Nephroprotective effect of gastrodin against lead-induced oxidative stress and inflammation in mice by the GSH, Trx, Nrf2 antioxidant system, and the HMGB1 pathway.

Gastrodin (GAS), the main phenolic glycoside derivative from Gastrodiaelata Blume, has several bio-activities. However, the molecular mechanisms of these protective actions currently remain unclear. This study aimed to investigate the mechanisms of GAS on lead (Pb)-induced oxidative stress and inflammation in the kidneys and primary kidney mesangial cells. Results indicated that GAS improved Pb-induced renal dysfunction and morphological changes in mice. GAS ameliorated Pb-induced inflammation in kidneys by reducing the TNF-α and IL-6 levels. GAS inhibited Pb-induced oxidative stress by regulating the glutathione, thioredoxin (Trx), and Nrf2 antioxidant systems. Furthermore, GAS supplementation increased the activation of SOD, GPx, HO-1, and NQO1 in the kidneys. GAS decreased the expression levels of HMGB1, TLR4, RAGE, MyD88, and NF-κB. These results were further confirmed in primary kidney mesangial cells. Collectively, this study demonstrated that GAS alleviated Pb-induced kidney oxidative stress and inflammation by regulating the antioxidant systems and the Nrf2 signaling pathway. Highlights Gastrodin ameliorated Pb-induced kidney injury in mice.Gastrodin inhibited oxidative stress and inflammation in kidneys.Gastrodin activated the GSH, Trx and Nrf2 antioxidant system in kidneys.Gastrodin inhibited the activities of HMGB1. RAGE, TLR4, and MyD88.

Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review.

BACKGROUND: Mesenchymal stem cells (MSCs) have been reported to possess immune regulatory effects in innate and adaptive immune reactions. MSCs can mediate intercellular communications by releasing extracellular vesicles (EVs), which deliver functional molecules to targeted cells. MSC derived EVs (MSC-EVs) confer altering effects on many immune cells, including T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages. A large number of studies have suggested that MSC-EVs participate in regulating autoimmunity related diseases. This characteristic of MSC-EVs makes them be potential biomarkers for the diagnosis and treatment of autoimmunity related diseases. AIM: To verify the potential of MSC-EVs for molecular targeted therapy of autoimmunity related diseases. METHODS: Literature search was conducted in PubMed to retrieve the articles published between 2010 and 2020 in the English language. The keywords, such as "MSCs," "EVs," "exosome," "autoimmunity," "tumor immunity," and "transplantation immunity," and Boolean operator "AND" and "NOT" coalesced admirably to be used for searching studies on the specific molecular mechanisms of MSC-EVs in many immune cell types and many autoimmunity related diseases. Studies that did not investigate the molecular mechanisms of MSC-EVs in the occurrence and development of autoimmune diseases were excluded. RESULTS: A total of 96 articles were chosen for final reference lists. After analyzing those publications, we found that it had been well documented that MSC-EVs have the ability to induce multiple immune cells, like T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages, to regulate immune responses in innate immunity and adaptive immunity. Many validated EVs-delivered molecules have been identified as key biomarkers, such as proteins, lipids, and nucleotides. Some EVs-encapsulated functional molecules can serve as promising therapeutic targets particularly for autoimmune disease. CONCLUSION: MSC-EVs play an equally important part in the differentiation, activation, and proliferation of immune cells, and they may become potential biomarkers for diagnosis and treatment of autoimmunity related diseases.

Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway.

Fisetin, a natural flavonoid found in plants, fruits and vegetables, exerts anti-cancer, anti-oxidant, anti-inflammatory and anti-mitotic effects. The current study instigates the protective effect of fisetin against lead-induced synaptic dysfunction, neuroinflammation and neurodegeneration in mice, and explores its underlying mechanisms. The results indicated fisetin can significantly ameliorated behavioral impairments in Pb-treated mice. Fisetin inhibited Pb-induced the apoptotic neurodegeneration, as indicated by the decreased levels of Bax and cleaved caspase-3. Fisetin suppressed activations of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), NF-κB and subsequently inactivate pro-inflammatory factor including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). It can also decrease the accumulation of p-tau and amyloid-beta (Aß) and increased the expression of the Aß remover neprilysin (NEP) in brains of mice. Fisetin also reversed Pb-induced synaptic dysfunction by increasing the levels of synaptosomal associated protein-25 (SNAP-25), postsynaptic density-95 (PSD-95), cyclic-AMP-response element-binding protein (CREB) phosphorylation and calcium/calmodulin kinase II (CaMKII) phosphorylation. Fisetin promoted Pb-induced autophagy in the brains of mice. Moreover, fisetin can increase levels of the denosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and SIRT1. Fisetin may be developed as a potential nutritional target for the prevention of Pb-induced neurotoxicity.

Role of AMPK pathway in lead-induced endoplasmic reticulum stress in kidney and in paeonol-induced protection in mice.

Paeonol is a natural flavonoid isolated from Moutan Cortex, which has been found to exhibit antioxidant, anti-apoptotic, anti-aging and anti-inflammatory bioactivities. Herein, we investigated the nephroprotective efficacy of paeonol against Pb-induced toxicity and elucidated the potential mechanisms. The results revealed that paeonol significantly ameliorated renal dysfunction and histology changes of Pb-treated mice. Paeonol inhibited oxidative stress and increased activities of antioxidant enzyme in the kidneys of Pb-treated mice. Paeonol decreased the nuclear factor-κB activation and over-production of inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Paeonol suppressed endoplasmic reticulum (ER) stress in kidneys of in the Pb treatment group and primary kidney mesangial cells. Moreover, paeonol increased the denosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and decreased the activations of glycogen synthase kinase-3 (GSK-3), protein kinase RNA-like ER kinase (PERK), inositol-requiring protein-1 (IRE1), c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These results were further confirmed in primary kidney mesangial cells. Taken together, these findings indicate that paeonol could protect kidney form Pb-induced injury by inhibiting oxidative stress, ER stress and inflammation via the AMPK and GSK-3 pathway. Paeonol might be a potential therapeutic agent to inhibit ER stress-associated inflammation in lead-stimulated kidneys.

Dihydromyricetin Inhibits Lead-Induced Cognitive Impairments and Inflammation by the Adenosine 5'-Monophosphate-Activated Protein Kinase Pathway in Mice.

Dihydromyricetin (DHM), a natural flavonoid derived from the medicinal and edible plant Ampelopsis grossedentata, exhibits antioxidant, antiapoptosis, antitumor, and anti-inflammatory bioactivities. This study evaluated the effects of DHM on Pb-induced neurotoxicity and explored the underlying mechanisms. DHM significantly ameliorated behavioral impairments of Pb-induced mice. It decreased the levels of lipid peroxidation and protein carbonyl and increased the activities of superoxide dismutase and catalase in the brains. DHM suppressed Pb-induced apoptosis, as indicated by the decreased levels of Bax and cleaved caspase-3. DHM also decreased inflammatory cytokines in the brains of Pb-treated mice. DHM decreased amyloid-beta (Aß) level and nuclear factor-κB nuclear translocation. Moreover, DHM induced the adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and inhibited the activation of p38, Toll-like receptor 4, myeloid differentiation factor 88, and glycogen synthase kinase-3. Collectively, this is the first report indicating that DHM could improve Pb-induced cognitive functional impairment by preventing oxidative stress, apoptosis, and inflammation and that the protective effect was mediated partly through the AMPK pathway.

Association of changes in ER stress-mediated signaling pathway with lead-induced insulin resistance and apoptosis in rats and their prevention by A-type dimeric epigallocatechin-3-gallate.

A-type dimeric epigallocatechin-3-gallate (A-type-EGCG-dimer, AEd), a new proanthocyanidins dimer from persimmon fruits, has been shown to have health benefit effects. However, A-type-EGCG-dimer affects gluose metabolism in the liver and the underlying mechanism is not clarified. The present study aims to examine the protective effects of A-type-EGCG-dimer on Pb-induced hepatic insulin resistance, endoplasmic reticulum (ER) stress and apoptosis in rats. Male wistar rats exposed to 0.05% w/v Pb acetate in the drinking water with or without A-type-EGCG-dimer coadministration (200 mg/kg body weight/day, intragastrically) for three months. We found that A-type-EGCG-dimer and pioglitazone supplementation significantly deceased glucose and insulin levels in plasma as compared with the Pb group. A-type-EGCG-dimer markedly prevents Pb-induced oxidative stress, ER stress and apoptosis in livers. A-type-EGCG-dimer and pioglitazone reduced the expression levels of the GRP78, PEPCK, G6Pase, p-PERK, p-IRE1, p-JNK, ATF4, CHOP and increased p-AKT in livers of the Pb group. Moreover, A-type-EGCG-dimer reduced ROS production and restored the activities of SOD and GPx in livers. A-type-EGCG-dimer decreased Bax, cytosolic cytochrome c and cleaved caspase-3 and increased Bcl-2 in livers of Pb-exposed rats. Our results suggest that A-type-EGCG-dimer might be a potential natural candidate for the prevention of hepatic insulin resistance and apoptosis induced by Pb.

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1.

Prostate cancer presents high occurrence worldwide. Medicinal plants are a major source of novel and potentially therapeutic molecules; therefore, the aim of the present study was to investigate the possible anti-prostate cancer activity of afzelin, a flavonol glycoside that was previously isolated from Nymphaea odorata. The effect of afzelin on the proliferation of androgen-sensitive LNCaP and androgen-independent PC-3 cells was evaluated by performing a water soluble tetrazolium salt-1 assay. In addition, the effect of afzelin on the cell cycle of the LNCaP and PC-3 prostate cancer cell lines was evaluated. Western blot analysis was performed to evaluate the effect of afzelin on the kinases responsible for the regulation of actin organization. Afzelin was identified to inhibit the proliferation of LNCaP and PC3 cells, and block the cell cycle in the G0 phase. The anticancer activity of afzelin in these cells was determined to be due to inhibition of LIM domain kinase 1 expression. Thus, the in vitro efficacy of afzelin against prostate cancer is promising; however, additional studies on different animal models are required to substantiate its anticancer potential.

Proanthocyanidins improves lead-induced cognitive impairments by blocking endoplasmic reticulum stress and nuclear factor-κB-mediated inflammatory pathways in rats.

Proanthocyanidins (PCs), a class of naturally occurring flavonoids, had been reported to possess a variety of biological activities, including anti-oxidant, anti-tumor and anti-inflammatory. In this study, we examined the protective effect of PCs against lead-induced inflammatory response in the rat brain and explored the potential mechanism of its action. The results showed that PCs administration significantly improved behavioral performance of lead-exposed rats. One of the potential mechanisms was that PCs decreased reactive oxygen species production and increased the total antioxidant capacity in the brains of lead-exposed rats. Furthermore, the results also showed that PCs significantly decreased the levels of tumor necrosis factor-α, interleukin 1ß and cyclooxygenase-2 in the brains of lead-exposed rats. Moreover, PCs significantly decreased the levels of beta amyloid and phosphorylated tau in the brains of lead-treated rats, which in turn inhibited endoplasmic reticulum (ER) stress. PCs also decreased the phosphorylation of protein kinase RNA-like ER kinase, eukaryotic translation initiation factor-2, inositol-requiring protein-1, c-Jun N-terminal kinase, p38 and inhibited nuclear factor-κB nuclear translocation in the brains of lead-exposed rats. In conclusion, these results suggested that PCs could improve cognitive impairments by inhibiting brain oxidative stress and inflammatory response.

Nickel-induced oxidative stress and apoptosis in Carassius auratus liver by JNK pathway.

Nickel (Ni) is ubiquitous in the biosphere and is a common component of natural fresh waters. When present in high concentrations, it becomes toxic to aquatic organisms. It is known that Ni toxicity may induce oxidative stress and apoptosis. However, the precise mechanism and the pathways that are activated in fish are still unclear. Thus, this study aimed to assess which apoptotic pathways are triggered by Ni in Carassius auratus liver, the main target of waterborne pollutants. Fish were exposed to 10, 25, 50 and 100mg/L of nickel sulfate for 96 h. Our data showed that Ni exposure caused fish weight loss (by 10-12%) and decreased locomotory activity (by 1-25%). Ni exposure significantly decreased the relative lymphocyte count (by 1-24%) and increased the relative count of monocytes (by 25-111%) and neutrophils (by 10-322%) as compared to controls. Ni induced oxidative stress, as evidenced by increasing of lipid peroxidation level (29-91%) and depleting of the glutathione levels (7-79%) in fish liver. Ni also suppressed the activities of superoxide dismutase (by 39-55%) and glutathione peroxidase (16-24%) and decreased ATP levels (13-51%) in livers. Moreover, liver caspase-3, one of the key executioners of apoptosis, was markedly activated by the Ni exposure. Ni exposure also increased expression levels of phosphorylated Jun N-terminal kinases (JNK) in liver, which in turn activated pro-apoptotic signaling events by breaking the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins. In conclusion, these results suggested that Ni induced oxidative stress and apoptosis, at least, via the JNK signaling pathway.

Quercetin protects mouse brain against lead-induced neurotoxicity.

Quercetin (QE), the major bioflavonoid in the human diet, has been reported to have many benefits and medicinal properties. However, its protective effects against lead (Pb)-induced neurotoxicity have not been clarified. The aim of the present study was to investigate the effects of QE on neurotoxicity in mice exposed to Pb. Mice were exposed to lead acetate (20 mg/kg body weight/day) intragastrically with or without QE (15 and 30 mg/kg body weight/day) coadministration for 3 months. The data showed that QE significantly prevented Pb-induced neurotoxicity in a dose-dependent manner. Exploration of the underlying mechanisms of QE action revealed that QE administration decreased Pb contents in blood (13.2, 19.1%) and brain (17.1, 20.0%). QE markedly increased NO production (39.1, 61.1%) and PKA activity (51.0, 57.8%) in brains of Pb-treated mice. Additionally, QE remarkably suppressed Pb-induced oxidative stress in mouse brain. Western blot analysis showed that QE increased the phosphorylations of Akt, CaMKII nNOS, eNOS, and CREB in brains of Pb-treated mice. The results suggest that QE can inhibit Pb-induced neurotoxicity and partly restore PKA, Akt, NOS, CaMKII, and CREB activities.

Protective effect of puerarin on lead-induced mouse cognitive impairment via altering activities of acetyl cholinesterase, monoamine oxidase and nitric oxide synthase.

Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. The present study aimed to investigate the protective effects of puerarin on neurotoxicity in mice exposed to lead. ICR mice were exposed to lead acetate in the drinking water (500 ppm) with or without puerarin coadministration (100 and 200 mgPU/kg intragastrically once daily) for three months. We found puerarin significantly prevented Pb-induced neurotoxicity in a dose-dependent manner, indicated by behavioral indicators. Puerarin also decreased Pb contents in blood and brain. Puerarin increased activities of acetyl cholinesterase (AChE) and monoamine oxidase (MAO) in brain of Pb-treated mice. Moreover, Pb-induced profound elevation of oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of total antioxidant capacity in brain, were suppressed by treatment with puerarin. Puerarin markedly increased NO production and PKA activity in brain of Pb-treated mice. Western blot analysis showed that puerarin dramatically increased the expression levels of nNOS, eNOS and phosphor-Akt in brains of Pb-treated mice. In conclusion, these results suggested that puerarin can inhibit Pb-induced neurotoxicity, at least in part, by suppressing oxidative stress, reversing the Pb-induced alterations in transmitters and enzymes and modulating the PKA/Akt/NOS signaling pathway.

MicroRNAs in androgen-dependent PCa.

Prostate cancer (PCa) is the most commonly diagnosed cancer among men in Western countries and is one of the leading causes of cancer deaths. The growth and progression of PCa is related to androgen levels. In cancer, nicroRNAs (miRs) function as either oncogenes or tumor suppressor genes. In androgen-dependent PCa, miRs play a role in the growth, development, progression, and metastasis of the disease, and are also involved in the response to therapy and therefore affect the prognosis. In this review, we focus on the role played by miRs concerning the mechanisms of androgen-dependent PCa.

Sesamin protects mouse liver against nickel-induced oxidative DNA damage and apoptosis by the PI3K-Akt pathway.

Sesamin (Ses), one of the major lignans in sesame seeds and oil, has been reported to have many benefits and medicinal properties. However, its protective effects against nickel (Ni)-induced injury in liver have not been clarified. The aim of the present study was to investigate the effects of sesamin on hepatic oxidative DNA injury and apoptosis in mice exposed to nickel. Kunming mice were exposed to nickel sulfate with or without sesamin coadministration for 20 days. The data showed that sesamin significantly prevented nickel-induced hepatotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Moreover, nickel-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by an increase of the lipid peroxidation level and depletion of the intracellular reduced glutathione (GSH) level in liver, were suppressed by treatment with sesamin. Sesamin also restored the activities of antioxidant enzymes (T-SOD, CAT, and GPx) and decreased 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in nickel-treated mice. Furthermore, a TUNEL assay showed that nickel-induced apoptosis in mouse liver was significantly inhibited by sesamin. Exploration of the underlying mechanisms of sesamin action revealed that activities of caspase-3 were markedly inhibited by the treatment of sesamin in the liver of nickel-treated mice. Sesamin increased expression levels of phosphoinositide-3-kinase (PI3K) and phosphorylated protein kinase B (PBK/Akt) in liver, which in turn inactivated pro-apoptotic signaling events, restoring the balance between pro- and anti-apoptotic Bcl-2 proteins in the liver of nickel-treated mice. In conclusion, these results suggested that the inhibition of nickel-induced apoptosis by sesamin is due at least in part to its antioxidant activity and its ability to modulate the PI3K-Akt signaling pathway.

Protective role of quercetin against lead-induced inflammatory response in rat kidney through the ROS-mediated MAPKs and NF-κB pathway.

BACKGROUND: Lead (Pb) exposure is considered as a risk factor for the development of renal dysfunction. The flavonoid quercetin (QE) in diets exerts the nephroprotective effects. This study investigated the effects of quercetin on renal oxidative stress and inflammation in rats exposed to Pb. METHODS: Wistar rats were divided into normal, lead exposure groups, lead plus quercetin groups and quercetin groups. Rats were exposed to lead acetate in the drinking water (500mgPb/L) with or without quercetin co-administration (25 and 50mgQU/kg intragastrically once daily). After 75days, serum uric acid, urea, creatinine, renal reactive oxygen species (ROS) production, thiobarbituric acid reactive substances (TBARS) and histopathological analysis were performed. Pb content in kidney was also assayed. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), the extracellular-receptor kinases (ERK1/2), the c-Jun N-terminal kinases (JNK1/2), p38 MAPK and nuclear factor-κB (NF-κB) were measured. RESULTS: Quercetin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators and histopathological analysis. Quercetin significantly decreased Pb content in kidney. Pb-induced profound elevations of oxidative stress in kidney were suppressed by quercetin. Furthermore, quercetin significantly inhibited Pb-induced inflammation in rat kidney. CONCLUSIONS: These results suggest that quercetin has the nephroprotective actions. The inhibition of Pb-induced kidney inflammation by quercetin is due at least in part to its anti-oxidant activity and its ability to modulate the MAPK and NF-κB signaling pathway. GENERAL SIGNIFICANCE: Quercetin might be a potent nephroprotective drug to protect Pb-induced kidney injury.