Folate receptor-targeting semiconducting polymer dots hybrid mesoporous silica nanoparticles against rheumatoid arthritis through synergistic photothermal therapy, photodynamic therapy, and chemotherapy.

With ideal optical properties, semiconducting polymer quantum dots (SPs) have become a research focus in recent years; a considerable number of studies have been devoted to the application of SPs in non-invasive and biosafety phototherapy with near-infrared (NIR) lasers. Nevertheless, the relatively poor stability of SPs in vitro and in vivo remains problematic. PCPDTBT was chosen to synthesize photothermal therapy (PTT) and photodynamic therapy (PDT) dual-model SPs, considering its low band gap and desirable absorption in the NIR window. For the first time, cetrimonium bromide was used as a stabilizer to guarantee the in vitro stability of SPs, and as a template to prepare SP hybrid mesoporous silica nanoparticles (SMs) to achieve long-term stability in vivo. The mesoporous structure of SMs was used as a reservoir for the hypoxia-activated prodrug Tirapazamine (TPZ). SMs were decorated with polyethylene glycol-folic acid (SMPFs) to specifically target activated macrophages in rheumatoid arthritis (RA). Upon an 808 nm NIR irradiation, the SMPFs generate intracellular hyperthermia and excessive singlet oxygen. Local hypoxia caused by molecular oxygen consumption simultaneously activates the cytotoxicity of TPZ, which effectively kills activated macrophages and inhibits the progression of arthritis. This triple PTT-PDT-chemo synergistic treatment suggests that SMPFs realize the in vivo application of SPs and may be a potential nano-vehicle for RA therapy with negligible side-toxicity.

PTU, a novel ureido-fatty acid, inhibits MDA-MB-231 cell invasion and dissemination by modulating Wnt5a secretion and cytoskeletal signaling.

Migration and invasion promote tumor cell metastasis, which is the leading cause of cancer death. At present there are no effective treatments. Epidemiological studies have suggested that ω-3 polyunsaturated fatty acids (PUFA) may decrease cancer aggressiveness. In recent studies epoxide metabolites of ω-3 PUFA exhibited anti-cancer activity, although increased in vivo stability is required to develop useful drugs. Here we synthesized novel stabilized ureido-fatty acid ω-3 epoxide isosteres and found that one analogue - p-tolyl-ureidopalmitic acid (PTU) - inhibited migration and invasion by MDA-MB-231 breast cancer cells in vitro and in vivo in xenografted nu/nu mice. From proteomics analysis of PTU-treated cells major regulated pathways were linked to the actin cytoskeleton and actin-based motility. The principal finding was that PTU impaired the formation of actin protrusions by decreasing the secretion of Wnt5a, which dysregulated the Wnt/planar cell polarity (PCP) pathway and actin cytoskeletal dynamics. Exogenous Wnt5a restored invasion and Wnt/PCP signalling in PTU-treated cells. PTU is the prototype of a novel class of agents that selectively dysregulate the Wnt/PCP pathway by inhibiting Wnt5a secretion and actin dynamics to impair MDA-MB-231 cell migration and invasion.

Mechanisms and Active Compounds Polysaccharides and Bibenzyls of Medicinal Dendrobiums for Diabetes Management.

BACKGROUND: Medicinal dendrobiums are used popularly in traditional Chinese medicine for the treatment of diabetes, while their active compounds and mechanism remain unclear. This review aimed to evaluate the mechanism and active compounds of medicinal dendrobiums in diabetes management through a systematic approach. METHODS: A systematic approach was conducted to search for the mechanism and active phytochemicals in Dendrobium responsible for anti-diabetic actions using databases PubMed, Embase, and SciFinder. RESULTS: Current literature indicates polysaccharides, bibenzyls, phenanthrene, and alkaloids are commonly isolated in Dendrobium genusin which polysaccharides and bibenzyls are most aboundant. Many animal studies have shown that polysaccharides from the species of Dendrobium provide with antidiabetic effects by lowering glucose level and reversing chronic inflammation of T2DM taken orally at 200 mg/kg. Dendrobium polysaccharides protect pancreatic ß-cell dysfunction and insulin resistance in liver. Dendrobium polysaccharides up-regulate the abundance of short-chain fatty acid to stimulate GLP-1 secretion through gut microbiota. Bibenzyls also have great potency to inhibit the progression of the chronic inflammation in cellular studies. CONCLUSION: Polysaccharides and bibenzyls are the major active compounds in medicinal dendrobiums for diabetic management through the mechanisms of lowering glucose level and reversing chronic inflammation of T2DM by modulating pancreatic ß-cell dysfunction and insulin resistance in liver as a result from gut microbita regulation.

A GdW10@PDA-CAT Sensitizer with High-Z Effect and Self-Supplied Oxygen for Hypoxic-Tumor Radiotherapy.

Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2 self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2 to O2 and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2 self-supplement composites provide a promising radiosensitizer for the radiotherapy field.

In Vitro Antifungal Activity and Mechanism of Ag3PW12O40 Composites against Candida Species.

Fungal infections pose a serious threat to human health. Polyoxometalates (POMs) are metal-oxygen clusters with potential application in the control of microbial infections. Herein, the Ag3PW12O40 composites have been synthesized and verified by Fourier transform infrared (FT-IR) spectrum, transmission electron microscopy (TEM), scanning electron microscope (SEM), elemental analysis, and X-ray diffraction (XRD). The antifungal activities of Ag3PW12O40 were screened in 19 Candida species strains through the determination of minimum inhibitory concentration (MIC) by the microdilution checkerboard technique. The minimum inhibitory concentration (MIC50) values of Ag3PW12O40 are 2~32 µg/mL to the Candida species. The MIC80 value of Ag3PW12O40 to resistant clinical isolates C. albicans HL963 is 8 µg/mL, which is lower than the positive control, fluconazole (FLC). The mechanism against C. albicans HL963 results show that Ag3PW12O40 can decrease the ergosterol content. The expressions of ERG1, ERG7, and ERG11, which impact on the synthesis of ergosterol, are all prominently upregulated by Ag3PW12O40. It indicates that Ag3PW12O40 is a candidate in the development of new antifungal agents.

In vitro and in vivo antifungal activities and mechanism of heteropolytungstates against Candida species.

The antifungal activities of heteropolytungstates, α-1,2,3-K6H[SiW9V3O40] (SiW-3), K13[Ce(SiW11O39)2]·17H2O (SiW-5), K13[Eu(SiW11O39)2]·25H2O (SiW-10), K6PV3W9O40 (PW-6), α-K4PVW11O40 (PW-8), were screened in 29 Candida albicans, 8 Candida glabrata, 3 Candida krusei, 2 Candida parapsilosis, 1 Candida tropicalis, and 1 Cryptococcus neoformans strains using the CLSI M27-A3 method. SiW-5 had the highest efficacy with a minimum inhibitory concentration (MIC) values of <0.2-10.2 µM in vitro. The antifungal mechanism, acute toxicity and in vivo antifungal activity of SiW-5 were then evaluated in C. albicans. The results showed that SiW-5 damaged the fungal cell membrane, reduce the ergosterol content and its main mode of action was through inhibition of ergosterol biosynthesis. Real-time PCR showed that ERG1, ERG7, ERG11 and ERG28 were all significantly upregulated by SiW-5. An acute toxicity study showed the 50% lethal dose (LD50) of SiW-5 for ICR mice was 1651.5 mg/kg. And in vivo antifungal studies demonstrated that SiW-5 reduced both the morbidity and fungal burden of mice infected with C. albicans. This study demonstrates that SiW-5 is a potential antifungal candidate against the Candida species.

Development of a capillary electrophoresis method for analyzing adenosine deaminase and purine nucleoside phosphorylase and its application in inhibitor screening.

A novel capillary electrophoresis (CE) method was developed for simultaneous analysis of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) in red blood cells (RBCs). The developed method considered and took advantage of the natural conversion from the ADA product, inosine to hypoxanthine. The transformation ratio was introduced for ADA and PNP analysis to obtain more reliable results. After optimizing the enzymatic incubation and electrophoresis separation conditions, the determined activities of ADA and PNP in 12 human RBCs were 0.237-0.833 U/ml and 9.013-10.453 U/ml packed cells, respectively. The analysis of ADA in mice RBCs indicated that there was an apparent activity difference between healthy and hepatoma mice. In addition, the proposed method was also successfully applied in the inhibitor screening from nine traditional Chinese medicines, and data showed that ADA activities were strongly inhibited by Rhizoma Chuanxiong and Angelica sinensis. The inhibition effect of Angelica sinensis on ADA is first reported here and could also inhibit PNP activity.

The Ayurvedic Medicine Salacia oblonga Attenuates Diabetic Renal Fibrosis in Rats: Suppression of Angiotensin II/AT1 Signaling.

In human diabetic nephropathy, the extent of tubulointerstitial fibrosis is the leading cause of end-stage renal disease; fibrosis is closely correlated with renal dysfunction. Although a wide array of medicinal plants play a role in the prevention and treatment of diabetes, there are few reports of the application of herbal medicines in amelioration of renal fibrosis, or the underlying mechanisms by which such benefits are mediated. The efficacy of the Ayurvedic antidiabetic medicine Salacia oblonga (SO) root on rat renal fibrosis was investigated. An aqueous extract from SO (100 mg/kg, p.o., 6 weeks) diminished renal glomerulosclerosis and interstitial fibrosis in Zucker diabetic fatty (ZDF) rats, as revealed by van Giesen-staining. SO also reduced renal salt-soluble, acid-soluble and salt-insoluble collagen contents. These changes were accompanied by normalization of hypoalbuminemia and BUN. Gene profiling revealed that the increase in transcripts encoding the glomerulosclerotic mediators collagen I, collagen IV, fibronectin, angiotensin II type 1 receptor (AT1), transforming growth factor (TGF)-ß1, plasminogen activator inhibitor (PAI)-1 observed in ZDF rat kidney was suppressed by SO. In rat-derived mesangial cells, similar to the effect of the AT1 antagonist telmisartan, SO and its major component mangiferin suppressed the stimulatory effect of angiotensin II on proliferation and increased mRNA expression and/or activities of collagen I, collagen IV, fibronectin, AT1, TGF-ß1 and PAI-1. Considered together the present findings demonstrate that SO attenuates diabetic renal fibrosis, at least in part by suppressing anigiotensin II/AT1 signaling. Further, it now emerges that mangiferin is an effective antifibrogenic agent.

NT79: A novel neurotensin analog with selective behavioral effects.

Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin's effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79, which exhibits selective behavioral effects. NT79 was tested in animal models for pain (thermal-hot plate test; visceral-acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphine-induced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79. Binding data at molecularly cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED(50) of 0.14 microg/kg while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, d-amphetamine-induced hyperactivity, and reducing d-amphetamine- and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.

Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-alpha/-gamma activator properties.

PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-alpha is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-gamma participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-alpha or PPAR-gamma agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-alpha and PPAR-gamma activators, as well as their potential to modulate vascular disease, combined PPAR-alpha/-gamma activation has recently emerged as a promising concept, leading to the development of mixed PPAR-alpha/-gamma activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-alpha and PPAR-gamma activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-alpha/-gamma activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications.