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Angiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 105) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P, Vascular endothelial growth factor secreted by placenta-derived mesenchymal stem cells (PD-MSCs) promotes follicular development and ovarian function after ovariectomy through vascular remodeling. These results provide fundamental data for understanding the therapeutic mechanisms of stem cell therapy based on placenta-derived mesenchymal stem cells PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.

Background: Vascular abnormalities in the ovary cause infertility accompanied by ovarian insufficiency due to a microenvironment of barren ovarian tissues. placenta-derived mesenchymal stem cells (PD-MSCs, Naïve) treatment in ovarian dysfunction shows angiogenic effect, however, the therapeutic mechanism between ovarian function and vascular remodeling still unclear. Therefore, we examined whether by phosphatase regenerating liver -1 (PRL-1), which is correlated with angiogenesis in reproductive systems, overexpressed PD-MSCs could maximize the angiogenic effects in an ovarian tissues injured of rat model with partial ovariectomy and their therapeutic mechanism by enhanced vascular function via PDGF signaling.Methods: PD-MSCsPRL-1 (PRL-1) were generated by nonviral AMAXA gene delivery system and analyzed the vascular remodeling and follicular development in ovary. One week after Sprague-Dawley (SD) rats ovariectomy, Naïve and PRL-1 was transplanted. The animals were sacrificed at 1, 3 and 5 weeks after transplantation and vascular remodeling and follicular development were analyzed. Also, human umbilical vein endothelial cells (HUVECs) and ovarian explantation culture were performed to prove the specific effects and mechanism of PRL-1.Results: Vascular structures in ovarian tissues (e.g., number of vessels, thickness and lumen area) showed changes in the Naïve and PRL-1-overexpressed PD-MSC (PRL-1) transplantation (Tx) groups compared to the nontransplantation (NTx) group. Especially, PRL-1 induce to increase the expression of platelet-derived growth factor (PDGF), which plays a role in vascular remodeling as well as follicular development, compared to the NTx. Also, the expression of genes related to pericyte and vascular permeability in arteries was significantly enhanced in the PRL-1 compared to the NTx (pConclusions: Our results show that PRL-1 restored ovarian function by enhanced vascular function via PDGF signaling pathway. These findings offer new insight into the effects of functionally enhanced stem cell therapy for reproductive systems and should provide new avenues to develop more efficient therapies in degenerative medicine.

NF00659B1 is a novel α-pyrone diterpenoid natural product with potent anti-colon cancer activity. A stereoselective approach to the 2,2-dimethyl oxepanol core of NF00659B1 is described enlisting a sequence of olefinic ester ring-closing metathesis, epoxidation, and Grignard addition. This strategy paves the way to a total synthesis of NF00659B1 for further biological studies.

The existence of cancer stem cells (CSCs) is the main reason for failure of cancer treatment caused by drug resistance. Therefore, eradicating cancers by targeting CSCs remains a significant challenge. In the present study, because of the important role of BMI-1 proto-oncogene, polycomb ring finger (BMI-1) and C-terminal Mucin1 (MUC1-C) in tumor growth and maintenance of CSCs, we aimed to confirm that microRNA miR-128, as an inhibitor of BMI-1 and MUC1-C, could effectively suppress paclitaxel (PTX)-resistant lung cancer stem cells. We showed that CSCs have significantly higher expression levels of BMI-1, MUC1-C, stemness proteins, signaling factors, and higher malignancy compared with normal tumor cells. After transfection with miR-128, the BMI-1 and MUC1-C levels in CSCs were suppressed. When miR-128 was stably expressed in PTX-resistant lung cancer stem cells, the cells showed decreased proliferation, metastasis, self-renewal, migration, invasive ability, clonogenicity, and tumorigenicity in vitro and in vivo and increased apoptosis compared with miR-NC (negative control) CSCs. Furthermore, miR-128 effectively decreased the levels of β-catenin and intracellular signaling pathway-related factors in CSCs. MiR-128 also decreased the luciferase activity of MUC1 reporter constructs and reduced the levels of transmembrane MUC1-C and BMI-1. These results suggested miR-128 as an attractive therapeutic strategy for PTX-resistant lung cancer via inhibition of BMI-1 and MUC1-C.

Rhodojaponin III is a grayanane-type diterpenoid natural product with a novel chemical scaffold. It shows potent antinociceptive activity and may represent a new class of natural non-opioid analgesics with a novel mode of action. We explored the Au(I)-catalyzed Conia-ene cyclization and the Mn(III)-mediated radical cyclization of alkynyl ketones for the synthesis of the bicyclo[3.2.1]octane fragment of rhodojaponin III. These strategies will be applicable in the synthesis of rhodojaponin III and analogs for future biological studies.

To develop novel, selective, and reversible MAO-B inhibitors for safer treatment of Parkinson’s disease, benzothiazole and benzoxazole derivatives with indole moiety were designed and synthesized. Most of the synthesized compounds showed inhibitory activities against MAO-B and selectivity over MAO-A. The most active compound was compound 5b, 6-fluoro-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole with an IC50 value of 28 nM with no apparent effect on MAO-A activity at 10 μM. Based on the reversibility assay, compound 5b turned out to be fully reversible with over 95% of recovery of enzyme activity after washout of the compound. Compound 5b showed a reasonable stability in human liver microsomes and did not affect the activities of CYP isozymes, suggesting an absence of high-risk drug–drug interaction. In an in vivo MPTP-induced animal model of Parkinson’s disease, oral administration of compound 5b showed neuroprotection of nigrostriatal dopaminergic neurons as revealed by tyrosine hydroxylase staining and pr...

In this study, as a bioisosteric alternative scaffold of the antiviral aryl diketoacids (ADKs), we used 5-hydroxychromone on which two arylmethyloxy substituents were installed. The 5-hydroxychromones (5b–5g) thus prepared showed anti-HCV activity and, depending on the aromatic substituents on the 2-arylmethyloxy moiety, some of the derivatives (5b–5f) were also active against SCV. In addition, unlike the ADKs which showed selective inhibition against the helicase activity of the SCV NTPase/helicase, the 5-hydroxychromones (5b–5f) were active against both NTPase and helicase activities of the target enzyme. Among those, 3-iodobenzyloxy-substituted derivative 5e showed the most potent activity against HCV (EC50 = 4 μM) as well as SCV (IC50 = 4 μM for ATPase activity, 11 μM for helicase activity) and this might be used as a platform structure for future development of the multi-target or broad-spectrum antivirals., Graphical abstract The 2,6-bis-arylmethyloxy-5-hydroxychromones were identified to have antiviral activity against both hepatitis C virus (HCV) and SARS-associated coronavirus (SCV). Highlights ► Investigation of bioisosteric alternative scaffold of antiviral arylmethyloxy-ADKs. ► 2,6-Bis-arylmethyloxy-5-hydroxychromones active against both HCV and SCV. ► Antiviral activity against HCV (EC50 = 4 μM). ► Inhibition of SCV NTPase (IC50 = 4 μM) as well as ATPase activity (IC50 = 11 μM). ► Potential platform structure for multi-target or broad-spectrum antivirals.

Anti-HCV activity of aryl diketoacid (ADK) has been characterized by its two pharmacophoric elements, α,β-diketo acid moiety and substituted aryl ring. In this study, as a part of our ongoing efforts to discover a novel anti-HCV compound mimicking the ADK scaffold, we designed 2-arylmethylaminomethyl-5,6-dihydroxychromone derivatives of which the dihydroxychromone moiety as well as the arylmethylaminomethyl substituent (R-PhCH 2 NHCH 2 –) were anticipated in exact match with the pharmacophore model of the ADK. The dihydroxychromone derivatives ( 3a – 3u ), thus prepared, showed biological activity in a substituent-dependent fashion, thereby leading to selective anti-HCV effect (EC 50 = 2.0–14.0 μM, CC 50 >100 μM) with the substituent groups such as Cl, Br, I, and Me specifically at the 3-position of the aromatic ring.

In order to increase stability of quercetin, its metabolically and chemically susceptible hydroxyl groups 7-OH and 3-OH respectively were transiently blocked with a pivaloxymethyl (POM) promoiety to provide two novel quercetin conjugates [7-O-POM-Q (2), 3-O-POM-Q (3)]. In the absence of stabilizer (ascorbic acid), the synthesized conjugates showed significantly increased stability in cell culture media [t1/2 = 4 h (2), 52 h (3)] compared with quercetin (t1/2 < 30 min) and quercetin prodrug 1 (t1/2 = 0.8 h). In addition, the quercetin conjugate 2 underwent efficient cellular uptake and intracellular levels of its hydrolysis product, quercetin, were maintained up to 12 h. Stability and intracellular accumulation of 2 were demonstrated by its stabilizer-independent cytostatic effect and induction of apoptotic cell death. Even though 3 was more stable than 2, it failed to penetrate cell membranes. However, the remarkable stability of 3 warrants further investigation of quercetin conjugates with various promoi...

The prevalence of metabolic syndrome associated with increased risk for cardiovascular disease, type 2 diabetes, or cancer has been increasing over the past decade. While traditional drug discovery efforts have been tackling these diseases by aiming at individual targets, recent studies in humans have suggested the possibility that the collection of the metabolic degenerative processes can be approached as a whole by controlling diet, especially calorie restriction. Studies of calorie restriction in a broad range of animals including primates, mice, worms, and yeast have suggested that a reduction in calorie intake lengthens lifespan and protects against cancer and other age-related diseases. There has therefore been much interest in developing pharmacological agents that mimic the effects of calorie restriction. Resveratrol, a natural product derived from grapes, is the first reported mimetic of calorie restriction. Ever since the mode of action of resveratrol was elucidated to activate SIRT1 [sirtuin (silent mating type information regulation 2 homolog) 1] which, in turn, deacetylates p53 and promotes cell survival in a NAD-dependent manner, numerous efforts have been devoted to discover novel activators of SIRT1. Through high throughput screening of a large selection of small molecules, Milne et al. identified three imidazothiazole derivatives as potent SIRT1 activators, which are structurally unrelated to but 1,000-fold more active than resveratrol. Recently, in order to improve the potency as well as the solubility of the imidazothiazole derivatives, two different libraries of analogues, imidazo[1,2-b]thiazole and oxazolo[4,5-b]pyridine, were constructed and extensively investigated. The aim of the present study is to derive a predictive method for designing novel potent SIRT1 activators through construction of 3D QSAR models. For this purpose, from the literature, SIRT1 activation data of 33 imidazothiazole and oxazolopyridine derivatives were obtained (Fig. 1). At first, the 33 compounds were divided into two groups: 27 compounds as a training set and the other 6 compounds as a test set. The CoMFA (comparative molecular force analysis) and CoMSIA (comparative molecular similarity indices analysis) methods were employed for deriving 3D-QSAR models consisting for a training set of 27 imidazothiazole and oxazolopyridine derivatives, keeping in vitro activity as a dependent variable. The 3D-QSAR models were then validated using a test set of 6 compounds, which were not included in the development of the models. Finally, the contour plots of the 3D-QSAR model were analyzed to

In this work, we describe a new sensor that specifically responds to biothiols, i.e., glutathione (GSH), in solution. An electrochemical transducing strategy was utilized and cyclic voltammetry (CV) was employed to monitor the presence of GSH in real time. Our approach harnessed self-assembled monolayers (SAMs) on gold consisting of an alkanethiolate which was terminated by electroactive quininoid moiety. Prior to thiol molecule treatment, the characterisitc reversible redox peaks of the electroactive quininoid group was observed, while the reduction peak was dramatically shifted upon a treatment of GSH. This sensor showed the capability to detect the GSH in solution in the range of 1 mM ∼ 100 aM. We believe that this strategy will provide an important tool for accurate, sensitive, rapid, and low-cost determination of GSH.

In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.

Aryl diketoacid (ADK) is well known for antiviral activity which can be enhanced by introduction of an aromatic arylmethyl substituent. A natural flavonoid quercetin has a 3,5-dihydroxychromone pharmacophore which is in bioisosteric relationship with the 1,3-diketoacid moiety of the ADK. Thus, it was of our interest to test the antiviral activity of the quercetin derivatives with an arylmethyl group attached. In this study, we prepared a series of the 7-O-arylmethylquercetin derivatives with various aromatic substituents and evaluated their antiviral activity against the SARS-associated coronavirus (SARS-CoV, SCV) as well as hepatitis C virus (HCV). Single difference in the aromatic substituent fine-tuned the biological activity of the 7-O-arylmethylquercetin derivatives to result in two different classes of derivatives selectively active against SCV and HCV.