Correlation study between A 3 adenosine receptor binding affinity and anti-renal interstitial fibrosis activity of truncated adenosine derivatives Abstract Truncated 4′-thionucleosides 1–4 and 4′-oxonucleosides 5–8 as potent and selective A3AR antagonists were synthesized from d-mannose and d-erythronic acid γ-lactone, respectively. These nucleosides were evaluated for their anti-fibrotic renoprotective activity in TGF-β1-treated murine proximal tubular (mProx) cells. Their antagonistic activities for A3AR were proportional to their inhibitory activities against TGF-β1-induced collagen I upregulation in mProx cells. This result suggests that the binding affinity of A3AR antagonists is closely correlated with their anti-fibrotic activity. Thus, A3AR antagonists might be novel therapeutic candidates for treating chronic kidney disease.

Ligustrazine attenuates inflammation and oxidative stress in a rat model of arthritis via the Sirt1/NF-κB and Nrf-2/HO-1 pathways Abstract Inflammation responses and oxidative stress are closely involved in the pathogenesis of arthritis. Ligustrazine (Lig), a natural four methyl which is isolated from Chinese herb ligusticum chuanxiong hort, has been proved significantly anti-inflammation and anti-oxidative stress effects. The present study aimed to evaluate the effect of Lig on inflammation and oxidative stress in Freund’s complete adjuvant (FCA)-induced arthritis in rats. The treatment of Lig significantly decreased the hind-paw volume change and alleviated the histopathological changes in sections of rat paws induced by arthritis. Lig also reduced the serum levels of pro-inflammatory cytokines (interleukin [IL]-6, IL-1 beta, and tumor necrosis factor-alpha), increased the activity of superoxide dismutase (SOD) and reduced the concentration of malondialdehyde (MDA). Besides that, the protein expressions of the sirtuin 1 (Sirt1)/nuclear factor kappa B (NF-κB) and nuclear factor (erythroid-derived 2)-like-2 factor (Nrf-2)/heme oxygenase (HO)-1 pathways determined by western bolt further confirmed that Lig effectively inhibited the Sirt1/NF-κB pathway and activated the Nrf-2/HO-1 pathway. Taken together, our results suggest Lig has therapeutic potential for arthritis, which might be via the regulation of Sirt1/NF-κB and Nrf-2/HO-1 pathways.

Induction of p53-mediated senescence is essential for the eventual anticancer therapeutic effect of RH1 Abstract RH1 (2, 5-diaziridinyl-3-(hydroxymethy)-6-methyl-1, 4-benzoquinone) is a bioreductive anticancer drug. The mechanism underlying its therapeutic properties has not yet been elucidated. In this study, we aimed to determine whether RH1 exerts its anticancer effect via p53-mediated apoptosis and senescence in vitro and in vivo. RH1 displayed dose-dependent biphasic effects in vitro, i.e., it induced apoptosis at higher dose and senescence at lower dose accompanied by marked activation of p53. Thus, RH1 primarily induced cell death by apoptosis. The cytotoxicity of RH1 was inhibited in A549 cells treated with the p53-inhibitor pifithrin-α or transfected p53 siRNA and in human colon cancer HCT116 isogenic (p53−/−) cells. At sub-lethal doses of RH1, the cells survived and underwent senescence. The senescent cells showed flattened and enlarged morphology, and exhibited blue color in senescence-associated β-galactosidase staining. These changes were found to be related to p53. RH1-induced senescence decreased in A549-E6 cells (suppressed p53 level) and HCT 116 p53−/− cells. The growth of A549 xenograft tumors in nude mice was significantly delayed by intraperitoneal injection of RH1, and senescent cells were observed in these xenograft tumors. These results suggest that the in vivo anticancer therapeutic effect of RH1 is mediated by senescence via p53 activation.

Mediators of the homeostasis and effector functions of memory Th2 cells as novel drug targets in intractable chronic allergic diseases Abstract Allergic patients have life-long chronic inflammatory diseases with repeated relapses and exacerbations. Currently used allergy therapeutics have some limitations, which warrants a search for novel drug targets for allergy treatment. The studies on conventional allergic disease therapeutics have been focused on the pathology of allergy involving effector type 2 helper T cells (Th2). However, it has been suggested that allergen-specific memory Th2 cells are developed after the initial allergen exposure, which may play a critical role in the allergic relapses. Here, we discuss the contribution of memory Th2 cells to allergic diseases and the microenvironmental factors for chronic allergic disease persistence. Since most allergy drugs are prescribed to suppress symptoms of the diseases, targeting the different types of cells or factors contributing to allergic diseases persistence may cure the disease.

The fungus Colletotrichum as a source for bioactive secondary metabolites Abstract Colletotrichum sp. is a widely distributed fungal genus, which is mainly known to cause anthracnose on cereals, legumes, fruit trees, and vegetables. Even though many of the Colletotrichum sp. are plant pathogens, a variety of secondary metabolites with diverse bioactivities have been reported to be produced by this fungus. At least 109 secondary metabolites from the fungus Colletotrichum have been reported to date. They mostly include nitrogen-containing metabolites, sterols, terpenes, pyrones, phenolics, and fatty acids. Herein, the authors review the structurally interesting secondary metabolites produced by Colletotrichum and their biological activities.

Effect of thiazolidinedione phenylacetate derivatives on wound-healing activity Abstract The aim of this work was to evaluate the synthesis and structure–activity relationship of 4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl 2-phenylacetate derivatives as potential wound-healing agents. The IC50 values of the lead compounds ranged from 0.01 to 0.05 µM. These compounds also increased the levels of extracellular prostaglandin E2 (PGE2) in A549 cells. Among the synthesized compounds, compounds 66, 67, 69, and 86 increased PGE2 levels 3- to 4-fold of those achieved with the negative control. Introduction of a halogen at the intermediate phenyl ring, compounds 66, 67, 69, and 86 resulted in higher IC50 values, which indicated lower cytotoxicity than that observed upon the introduction of other substituents at the same position. In particular, cells exposed to compound 69 showed significantly improved wound healing, and the wound closure rate achieved was approximately 3.2-fold higher than that of the control. Therefore, compound 69 can be used for tissue regeneration and treatment of diverse diseases caused by PGE2 deficiency. Overall, our findings suggested that compound 69 might be a novel candidate for skin wound therapy.

Non-glycosidic iridoids from the roots of Patrinia scabra and their nitric oxide production inhibitory effects Abstract Phytochemical investigation on the 70% aqueous EtOH extract from the roots of Patrinia scabra led to the isolation and characterization of five new non-glycosidic iridoids, patriscabrins F–J (1–5), along with a known iridoid 11-ethoxyviburtinal (6). The structures of the new compounds 1–5 were determined by interpretation of spectroscopic data, particularly by 1D- and 2D-NMR and ECD studies. Thereafter, the isolates 1–6 were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells. Of these, patriscabrin F (1) exhibited the most potent inhibitory effect with observed IC50 value of 14.1 μM. In addition, patriscabrin G (2) and 11-ethoxyviburtinal (6) showed IC50 values 24.6 and 35.5 μM, respectively.

Synthesis and anti-HIV activity of l -2′,3′-Dideoxy-4′-selenonucleosides ( l -4′-Se-ddNs) Abstract Based on the potent anti-HIV activity of l-2′,3′-dideoxycytidine (l-ddC), l-2′,3′-dideoxy-4′-selenonucleosides (l-4′-Se-ddNs) have been synthesized from natural chiral template, l-glutamic acid, using Pummerer-type condensation as a key step. All synthesized compounds were assayed for anti-HIV-1 activity, but none of them did show any significant antiviral activity up to 100 μM, probably due to conformational differences between l-ddC and l-4′-Se-ddC, induced by the bulky selenium atom, which might play an important role in phosphorylation by cellular kinase.

Warburg effect and its role in tumourigenesis Abstract Glucose is a crucial molecule in energy production and produces different end products in non-tumourigenic- and tumourigenic tissue metabolism. Tumourigenic cells oxidise glucose by fermentation and generate lactate and adenosine triphosphate even in the presence of oxygen (Warburg effect). The Na+/H+-antiporter is upregulated in tumourigenic cells resulting in release of lactate- and H+ ions into the extracellular space. Accumulation of lactate- and proton ions in the extracellular space results in an acidic environment that promotes invasion and metastasis. Otto Warburg reported that tumourigenic cells have defective mitochondria that produce less energy. However, decades later it became evident that these mitochondria have adapted with alterations in mitochondrial content, structure, function and activity. Mitochondrial biogenesis and mitophagy regulate the formation of new mitochondria and degradation of defective mitochondria in order to combat accumulation of mutagenic mitochondrial deoxyribonucleic acid. Tumourigenic cells also produce increase reactive oxygen species (ROS) resulting from upregulated glycolysis leading to pathogenesis including cancer. Moderate ROS levels exert proliferative- and prosurvival signaling, while high ROS quantities induce cell death. Understanding the crosstalk between aberrant metabolism, redox regulation, mitochondrial adaptions and pH regulation provides scientific- and medical communities with new opportunities to explore cancer therapies.

Pifithrin-μ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial–mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis Abstract Heat shock protein 70 (HSP70), a chaperone protein associated with tumorigenesis and chemoresistance, has attracted significant attention as a potential therapeutic target for the development of anticancer drugs. Here, the effects of pifithrin-μ, an effective dual inhibitor of HSP70 and p53, on anticancer activities and epithelial–mesenchymal transition (EMT) were investigated in malignant mesothelioma (MM) cells. MSTO-211HAcT cells, pre-incubated in a medium containing lactic acid, showed more potent resistance to cisplatin and gemcitabine, compared with their acid-sensitive parental MSTO-211H cells. Pifithrin-μ treatment induced both apoptosis and necroptosis, which were accompanied by an EMT-like phenomenon, as evidenced by an elongated cell morphology, decreased levels of epithelial cell markers including E-cadherin, claudin-1, and β-catenin, increased levels of mesenchymal markers including Snail, Slug, and vimentin, and increased cell migratory property. Moreover, pifithrin-μ increased intracellular ROS levels, which is associated with mitochondrial dysfunction and decreased cellular ATP content. A series of changes caused by pifithrin-μ treatment were effectively restored by lowering the ROS level through pretreatment with N-acetylcysteine. Collectively, our results suggest that pifithrin-μ may promote the metastatic behavior of surviving cells by triggering the EMT, despite its effective cell-killing action against MM cells, possibly linked to oxidative mitochondrial dysfunction and ATP depletion.