The current study defined the potential role of ABP in inhibiting the development of epilepsy, indicating that ABP could upregulate TREM2 to alleviate neuronal apoptosis, by activating the PI3K/Akt/GSK-3β pathway and oxidative stress in epilepsy.

Meta-Inflammation and De Novo Lipogenesis Markers Are Involved in Metabolic Associated Fatty Liver Disease Progression in BTBR ob/ob Mice.

Metabolic associated fatty liver disease (MAFLD) is a hepatic manifestation of metabolic syndrome and usually associated with obesity and diabetes. Our aim is to characterize the pathophysiological mechanism involved in MAFLD development in Black Tan and brachyuric (BTBR) insulin-resistant mice in combination with leptin deficiency (ob/ob). We studied liver morphology and biochemistry on our diabetic and obese mice model (BTBR ob/ob) as well as a diabetic non-obese control (BTBR + streptozotocin) and non-diabetic control mice (BTBR wild type) from 4–22 weeks. Lipid composition was assessed, and lipid related pathways were studied at transcriptional and protein level. Microvesicular steatosis was evident in BTBR ob/ob from week 6, progressing to macrovesicular in the following weeks. At 12th week, inflammatory clusters, activation of STAT3 and Nrf2 signaling pathways, and hepatocellular ballooning. At 22 weeks, the histopathological features previously observed were maintained and no signs of fibrosis were detected. Lipidomic analysis showed profiles associated with de novo lipogenesis (DNL). BTBR ob/ob mice develop MAFLD profile that resemble pathological features observed in humans, with overactivation of inflammatory response, oxidative stress and DNL signaling pathways. Therefore, BTBR ob/ob mouse is an excellent model for the study of the steatosis to steatohepatitis transition.

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

SummaryBAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis, and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer. Here, we show that BAG1L regulates AR dynamics in the nucleus and its ablation attenuates AR target gene expression especially those involved in oxidative stress and metabolism. We show that a small molecule, A4B17, that targets the BAG domain downregulates AR target genes similar to a complete BAG1L knockout and upregulates the expression of oxidative stress-induced genes involved in cell death. Furthermore, A4B17 outperformed the clinically approved antagonist enzalutamide in inhibiting cell proliferation and prostate tumor development in a mouse xenograft model. BAG1 inhibitors therefore offer unique opportunities for antagonizing AR action and prostate cancer growth.

Potential Natural Small Molecular Compounds for the Treatment of Chronic Obstructive Pulmonary Disease: An Overview.

Chronic obstructive pulmonary disease (COPD) is one of the major diseases threatening human life and health. According to the report released by the World Health Organization (WHO) in 2020, COPD has become the third leading cause of death in the world, featuring a sustainable growth of incidence rate as well as population age. The purpose of this review focuses on the advancement of bioactive natural compounds, such as baicalin, quercetin, resveratrol, and curcumin, which demonstrate promising therapeutic/interventional effects on CODP in vitro and in vivo. Information emphasizing on COPD was systematically collected from several authoritative internet databases including Web of Science, PubMed, Elsevier, Wiley Online Library, and Europe PMC, with a combination of keywords containing “COPD” and “natural small molecular compounds”. The new evidence indicated that these valuable molecules featured unique functions in the treatment of COPD through various biological processes such as anti-inflammatory, anti-oxidant, anti-apoptosis, and anti-airway fibrosis. Moreover, we found that the promising effects of these natural compounds on COPD were mainly achieved through JAK3/STAT3/NF-κB and MAPK inflammatory signaling pathways, Nrf2 oxidative stress signaling pathway, and TGF-β1/Smad 2/3 fibrosis signaling pathway, which referenced to multiple targets like TNF-α, IL-6, IL-8, TIMP-1, MMP, AKT, JAK3, IKK, PI3K, HO-1, MAPK, P38, ERK, etc. Current challenges and future directions in this promising field are also discussed at the end of this review. For the convenience of the readers, this review is divided into ten parts according to the structures of potential natural small molecular compounds. We hope that this review brings a quick look and provides some inspiration for the research of COPD.

Oxidative Stress and AKT-Associated Angiogenesis in a Zebrafish Model and Its Potential Application for Withanolides

Oxidative stress and the AKT serine/threonine kinase (AKT) signaling pathway are essential regulators in cellular migration, metastasis, and angiogenesis. More than 300 withanolides were discovered from the plant family Solanaceae, exhibiting diverse functions. Notably, the relationship between oxidative stress, AKT signaling, and angiogenesis in withanolide treatments lacks comprehensive understanding. Here, we summarize connecting evidence related to oxidative stress, AKT signaling, and angiogenesis in the zebrafish model. A convenient vertebrate model monitored the in vivo effects of developmental and tumor xenograft angiogenesis using zebrafish embryos. The oxidative stress and AKT-signaling-modulating abilities of withanolides were highlighted in cancer treatments, which indicated that further assessments of their angiogenesis-modulating potential are necessary in the future. Moreover, targeting AKT for inhibiting AKT and its AKT signaling shows the potential for anti-migration and anti-angiogenesis purposes for future application to withanolides. This particularly holds for investigating the anti-angiogenetic effects mediated by the oxidative stress and AKT signaling pathways in withanolide-based cancer therapy in the future.

The Comparative Effects of Inulin and Bacillus clausii on LPS-Induced Endotoxemic Rat Liver

ABSTRACT Background This paper sought to investigate the modifies of inulin and Bacillus clausii on the lipopolysaccharides (LPS) inducing oxidative stress signaling pathway in the endotoxemic rat model. Methods Wistar albino male rats (n = 36), divided into six groups, were formed randomly in the following stages: the control group; the prebiotic group (Inulin; 500 mg/kg); the probiotic group (Bacillus clausii; 1x109 CFU); the LPS group (1.5 mg/kg) as the endotoxemic model; the prebiotic group + LPS; and the probiotic group + LPS as treatment groups. Results The reactive oxygen species (ROS), advanced oxidation products of protein (AOPP), thiobarbituric acid reactive substances (TBARS), total oxidant status (TOS), oxidative stress index (OSI), and myeloperoxidase activity (MPO) levels increased in LPS-induced toxicity. Prebiotic treatment decreased LPS-induced hepatotoxicity on rat liver as observed in the decrease in the levels of oxidative stress parameters, such as ROS, TBARS, TOS, and OSI. The effect of the probiotic treatment on the ROS, AOPP, TOS, OSI levels was not statistically significant. However, it was determined that probiotic application was effective in the TBARS, TAS, and GSH levels. When the biochemical results of the prebiotic and probiotic treatment applications were compared, it was found that the prebiotic treatment was more effective on oxidative stress parameters (ROS, TBARS, TOS, and OSI). In addition, the histological damage score and MPO-staining results of the prebiotic treatment group were found to be more effective than the probiotic group. Conclusion In this first study, where inulin and Bacillus clausii spores are used against liver damage caused by LPS, inulin provides much more effective protection than Bacillus clausii spores.

Exploring the Mechanism of Astragalus propinquus Schischkin and Panax Notoginseng (A&P) Compounds in the Treatment of Renal Fibrosis and Chronic Kidney Disease Based on Integrated Network Analysis.

Astragalus propinquus Schischkin and Panax notoginseng (A&P) has been widely used in clinical practice to treat chronic kidney disease (CKD) for many years and achieved a remarkable improvement of these outcomes. However, its mechanisms for ameliorating CKD are still poorly obscure. In the current study, integrated network analysis was carried out to analyze the potential active ingredients and molecular mechanism of A&P on CKD, and 39 active ingredients and a total of 570 targets were obtained. Furthermore, the potential disease-related genes were obtained from the NCBI GEO database by integrating 2 microarray datasets, and 24 significant genes were utilized for subsequent analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis displayed that pathways including cell oxidative stress and Akt signaling pathway are medicated by A&P. Of note, Heat Shock Transcription Factor 1 (HSF1) and RELA Proto-Oncogene (RELA) were regarded as hub genes considering their central roles in the gene regulatory network. What's more, the effect of A&P and potential genes was furthermore verified by using unilateral ureteral ligation (UUO) in rodent model. The results showed that the expression of HSF1 and RELA both at transcript and protein level was significantly upregulated in UUO model, but the expression was markedly reversed after A&P intervention. To further guide the interpretation of active ingredients from A&P on the effect of HSF1 and RELA, we performed a molecular docking assay and the results showed that active ingredients such as coptisine docked well into HSF1 and RELA. In total, these results suggest that A&P may improve RF in CKD by regulating HSF1 and RELA, which provides a basis for further understanding the mechanism of A&P in the treatment of RF and CKD.

Honokiol improves endothelial function in type 2 diabetic rats via alleviating oxidative stress and insulin resistance

We aimed to examine the effect of Honokiol (HKL) on endothelial dysfunction in type 2 diabetic rats and its possible mechanism. A high-fat diet and streptozotocin (STZ) were used to establish the type 2 diabetic model in rats. Part of these rats were intraperitoneally injected with HKL 10 mg/kg daily. Then the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), eNOS, and CD31, vasodilation function, insulin signaling, indicators of oxidative stress and relative signaling pathway were measured. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanism of the effect of HKL on high glucose-related endothelial injury in vitro. The data showed that HKL could reverse the decline of the expression of p-eNOS and CD31, endothelium-related vasodilation dysfunction, insulin resistance and activation of oxidative stress induced by type 2 diabetes in vivo. The similar results were obtained in vitro. In summary, our study demonstrates that HKL improves endothelial function and diminishes insulin resistance and oxidative stress, suggesting that HKL could be used as a treatment option for diabetes in the future.

Indole-Based Small Molecules as Potential Therapeutic Agents for the Treatment of Fibrosis.

Indole alkaloids are widely distributed in nature and have been particularly studied because of their diverse biological activities, such as anti-inflammatory, anti-tumor, anti-bacterial, and anti-oxidant activities. Many kinds of indole alkaloids have been applied to clinical practice, proving that indole alkaloids are beneficial scaffolds and occupy a crucial position in the development of novel agents. Fibrosis is an end-stage pathological condition of most chronic inflammatory diseases and is characterized by excessive deposition of fibrous connective tissue components, ultimately resulting in organ dysfunction and even failure with significant morbidity and mortality. Indole alkaloids and indole derivatives can alleviate pulmonary, myocardial, renal, liver, and islet fibrosis through the suppression of inflammatory response, oxidative stress, TGF-β/Smad pathway, and other signaling pathways. Natural indole alkaloids, such as isorhynchophylline, evodiamine, conophylline, indirubin, rutaecarpine, yohimbine, and vincristine, are reportedly effective in organ fibrosis treatment. In brief, indole alkaloids with a wide range of pharmacological bioactivities are important candidate drugs for organ fibrosis treatment. The present review discusses the potential of natural indole alkaloids, semi-synthetic indole alkaloids, synthetic indole derivatives, and indole-contained metabolites in organ fibrosis treatment.