Abstract Patients undergoing orthotopic allograft transplantation (OAT) will certainly suffer from vasculopathy. Although there are many immunosuppressive and immunomodulatory agents that are administered to patients, chronic rejection- induced vasculopathy cannot be entirely managed. Moreover, the implanted graft might become dysfunctional. In the past, we have used deionized reverse osmosis water (ROW) to stream via gold nanoparticles (AuNPs) at room temperature under powerful illumination, in order to prepare plasmon-activated water (PAW) with fewer hydrogen bonds. Compared to ROW, stable PAW can successfully remove free hydroxyl and 2,2-diphenyl-1-picrylhydrazyl radicals, and efficiently reduce lipopolysaccharide (LPS)-induced monocytes to release nitric oxide. Moreover, PAW can considerably induce the expression of the antioxidant gene Nrf2 in human gingival fibroblasts. Moreover, it might lower amyloid burden in mice with Alzheimer's disease. Furthermore, PAW decreased metastasis in mice grafted with Lewis lung carcinoma cells and boosted the overall survival in combination with cisplatin. Because of this possibility that PAW could prevent systemic disease, we aimed to evaluate the influence of PAW on OAT-induced vasculopathy. Here, we demonstrated that daily intake of PAW lowered the progression of vasculopathy in OAT-recipient ACI/NKyo rats by inhibiting collagen accumulation, proliferation of smooth muscle cells and fibroblasts, and T lymphocyte infiltration in the vessel wall. Moreover, the results showed reduced T and B lymphocytes, plasma cells, and macrophage activation in the spleen of the OAT-recipient ACI/NKyo rats that were administered PAW. Finally, in contrast to the control group, the OAT-recipient ACI/NKyo rats that were administered PAW exhibited higher mobilization and levels of circulating endothelial progenitor cells associated with vessel repair. Therefore, this study highlights the therapeutic roles of PAW in vasculopathy.
Ursolic acid (UA), a triterpenoid compound found in plants, is used in both the human diet and in medicinal herbs and possesses a wide range of benefits, including antioxidative and anti-inflammatory effects. Additionally, UA may inhibit lipid absorption in pancreatic cells and enhance lipolysis in adipocytes. Oxidized LDL (oxLDL) acts as a major mediator of endothelium dysfunction, which mediates atherogenesis. Until now, we have not known what role UA plays in the absorption of oxidized LDL in vascular endothelial cells. Regardless of whether UA affects oxLDL uptake mediated by specific oxLDL receptors (such as lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), scavenger receptor expressed by endothelial cells (SREC), and scavenger receptor B1 (SR-B1)), it is unclear if UA acts on endothelial cells. However, high-mobility group box 1 (HMGB1) is known to accumulate in atherosclerotic lesions and mediates vascular inflammation, although the mechanisms are not understood. Therefore, in this study, human coronary artery endothelial cells (HCAECs) were used in vitro and hypercholesterolemic mice were used in vivo to investigate the effects and mechanisms of HMGB1 and UA on oxLDL uptake. The results demonstrated that HMGB1 enhances oxLDL uptake through induction of LOX-1 in HCAECs and hypercholesterolemic mice. In vitro data showed that exposing HMGB1- stimulated HCAECs to UA decreased the LOX-1-mediated absorption of oxLDL through a cyclooxygenase (COX)-2- related nitric oxide (NO) signaling pathway. Similarly, UA administration decreased LOX-1, but not SREC and SR-B1 expression, in HMGB1-treated hypercholesterolemic mice. These findings suggest that UA may be a potential therapeutic agent for hypercholesterolemia-induced atherosclerosis. Keywords: Cyclooxygenase (COX), high-mobility group box 1 (HMGB1), nitric oxide synthase (NOS), ursolic acid, scavenger receptor B1, (SR-B1), scavenger receptor expressed by endothelial cells (SREC), lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1).
Abstract Angiogenesis plays a critical role in sustaining the microenvironment, growth, and metastatic potential of a variety of tumors, such as lung cancer, colorectal cancer, and renal cancer. However, the rapid development of resistance to anti-angiogenesis agents has limited the clinical benefits. To improve the therapeutic efficacy, the designed dual functional inhibitors, composed of benzophthalazine (anti-angiogenesis moiety) and bis(hydroxymethyl)pyrrole (DNA interstrand crosslinking moiety), were synthesized. We first demonstrated that 1,2-bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazines displayed dual functions, inducing DNA crosslinking and inhibiting angiogenesis. By aid of DIVAA, we confirmed the in vivo anti-angiogenetic activity. They were cytotoxic to a panel of cancer cell lines, including leukemia, colorectal, renal, and lung cancer cells. Among them, small cell lung cancer (SCLC) cells were the most susceptible cells with the IC50 values ranged from subnanomolar to micromolar. Significantly, we observed tumor suppression by treatment of compound 8 in a given formulation at the dose of 20 mg/kg (10 times in 2 weeks) in SCLC H526, squamous lung cancer H520 and renal cancer 786-O xenograft models. In addition, orally admission of 60 mg/kg compound 8 daily for 14 days was also more potent than cisplatin in suppression of growth of SCLC H526 xenografts. Importantly, compound 8 at the dose given did not cause body weight lost. In summary, our results indicate that bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine hybrids are potent than anticancer agents against a wide spectrum of cancers. They deserve our further development. Citation Format: Tai-Lin Chen, Vicky Jain, Anilkumar S. Patel, Yi-Wen Lin, Tsann-Long Su, Te-Chang Lee. Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A002. doi:10.1158/1535-7163.TARG-19-A002
Muscle afferent neurons that express transient receptor potential vanilloid type I (TRPV1) are responsible for muscle pain associated with tissue acidosis. We have previously found that TRPV1 of isolectin B4 (IB4)-negative muscle nociceptors plays an important role in the acid-induced hyperalgesic priming and the development of chronic hyperalgesia in a mouse model of fibromyalgia. To understand the electrophysiological properties of the TRPV1-expressing muscle afferent neurons, we used whole-cell patch clamp recording to study the acid responsiveness and action potential (AP) configuration of capsaicin-sensitive neurons innervating to gastrocnemius muscle. Here we showed that IB4-negative TRPV1-expressing muscle afferent neurons are heterogeneous in terms of cell size, resting membrane potential, AP configuration, tetrodotoxin (TTX)-resistance, and acid-induced current (I acid), as well as capsaicin-induced current (I cap). TRPV1-expressing neurons were all acid-sensitive and could be divided into two acid-sensitive groups depending on an acid-induced sustained current (type I) or an acid-induced biphasic ASIC3-like current (type II). Type I TRPV1-expressing neurons were distinguishable from type II TRPV1-expressing neurons in AP overshoot, after-hyperpolarization duration, and all I acid parameters, but not in AP threshold, TTX-resistance, resting membrane potential, and I cap parameters. These differential biophysical properties of TRPV1-expressing neurons might partially annotate their different roles involved in the development and maintenance of chronic muscle pain.
The plasmon-activated water (PAW) that reduces hydrogen bonds is made of deionized reverse osmosis water (ROW). However, compared with ROW, PAW has a significantly higher diffusion coefficient and electron transfer rate constant in electrochemical reactions. PAW has a boiling point of 97 °C and specific heat of0.94; the energy of PAW is also 1121 J/mol higher than ordinary water. The greater the force of hydrogen bonds between H2O, the larger the volume of the H2O cluster, and the easier it is to lose the original characteristics. The hydrogen bonding force of PAW is weak, so the volume of its cluster is small, and it exists in a state very close to a single H2O. PAW has a high permeability and diffusion rate, which can improve the needs of biological applications and meet the dependence of biological organisms on H2O when performing physiological functions. PAW can successfully remove free radicals, and efficiently reduce lipopolysaccharide (LPS)-induced monocytes to release nitric oxide. PAW can induce expression of the antioxidant gene Nrf2 in human gingival fibroblasts, lower amyloid burden in mice with Alzheimer’s disease, and decrease metastasis in mice grafted with Lewis lung carcinoma cells. Because the transferring plasmon effect may improve the abnormality of physiological activity in a biological system, we aimed to evaluate the influence of PAW on orthotopic allograft transplantation (OAT)-induced vasculopathy in this study. Here, we demonstrated that daily intake of PAW lowered the progression of vasculopathy in OAT-recipient ACI/NKyo rats by inhibiting collagen accumulation, proliferation of smooth muscle cells and fibroblasts, and T lymphocyte infiltration in the vessel wall. The results showed reduced T and B lymphocytes, plasma cells, and macrophage activation in the spleen of the OAT-recipient ACI/NKyo rats that were administered PAW. In contrast to the control group, the OAT-recipient ACI/NKyo rats that were administered PAW exhibited higher mobilization and levels of circulating endothelial progenitor cells associated with vessel repair. We use the transferring plasmon effect to adjust and maintain the biochemical properties of water, and to meet the biochemical demand of organisms. Therefore, this study highlights the therapeutic roles of PAW and provides more biomedical applicability for the transferring plasmon effect.
Abstract The object of the present study is to investigate the role of endogenous adrenergic innervation in regulating bi‐directional synaptic plasticity in rat hippocampal CA1 synapses. The endogenous adrenergic system was eliminated by giving subcutaneous injection of 6‐hydroxydopamine (6‐OHDA) to rats immediately after birth, and the animals were killed for experiments at postnatal ages of 25–35 days. In hippocampal slices taken from 6‐OHDA‐treated animals, theta‐burst stimulation at 100 Hz failed to induce long‐term potentiation (LTP) at CA1 synapses. However, the induction of long‐term depression (LTD) by prolonged low frequency stimulation at 1 Hz was unaffected in slices from 6‐OHDA‐treated animals. Bath application of norepinephrine (NE) restored LTP to control levels and blocked LTD. This effect was mimicked by β‐ but not α‐adrenergic receptor agonists, i.e. by isoproterenol but not phenylephrine. The activators of adenylyl cyclase and protein kinase A (PKA), i.e. forskolin and 8‐bromoadenosine‐3′, 5′‐cyclic monophosphate, respectively, restored LTP in slices from 6‐OHDA‐treated animals. In addition, application of the D1/D5 receptor agonist, dihydrexidine, also restored LTP in slices from 6‐OHDA‐treated animals. These results suggest that physiologically the recruitment of catecholamine innervation may be important for induction of LTP at hippocampal CA1 synapses during tetanic stimulation, while it may not be essential for LTD induction by prolonged 1 Hz stimulation. The released NE and dopamine exert their role in modulating synaptic plasticity via activation of β‐adrenergic and D1/D5 receptors, respectively, which in turn increase the levels of cytoplasm adenosine‐3′,5′‐cyclic monophosphate and PKA.
Conspecific male animals fight for resources such as food and mating opportunities but typically stop fighting after assessing their relative fighting abilities to avoid serious injuries. Physiologically, how the fighting behavior is controlled remains unknown. Using the fighting fish Betta splendens, we studied behavioral and brain-transcriptomic changes during the fight between the two opponents. At the behavioral level, surface-breathing, and biting/striking occurred only during intervals between mouth-locking. Eventually, the behaviors of the two opponents became synchronized, with each pair showing a unique behavioral pattern. At the physiological level, we examined the expression patterns of 23,306 brain transcripts using RNA-sequencing data from brains of fighting pairs after a 20-min (D20) and a 60-min (D60) fight. The two opponents in each D60 fighting pair showed a strong gene expression correlation, whereas those in D20 fighting pairs showed a weak correlation. Moreover, each fighting pair in the D60 group showed pair-specific gene expression patterns in a grade of membership analysis (GoM) and were grouped as a pair in the heatmap clustering. The observed pair-specific individualization in brain-transcriptomic synchronization (PIBS) suggested that this synchronization provides a physiological basis for the behavioral synchronization. An analysis using the synchronized genes in fighting pairs of the D60 group found genes enriched for ion transport, synaptic function, and learning and memory. Brain-transcriptomic synchronization could be a general phenomenon and may provide a new cornerstone with which to investigate coordinating and sustaining social interactions between two interacting partners of vertebrates.
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