Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson's disease

Parkinson＇s disease （PD） is the most common motor neurode- generative disorder affecting approximately 4 million people worldwide. Although PD presents primarily with motor dysfunction, non-motor symptoms including cognitive decline, mood disorders, reduced olfaction and constipation are also of- ten present, with some of these non-motor symptoms even pre- senting prior to the onset of motor symptoms. It is well known that PD is largely caused by the gradual degeneration of dopa- minergic neurons within the substantia nigra pars compacta （SNc）, along with the presence of protein aggregates called Lewy bodies, which consist primarily of ct-synuclein and are found in the cytoplasm of surviving neurons. This ongoing cell loss and Lewy body pathology is not confined to the SNc, but is also seen in other brain regions implicated in PD pathogenesis such as the locus ceruleus.

Human NK cells: surface receptors, inhibitory checkpoints, and translational applications

NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors.In humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and NKG2D.Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor transformation.The HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells.Other receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell tolerance.PD-1 also may be expressed by NK cells in cancer patients.Since PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK cells.Thus,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions.Recently,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation.Since most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging results.The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.

Bladder-colon chronic cross-sensitization involves neuro-glial pathways in male mice

BACKGROUND Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity.Since pelvic organs share common sensory pathways,it is likely that those syndromes involve a cross-sensitization of the bladder and the colon.The precise pathophysiology remains poorly understood.AIM To develop a model of chronic bladder-colon cross-sensitization and to investigate the mechanisms involved.METHODS Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia.Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions.Myeloperoxidase,used as a marker of colorectal inflammation,was measured in the colon,and colorectal permeability was measured using chambers.c-Fos protein expression,used as a marker of neuronal activation,was assessed in the spinal cord(L6-S1 level)using immunohistochemistry.Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord.The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot.RESULTS Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline(P<0.0001).This effect started 1 h post-injection and lasted up to 7 d postinjection.No increased permeability or inflammation was shown in the bladder or colon 7 d postinjection.Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord(P<0.0001).In green fluorescent protein on the fractalkine receptor-positive mice,intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord(P<0.0001).NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection(P=0.007 and 0.023 respectively).Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline,a microglia inhibitor,by intracerebroventricular injection of CP-99994 dihydrochloride,a NK1 antagonist,and by intracerebroventricular injection of SB203580,a MAPK-p38 inhibitor.CONCLUSION We describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice.Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension,mediated by neuroglial interactions,MAPK-p38 phosphorylation and the NK1 receptor.

Effect of gingerol on substance P and NK1 receptor expression in a vomiting model of mink

Background Gingerol is the generic term for pungent constituents in ginger, which has been reported to be effective for inhibiting vomiting. We attempted to investigate the antiemetic effect of gingerol and its effective mechanism on substance P and NK1 receptors in minks. Methods The antiemetic effect of gingerol was investigated during a 6-hour observation on a vomiting model in minks induced by cisplatin, （7.5 mg/kg, intraperitoneal）. The distribution of substance P and NK1 receptors in the area postrema and ileum were measured by immunohistochemistry, and the expression of NK1 receptor in the area postrema and ileum were measured by Western blotting. Results The frequency of cisplatin induced retching and vomiting was significantly reduced by pretreatment with gingerol in a dose-dependent manner （P 〈0.05）. Substance P-immunoreactive was mainly situated in the mucosa and submucosa of the ileum as well as in the neurons of the area postrema. The immunoreactive production of NK1 receptor was mainly situated in the muscular and submucosa of ileum and the neurons of area postrema, gingerol markedly suppressed the increased immunoreactivity of substance P and NK1 receptor induced by cisplatin in a dose-dependent manner （P 〈0.05）, and exhibited effective inhibition on the increased expression levels of NK1 receptor in both the ileum and area postrema dose-dependently （P 〈0.05）. Conclusions Gingerol has good activity against cisplatin-induced emesis in minks possibly by inhibiting central or peripheral increase of substance P and NK1 receptors.

High Expression of NKG2A/CD94 and Low Expression of Granzyme B Are Associated with Reduced Cord Blood NK Cell Activity

Human umbilical cord blood （CB） has recently been used as a source of stem cells in transplantation. NK cells derived from CB are the key effector cells involved in graft-versus-host disease （GVHD） and graft-versus-leukemia （GVL）. It was reported that the activity of CB NK cells was lower than that of adult peripheral blood （PB） NK cells. In this study, we analyzed the expression of some NK cell receptors and cytotoxicity-related molecules in CB and PB NK cells. The expressions of activating NK receptors, CD16, NKG2D and NKp46, did not show significant difference between CB and PB NK cells. But the expression of inhibitory receptor NKG2A/CD94 was significantly higher on CB NK cells. As to the effector function molecules, granzyme B was expressed significantly lower in CB NK cells, but the expressions of intracellular perforin, IFN-γ, TNF-α and cell surface FasL and TRAIL did not show difference between CB and PB NK cells. The results indicated that the high expression of NKG2A/CD94 and low expression of granzyme B may be related with the reduced activity of CB NK cells.

Distribution of natural killer cell receptors in HIV infected individuals

Natural killer （NK） cells are bone marrow derived, large granular lymphocytes, comprising approximately 10% to 20% of the mononuclear cell fraction in normal peripheral blood. They form a part of the first line defense mechanism against tumoural and viral spreading^1-4 Unlike T and B cells, NK cells do not require gene rearrangement for assembly of their receptor genes; rather, NK cells discriminate potential target cells based on the levels of self major histocompatibility complex （MHC） class I expression on such cells^5.6 There are two kinds of NK cell receptors^2.7.8 Inhibitory receptors recognize MHC class I molecules and deliver a downregulatory signal that inactivates the lytic machinery of NK cells. Stimulatory receptors expressed by NK cells deliver an activation signal.