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Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene‐ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1–6 with oxoglaucine derivatives as ligands were synthesized and their anti‐tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming. [ABSTRACT FROM AUTHOR]

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene‐ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1–6 with oxoglaucine derivatives as ligands were synthesized and their anti‐tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming. [ABSTRACT FROM AUTHOR]

Abstract: AMP-activated protein kinase (AMPK) is a master regulator of energy metabolism in skeletal muscle; AMPK induces muscle protein degradation but the underlying mechanisms are unclear. Myostatin is a powerful negative regulator of skeletal muscle mass and growth in mammalian species. We hypothesized that AMPK stimulates myostatin expression, which provides an explanation for the negative role of AMPK in muscle growth. The objective of this study is to demonstrate that AMPK stimulates myostatin expression using C2C12 cells as a model. Activation of AMPK by 5-aminoimidazole-4-carboxamide-1-β-d-riboruranoside (AICAR) dramatically increased the mRNA expression and protein content of myostatin in C2C12 myotubes, and to a lesser degree in myoblasts. Metformin, another AMPK activator, also stimulated myostatin expression at low concentrations. In addition, ectopic expression of AMPK wild-type α subunit (enhancing AMPK activity) and AMPK K45R mutant (knockdown AMPK activity) enhanced and reduced myostatin expression, respectively. These results indicate that AMPK stimulates myostatin expression in C2C12 cells, providing an explanation for the negative effect of AMPK on muscle growth. [Copyright &y& Elsevier]

The rare earth metal Gd(III), Yb(III), Lu(III), Eu(III), Tb(III) and Ho(III) complexes 1 – 6 with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (H-L) as ligands were synthesized. The in vitro cytotoxicity assay indicated that the cytotoxicity of 1 was equivalent to cisplatin and higher than that of H-L and other complexes towards T24 tumor cells. The mechanism study indicated that 1 caused significant up-regulation of the proteins p27, p21 and p53 in T24 cells and cell cycle arrest in G2 phase. In addition, 1 induced effective T24 cells apoptosis via mitochondrial dysfunction pathway, which was indicated by changes in mitochondrial membrane potential (Δψ), reactive oxygen species (ROS), intracellular Ca2+ and the mitochondria-related proteins (including cytochrome C (Cyt C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated x (Bax) and apoptotic protease activating factor-1 (Apaf-1)). Moreover, 1 could activate caspase-3/8/9 in T24 cells. Therefore, complex 1 is a promising and potent anticancer drug candidate. Non-anionic-cationic type Gd(III) complex 1 , which exhibited hight cytotoxicity to towards T24 cells and low cytotoxicity towards HL-7702 cells, induced T24 cells arrest in the G2 phase and apoptosis via a mitochondrial dysfunction pathway. Unlabelled Image • Six new rare earth complexes with quinolinyl hydrazine were synthesized. • Complex 1 exhibited selective cytotoxicity to tumor cells versus HL-7702 cells. • Complex 1 caused T24 cell apoptosis via a mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1–3, n = 1–3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft. [ABSTRACT FROM AUTHOR]

[Display omitted] Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids (GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue (BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone (DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates; such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1a transcription from the alternative promoter (Ppargc1a -AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1a -AP expression and mitochondrial biogenesis; and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1a -AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate (cAMP) -responsive element-binding protein (CREB) binding to the cAMP regulatory element (CRE) in Ppargc1a -AP promoter, leading to Ppargc1a- AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1 - Ppargc1a -AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring. [ABSTRACT FROM AUTHOR]

Six pyrazolopyrimidine Rh (III)/Pd(II) complexes were prepared and exhibited excellent cytotoxic activity, complex 5 and 6 induced cell cycle arrest, apoptosis and ER stress, suppressed cells proliferation in vivo. [Display omitted] • Six pyrazolopyrimidine Rh(III)/pd(II) complexes were synthesized and characterized. • Structure activity relationship (SAR) of the complexes was studied. • Complexes 1 – 6 exhibited excellent antitumor activity against various tumor cells. • Complexes 5 and 6 induced cell cycle arrest, apoptosis and ER stress. • Complex 5 and 6 inhibited the growth of T-24 in vivo. Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H 2 O)Cl 3 ] (1), [Rh(L2)(CH 3 OH)Cl 3 ] (2), [Rh(L3)(H 2 O)Cl 3 ] (3), [Rh 2 (L4)Cl 6 ]·CH 3 OH (4), [Rh(L5)(CH 3 CN)Cl 3 ]·0.5CH 3 CN (5), and [Pd(L5)Cl 2 ] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6. [ABSTRACT FROM AUTHOR]

Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in Ppargc1a promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the Ppargc1a promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions. [ABSTRACT FROM AUTHOR]

The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp. • CcGPR84 is highly expressed in the intestine and spleen of common carp. • Lauric acid exhibits the strongest inhibitory potency on the cAMP signaling pathway via ccGPR84. • Nonanoic acid exhibits the highest activation potency on the MAPK/ERK signaling pathway via ccGPR84. [ABSTRACT FROM AUTHOR]

• ccMc3r is highly expressed in common carp brain and intestine. • For cAMP signaling pathway, the original ligand adrenocorticotropic hormone (ACTH) (1–24) has the highest activating potency; while for MAPK/ERK signaling pathway, β-MSH has the highest activating potency. • (ACTH) (1–24) have the strongest inhibitory effect on the NF-κB signaling pathway downstream of ccMc3r. • ccMc3r exhibits strong constitutive activity in inhibiting NF-κB signaling pathway. Melanocortin-3 receptor (MC3R) not only regulates energy homeostasis in animals, but also is an important regulator of inflammation. As one of the most widely farmed freshwater fish, common carp has attracted great interest for its feeding and inflammation regulation. In this study, we cloned the coding sequence (CDS) of common carp Mc3r (ccMc3r), examined its tissue expression profile, and investigated the function of this receptor in mediating downstream signaling pathways. The results showed that the CDS of ccMc3r was 975 bp, encoding a putative protein of 324 amino acids. Homology, phylogeny, and chromosomal synteny analyses revealed that ccMc3r is evolutionarily close to the orthologs of cyprinids. Quantitative real-time PCR (qPCR) indicated that ccMc3r was highly expressed in the brain and intestine. The luciferase reporter systems showed that four ligands, ACTH (1–24), α-MSH, β-MSH, and NDP-MSH, were able to activate the cAMP and MAPK/ERK signaling pathways downstream of ccMc3r with different potencies. For the cAMP signaling pathway, ACTH (1–24) had the highest activation potency; while for the MAPK/ERK signaling pathway, β-MSH had the greatest activation effect. In addition, we found that the four agonists were able to inhibit TNF-α-induced NF-κB signaling in approximately the same order of potency as cAMP signaling activation. This study may facilitate future studies on the role of Mc3r in common carp feed efficiency and immune regulation. [ABSTRACT FROM AUTHOR]

The G protein-coupled receptor 84 (GPR84) is a putative medium-chain fatty acids (MCFAs) receptor involved in immune regulation and other metabolic processes. Most available studies focused on the GPR84 characterization from mammals, neglecting vital information that could be obtained from other levels of life, such as amphibians, necessary for an apt evolutionary understanding of the orphan GPR84. Hence, this study molecularly characterized and functionally explored the GPR84 from the Chinese Giant Salamander (Andrias davidianus). Therefore, we report that the Chinese Giant Salamander (CGS), one of the world's largest amphibian s, expresses a GPR84 protein having 376 amino acids, with about 70% homologous to other amphibians and around 50% to human GPR84. Investigating the relative localized expression of gpr 84 mRNA in CGS using quantitative PCR revealed the highest expression in the kidney and liver. Furthermore, four medium-chain fatty acids (MCFAs) at micromolar levels activated CGS-GPR84 transfected and expressed in HEK293 cells. In HEK293 cells, four different concentrations of MCFAs inhibited forskolin-induced cAMP accumulation and resulted in a dose-dependent increase in extracellular signal-regulated kinases 1 and 2 (ERK1/2). Interestingly, MCFAs activation of GPR84 concomitantly led to the upregulation of inflammatory mediators such as Nuclear Factor Kappa B (NF-κB) and IL-6. Conclusively, this study successfully elucidated the intriguing molecular and functional properties of CGS GPR84, particularly as an immune modulator, and has positioned the findings within the existing body of knowledge for a better overall understanding of GPR84, especially in amphibians. • -Chinese giant salamander GPR84 contains an open reading frame of 1131 bp encoding a putative protein of 376 amino acids. • The gpr8 4 has the highest expression in the kidney and liver. • The GPR84 can activate cAMP and extracellular signal-regulated kinase 1/2 signaling pathways. • Activation of GPR84 by medium-chain fatty acids upregulates the expression of NF-kappa B and IL-6. [ABSTRACT FROM AUTHOR]

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC 50 value of 0.5 μM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by −NO 2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4 , 4B and 4V , suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24. [Display omitted] • One-pot reaction for synthesis of oxoaporphine alkaloids was developed. • A series of oxoaporphine alkaloids were synthesized. • 4B induced DNA damage, and caused significant G2/M cell cycle arrest. • 4B induced caspase-3/9-dependent apoptosis through mitochondrial dysfunction. • 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24. [ABSTRACT FROM AUTHOR]