Authorship note: KJL and DK are co-senior authors. Conflict of interest: DK serves on The Scientific Advisory Board of and receives research support from Compass Therapeutics. DK and KJL have a pending patent entitled "Compositions and methods for detecting CCR2 receptors" (US patent application no. 15/611,577).

Rationale: Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady state conditions, the heart is largely populated by CCR2-macrophages of embryonic descent. Following tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to

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Background: Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2 + monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation. Methods: We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects. Results: We demonstrated that CCL17 is expressed in CCR2 + macrophages and cluster of differentiation 11b + conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17 + macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. Ccl17 deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured Ccl17 knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of Ccl17 deletion on myocardial inflammation and adverse LV remodeling. Conclusions: These findings identify CCL17 as a proinflammatory mediator of CCR2 + macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.

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We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. In the present study, we reported a new synthesis route for 6014, and investigated its protective effects on Ang II-induced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice. We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study. C57BL/6J mice were infused with Ang II and treated with 6014 (10, 30, 90 mg·kg·d, ig) for 4 weeks. Then two-dimensional echocardiography was performed to assess the cardiac function and structure. Histological changes of the hearts were examined with HE staining and Masson's trichrome staining. The protein expression was evaluated by Western blot, immunohistochemistry and immunofluorescence assays. The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits. Treatment with 6014 dose-dependently improved cardiac function, including LVEF, CO and SV and reversed the changes of cardiac structure in Ang II-infused mice: it significantly ameliorated Ang II-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes, decreased HW/BW and LVW/BW, and decreased expression of hypertrophic markers ANF, BNP and β-MHC; it also prevented Ang II-induced cardiac fibrosis, as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen I, collagen III and FN. Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1, but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1. In conclusion, the novel PARP-1 inhibitor 6014 effectively protects mice against AngII-induced cardiac remodeling and improves cardiac function. Thus, 6014 might be a potential therapeutic agent for heart diseases..

The aims of this study were to investigate the effect of chinonin in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in C57BL/6 mice and to examine the possible mechanisms. The neurotoxin MPTP was employed to create a subacute Parkinson's disease (PD)-like model in C57BL/6 mice. Chinonin (10, 20, 40 mg/kg body weight) was intraperitoneally administered 0.5 h after MPTP (30 mg/kg) injection for 7 d consecutively. Chinonin showed neuroprotective effects in the MPTP-treated mice PD model by ameliorating motor impairment in the catwalk and open-field tests. Consistently, chinonin reduced loss of dopaminergic neurons in the substantia nigra and prevented depletion of dopamine and its metabolites 3-methoxy-4-hydroxy-phenylacetic acid and homovanillic acid in the striatum of mice. Compared with the MPTP group, in the chinonin plus MPTP groups significant increases of superoxide dismutase activity and glutathione levels were observed as well as a distinct reduction of lipid peroxidation product malondialdehyde in the striatum. Taken together, we propose that chinonin exerts neuroprotective effects in C57BL/6 mouse model of PD and these effects may be due to chinonin's antioxidative property. Key words chinonin; Parkinson's disease (PD); neuroprotection; behavior; oxidative stressParkinson's disease (PD) is a major neurodegenerative disorder characterized pathologically by a progressive loss of dopaminergic neurons and clinically by resting tremors, rigidity, slowness of movement and postural instability.1) Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), produces neuropathological and clinical hallmarks in humans, monkeys and mice that closely resemble idiopathic parkinsonism.2,3) MPTP is transformed to the 1-methyl-4-phenylpyridinium ion (MPP + ) by monoamine oxidase type B after administration. 4) Then MPP + is selectively absorbed by the dopaminergic neurons in the substantial nigra via the dopamine transporter and impairs mitochondrial respiration by inhibiting complex I, thereby blocking the production of ATP and lead to the production of reactive oxygen species (ROS). 5) Therefore, MPTP acted as a pro-oxidant in the progress of PD in MPTP-induced mouse.Although the etiologic mechanisms of PD are still obscure, oxidative injury is considered as a pivotal role in disease pathogenesis.6,7) Chinonin (Fig. 1), a natural multi-phenols compound also named Mangifera indica, has been reported to possess anti-oxidative, anti-inflammatory, anti-diabetic, anti-platelet aggregator, antiviral, and anti-depressant properties.8) Given its anti-oxidative property, chinonin have been extensively used in the Indian sub-continent as food additives and in cosmetics and medicines. 9) Besides, chinonin is able to cross the blood brain barrier and has the real potential to ameliorate the oxidative stress observed in neurodegenerative disorders.10,11) Its antioxidant properties have been extensively evaluated in various cell lines, including neurons.12) For example, A...

Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 μmol/L) or ISO (1 μmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 μmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg·d, for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases.