Single-neuron projectome-guided analysis reveals the neural circuit mechanism underlying endogenous opioid antinociception.

Endogenous opioid antinociception is a self-regulatory mechanism that reduces chronic pain, but its underlying circuit mechanism remains largely unknown. Here, we showed that endogenous opioid antinociception required the activation of mu-opioid receptors (MORs) in GABAergic neurons of the central amygdala nucleus (CEA) in a persistent-hyperalgesia mouse model. Pharmacogenetic suppression of these CEA neurons, which mimics the effect of MOR activation, alleviated the persistent hyperalgesia.

PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization.

Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons.

Polymeric coating lubricates nanocontainers to escape macrophage uptake for bioreceptor recognition.

Accurate drug delivery to the lesion has been deliberated for several decades, but one important phenomenon is usually neglected that the immune system can prevent smooth transportation of nanomedicine. Although injection would reduce first-pass effect, macrophages in the blood can still recognize and phagocytose nanomedicine. Here we show that a lubricated nanocontainer, which is prepared based on polyelectrolytes and mesoporous silica nanoparticles, can accurately target muscarinic bioreceptor while escaping from the identification of macrophages.

Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.

Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization.

Different neuronal populations mediate inflammatory pain analgesia by exogenous and endogenous opioids.

Mu-opioid receptors (MORs) are crucial for analgesia by both exogenous and endogenous opioids. However, the distinct mechanisms underlying these two types of opioid analgesia remain largely unknown. Here, we demonstrate that analgesic effects of exogenous and endogenous opioids on inflammatory pain are mediated by MORs expressed in distinct subpopulations of neurons in mice.

Cholinergic system is involved in the therapeutic effect of madecassoside on collagen-induced arthritis in rats.

Our previous studies demonstrated that oral administration of madecassoside could markedly attenuate collagen-induced arthritis in rats, a rodent model of rheumatoid arthritis. As the autonomic nervous system is critically involved in the modulation of peripheral inflammation and immune response, the present study aims to explore the possible involvement of adrenergic and cholinergic nerves in the effect of madecassoside on rheumatoid arthritis. Arthritis was induced by chicken collagen in rats, and madecassoside was orally administered daily for two weeks from day 14 after the primary immunization.

Topography of Reward and Aversion Encoding in the Mesolimbic Dopaminergic System.

Dopamine (DA) neurons in the VTA play essential roles in adaptive motivated behavior, which requires rapid discrimination between positive and negative motivational signature. However, the precise functional DA circuitry processing reward and aversive information remain elusive. Here, we report that the encoding of reward and aversion by the DA system in the NAc is tightly associated with its anatomical location.

Gut-Sourced Vasoactive Intestinal Polypeptide Induced by the Activation of α7 Nicotinic Acetylcholine Receptor Substantially Contributes to the Anti-inflammatory Effect of Sinomenine in Collagen-Induced Arthritis.

Sinomenine has long been used for the treatment of rheumatoid arthritis in China. However, its anti-inflammatory mechanism is still debatable because the minimal effective concentration (≥250 μM) is hardly reached in either synovium or serum after oral administration at a therapeutic dose. Recent findings suggest that the α7 nicotinic acetylcholine receptor (α7nAChR) might mediate the inhibitory effect of sinomenine on macrophage activation, which attracts us to explore the anti-arthritis mechanism of sinomenine by taking neuroendocrine-inflammation axis into consideration.

Curcumin attenuates collagen-induced inflammatory response through the "gut-brain axis".

Background: Previous studies have demonstrated that oral administration of curcumin exhibited an anti-arthritic effect despite its poor bioavailability. The present study aimed to explore whether the gut-brain axis is involved in the therapeutic effect of curcumin.

Methods: The collagen-induced arthritis (CIA) rat model was induced by immunization with an emulsion of collagen II and complete Freund's adjuvant.

Orai1 Plays a Crucial Role in Central Sensitization by Modulating Neuronal Excitability.

Pathological pain is a common and debilitating condition that is often poorly managed. Central sensitization is an important mechanism underlying pathological pain. However, candidate molecules involved in central sensitization remain unclear.

Asiaticoside hinders the invasive growth of keloid fibroblasts through inhibition of the GDF-9/MAPK/Smad pathway.

Higher expression of growth differentiation factor-9 (GDF-9) in keloids compared with hypertrophic scars and normal skin tissues has been reported recently. The present study was performed to investigate the role of GDF-9 in keloid pathogenesis, and to elucidate its implication for asiaticoside in the keloid management. The data showed that GDF-9 could enhance the proliferation, migration, and invasion of keloid fibroblasts (KFs), while it only slightly elevated collagen expression, indicating that the effect of GDF-9 was opposite to that of TGF-β1.

Tetrandrine, an agonist of aryl hydrocarbon receptor, reciprocally modulates the activities of STAT3 and STAT5 to suppress Th17 cell differentiation.

Tetrandrine, a bisbenzylisoquinoline alkaloid constituent of the root of Stephania tetrandra S. Moore, was previously shown to suppress the differentiation of T helper 17 (Th17) cells and consequently ameliorate the collagen-induced arthritis (CIA) in mice by activating the aryl hydrocarbon receptor (AhR), but its underlying mechanism is incompletely understood. Here, we investigated how tetrandrine suppressed Th17 cell differentiation through the AhR pathway.

Sinomenine induces the generation of intestinal Treg cells and attenuates arthritis via activation of aryl hydrocarbon receptor.

Sinomenine (SIN), an anti-arthritis drug, has previously been proven to exert immunomodulatory activity in rats by inducing intestinal regulatory T-cells (Treg cells). Here, we assessed the effect of SIN on the generation and function of Treg cells in autoimmune arthritis, and the underlying mechanisms in view of aryl hydrocarbon receptor (AhR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from naive T-cells were analyzed by flow cytometric analysis.

Paeoniflorin suppresses TGF-β mediated epithelial-mesenchymal transition in pulmonary fibrosis through a Smad-dependent pathway.

Aim: Paeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-β mediated pulmonary EMT in bleomycin-induced PF mice.

Methods: PF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg).

Norisoboldine, an isoquinoline alkaloid, acts as an aryl hydrocarbon receptor ligand to induce intestinal Treg cells and thereby attenuate arthritis.

Objective: Norisoboldine (NOR), an isoquinoline alkaloid with very poor oral bioavailability, was previously proven to have a unique anti-arthritis activity in rats by inducing intestinal Treg cells. Herein, we explored its underlying mechanism in view of aryl hydrocarbon receptor (AhR).

Methods: The differentiation of regulatory T cells (Treg cells) and IL-17-producing T cells (Th17 cells) from naïve T cells was analyzed in vitro.

Antiarthritis Effect of Morin is Associated with Inhibition of Synovial Angiogensis.

Morin, a flavonoid isolated from Morus alba L. (Moraceae), possesses anti-inflammatory, antiangiogenic among other biological activities. This study investigated its effect on type II collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms in view of synovial angiogenesis.

Tetrandrine ameliorates collagen-induced arthritis in mice by restoring the balance between Th17 and Treg cells via the aryl hydrocarbon receptor.

Tetrandrine is an alkaloid constituent of the root of Stephania tetrandra S. Moore. The long-term clinical uses of tetrandrine for treatments of rheumatalgia and arthralgia as well as the inhibition of rat adjuvant-induced arthritis imply that tetrandrine may have therapeutic potential in rheumatoid arthritis (RA).

DGAEE, a newly synthesized derivative of glycyrrhetinic acid, potently attenuates mouse septic shock via its main metabolite DGA in an IL-10-dependent manner.

Endotoxin can stimulate inflammatory cytokine release from monocytes/macrophages and result in septic shock. Glycyrrhetinic acid (GA), the main bioactive component of licorice, possesses substantial anti-inflammatory activity. Here, we explored effect of 11-deoxy-18α-glycyrrhetinic acid-30-ethyl ester (DGAEE), a newly synthesized derivative of GA, on septic shock.

[Effect of Madecassoside on Intestinal Mucosal Immunity in Collagen-Induced Arthritis Rats].

Objective: To explore the changes of intestinal mucosal immunity in collagen-induced arthritis rats and the impact of madecassoside on these changes.

Methods: Collagen-induced arthritis was established in female Wistar rats. Treatment group was orally administrated madecassoside once daily for consecutive 21 days, while blank control and model groups were orally administered saline at the same volume.

Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells.

SC-III3, a novel scopoletin derivative, induces autophagy of human hepatoma HepG2 cells through AMPK/mTOR signaling pathway by acting on mitochondria.

(E)-3-(4-chlorophenyl)-N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl) acrylamide (SC-III3), a newly synthesized derivative of scopoletin, was previously shown to reduce the viability of HepG2 cells and tumor growth of HepG2 xenograft mouse model. It induces the death of HepG2 cells by a way irrelevant to apoptosis and necrosis. To shed light on the cytotoxic mechanisms of SC-III3, the present study addresses whether and how it can induce autophagic cell death.

Oral curcumin has anti-arthritic efficacy through somatostatin generation via cAMP/PKA and Ca(2+)/CaMKII signaling pathways in the small intestine.

Curcumin (CUR) has been proven to be clinically effective in rheumatoid arthritis (RA) therapy, but its low oral bioavailability eclipses existent evidence that attempts to explain the underlying mechanism. Small intestine, the only organ exposed to a relatively high concentration of CUR, is the main site that generates gut hormones which are involved in the pathogenesis of RA. This study aims at addressing the hypothesis that one or more gut hormones serve as an intermediary agent for the anti-arthritic action of CUR.

Sinomenine suppresses collagen-induced arthritis by reciprocal modulation of regulatory T cells and Th17 cells in gut-associated lymphoid tissues.

Sinomenine (SIN) has long been used as a therapeutic agent of rheumatoid arthritis (RA) in China. However, the discrepancy between low oral bioavailability and higher minimal effective concentration made its action mode mysterious. The present study aimed to gain insight into the mechanisms by which SIN suppressed collagen-induced arthritis (CIA) in rats in view of Th17 and regulatory T (Treg) cell balance.