Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases.

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a highly conserved eukaryotic enzyme discovered as a key regulator of cellular energy homeostasis, with anti-inflammation, antioxidative stress, anticancer, and antifibrosis beneficial effects. AMPK is dysregulated in human pulmonary diseases such as acute lung injury, nonsmall cell lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. This review provides an overview of the beneficial role of natural, synthetic, and Chinese traditional medicines AMPK modulators in pulmonary diseases, and highlights the role of the AMPK signaling pathway in the lung, emphasizing the importance of finding lead compounds and drugs that can target and modulate AMPK to treat the lung diseases.

Artemisinin conferred cytoprotection to human retinal pigment epithelial cells exposed to amiodarone-induced oxidative insult by activating the CaMKK2/AMPK/Nrf2 pathway.

BACKGROUND: Ocular toxicity is a severe adverse effect that limits the chronic clinical use of the antiarrhythmic drug amiodarone. Here, we aimed to evaluate the cytoprotective effect of artemisinin and explore the potential signalling pathways in human retinal pigment epithelial (RPE) cell cultures. METHODS: D407 cell cultures were exposed to amiodarone and the impact of artemisinin was evaluated. The key parameters included lactate dehydrogenase (LDH) release, intracellular reactive oxygen species (ROS) generation, and the mitochondrial membrane potential (MMP). We also assessed the protein levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), phosphorylated adenosine monophosphate-activated protein kinase (AMPK)ɑ (p-AMPK), calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and nuclear factor erythroid 2-related factor 2 (Nrf2). RESULTS: Artemisinin reduced the cytotoxicity induced by amiodarone, as reflected by decreased LDH release, ROS generation, and MMP disruption. Additionally, artemisinin increased p-AMPK, CaMKK2, and Nrf2 protein levels. Inhibition of AMPK, CaMKK2, or Nrf2 abolished the cytoprotective effect of artemisinin. AMPK activation and Nrf2 knockdown further supported its protective role. CONCLUSIONS: Artemisinin protected RPE cells from amiodarone-induced damage via the CaMKK2/AMPK/Nrf2 pathway. The in vivo experiments in mice confirmed its efficacy in preventing retinal injury caused by amiodarone. These results suggest that an artemisinin-based eye formulation could be repurposed for treating amiodarone-induced ocular toxicity.

Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1.

Ferroptosis, a form of cell death characterized by lipid peroxidation, is involved in neurodegenerative diseases such as Alzheimer´s disease (AD). Recent studies have shown that a first-line antimalarial drug artemisinin is effective to counteract AD pathology. In this study, we investigated the protective effect of artemisinin against neuronal ferroptosis and the underlying mechanisms. In hippocampal HT22 cells, pretreatment with artemisinin dose-dependently protected against Erastin-induced cell death with an EC50 value of 5.032 µM, comparable to the ferroptosis inhibitor ferrostatin-1 (EC50 = 4.39 µM). We demonstrated that artemisinin (10 µM) significantly increased the nuclear translocation of Nrf2 and upregulated SLC7A11 and GPX4 in HT22 cells. Knockdown of Nrf2, SLC7A11 or GPX4 prevented the protective action of artemisinin, indicating that its anti-ferroptosis effect is mediated by the Nrf2-SLC7A11-GPX4 pathway. Molecular docking and Co-Immunoprecipitation (Co-IP) analysis revealed that artemisinin competitively binds with KEAP1, promoting the dissociation of KEAP1-Nrf2 complex and inhibiting the ubiquitination of Nrf2. Intrahippocampal injection of imidazole-ketone-Erastin (IKE) induced ferroptosis in mice accompanied by cognitive deficits evidenced by lower preference for exploration of new objects and new object locations in the NOR and NOL tests. Artemisinin (5, 10 mg/kg, i.p.) dose-dependently inhibited IKE-induced ferroptosis in hippocampal CA1 region and ameliorated learning and memory impairments. Moreover, we demonstrated that artemisinin reversed Aß1-42-induced ferroptosis, lipid peroxidation and glutathione depletion in HT22 cells, primary hippocampal neurons, and 3×Tg mice via the KEAP1-Nrf2 pathway. Our results demonstrate that artemisinin is a novel neuronal ferroptosis inhibitor that targets KEAP1 to activate the Nrf2-SLC7A11-GPX4 pathway.

Three hertz orthostatic tremor as "red flag sign" candidate for multiple system atrophy.

AIM: This study investigates the potential of 3-Hz orthostatic tremor (OT) as a diagnostic red-flag sign for differentiating multiple system atrophy (MSA) from Parkinson's disease (PD). PATIENTS AND METHODS: A total of 615 PD patients and 234 MSA patients (120 MSA-P and 114 MSA-C) participated. OT at ~ 3 Hz and other frequencies was identified through rhythmic postural sway on the stabilogram map and confirmed by fast Fourier transform (FFT) analysis. Extensive assessment of OT occurrence, preferential stance conditions, sway direction, frequency spectrum, and intensity was performed and compared between the two diseases. RESULTS: Significant differences in OT features were observed. In PD, 104 patients (16.9%) exhibited tremors, mainly on a firm platform (79.8%), and preferentially in the medial-lateral direction (59.6%). About 40% of PD-related OT showed double peaks in the FFT map, with a frequency spectrum from 3.3 to 12.4 Hz. MSA tremors were observed in 133 patients (56.8%, including 46 MSA-P and 87 MSA-C patients), occurring after proprioceptive sensory input deprivation (94.7%). OT in MSA occurred exclusively in the anterior-posterior direction (100%), with no sub- or ultra-harmonics in the FFT map. Binominal logistic regression analyses demonstrated that frequency and stance conditions independently contributed to differentiating PD- and MSA-related OT. The 3-Hz tremor exhibited a sensitivity of 0.568, perfect specificity (1), an approximate negative predictive value of 0.8592, and a positive predictive value of 1 for MSA identification. CONCLUSIONS: This study establishes the 3-Hz orthostatic tremor as a promising red flag sign for MSA identification.

Artemisinin Confers Cytoprotection toward Hydrogen Peroxide-Induced Cell Apoptosis in Retinal Pigment Epithelial Cells in Correlation with the Increased Acetylation of Histone H4 at Lysine 8.

Increased oxidative stress is one of the critical pathologies inducing age-related macular degeneration (AMD), characterized by retinal pigment epithelial (RPE) cell damage and death. The unbalanced acetylation and deacetylation of histones have been implicated in AMD pathogenesis or hydrogen peroxide (H2O2)-induced cell damage. Therefore, strategies aimed at controlling the balance between acetylation and deacetylation may effectively protect RPE cells from oxidative damage. Artemisinin is an antimalarial lactone drug derived from Artemisia annua, with antioxidant activity known to modulate histone acetylation in the brain, but its effect on the retina is unknown. In this study, we aimed to investigate whether Artemisinin exerts a cytoprotective effect on oxidative stress-induced apoptosis in RPE cells by regulating histone acetylation. We hypothesized that Artemisinin confers cytoprotection toward H2O2-induced apoptosis in RPE cells through this mechanism. In the present study, we found that Artemisinin at a sub-clinic dosage of 20 µM inhibited the H2O2-induced cell viability decrease and B-cell lymphoma 2 (Bcl-2) protein level decrease and attenuated the H2O2-induced decrease in the histone H4 lysine (Lys) 8 acetylation [Acetyl-H4 (Lys 8)] level in the retinal RPE cell line D407. As expected, histone deacetylase inhibitor Trichostatin A at the concentration of 250 nM increased the Acetyl-H4 (Lys 8) level in D407 cells and attenuated the H2O2-induced cell viability decrease and apoptosis. Similar findings were obtained using adult RPE (ARPE)19 cells, another human RPE cell line, and primary human RPE cell cultures. In conclusion, these results confirmed our hypothesis and indicated that Artemisinin attenuated H2O2-induced apoptosis in apparent correlation with the increase in the Acetyl-H4 (Lys 8) level, which is associated with gene transcription and cell survival. By modulating histone acetylation, Artemisinin may restore the balance between acetylation and deacetylation and enhance the resistance and survival of RPE cells under oxidative stress. Our study provides novel mechanistic insights into the effect of Artemisinin on histone acetylation and apoptosis in RPE cells and supports the potential application of Artemisinin in the prevention and/or treatment of AMD.

Synthesis of a C2-Symmetric Chiral Borinic Acid and Its Application in Catalytic Desymmetrization of 2,2-Disubstituted-1,3-Propanediols.

Notwithstanding the common use of boronic acids in catalysis, the design and synthesis of efficient chiral boronic acids remains a formidable challenge. Herein we disclose a rational design and a concise synthesis of a series of novel C2-symmetric disubstituted boronic acids, or borinic acids. Chiral borinic acids have been found to be excellent agents that can achieve highly enantioselective desymmetrization of 2,2-disubstituted-1,3-propanediols, providing chiral diols with a quaternary stereocenter, which has been regarded in recent years as challenging. A wide range of substrates are tolerated in this reaction, providing a series of chiral diols with high enantioselectivity. The presence of the tetracoordinate borinate in the catalytic cycle has been proven by 11B NMR studies, and a stereocontrol model has been proposed.

Dihydroartemisinin inhibits EMT of glioma via gene BASP1 in extrachromosomal DNA.

The mechanism of dihydroartemisinin (DHA) inhibiting the migration and invasion of glioma in an ROS-DSB-dependent manner has been revealed. Extrachromosomal DNAs (ecDNAs) which are generated by DNA damage have great potential in glioma treatment. However, the role of ecDNAs in DHA's pharmacological mechanisms in glioma is still unknown. In this study, DHA was found to inhibit proliferative activity, increase ROS levels and promote apoptosis in U87 and U251 cells. Migration and invasion have also been suppressed. ecDNA expression profiles were found in gliomas. EcDNA-BASP1 was found, by means of bioinformatics analysis, to be present in GBM tissues and positively correlated with patient prognosis. Proliferation, migration and invasion were upregulated after knockdown of ecDNA-BASP1. The expression of vimentin and N-cadherin also had the same tendency. Finally, we found that the ecDNA-BASP1 content in nude mouse transplant tumors was significantly increased after DHA treatment, which might exert a better suppressive effect on glioma. The upregulation of tumor suppressor ecDNA-BASP1 played an important role in the suppression of glioma progression induced by DHA. EcDNA-BASP1 may inhibit glioma migration and invasion through repressing epithelial-mesenchymal transition (EMT).

Induced CPL-Active Materials Based on Chiral Supramolecular Co-Assemblies.

Circularly polarized luminescence (CPL) has attracted much interest due to its potential applications on chiral photonic techniques and optoelectronic materials science. As known, dissymmetry factor (gem ) of CPL is one essential factor for evaluating the features of CPL-active materials. Much attention has focused on how to increase the gem value, which is one of the most important issues for CPL practical applications. Recently, more and more works have demonstrated that chiral supramolecular could provide the significant strategy to improve the gem value through the orderly helical superstructure of chiral building blocks. Normally, this kind of chiral supramolecular assembly process can be accompanied by chirality transfer and induction mechanism, which can promote the amplification effect on the induced CPL of achiral dyes. In this review, we fully summarized recent advances on the induced CPL-active materials of chiral supramolecular co-assemblies, their applications in circularly polarized organic light-emitting diodes (CP-OLEDs) and current challenges.

Causal effect of gut-microbiota-derived metabolite trimethylamine N-oxide on Parkinson's disease: A Mendelian randomization study.

BACKGROUND AND PURPOSE: It has been suggested that trimethylamine N-oxide (TMAO) is related to Parkinson's disease (PD) in observational studies. However, the direction of this association is inconsistent. An exploratory Mendelian randomization study was conducted to investigate whether TMAO and its precursors have a causal relationship with PD. METHODS: Summary statistics were obtained for single nucleotide polymorphisms related to circulating levels of TMAO, betaine, carnitine and choline, and the corresponding data for the risk, age at onset and progression of PD from genome-wide association studies. Inverse-variance weighting was used as the primary method for effect estimation. The false discovery rate was applied to the correction of multiple testing. A p value of association <0.05 but above the false discovery rate corrected threshold was deemed suggestive evidence of a possible association. A range of robust Mendelian randomization methods were used for sensitivity analysis. RESULTS: Suggestive evidence was observed of an inverse causal effect of TMAO on motor fluctuations (odds ratio [OR] 0.851, 95% confidence interval [CI] 0.731, 0.990, p = 0.037) and carnitine on insomnia (OR 0.817, 95% CI 0.700, 0.954, p = 0.010) and a positive causal effect of betaine on Hoehn-Yahr stage (OR 1.397, 95% CI 1.112, 1.756, p = 0.004), Unified Parkinson's Disease Rating Scale (UPDRS) III score (ß = 0.138, 95% CI 0.051, 0.225, p = 0.002), motor fluctuations (OR 1.236, 95% CI 1.011, 1.511, p = 0.039), and choline on UPDRS IV (ß = 0.106, 95% CI 0.026, 0.185, p = 0.009) and modified Schwab and England Activities of Daily Living Scale score (ß = 0.806, 95% CI 0.127, 1.484, p = 0.020). CONCLUSIONS: Our findings provide suggestive evidence that TMAO and its precursors have a causal effect on the progression of PD. Further investigation of the underlying mechanisms is required.

Dopamine D1- and D2-like receptors oppositely regulate lifespan via a dietary restriction mechanism in Caenorhabditis elegans.

BACKGROUND: Despite recent progress in understanding the molecular mechanisms regulating aging and lifespan, and the pathways involved being conserved in different species, a full understanding of the aging process has not been reached. In particular, increasing evidence suggests an active role for the nervous system in lifespan regulation, with sensory neurons, as well as serotonin and GABA signaling, having been shown to regulate lifespan in Caenorhabditis elegans (C. elegans). However, the contribution of additional neural factors, and a broad understanding of the role of the nervous system in regulating aging remains to be established. Here, we examine the impact of the dopamine system in regulating aging in C. elegans. RESULTS: We report that mutations of DOP-4, a dopamine D1-like receptor (D1R), and DOP-2, a dopamine D2-like receptor (D2R) oppositely affected lifespan, fast body movement span, reproductive lifespan, and developmental rate in C. elegans. Activation of D2R using aripiprazole, an antipsychotic drug, robustly extended both lifespan and healthspan. Conversely, inhibition of D2R using quetiapine shortened worm lifespan, further supporting the role of dopamine receptors in lifespan regulation. Mechanistically, D2R signaling regulates lifespan through a dietary restriction mechanism mediated by the AAK-2-DAF-16 pathway. The DAG-PKC/PKD pathway links signaling between dopamine receptors and the downstream AAK-2-DAF-16 pathway to transmit longevity signals. CONCLUSIONS: These data demonstrated a novel role of dopamine receptors in lifespan and dietary restriction regulation. The clinically approved antipsychotic aripiprazole holds potential as a novel anti-aging drug.

Artemisia annua Extract Improves the Cognitive Deficits and Reverses the Pathological Changes of Alzheimer's Disease via Regulating YAP Signaling.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the occurrence of cognitive deficits. With no effective treatments available, the search for new effective therapies has become a major focus of interest. In the present study, we describe the potential therapeutic effect of Artemisia annua (A. annua) extract on AD. Nine-month-old female 3xTg AD mice were treated with A. annua extract for three months via oral administration. Animals assigned to WT and model groups were administrated with an equal volume of water for the same period. Treated AD mice significantly improved the cognitive deficits and exhibited reduced Aß accumulation, hyper-phosphorylation of tau, inflammatory factor release and apoptosis when compared with untreated AD mice. Moreover, A. annua extract promoted the survival and proliferation of neural progenitor cells (NPS) and increased the expression of synaptic proteins. Further assessment of the implicated mechanisms revealed that A. annua extract regulates the YAP signaling pathway in 3xTg AD mice. Further studies comprised the incubation of PC12 cells with Aß1-42 at a concentration of 8 µM with or without different concentrations of A. annua extract for 24 h. Obtained ROS levels, mitochondrial membrane potential, caspase-3 activity, neuronal cell apoptosis and assessment of the signaling pathways involved was performed using western blot and immunofluorescence staining. The obtained results showed that A. annua extract significantly reversed the Aß1-42-induced increase in ROS levels, caspase-3 activity and neuronal cell apoptosis in vitro. Moreover, either inhibition of the YAP signaling pathway, using a specific inhibitor or CRISPR cas9 knockout of YAP gene, reduced the neuroprotective effect of the A. annua extract. These findings suggest that A. annua extract may be a new multi-target anti-AD drug with potential use in the prevention and treatment of AD.

Artemisinin Confers Neuroprotection against 6-OHDA-Induced Neuronal Injury In Vitro and In Vivo through Activation of the ERK1/2 Pathway.

Parkinson's disease (PD) is an age-related, progressive neurodegenerative disease characterized by the gradual and massive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). We have recently reported that artemisinin, an FDA-approved first-line antimalarial drug, possesses a neuroprotective effect. However, the effects and underlying mechanisms of artemisinin on Parkinson's disease remain to be elucidated. In this study, we investigated the neuroprotective effects of artemisinin on 6-OHDA and MPP+ in neuronal cells and animal models, as well as the underlying mechanisms. Our results showed that artemisinin significantly attenuated the loss of cell viability, LDH release, elevated levels of reactive oxygen species (ROS), the collapse of the mitochondria trans-membrane potential and cell apoptosis in PC12 cells. Western blot results showed that artemisinin stimulated the phosphorylation of ERK1/2, its upstream signaling proteins c-Raf and MEK and its downstream target CREB in PC12 cells in a time- and concentration-dependent manner. In addition, the protective effect of artemisinin was significantly reduced when the ERK pathway was blocked using the ERK pathway inhibitor PD98059 or when the expression of ERK was knocked down using sgRNA. These results indicate the essential role of ERK in the protective effect of artemisinin. Similar results were obtained in SH-SY5Y cells and primary cultured neurons treated with 6-OHDA, as well as in cellular models of MPP+ injury. More interestingly, artemisinin attenuated PD-like behavior deficit in mice injected with 6-OHDA evaluated by behavioral tests including swimming test, pole-test, open field exploration and rotarod tests. Moreover, artemisinin also stimulated the phosphorylation of ERK1/2, inhibited apoptosis, and rescued dopaminergic neurons in SNc of these animals. Application of ERK pathway inhibitor PD98059 blocked the protective effect of artemisinin in mice during testing. Taking these results together, it was indicated that artemisinin preserves neuroprotective effects against 6-OHDA and MPP+ induced injury both in vitro and in vivo by the stimulation of the ERK1/2 signaling pathway. Our findings support the potential therapeutic effect of artemisinin in the prevention and treatment of Parkinson's disease.

Planar Chiral Multiple Resonance Thermally Activated Delayed Fluorescence Materials for Efficient Circularly Polarized Electroluminescence.

Chiral boron/nitrogen doped multiple resonance thermally activated delayed fluorescence (MR-TADF) emitters are promising for highly efficient and color-pure circularly polarized organic light-emitting diodes (CP-OLEDs). Herein, we report two pairs of MR-TADF materials (Czp-tBuCzB, Czp-POAB) based on planar chiral paracyclophane with photoluminescence quantum yields of up to 98 %. The enantiomers showed symmetric circularly polarized photoluminescence spectra with dissymmetry factors |gPL | of up to 1.6×10-3 in doped films. Meanwhile, the sky-blue CP-OLEDs with (R/S)-Czp-tBuCzB showed an external quantum efficiency of 32.1 % with the narrowest full-width at half-maximum of 24 nm among the reported CP-OLEDs, while the devices with (R/S)-Czp-POAB displayed the first nearly pure green CP electroluminescence with |gEL | factors at the 10-3 level. These results demonstrate the incorporation of planar chirality into MR-TADF emitter is a reliable strategy for constructing of efficient CP-OLEDs.

Enantioselective Construction of Tertiary α-Alkyl Fluoride via BTM-Catalyzed Fluorination of α-Alkynyl-Substituted Acetic Acids.

The isothiourea-catalyzed enantioselective construction of tertiary α-fluoro stereogenic centers has been demonstrated by using branched alkynyl-substituted acetic acids as starting materials, providing a broad range of optically active tertiary α-alkyl fluorides in high enantioselectivity (up to 97% ee). Furthermore, this methodology was proven to be scaled up to a Gram scale without loss of enantioselectivity.

Artemisinin Attenuates Amyloid-Induced Brain Inflammation and Memory Impairments by Modulating TLR4/NF-κB Signaling.

The abnormal immune response is an early change in the pathogenesis of Alzheimer's disease (AD). Microglial activation is a crucial regulator of the immune response, which contributes to progressive neuronal injury by releasing neurotoxic products. Therefore, finding effective drugs to regulate microglial homeostasis and neuroinflammation has become a new AD treatment strategy. Artemisinin has potent anti-inflammatory and immune activities. However, it is unclear whether Artemisinin contributes to the regulation of microglial activation, thereby improving AD pathology. This study found that Artemisinin significantly reduced amyloid beta-peptide 1-42 (Aß1-42)-induced increases in nitric oxide and reactive oxygen species and inflammatory factors in BV2 cells. In addition, Artemisinin inhibited the migration of microglia and prevented the expansion of the inflammatory cascade. The mechanical studies showed Artemisinin inhibited neuroinflammation and exerted neuroprotective effects by regulating the Toll-like receptor 4 (TLR4)/Nuclear factor-kappa B (NF-κB) signaling pathway. Similar results were obtained in AD model mice, in which Artemisinin administration attenuated Aß1-42-induced neuroinflammation and neuronal injury, reversing spatial learning and memory deficits. The anti-inflammatory effect of Artemisinin is also accompanied by the activation of the TLR4/NF-κB signaling pathway in the animal model. Our results indicate that Artemisinin attenuated Aß1-42-induced neuroinflammation and neuronal injury by stimulating the TLR4/NF-κB signaling pathway. These findings suggest that Artemisinin is a potential therapeutic agent for AD.

Quetiapine Shortens the Lifespan of Caenorhabditis elegans through DOP-2, DAF-2 and RSKS-1.

Recent studies implicate a key role of dopamine signaling in lifespan regulation. Our previous study found that quetiapine, an atypical antipsychotic drug that has antagonistic activity on dopamine D2-like receptors (D2Rs), shortened the lifespan of Caenorhabditis elegans (C. elegans). However, the detailed mechanism of this effect was not clear. In the present study, we evaluate the effect of quetiapine on aging and explore its underlying molecular mechanism. The results show that quetiapine shortened healthspan in C. elegans. The lifespan-shortening effect is dependent on DOP-2, a D2R expressed in worms. Quetiapine shortens lifespan through the C. elegans insulin and IGF-1 receptor DAF-2, but not the downstream Akt pathway. Quetiapine-induced lifespan reduction is dependent on RSKS-1, a key protein kinase that functions in mTOR signaling. In addition, the quetiapine effect is also related to mitochondrial function. These findings further support the key role of dopamine signaling in lifespan regulation and promote our insight into the mechanism of action of antipsychotic drugs.

Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells.

AIMS: G protein-coupled receptor (GPCR) transactivation of kinase receptors greatly expands the actions attributable to GPCRs. Thrombin, via its cognate GPCR, protease-activated receptor (PAR)-1, transactivates tyrosine and serine/threonine kinase receptors, specifically the epidermal growth factor receptor and transforming growth factor-ß receptor, respectively. PAR-1 transactivation-dependent signalling leads to the modification of lipid-binding proteoglycans involved in the retention of lipids and the development of atherosclerosis. The mechanisms of GPCR transactivation of kinase receptors are distinct. We aimed to investigate the role of proximal G proteins in transactivation-dependent signalling. MAIN METHODS: Using pharmacological and molecular approaches, we studied the role of the G⍺ subunits, G⍺q and G⍺11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. KEY FINDINGS: Pan G⍺q subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The G⍺q/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous G⍺q members, G⍺q and G⍺11, only the G⍺q was involved in regulating PAR-1 mediated proteoglycan modification. Although G⍺q and G⍺11 share approximately 90% homology at the protein level, we show that the two isoforms exhibit different functional roles. SIGNIFICANCE: Our findings may be extrapolated to other GPCRs involved in vascular pathology and highlight the need for novel pharmacological tools to assess the role of G proteins in GPCR signalling to expand the preeminent position of GPCRs in human therapeutics.

The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development.

Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.

Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway.

Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA-approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti-angiogenic, anti-cancer and anti-inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM-1 cells, increased the expression of pro-apoptotic proteins Bim、p27Kip1 , cleaved caspase-3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl-2. LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.

Computational Design of Enhanced Enantioselectivity in Chiral Phosphoric Acid-Catalyzed Oxidative Desymmetrization of 1,3-Diol Acetals.

A general method for the highly enantioselective desymmetrization of 2-alkyl-substituted 1,3-diols is presented. A combination of computational and experimental studies has been utilized to understand the origin of the stereocontrol of oxidative desymmetrization of 1,3-diol benzylideneacetals. DFT calculations demonstrate that the acetal protecting group is highly influential for high enantioselectivity, and a simple but effective new protecting group has been designed. The desymmetrization reactions proceed with high enantioselectivity for a variety of substrates. Moreover, the reaction conditions are also shown to be effective for desymmetrization of 2,2-dialkyl-substituted 1,3-diols, which provides chiral products bearing acyclic all-carbon quaternary stereocenters. The method has been applied to the formal synthesis of indoline alkaloids.