Search Results (17)

This study aimed to investigate the preventive effects of isostrictiniin (ITN) from Nymphaea candida against acute lung injury (ALI) through lipopolysaccharide (LPS)-induced ALI mice and LPS-induced A549 cells. Compared with the model group, ITN (50 and 100 mg/kg) significantly reduced the lung indexes, W/D rates, BALF WBC counts, and total protein contents in ALI mice (p < 0.05), as well as the blood neu counts (p < 0.01), while increasing the blood lym counts (p < 0.01). ITN (50 and 100 mg/kg) also markedly decreased the lung tissue TNF-α, IL-6, IL-1β, MDA, and MPO activities in ALI mice (p < 0.01) and enhanced the SOD and GSH levels (p < 0.01). Additionally, ITN (50 and 100 mg/kg) significantly improved lung histopathological damage in ALI mice. Moreover, ITN (10 and 25 µM) significantly reduced the NO, PGE2, IL-1β, IL-6, TNF-α, and MDA levels in LPS-induced A549 cells (p < 0.01) while significantly increasing the SOD and GSH activities (p < 0.01). After LPS-induced A549 cells, the Keap1, p-JNK/JNK, p-ERK1/2/ERK1/2, p-P38/P38, p-IκBα/IκBα, and p-NF-κBp65/NF-κB p65 levels were significantly upregulated (p < 0.05), whereas the Nrf2 and HO-1 protein expressions were downregulated (p < 0.05). After treatment with ITN (25 μM), the changes in these relative protein expressions in LPS-induced A549 cells were significantly reversed (p < 0.05). The above results indicate that ITN has a better preventive effect against ALI, and its mechanisms are related to the regulation of the Keap1-Nrf2/HO-1 and MAPK/NF-κB signaling pathways. Full article

Methylglyoxal (MGO), a by-product of glycolysis, plays a significant role in cellular metabolism, particularly under stress conditions. However, MGO is a potent glycotoxin, and its accumulation has been linked to the development of several pathological conditions due to oxidative stress, including diabetes mellitus and neurodegenerative diseases. This paper focuses on the biochemical mechanisms by which MGO contributes to oxidative stress, particularly through the formation of advanced glycation end products (AGEs), its interactions with antioxidant systems, and its involvement in chronic diseases like diabetes, neurodegeneration, and cardiovascular disorders. MGO exerts its effects through multiple signaling pathways, including NF-κB, MAPK, and Nrf2, which induce oxidative stress. Additionally, MGO triggers apoptosis primarily via intrinsic and extrinsic pathways, while endoplasmic reticulum (ER) stress is mediated through PERK-eIF2α and IRE1-JNK signaling. Moreover, the activation of inflammatory pathways, particularly through RAGE and NF-κB, plays a crucial role in the pathogenesis of these conditions. This study points out the connection between oxidative and carbonyl stress due to increased MGO formation, and it should be an incentive to search for a marker that could have prognostic significance or could be a targeted therapeutic intervention in various diseases. Full article

Parkinson’s disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl₂), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl₂), G4 (SI + MnCl₂), G5 (SI + PUN), G6 (MnCl₂ + PUN), and G7 (SI + PUN + MnCl₂). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl₂, with the most pronounced effects detected in the SI rats concurrently exposed to MnCl₂. These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3β/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl₂. These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN’s mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3β/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2. Full article

Chronic gastritis (CG) is a common clinical digestive system disease, which is not easyily cured and is prone to recurrence. Traditional Chinese medicine (TCM) plays a significant role in the treatment of CG and has attracted increasing attention for clinical applications. In recent years, a large number of reports have shown that TCM has good therapeutic effect on CG. The aim of this paper is to investigate the pharmacological activities and mechanism of action of TCM in the treatment of CAG. Therefore, by searching the databases of Pubmed, China National Knowledge Infrastructure, Wanfang, and Baidu academic databases, this paper has summarized the molecular mechanisms of TCM in improving CG. The results show that the improvement of GC by TCM is closely related to a variety of molecular mechanisms, including the inhibition of Helicobacter pylori (Hp) infection, alleviation of oxidative stress, improvement of gastric function, repair of gastric mucosa, inhibition of inflammatory response, and apoptosis. More importantly, IRF8-IFN-γ, IL-4-STAT6, Hedgehog, pERK1/2, MAPK, PI3K-Akt, NF-κB, TNFR-c-Src-ERK1/2-c-Fos, Nrf2/HO-1, and HIF-1α/VEGF signaling pathways are considered as important molecular targets for TCM in the treatment of GC. These important findings will provide a direction and a basis for further exploring the pathogenesis of GC and tapping the potential of TCM in clinical treatment. This review also puts forward a bright prospect for future research of TCM in the treatment of CG. Full article

Alzheimer’s disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl₃) alone, AlCl₃ with cocoa alone, AlCl₃ with vinpocetine (VIN), AlCl₃ with epigallocatechin-3-gallate (EGCG), AlCl₃ with coenzyme Q10 (CoQ10), AlCl₃ with wheatgrass (WG), AlCl₃ with vitamin (Vit) B complex, and AlCl₃ with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3β/β-catenin signaling, ER stress, autophagy, and apoptosis. AlCl₃ administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-catenin pathway. Furthermore, AlCl₃ intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl₃-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3β-Wnt/β-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways. Full article

Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5′ untranslated region (5′-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment. Full article

Chemotherapy-provoked peripheral neuropathy and its linked comorbidities severely reduce the quality of a patient’s life. Its therapy is not completely resolved and has become an important clinical challenge. The protective actions of molecular hydrogen (H₂) in many neurological disorders have been described, but its effects on memory and the emotional deficits accompanying neuropathic pain induced by chemotherapy remain unknown. In this study, using male mice injected with paclitaxel (PTX), we examined the effects of systemic treatment with hydrogen-rich water (HRW) in: (i) the mechanical and thermal allodynia provoked by PTX and the pathways involved; (ii) the memory deficits, anxiety- and depressive-like behaviors associated with PTX-induced peripheral neuropathy (PIPN); and (iii) the plasticity (p-extracellular signal-regulated protein kinase; p-ERK ½), nociceptive (p-protein kinase B, p-Akt), inflammatory (p-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; p-IKBα), and oxidative (4-hydroxynonenal: 4-HNE) alterations provoked by PIPN in the prefrontal cortex (PFC). The results revealed: (1) the antiallodynic actions of HRW administered at one or two times per day during 7 and 3 consecutive days; (2) the participation of Kv7 potassium channels and the Nrf2-heme oxygenase 1-NAD(P)H: quinone oxidoreductase 1 pathway in the painkiller effects of HRW; (3) the inhibition of memory deficits and the anxiodepressive-like behaviors related with PIPN induced by HRW; and (4) the normalization of p-ERK ½, p-Akt and 4-HNE up-regulation and the activation of antioxidant enzymes produced by this treatment in PFC. This study proposes HRW as a possible effective and safe therapy for PIPN and its associated cognitive and emotional deficits. Full article

Piper nigrum Linnaeus is often used as a treatment for chills, stomach diseases, and other ailments. Piperine has many biological functions; however, its mechanism for preventing gastric mucosal damage is still unclear. The objective of this study was to investigate the preventive effects of piperine on ethanol-induced gastric mucosal injury by using GES-1 cells and rats. SOD, CAT, GSH-Px and MDA were effectively regulated in GES-1 cells pre-treated with piperine. Piperine significantly increased SOD, CAT and GSH-Px activities, but decreased the ulcer area, MDA, ROS and MPO levels in the gastric tissues of rats. RT-PCR analysis showed that piperine downregulated the mRNA expression levels of keap1, JNK, ERK and p38, and upregulated the mRNA transcription levels of Nrf2 and HO-1. Western blotting results indicated that piperine could activate the protein expression levels of Nrf2 and HO-1 and inhibit the protein expression levels of keap1, p-JNK, p-ERK and p-p38. In conclusion, piperine suppressed ethanol-induced gastric ulcers in vitro and in vivo via oxidation inhibition and improving gastric-protecting activity by regulating the Nrf2/HO-1 and MAPK signalling pathways. Full article

Damiana (Turnera diffusa), of the family Passifloraceae, has been widely studied for its pharmacological effects, especially for antioxidant and antibacterial actions. However, there are limited scientific findings describing its antiphotoaging effects on the skin. In the present study, the underlying molecular mechanisms of the protective effect of Damiana were investigated in keratinocytes (HaCaTs) and normal human dermal fibroblasts (HDFs) subject to UVB irradiation. The mRNA expression of matrix metalloproteinases (MMPs) and procollagen type I was determined by reverse transcription-polymerase chain reaction. The protein expression of antiphotoaging-related signaling molecules in the activator protein-1 (AP-1) and nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element (ARE) pathways was assessed by Western blotting. We observed that Damiana blocked the upregulated production of reactive oxygen species induced in UVB-irradiated HaCaTs and HDFs in a dose-dependent manner. Treatment with Damiana also significantly ameliorated the mRNA expression of MMPs and procollagen type I. In addition, the phosphorylation level of c-Jun and c-Fos was also decreased through the attenuated expression of p-38, p-ERK, and p-JNK after treatment with Damiana. Furthermore, the treatment of cells with Damiana resulted in the inhibition of Smad-7 expression in the TGF-β/Smad pathway and upregulated the expression of the Nrf2/ARE signaling pathway. Hence, the synthesis of procollagen type I, a precursor of collagen I, was promoted. Collectively, these results provide us with the novel insight that Damiana is a potential source of antiphotoaging compounds. Full article

Exploration of lead compounds against Parkinson’s disease (PD), a neurodegenerative disease, is of great important. Dioscin, a bioactive natural product, shows various pharmacological effects. However, the activities and mechanisms of dioscin against PD have not been well investigated. In this study, the tests on 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats were carried out. The results showed that dioscin dramatically improved cell viability, decreased reactive oxygen species (ROS) levels, improved motor behavior and tyrosine hydroxylase(TH) levels and restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats. Mechanism investigation showed that dioscin not only markedly increased the expression level of dual- specificity phosphatase 6 (DUSP6) by 1.87-fold in cells and 2.56-fold in rats, and decreased phospho-extracellular regulated protein kinases (p-ERK) level by 2.12-fold in cells and 2.34-fold in rats, but also increased the levels of nuclear factor erythroid2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), superoxide dismutase (SOD) and decreased the levels of kelch-1ike ECH-associated protein l (Keap1) in vitro and in vivo. Furthermore, DUSP6 siRNA transfection experiment in PC12 cells validated the protective effects of dioscin against PD via regulating DUSP6 to adjust the Keap1/Nrf2 pathway. Our data supported that dioscin has protection against PD in regulating oxidative stress via DUSP6 signal, which should be considered as an efficient candidate for the treatment of PD in the future. Full article

Oxidative stress is one of the main factors affecting animal health and reducing performance. The small intestine is the primary site of free-radical attacks. Dihydromyricetin (DHM) is a flavonoid compound with antioxidant, anti-inflammatory, and other biological activities, which is mainly extracted from Rattan tea. However, the effects of DHM on the intestinal antioxidant function of growing-finishing pigs and related mechanisms remain unclear. The aim of this study was to investigate the effect of dietary DHM supplementation on the intestinal antioxidant capacity of growing-finishing pigs and its mechanism. Our results show that dietary 0.03% DHM increased the activities of the total antioxidant capacity (T-AOC), catalase (CAT), and glutathione peroxidase (GSH-Px), decreased malondialdehyde (MDA) level, and upregulated protein expressions of HO-1, NQO1, nuclear Nrf2, and phospho-ERK (p-ERK) in the jejunum of growing-finishing pigs. Again, we found that 20 μmol/mL and 40 μmol/mL DHM treatment significantly upregulated the protein expression of HO-1 and promoted the nuclear translocation of Nrf2 and ERK phosphorylation in IPCE-J2 cells. ERK inhibitor PD98059 eliminated the DHM-induced upregulation of p-ERK, nuclear Nrf2, and HO-1. Our findings provided the first evidence that DHM enhanced the intestinal antioxidant capacity of growing-finishing pigs by activating the ERK/Nrf2/HO-1 signaling pathway. Full article

Dysregulated glutamate signaling, leading to neuronal excitotoxicity and death, has been associated with neurodegenerative pathologies. 17β-estradiol (E2) is a human steroid hormone having a role in reproduction, sexual maturation, brain health and biological activities. The study aimed to explain the neuroprotective role of E2 against glutamate-induced ROS production, MAP kinase-dependent neuroinflammation, synaptic dysfunction and neurodegeneration in the cortex and hippocampus of postnatal day 7 rat brain. Biochemical and immunofluorescence analyses were applied. Our results showed that a single subcutaneous injection of glutamate (10 mg/kg) induced brain oxidative stress after 4 h by disturbing the homeostasis of glutathione (GSH) and revealed an upsurge in ROS and LPO levels and downregulated the expression of Nrf2 and HO-1 antioxidant protein. The glutamate-exposed P7 pups illustrated increased phosphorylation of stress-activated c-Jun N-terminal kinase (JNK) and p38 kinase (p38) and downregulated expression of P-Erk1/2. This was accompanied by pathological neuroinflammation as revealed by enhanced gliosis with upregulated expression of GFAP and Iba-1, and the activation of proinflammatory cytokines (TNF-α) in glutamate-injected P7 pups. Moreover, exogenous glutamate also reduced the expression of synaptic markers (PSD-95, SYP) and induced apoptotic neurodegeneration in the cortical and hippocampal regions by dysregulating the expression of Bax, Bcl-2 and caspase-3 in the developing rat brain. On the contrary, co-treatment of E2 (10 mg/kg) with glutamate significantly abrogated brain neuroinflammation, neurodegeneration and synapse loss by alleviating brain oxidative stress by upregulating the Nrf2/HO-1 antioxidant pathway and by deactivating pro-apoptotic P-JNK/P-p38 and activation of pro-survival P-Erk1/2 MAP kinase pathways. In brief, the data demonstrate the neuroprotective role of E2 against glutamate excitotoxicity-induced neurodegeneration. The study also encourages future studies investigating if E2 may be a potent neuroprotective and neurotherapeutic agent in different neurodegenerative diseases. Full article

Zinc is an essential metal ion involved in many biological processes. Studies have shown that zinc can activate several molecules in the insulin signalling pathway and the concomitant uptake of glucose in skeletal muscle cells. However, there is limited information on other potential pathways that zinc can activate in skeletal muscle. Accordingly, this study aimed to identify other zinc-activating pathways in skeletal muscle cells to further delineate the role of this metal ion in cellular processes. Mouse C2C12 skeletal muscle cells were treated with insulin (10 nM), zinc (20 µM), and the zinc chelator TPEN (various concentrations) over 60 min. Western blots were performed for the zinc-activation of pAkt, pErk, and pCreb. A Cignal 45-Reporter Array that targets 45 signalling pathways was utilised to test the ability of zinc to activate pathways that have not yet been described. Zinc and insulin activated pAkt over 60 min as expected. Moreover, the treatment of C2C12 skeletal muscle cells with TPEN reduced the ability of zinc to activate pAkt and pErk. Zinc also activated several associated novel transcription factor pathways including Nrf1/Nrf2, ATF6, CREB, EGR1, STAT1, AP-1, PPAR, and TCF/LEF, and pCREB protein over 120 min of zinc treatment. These studies have shown that zinc’s activity extends beyond that of insulin signalling and plays a role in modulating novel transcription factor activated pathways. Further studies to determine the exact role of zinc in the activation of transcription factor pathways will provide novel insights into this metal ion actions. Full article

The anti-inflammatory effect of hispolon has identified it as one of the most important compounds from Sanghuangporus sanghuang. The research objectives were to study this compound using an animal model by lipopolysaccharide (LPS)-induced acute lung injury. Hispolon treatment reduced the production of the pro-inflammatory mediator NO, TNF-α, IL-1β, and IL-6 induced by LPS challenge in the lung tissues, as well as decreasing their histological alterations and protein content. Total cell number was also reduced in the bronchoalveolar lavage fluid (BALF). Moreover, hispolon inhibited iNOS, COX-2 and IκB-α and phosphorylated IKK and MAPK, while increasing catalase, SOD, GPx, TLR4, AKT, HO-1, Nrf-2, Keap1 and PPARγ expression, after LPS challenge. It also regulated apoptosis, ER stress and the autophagy signal transduction pathway. The results of this study show that hispolon regulates LPS-induced ER stress (increasing CHOP, PERK, IRE1, ATF6 and GRP78 protein expression), apoptosis (decreasing caspase-3 and Bax and increasing Bcl-2 expression) and autophagy (reducing LC3 I/II and Beclin-1 expression). This in vivo experimental study suggests that hispolon suppresses the LPS-induced activation of inflammatory pathways, oxidative injury, ER stress, apoptosis and autophagy and has the potential to be used therapeutically in major anterior segment lung diseases. Full article

The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell surface biotinylation, and co-immunoprecipitation analyses of bichalcone analog ((E)-1-(4-Hydroxy-3-((4-(4-((E)-3-(pyridin-3-yl)acryloyl)phenyl)piperazin-1-yl)methyl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWU-BR4)-treated cancer cells showed dissociation between GRP78 and p85α conferring the recruitment of PTEN to lipid raft membranes associated with p85α. Ectopic expression of GRP78 could overcome induction of lipid raft membrane-associated p85α–unphosphorylated PTEN complex formation and suppression of GRP78−PI3K−Akt−GTP-Rac1-mediated and GRP78-regulated PERK−Nrf2 antioxidant pathway and cancer cell invasion by TSWU-BR4. Using specific inducer, inhibitor, or short hairpin RNA for ASM demonstrated that induction of the lipid raft membrane localization and activation of ASM by TSWU-BR4 is responsible for perturbing homeostasis of cholesterol and ceramide levels in the lipid raft and ER membranes, leading to alteration of GRP78 membrane trafficking and subsequently inducing p85α–unphosphorylated PTEN complex formation, causing disruption of GRP78−PI3K−Akt−GTP-Rac1-mediated signal and ER membrane-associated GRP78-regulated oxidative stress balance, thus inhibiting cancer cell invasion. The involvement of the enrichment of ceramide to lipid raft membranes in inhibition of NF-κB-mediated MMP-2 expression was confirmed through attenuation of NF-κB activation using C2-ceramide, NF-κB specific inhibitors, ectopic expression of NF-κB p65, MMP-2 promoter-driven luciferase, and NF-κB-dependent reporter genes. In conclusion, localization of ASM in the lipid raft membranes by TSWU-BR4 is a key event for initiating formation of ceramide-enriched lipid raft membrane platforms, which causes delocalization of GRP78 from the lipid raft and ER membranes to the cytosol and formation of p85α–unphosphorylated PTEN complexes to attenuate the GRP78-regulated oxidative stress balance and GRP78−p85α−Akt−GTP-Rac1−NF-κB−MMP-2-mediated cancer cell invasion. Full article