Oxyimperatorin attenuates LPS-induced microglial activation in vitro and in vivo via suppressing NF-κB p65 signaling.

BACKGROUND: Microglia-mediated neuroinflammation is an important pathological feature in many neurological diseases; thus, suppressing microglial activation is considered a possible therapeutic strategy for reducing neuronal damage. Oxyimperatorin (OIMP) is a member of furanocoumarin, isolated from the medicinal herb Glehnia littoralis. However, it is unknown whether OIMP can suppress the neuroinflammation. PURPOSE: To investigate the neuroprotective activity of oxyimperatorin (OIMP) in LPS-induced neuroinflammation in vitro and in vivo models. METHODS: In vitro inflammation-related assays were performed with OIMP in LPS-induced BV-2 microglia. In addition, intraperitoneal injection of LPS-induced microglial activation in the mouse brain was used to validate the anti-neuroinflammatory activity of OIMP. RESULTS: OIMP was found to suppress LPS-induced neuroinflammation in vitro and in vivo. OIMP significantly attenuated LPS-induced the production of free radicals, inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines in BV-2 microglia without causing cytotoxicity. In addition, OIMP could reduce the M1 pro-inflammatory transition in LPS-stimulated BV-2 microglia. The mechanistic study revealed that OIMP inhibited LPS-induced NF-κB p65 phosphorylation and nuclear translocation. However, OIMP did not affect LPS-induced IκB phosphorylation and degradation. In addition, OIMP also was able to reduce LPS-induced microglial activation in mice brain. CONCLUSION: Our findings suggest that OIMP suppresses microglia activation and attenuates the production of pro-inflammatory mediators and cytokines via inhibition of NF-κB p65 signaling.

Recent Advances in Quaternary Ammonium Monomers for Dental Applications.

Resin-based dental materials have been one of the ideal choices among various materials in the treatment of dental caries. However, resin-based dental materials still have some drawbacks, such as the lack of inherent antibacterial activity. Extensive research has been conducted on the use of novel quaternary ammonium monomers (QAMs) to impart antibacterial activity to dental materials. This review provides a comprehensive overview of the recent advances in quaternary ammonium monomers (QAMs) for dental applications. The current progress and limitations of QAMs are discussed based on the evolution of their structures. The functional diversification and enhancement of QAMs are presented. QAMs have the potential to provide long-term antibacterial activity in dental resin composites, thereby prolonging their service life. However, there is a need to balance antibacterial performance with other material properties and the potential impact on the oral microbiome and general health. Finally, the necessity for further scientific progress in the development of novel quaternary ammonium monomers and the optimization of dental resin formulations is emphasized.

Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.

The effects of bioactive components from the rhizome of gastrodia elata blume (Tianma) on the characteristics of Parkinson's disease.

Parkinson's disease (PD) is an age-related chronic neurodegenerative disease caused by the death and degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The decrease of the neurotransmitter dopamine in the patient's brain leads to various motor symptoms. PD drugs mainly enhance dopamine levels but cannot prevent or slow down the loss of dopaminergic neurons. In addition, they exhibit significant side effects and addiction issues during long-term use. Therefore, it is particularly urgent to develop novel drugs that have fewer side effects, can improve PD symptoms, and prevent the death of dopaminergic neurons. The rhizome of Gastrodia elata Blume (Tianma) is a well-known medicinal herb and has long been used as a treatment of nervous system-related diseases in China. Several clinical studies showed that formula comprising Tianma could be used as an add-on therapy for PD patients. Pharmacological studies indicated that Tianma and its bioactive components can reduce the death of dopaminergic neurons, α-synuclein accumulation, and neuroinflammation in various PD models. In this review, we briefly summarize studies regarding the effects of Tianma and its bioactive components' effects on major PD features and explore the potential use of Tianma components for the treatment of PD.

Targeting PGAM1 in cancer: An emerging therapeutic opportunity.

Glycolysis is a preferred metabolic pattern of cancer cells. Phosphoglycerate mutase 1 (PGAM1) is a pivotal glycolytic enzyme that catalyzes the reciprocal conversion between 2-phosphoglycerate and 3-phosphoglycerate. It also stimulates anabolic pathways, generates adenosine triphosphate, and keeps redox balance under hypoxic conditions. Mounting evidence supports that PGAM1 is overexpressed in many cancers and promotes their progression. The critical roles of PGAM1 in tumorigenesis make it a promising theranostical target for cancer. The aberrant expression of PGAM1 enables it to become a potential diagnosis gene for several cancers, and its heterogeneous regulations via interacting with its different ligands increase the possibility of it as a target for cancer therapy and discovery of tens of PGAM1 inhibitors, which can provide the potential feasibility for cancer treatment. This review provides insights into structure, function, and regulation of PGAM1, summarizes its mechanism in tumorigenesis, reviews the advanced status of PGAM1 inhibitors in cancer diagnosis and treatment, and finally emphasizes PGAM1 as an appealing theranostical target for cancer.

The Potentials of Uncariae Ramulus Cum Uncis for the Treatment of Migraine: Targeting CGRP in the Trigeminovascular System.

Migraine is a common chronic neurovascular disease characterized by headaches. Calcitonin gene-related peptide (CGRP) signaling in the trigeminovascular system plays a critical role in the development of migraine. The monoclonal antibodies against CGRP and its receptor have been used clinically for the prevention of migraine; however, they may not be a cost-effective option for patients with low-frequency episodic migraine. Thus, it is quite valuable to search for an alternative strategy to downregulate CGRP signaling. Uncariae Ramulus Cum Uncis (UR) has a longterm history for the treatment of cardiovascular and central nervous systems disorders in China and Eastern Asia. Several clinical studies showed that famous herbal formulas comprising UR were able to improve headaches in migraineurs. In addition, increasing in vivo studies further indicated that migraine-related changes, such as CGRP increase, inflammation, nitric oxide increase, and spontaneous behavior problems could be reduced by UR extraction and its active constituents. In this review, we summarize the pathophysiological factors affecting abnormal CGRP release in the trigeminovascular system during a migraine, and for the first time, analyze the effects of UR on these factors and evaluate the potentials of UR for the treatment of migraine.

Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines.

Breast cancer is the one of the most frequent causes of female cancer mortality. KDM5A, a histone demethylase, can increase the proliferation, metastasis, and drug resistance of cancers, including breast cancer, and is thus an important therapeutic target. In the present work, we performed hierarchical virtual screening towards the KDM5A catalytic pocket from a chemical library containing 90,000 compounds. Using multiple biochemical methods, the cyclopenta[c]chromen derivative 1 was identified as the top candidate for KDM5A demethylase inhibitory activity. Compared with the well-known KDM5 inhibitor CPI-455 (18), 1 exhibited higher potency against KDM5A and much higher selectivity for KDM5A over both KDM4A and other KDM5 family members (KDM5B and KDM5C). Additionally, compound 1 repressed the proliferation of various KDM5A-overexpressing breast cancer cell lines. Mechanistically, 1 promoted accumulation of p16 and p27 by blocking KDM5A-mediated H3K4me3 demethylation, leading to cell cycle arrest and senescence. To date, compound 1 is the first cyclopenta[c]chromen-based KDM5A inhibitor reported, and may serve as a novel motif for developing more selective and efficacious pharmacological molecules targeting KDM5A. In addition, our research provides a possible anti-cancer mechanism of KDM5A inhibitors and highlights the feasibility and significance of KDM5A as a therapeutic target for KDM5A-overexpressing breast cancer.

Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy.

Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.

Cell imaging of dopamine receptor using agonist labeling iridium(iii) complex.

Dopamine receptor expression is correlated with certain types of cancers, including lung, breast and colon cancers. In this study, we report luminescent iridium(iii) complexes (11-14) as intracellular dopamine receptor (D1R/D2R) cell imaging agents. Complexes 11 and 13, which are conjugated with a dopamine receptor agonist, showed superior cell imaging characteristics, high stability and low cytotoxicity (>100 µM) in A549 lung cancer cells. siRNA knockdown and dopamine competitive assays indicated that complexes 11 and 13 could selectively bind to dopamine receptors (D1R/D2R) in A549 cells. Fluorescence lifetime microscopy demonstrated that complex 13 has a longer luminescence lifetime at the wavelength of 560-650 nm than DAPI and other chromophores in biological fluids. The long luminescence lifetime of complex 13 not only provides an opportunity for efficient dopamine receptor tracking in biological media, but also enables the temporal separation of the probe signal from the intense background signal by fluorescence lifetime microscopy for efficient analysis. Complex 13 also shows high photostability, which could allow it to be employed for long-term cellular imaging. Furthermore, complex 13 could selectively track the internalization process of dopamine receptors (D1R/D2R) in living cells. To the best of our knowledge, complex 13 is the first metal-based compound that has been used to monitor intracellular dopamine receptors in living cells.

Identification of a rhodium(iii) complex as a Wee1 inhibitor against TP53-mutated triple-negative breast cancer cells.

The rhodium(iii) complex 1 was identified as a potent Wee1 inhibitor in vitro and in cellulo. It decreased Wee1 activity and unscheduled mitotic entry, and induced cell damage and death in TP53-mutated triple-negative breast cancer cells. 1 represents a promising scaffold for further development of more potent metal-based Wee1 antagonists.

Small Molecule Pin1 Inhibitor Blocking NF-κB Signaling in Prostate Cancer Cells.

Prolyl-isomerase 1 (Pin1) is a conserved enzyme that regulates cell processes such as cell cycle progression, transcriptional regulation, and apoptosis. However, overexpression of Pin1 is correlated with a higher probability of prostate tumor recurrence. We utilized a molecular docking technique to identify Pin1 inhibitors from a database of natural product and natural product-like compounds. The action of the hit compounds against Pin1 activity was studied using multiple methods, including a fluorometric enzymatic assay, co-immunoprecipitation, western blotting, cell thermal shiftm, and other techniques. We have identified compound 1 as a natural-product-like inhibitor of Pin1 activity via structure-based virtual screening and showed that compound 1 could target Pin1 and disrupt the interaction between Pin1 and the p65 subunit of NF-κB in cells. Furthermore, compound 1 reduced nuclear p65 (Thr254) phosphorylation and attenuated NF-κB activity in cells. Finally, compound 1 induced apoptosis in prostate cancer cells. Compound 1 represents a natural product-like Pin1 inhibitor that acts via targeting the Pin1-NF-κB interaction.

Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing.

NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53.

Recent development of transition metal complexes with in vivo antitumor activity.

The often severe side effects displayed by currently used platinum and ruthenium complexes have motivated researchers to design and develop transition metal-based anti-tumor agents with reduced toxicity. Distinct from organic anti-tumor drugs, transition metal complexes possess several properties that render them as promising scaffolds for anti-cancer drug discovery. While a vast number of metal complexes have been synthesized and reported to be promising and potent in vitro anticancer active compounds, fewer have shown efficacy in in vivo models. The demonstration of in vivo potency is an essential step for lead candidates for clinical trials. In this review, we highlight examples of transition metal-based complexes that have shown in vivo anti-tumor activities that have been described in recent years.

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells.

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

An anti-prostate cancer benzofuran-conjugated iridium(III) complex as a dual inhibitor of STAT3 and NF-κB.

Four benzofuran-conjugated iridium(III) or rhodium (III)-based metal complexes are synthesized to screen as an inhibitor of STAT3 activity in prostate cancer cells. All complexes show the high stability and solubility in the biological system. In this study, an iridium(III) complex engages STAT3 and NF-κB to inhibit their translocation and transcriptional activities. Moreover, complex 1 shows more potential antiproliferative activity against DU145 cells and suppresses tumor growth in a prostate cancer xenograft mouse without observable adverse effects. Complex 1 may provide the basis for developing new therapeutic strategy in vivo and in vitro for the treatment of advanced prostate cancer.

Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction.

The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α-p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α-p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 µM. Complex 1 interfered with the HIF-1α-p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.

A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease.

We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease.