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Introduction Diabetes is an independent predictor of poor outcomes in patients with COVID-19. We compared the effects of the preadmission use of antidiabetic medications on the in-hospital mortality of patients with COVID-19 having type 2 diabetes. Methods A systematic search was performed until November 30, 2021. We used a random-effects meta-analysis to calculate the pooled OR (95% CI). Results We included 61 studies (3,061,584 individuals). We found some medications protective against COVID-related death, including metformin, GLP-1RA and SGLT-2i. DPP-4i and insulin users were more likely to die during hospitalization. SU, TZD, and AGI were mortality neutral. Metformin use was associated with better outcome in a dose-response manner. Conclusions Metformin, GLP-1RA, and SGLT-2i were associated with lower mortality rate in patients with COVID-19 having type 2 diabetes. DPP-4i and insulin were linked to increased mortality. SU, TZD and AGI were mortality neutral. Presentation: No date and time listed

Developmental dyslexia is typically defined as a difficulty with an individual’s command of written language, arising from deficits in phonological awareness. However, motor entrainment difficulties in non-linguistic synchronization and time-keeping tasks have also been reported. Such findings gave rise to proposals of an underlying rhythm processing deficit in dyslexia, even though to date, evidence for impaired motor entrainment with the rhythm of natural speech is rather scarce, and the role of speech rhythm in phonological awareness is unclear. The present study aimed to fill these gaps. Dyslexic adults and age-matched control participants with variable levels of previous music training completed a series of experimental tasks assessing phoneme processing, rhythm perception, and motor entrainment abilities. In a rhythm entrainment task, participants tapped along to the perceived beat of natural spoken sentences. In a phoneme processing task, participants monitored for sonorant and obstruent phonemes embedded in nonsense strings. Individual sensorimotor skills were assessed using a number of screening tests. The results lacked evidence for a motor impairment or a general motor entrainment difficulty in dyslexia, at least among adult participants of the study. Instead, the results showed that the participants’ performance in the phonemic task was predictive of their performance in the rhythmic task, but not vice versa, suggesting that atypical rhythm processing in dyslexia may be the consequence, but not the cause, of dyslexic difficulties with phoneme-level encoding. No evidence for a deficit in the entrainment to the syllable rate in dyslexic adults was found. Rather, metrically weak syllables were significantly less often at the center of rhythmic attention in dyslexic adults as compared to neurotypical controls, with an increased tendency in musically trained participants. This finding could not be explained by an auditory deficit in the processing of acoustic-prosodic cues to the rhythm structure, but it is likely to be related to the well-documented auditory short-term memory issue in dyslexia.

Impairment in mitophagy contributes to the pathology of Parkinson's disease. This study investigated whether Phosphatase and tensin homologue (PTEN)-induced kinase 1 (PINK1)/parkin-mediated mitophagy is linked to the protective effect of carnosic acid (CA) from rosemary. Treatment of SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) disrupted the mitochondrial membrane potential, inhibited voltage-dependent anion channel 1 (VDAC1) protein, and induced cytosolic cytochrome c, but CA pretreatment reversed these findings. By immunofluorescence, CA pretreatment was shown to increase the co-localization of red fluorescence (parkin) and MitoTracker green FM fluorescence (mitochondria), indicating that CA promoted the translocation of parkin into mitochondria. Immunoprecipitation with VDAC1 antibody showed that 6-OHDA treatment decreased the interaction of ubiquitinated protein with VDAC1. However, CA pretreatment reversed this reduction in the interaction of ubiquitinated protein with VDAC1. Silencing of PINK1 and parkin by use of small interfering RNA (siRNA) attenuated the ability of CA to reverse 6-OHDA-inhibited autophagic vacuoles. Moreover, in PINK1 siRNA-transfected cells, CA no longer reversed these actions of 6-OHDA on the inhibition of mitophagy-related proteins (PINK1, parkin, VDAC1, and LC3-II) and anti-apoptotic Bcl-2 protein, as well as the induction of apoptotic-related proteins, and nuclear condensation. In conclusion, CA appears to counteract the neurotoxicity of 6-OHDA by activating PINK1/parkin-mediated mitophagy.

Diabetes is an independent predictor of poor outcomes in patients with COVID-19. We compared the effects of the preadmission use of antidiabetic medications on the in-hospital mortality of patients with COVID-19 having type 2 diabetes.A systematic search of PubMed, EMBASE, Scopus and Web of Science databases was performed to include studies (except case reports and review articles) published until November 30, 2021. We excluded papers regarding in-hospital use of antidiabetic medications. We used a random-effects meta-analysis to calculate the pooled OR (95% CI) and performed a sensitivity analysis to confirm the robustness of the meta-analyses.We included 61 studies (3,061,584 individuals), which were rated as having low risk of bias. The OR (95% CI) indicated some medications protective against COVID-related death, including metformin [0.54 (0.47-0.62), IMetformin, GLP-1RA, and SGLT-2i were associated with lower mortality rate in patients with COVID-19 having type 2 diabetes. DPP-4i and insulin were linked to increased mortality. Sulfonylurea, thiazolidinedione, and alpha-glucosidase inhibitors were mortality neutral. These findings can have a large impact on the clinicians' decisions amid the COVID-19 pandemic.

Induction of 4-hydroxynonenal (4-HNE), a major lipid peroxidation aldehyde, is observed in patients with obesity and type 2 diabetes mellitus. The lipolytic response by 4-HNE has been linked to insulin resistance. In this study, we investigated the effects of carnosic acid (CA) on 4-HNE-induced lipolysis and the inhibition of β-oxidation in 3T3-L1 adipocytes. The results indicated that cells pretreated with CA reduced 4-HNE-mediated free fatty acid (FFA) release. Furthermore, CA reversed the inhibition of phosphorylation of Tyr632 of insulin receptor substrate-1 (IRS-1) and Akt and the phosphorylation of Ser307 of IRS-1. CA inhibited 4-HNE-induced phosphorylation of protein kinase A (PKA) and hormone-sensitive lipase (HSL), and reversed the suppression by 4-HNE of phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (p

Rhythmic properties of speech and language have been a matter of long-standing debates, with both traditional production and perception studies delivering controversial findings. The present study examines the possibility of investigating linguistic rhythm using movement-based paradigms. Informed by the theory and methods of sensorimotor synchronization, we developed two finger-tapping tasks (synchronization and reproduction), and tested them with English participants. The synchronization task required participants to tap along with the beat of a looped sentence while the reproduction task asked them to tap out the perceived beat patterns after listening to a sentence loop. The results showed that both tasks engaged participants in period tracking of a beat-like structure in the linguistic stimuli, though synchronization did so to a greater extent. Patterns obtained in the reproduction task tended to converge toward participants’ spontaneous tapping rates and showed a degree of regularization. Data collected in the synchronization task displayed a consistent anchoring of taps with the vowel onsets. Overall, synchronization performance with language resembled many well-established findings of sensorimotor synchronization with metronome and music. We conclude that our setting of the sensorimotor synchronization paradigm—finger tapping along with looped spoken phrases—is a valid experimentation tool for studying rhythm perception in language. published

Pi class of glutathione S-transferase (GST) is known to suppress c-Jun N-terminal kinase (JNK)-related apoptosis through protein-protein interactions. Moreover, signaling by PKA/cAMP response element binding protein (CREB) is necessary for GSTP up-regulation. This study explored whether carnosic acid (CA) from rosemary prevents 6-hydroxydopamine (6-OHDA)-induced neurotoxicity by inhibition of JNK through GSTP via PKA/CREB signaling. Results indicated that the GSTP protein was increased in SH-SY5Y cells treated with CA for 18 and 24 h. However, CA had no significant effect on alpha or mu class of GST. Treatment of CA increased the induction of p-PKAα, nuclear p-CREB, and CRE-DNA binding activity. These effects of CA were attenuated in cells pretreated with the PKA inhibitor H89. CA pretreatment suppressed 6-OHDA-induced apoptosis by inhibition of JNK phosphorylation, poly(ADP)-ribose polymerase cleavage, and nuclear condensation. Pretreatment with H89 and GSTP siRNA attenuated the ability of CA to reverse 6-OHDA-induced apoptosis. By use of immunoprecipitation with JNK antibody to examine the interaction of GSTP-JNK with CA, we showed that CA pretreatment increased the immunoprecipitation of GSTP after 6-OHDA treatment, which suggests that CA promoted the interaction between GSTP and JNK. Conclusion: CA prevents 6-OHDA-induced apoptosis via inhibition of JNK by GSTP through the PKA/CREB pathway.

The mediation of apoptosis-related protein in the TGF-β signaling pathway (ARTS) and X-liked inhibitor of apoptosis protein (XIAP) by parkin plays a critical role in preventing Parkinson's disease. We studied whether carnosic acid (CA) could prevent 6-hydroxydopamine (6-OHDA)-induced apoptosis by modulating ARTS and XIAP through parkin in SH-SY5Y cells. In cells treated with 6-OHDA, the protein expression of ARTS is increased and XIAP is decreased. Pretreatment of cells with CA reversed these effects. Moreover, CA attenuated the activation of caspase 9 and caspase 7 by 6-OHDA. By immunoprecipitation with ARTS antibody, we found that 6-OHDA increased the protein expression of XIAP. However, pretreatment of cells with CA reduced XIAP protein and increased the ubiquitination of ARTS. Silencing of parkin attenuated the ability of CA to reverse the induction of ARTS and apoptotic-related proteins and the reduction of XIAP and parkin protein by 6-OHDA. Similarly, reversal of 6-OHDA-induced nuclear condensation and apoptotic-related proteins by CA was inhibited in cells with XIAP silencing. In conclusion, CA induces parkin by enhancing the ubiquitination of ARTS, leading to induction of XIAP. This may be a novel strategy for preventing Parkinson's disease.

Moving seamlessly between spoken number words and Arabic digits is common in everyday life. In this study, we systematically investigated the correspondence between auditory number words and visual Arabic digits in adults. Auditory number words and visual Arabic digits were presented concurrently or sequentially and participants had to indicate whether they described the same quantity. We manipulated the stimulus onset asynchronies (SOAs) between the two stimuli (Experiment 1: −500 ms to +500 ms; Experiment 2: −200 ms to +200 ms). In both experiments, we found a significant cross-modal distance effect. This effect was strongest for simultaneous stimulus presentation and decreased with increasing SOAs. Numerical distance emerged as the most consistent significant predictor overall, in particular for simultaneous presentation. However, physical similarity between the stimuli was often a significant predictor of response times in addition to numerical distance, and at longer SOAs, physical similarity between the stimuli was the only significant predictor. This shows that SOA modulates the extent to which participants access quantity representations. Our results thus support the idea that a semantic quantity representation of auditory and visual numerical symbols is activated when participants perform a concurrent matching task, while at longer SOAs participants are more likely to rely on physical similarity between the stimuli. We also investigated whether individual differences in the efficiency of the cross-modal processing were related to differences in mathematical performance. Our results are inconclusive about whether the efficiency of cross-format numerical correspondence is related to mathematical competence in adults.

Background Impairment of mitochondrial biogenesis is associated with the pathological progression of Parkinson's disease (PD). Parkin-interacting substrate (PARIS) can be ubiquitinated by parkin and prevents the repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α). Purpose This study investigated whether the neuroprotective mechanism of carnosic acid (CA) from rosemary is mediated via the regulation of PARIS and PGC-1α by parkin. Methods The Western blotting and RT-PCR were used to determine protein and mRNA, respectively. To investigate the protein-protein interaction of between PARIS and ubiquitin, the immunoprecipitation assay (IP assay) was utilized. Silencing of endogenous parkin or PGC-1α was performed by using transient transfection of small interfering RNA (siRNA). Results SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) increased PARIS protein, decreased PGC-1α protein, and reduced protein and mRNA of mitochondrial biogenesis-related genes. CA pretreatment reversed the effects of 6-OHDA. By IP assay, the interaction of PARIS with ubiquitin protein caused by CA was stronger than that caused by 6-OHDA. Moreover, knockdown of parkin attenuated the ability of CA to reverse the 6-OHDA-induced increase in PARIS and decrease in PGC-1α expression. PGC-1α siRNA was used to investigate how CA influenced the effect of 6-OHDA on the modulation of mitochondrial biogenesis and apoptosis. In the presence of PGC-1α siRNA, CA could no longer significantly reverse the reduction of mitochondrial biogenesis or the induction of cleavage of apoptotic-related proteins by 6-OHDA. Conclusion The cytoprotective of CA is related to the enhancement of mitochondrial biogenesis by inhibiting PARIS and inducing PGC-1α by parkin. The activation of PGC-1α-mediated mitochondrial biogenesis by CA prevents the degeneration of dopaminergic neurons, CA may have therapeutic application in PD.

An imbalance in mitochondrial dynamics is strongly associated with Parkinson's disease. The fusion protein optic atrophy 1 (OPA1) is up-regulated through the activation of parkin-mediated IκB kinase γ (IKKγ)/p65 signaling. This study investigated whether the neuroprotection of carnosic acid (CA) from rosemary is involved in mitochondrial dynamics and OPA1 protein induction by parkin/IKKγ/p65 signaling. The neurotoxin 6-hydroxydopamine (6-OHDA) treated with SH-SY5Y cells decreased OPA1 and mitofusin 2 fusion proteins, but increased fission 1 and dynamin related protein 1 (DRP1) fission proteins. By immunofluorescence, 6-OHDA induced the fluorescence of green spots outside the mitochondria, indicating that cytochrome c was released to the cytoplasm. Except for the effects on DRP1 protein, CA pretreatment reversed these effects of 6-OHDA. Additionally, CA treatment increased the ubiquitination of IKKγ, nuclear p65 protein, OPA1-p65 DNA binding activity, and OPA1 protein. However, transfection of parkin small interfering RNA (siRNA) attenuated these effects of CA. Furthermore, transfection of OPA1 siRNA abolished the action of CA to reverse 6-OHDA-increased cytosolic cytochrome c protein, apoptotic-related protein cleavage, and cell death. In conclusion, the mechanism by which CA counteracts the toxicity of 6-OHDA is through modulation of mitochondrial dynamics and upregulation of OPA1 via activation of the parkin/IKKγ/p65 pathway.

This paper implements an automatic bird data capture system which uploads data captured from social network websites to the server and stores them in the database. When using the Facebook API to capture data of interest, the system needs to filter the captured data to avoid false data storage. This paper takes building an automatic system that includes reinforcing the training database of the bird community as a top priority.

Induction of phase II enzymes is important in cancer chemoprevention. We compared the effect of rosemary diterpenes on the expression of the pi class of glutathione S-transferase (GSTP) in rat liver Clone 9 cells and the signaling pathways involved. Culturing cells with 1, 5, 10, or 20 μM carnosic acid (CA) or carnosol (CS) for 24 h in a dose-dependent manner increased the GSTP expression. CA was more potent than CS. The RNA level and the enzyme activity of GSTP were also enhanced by CA treatment. Treatment with 10 μM CA highly induced the reporter activity of the enhancer element GPEI. Furthermore, CA markedly increased the translocation of nuclear factor erythroid-2 related factor 2 (Nrf2) from the cytosol to the nucleus after 30 to 60 min. CA the stimulated the protein induction of p38, nuclear Nrf2, and GSTP was diminished in the presence of SB203580 (a p38 inhibitor). In addition, SB203580 pretreatment or silencing of Nrf2 by siRNA suppressed the CA-induced GPEI-DNA binding activity and GSTP protein expression. Knockdown of p38 or Nrf2 by siRNA abolished the activation of p38 and Nrf2 as well as the protein induction and enzyme activity of GSTP by CA. These results suggest that CA up-regulates the expression and enzyme activity of GSTP via the p38/Nrf2/GPEI pathway.

The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of γ-glutamate-cysteine ligase catalytic subunit, γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH-SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c-Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on the different cellular contexts. EZH2 interacts with both histone and non-histone proteins to modulate diverse physiological functions including cancer progression and malignancy. In this review article, we focused on the updated information regarding microRNAs (miRNAs) and long non coding RNAs (lncRNAs) in regulation of EZH2, the oncogenic and tumor suppressive roles of EZH2 in cancer progression and malignancy, as well as current pre-clinical and clinical trials of EZH2 inhibitors.

Enhanced removal of abnormal protein aggregates or injured organelles through autophagy is related to neuroprotection in Parkinson's disease. In this study, we explored whether the induction of autophagy is associated with the neuroprotection of rosemary carnosic acid (CA) against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. The results indicated that cells treated with CA had increased protein levels of parkin and autophagy-related markers, including phosphatidylinositol 3-kinase p100, Beclin1, autophagy-related gene 7, and microtubule-associated protein 1 light chain 3-II, as well as enhanced formation of autophagic vacuoles. Treatment of cells with 6-OHDA decreased the levels of parkin and the autophagy markers, but CA pretreatment reversed these effects. However, wortmannin (an autophagosome formation blocker) pretreatment attenuated the effect of CA. After CA pretreatment, the induction of cleaved caspase 3, cleaved poly-ADP ribose polymerase, and nuclear condensation by 6-OHDA were alleviated. Both wortmannin and bafilomycin A1 (an autophagosome-lysosome fusion blocker) inhibited the anti-apoptosis effects of CA. Additionally, we performed immunoprecipitation with anti-parkin antibody and found that the interaction of parkin and Beclin1 protein was reduced by 6-OHDA but that this effect was reversed in cells pretreated with CA. Moreover, transfection of parkin siRNA in cells inhibited the ability of CA to alleviate 6-OHDA-decreased autophagy-related markers and nuclear condensation. In conclusion, CA protects against 6-OHDA-induced apoptosis by inducing autophagy through the interaction of parkin and Beclin1. These results provide a future strategy for use of CA in the prevention of Parkinson's disease.

Parkin is a Parkinson's disease (PD)-linked gene that plays an important role in the ubiquitin-proteasome system (UPS). This study explored whether carnosic acid (CA) from rosemary protects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via upregulation of parkin in vivo and in vitro. We found that the reduction in proteasomal activity by 6-OHDA was attenuated in SH-SY5Y cells pretreated with 1 μM CA. Immunoblots showed that CA reversed the induction of ubiquitinated protein and the reduction of PTEN-induced putative kinase 1 (PINK1) and parkin protein in 6-OHDA-treated SH-SY5Y cells and rats. Moreover, in a transgenic OW13 Caenorhabditis elegans model of PD that expresses human α-synuclein in muscle cells, CA reduced α-synuclein accumulation in a dose-dependent manner. In cells pretreated with the proteasome inhibitor MG132, CA no longer reversed the 6-OHDA-mediated induction of cleavage of caspase 3 and poly(ADP)-ribose polymerase and no longer reversed the suppression of proteasome activity. When parkin expression was silenced by use of small interfering RNA, the ability of CA to inhibit apoptosis and induce proteasomal activity was significantly reduced. The reduction in 6-OHDA-induced neurotoxicity by CA was associated with the induction of parkin, which in turn upregulated the UPS and then decreased cell death.

Carnosic acid (CA), a rosemary phenolic compound, has been shown to display anti-cancer activity. We examined the apoptotic effect of CA in human neuroblastoma IMR-32 cells and elucidated the role of the reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) associated with carcinogenesis. The result indicated that CA decreased the cell viability in a dose-dependent manner. Further investigation in IMR-32 cells revealed that cell apoptosis following CA treatment is the mechanism as confirmed by flow cytometry, hoechst 33258, and caspase-3/-9 and poly(ADP-ribose) polymerase (PARP) activation. Immunoblotting suggested a down-regulation of anti-apoptotic Bcl-2 protein in the CA-treated cells. In flow cytometric analysis, CA caused the generation of reactive oxygen species (ROS); however, pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated the CA-induced generation of ROS and apoptosis. This effect was accompanied by increased activation of p38 and by decreased activation of extracellular signal-regulated kinase (ERK) as well as activation of c-Jun NH(2)-terminal kinase (JNK). Moreover, NAC attenuated the CA-induced phosphorylation of p38. Silencing of p38 by siRNA gene knockdown reduced the CA-induced activation of caspase-3. In conclusion, ROS-mediated p38 MAPK activation plays a critical role in CA-induced apoptosis in IMR-32 cells.

Allium organosulfides are potential chemopreventive compounds due to their effectiveness on the induction of phase II detoxification enzyme expression. In this study, we examined the structure and function relationship among various alk(en)yl sulfides on the expression of the pi class of glutathione S-transferase (GSTP) in rat Clone 9 cells, and what mechanism is involved. Cells were treated with 300 μM dipropyl sulfide (DPS), dipropyl disulfide (DPDS), propyl methyl sulfide (PMS), and propyl methyl disulfide (PMDS) for 48 h. DPDS and PMDS displayed more potency on GSTP protein and mRNA induction than that of DPS and PMS. Next, we compared the effectiveness of DPDS, PMDS, and diallyl disulfide (DADS), which have the same number of sulfur atoms but differ in the side alk(en)yl groups. The maximum increases on protein expression, mRNA level, and enzyme activity were noted in cells treated with DADS, followed by DPDS and PMDS. A reporter assay showed that three disulfides increased GSTP enhancer I (GPE I) activity (P0.05) in the order DADSDPDS ≥ PMDS. Electromobility gel shift assays showed that the DNA binding of GPE I to nuclear proteins reached a maximum at 1 to 3 h after alk(en)yl disulfide treatment. Supershift assay revealed that c-jun bound to GPE I. Silencing of extracellular signal-regulated kinase (ERK) 2 expression inhibited c-jun activation and GSTP induction. Results suggest that both the type of alk(en)yl groups and number of sulfur atoms are determining factors of allium organosulfides on inducing GSTP expression, and it is likely related to the ERK-c-Jun-GPE I pathway.

Baicalein is known as a 12-lipoxygenase (12-LOX) inhibitor. The 12-LOX is found to be involved in the progression of human cancers and the inhibitor of 12-LOX offers a target for the prevention cancer. We demonstrated the inhibitory effect of baicalein on the gene and protein expression of 12-LOX in H460 human lung nonsmall carcinoma cell line. Treatment of baicalein inhibited the growth of H460 cells in a dose-dependent manner. Following 24 h exposure to 50 μM baicalein, cell cycle analysis revealed an increase in the cell population in S-phase. During the S-phase arrest, baicalein decreased the protein levels of cdk1 and cyclin B1, which are the regulating proteins of S-phase transition to G2/M-phase, in this study. Furthermore, baicalein induced the most of H460 cell apoptosis after treatment for 48 h. H460 cells formed vesicles and apoptotic body, and then floated after treatment with baicalein. Baicalein-induced H460 cell apoptosis was confirmed by DNA condensation and fragmentation. Baicalein-induced apoptosis were also accompanied by decreasing in Bcl-2 and proform of caspase-3 and increasing p53 and Bax protein levels. Pretreatment with a specific caspase-3 inhibitor, Ac-DEVD-CHO, partially reduced baicalein-induced cell death, indicating baicalein induces apoptosis is partially dependent on caspase-3 pathway in H460 cells. These data suggest that baicalein, a 12-LOX inhibitor, inhibits the proliferation of H460 cells via S-phase arrest and induces apoptosis in association with the regulation of molecules in the cell cycle and apoptosis-related proteins.

Carnosic acid (CA), a diterpene found in the rosemary (Rosmarinus officinalis), has been reported to have a neuroprotective effect. Glutathione S-transferase (GST) P (GSTP) is a phase II detoxifying enzyme that provides a neuroprotective effect. The aim of this study was to explore whether the neuroprotective effect of CA is via an upregulation of GSTP expression and the possible signaling pathways involved. SH-SY5Y cells were pretreated with 1 μM CA followed by treatment with 100 μM 6-hydroxydopamine (6-OHDA). Both immunoblotting and enzyme activity results show that CA also induced protein expression and enzyme activity of GSTP. Moreover, CA significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt, the nuclear translocation of p65, but not mitogen-activated protein kinases (p < 0.05). Pretreatment with LY294002 (a PI3K/Akt inhibitor) suppressed the CA-induced phosphorylation of IκB kinase (IKK) and IκBα, p65 nuclear translocation, and nuclear factor-kappa B (NF-κB)-DNA binding activity as well as GSTP protein expression. Furthermore, CA attenuated 6-OHDA-induced caspase 3 activation, and cell death was reversed by GSTP siRNA or LY294002 treatment. Additionally, male Wistar rats with lesions induced by 6-OHDA treatment in the right striatum responded to treatment with CA, which significantly reversed the reduction in GSTP protein expression that resulted from lesioning. We suggest that CA prevents 6-OHDA-induced apoptosis through an increase in GSTP expression via activation of the PI3K/Akt/NF-κB pathway. Therefore, CA may be a promising candidate for use in the prevention of Parkinson's disease.

Understanding the neuroprotective effects of the rosemary phenolic diterpene carnosic acid (CA) has attracted increasing attention. We explored the mechanism by which CA modulates the neurotoxic effects of 6-hydroxydopamine (6-OHDA) in SH-SY5Y cells. Cells were pretreated with CA for 12 h followed by treatment with 100 μM 6-OHDA for 12 or 24 h. Cell viability determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolim bromide (MTT) assay indicated that 0.1 to 1 μM CA dose-dependently attenuated the cell death induced by 6-OHDA, whereas the effect of 3-5 μM CA was weaker. CA at 1 μM suppressed the 6-OHDA-induced nuclear condensation, reactive oxygen species generation, and cleavage of caspase 3 and PARP. Immunoblots showed that the phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38 by 6-OHDA was reduced in the presence of CA. Incubation of cells with CA resulted in significant increases in the total glutathione (GSH) level and the protein expression of the γ-glutamylcysteine ligase catalytic subunit and modifier subunit. L-Buthionine-sulfoximine, an inhibitor of GSH synthesis, attenuated the effect of CA on cell death and apoptosis. Treatment with CA also led to an increase in nuclear factor erythroid-2 related factor 2 (Nrf2) activation, antioxidant response element (ARE)-luciferase reporter activity, and DNA binding to the ARE. Silencing of Nrf2 expression alleviated the reversal of p38 and JNK1/2 activation by CA. These results suggest that the attenuation of 6-OHDA-induced apoptosis by CA is associated with the Nrf2-driven synthesis of GSH, which in turn down-regulates the JNK and p38 signaling pathways. The CA compound may be a promising candidate for neuroprotection in Parkinson's disease.

The anticarcinogenic effect of rosemary has been partly attributed to the modulation of the activity and expression of phase II detoxification enzymes. Here we compared the effects of phenolic diterpenes from rosemary on the expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) in rat Clone 9 liver cells. Cells were treated with 1‐20 mmol/L of carnosic acid (CA) or carnosol (CS) for 24 h. Both CA and CS dose dependently increased NQO1 enzyme activity and protein expression, and the induction potency of CA was stronger than that of CS. The increase in NQO1 enzyme activity in cells treated with 10 mmol/L CA and CS was 4.1- and 1.9-fold, respectively (P , 0.05). RT-PCR showed that CA and CS induced NQO1 mRNA in a dose-dependent manner. Furthermore, CA dose dependently induced transcription of nuclear factor erythroid-2 related factor 2 (Nrf2) and antioxidant response element (ARE)-luciferase reporter activity. Silencing of Nrf2 expression alleviated NQO1 protein expression and ARE-luciferase activity by CA. Moreover, the phosphorylation of p38 was mainly stimulated in the presence of CA. Pretreatment with SB203580 or silencing of p38 expression inhibited Nrf2 activation and NQO1 induction. These results suggest that the increased NQO1 expression by CA is likely related to the p38-Nrf2 pathway and help to clarify the possible molecular mechanism of action of rosemary phenolic compounds in drug metabolism and cancer prevention. J. Nutr. doi: 10.3945/jn.111.146779.

Kaempferol (3, 4',5,7-tetrahydroxyflavone) is one of the most commonly found dietary flavonols. The biological and pharmacological effects of kaempferol may depend upon its behavior as either an antioxidant or a prooxidant. However, the clear biological effects of prooxidant or antioxidant character of kaempferol has not been clarified yet. The overall objective of the present study is to explore the role of prooxidant or antioxidant in kaempferol-induced cell toxicity. In this paper, we have proved that antioxidant pathway may be involved in kaempferol induces H460 cell apoptosis. Kaempferol-induced H460 cell apoptosis is a typical apoptosis that was accompanied by a significant DNA condensation and increasing intracellular ATP levels. Kaempferol-induced apoptosis is related to its ability to change the expression of apoptotic markers, such as caspase-3 (caspase-dependent) and AIF (caspase-independent). The overexpression of antioxidant enzyme Mn SOD protein levels, which was promoted to a new type tumor suppressor gene in several human cancer cells recently, may be an important role in kaempferol-induced H460 cell apoptosis.