Substance P Promotes Leukocyte Infiltration in the Liver and Lungs of Mice with Sepsis: A Key Role for Adhesion Molecules on Vascular Endothelial Cells.

Substance P (SP), encoded by the Tac1 gene, has been shown to promote leukocyte infiltration and organ impairment in mice with sepsis. Neurokinin-1 receptor (NK1R) is the major receptor that mediates the detrimental impact of SP on sepsis. This investigation studied whether SP affects the expression of adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) on vascular endothelial cells in the liver and lungs, contributing to leukocyte infiltration in these tissues of mice with sepsis. Sepsis was induced by caecal ligation and puncture (CLP) surgery in mice. The actions of SP were inhibited by deleting the Tac1 gene, blocking NK1R, or combining these two methods. The activity of myeloperoxidase and the concentrations of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, were measured. The activity of myeloperoxidase and the concentration of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, increased in mice with CLP surgery-induced sepsis. Suppressing the biosynthesis of SP and its interactions with NK1R attenuated CLP surgery-induced alterations in the liver and lungs of mice. Our findings indicate that SP upregulates the expression of ICAM1 and VCAM1 on vascular endothelial cells in the liver and lungs, thereby increasing leukocyte infiltration in these tissues of mice with CLP surgery-induced sepsis by activating NK1R.

Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway.

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims to investigate the role and underlying mechanisms of SP in colitis. Here, activated SP-positive neurons and increased SP expression were observed in dextran sodium sulfate (DSS)-induced colitis lesions in mice. Administration of exogenous SP efficiently ameliorated the clinical symptoms, impaired intestinal barrier function, and inflammatory response. Mechanistically, SP protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. SP can also directly prevent STING phosphorylation through the neurokinin-1 receptor (NK1R), thereby inhibiting the activation of the TBK1-IRF3 signaling pathway. Further studies revealed that SP alleviated the DSS or TNF-α-induced ferroptosis process, which was associated with repressing the cGAS-STING signaling pathway. Notably, we identified that the NK1R inhibition reversed the effects of SP on inflammation and ferroptosis via the cGAS-STING pathway. Collectively, we unveil that SP attenuates inflammation and ferroptosis via suppressing the mtDNA-cGAS-STING or directly acting on the STING pathway, contributing to improving colitis in an NK1R-dependent manner. These findings provide a novel mechanism of SP regulating ulcerative colitis (UC) disease.

Effect of submucosal cryotherapy compared with steroids and NSAIDs injections on Substance P and Interleukin 6 pulpal release in experimentally induced pulpal inflammation in rabbits.

OBJECTIVE: To compare the effect of submucosal cryotherapy using cold saline to dexamethasone sodium phosphate and diclofenac sodium injections on substance P and interleukin 6 release in experimentally induced pulpal inflammation in rabbits' molar teeth. METHODOLOGY: Fifteen rabbits were randomly classified into 3 groups according to the submucosal injection given: cold saline, dexamethasone sodium phosphate, and diclofenac sodium. A split-mouth design was adopted, the right mandibular molars were experimental, and the left molars served as the control without injections. Intentional pulp exposures were created and left for 6 hours to induce pulpitis. Pulpal tissue was extracted and examined for SP and IL-6 levels using ELISA. Within each group, the level of cytokines released was measured for both control and experimental groups for intragroup comparison to determine the effect of injection. The percentage reduction of each mediator was calculated compared with the control side for intergroup comparison then the correlation between SP and IL-6 levels was analyzed using Spearman's rank order correlation coefficient. Statistical analysis was performed, and the significance level was set at p<0.05. RESULTS: Submucosal cryotherapy, dexamethasone sodium phosphate, and diclofenac sodium significantly reduced SP and IL-6 pulpal release. Submucosal cryotherapy significantly reduced SP more than and IL-6 more than dexamethasone sodium phosphate and diclofenac sodium. Pulpal reduction of SP and IL-6 showed a strong positive significant correlation. CONCLUSIONS: Submucosal cryotherapy reduces the pulpal release of SP and IL-6 and could be tested as an alternative to premedication to potentiate the effect of anesthesia and control postoperative endodontic pain.

Aprepitant Alleviates Poststroke Pneumonia in a Mouse Model of Middle Cerebral Artery Occlusion.

Elevated substance P can be utilized to predict early mortality during the first week of cerebral infarction. Whether aprepitant, a substance P receptor blocker could be utilized to alleviate poststroke pneumonia which is investigated in this study. Intraluminal monofilament model of middle cerebral artery occlusion (MCAO) was constructed in C57BL/6J male mice, and the relative expression of substance P was detected in collected bronchoalveolar lavage fluid (BALF) and lung tissue homogenate at 24 hours, 48 hours, and 72 hours poststroke. On the other hand, different concentrations of aprepitant (0.5, 1, and 2 mg/kg) were atomized and inhaled into MCAO mice. Inflammation cytokines and bacterial load were detected in collected BALF and lung tissue homogenate at 72-hour poststroke, and lung injury was revealed by histological examination. Aprepitant administration decreased total proteins, total cells, neutrophils, and macrophages in BALF. The concentrations of interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, interferon γ, monocyte chemoattractant protein-1, and IL-10 in lung tissue homogenates were also diminished by the administration of aprepitant. In conclusion, aprepitant could attenuate poststroke pneumonia in mice suggesting its potential therapeutic use in the clinic.

Analgesic Mechanism of Dexmedetomidine and Esketamine in Rats with Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI) is usually caused by external direct or indirect factors, and with a high morbidity and mortality rate. The aim of this study was to observe the effects of Dexmedetomidine (DEX) combined with Esketamine (ESK) on pain behavior and potential analgesic mechanisms in rats with SCI. The goal was to provide a reliable multimodal analgesic medication regimen for SCI. METHODS: Thirty rats were divided into five groups with six rats in each group: Sham group, SCI group, DEX group, ESK group, and DEX+ESK group. The SCI model in rats was constructed, and the motor function of hind limbs of rats was measured using Basso Beattie Bresnahan (BBB) locomotor rating scale and inclined plate test. The levels of interleukin 18 (IL-18), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) in the spinal cord were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of substance P (SP), neurokinin-1 receptor (NK-1R), B cell lymphoma-2 (Bcl-2), and Bcl2-associated X protein (Bax) in the rats' spinal cord were measured by Western blot assay. The viability of spinal astrocytes was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: After 7 days, the BBB scores were significantly higher in the DEX, ESK, and DEX+ESK groups compared to the SCI group (p < 0.01). Additionally, the DEX+ESK group had significantly higher scores than both the DEX and ESK groups (p < 0.01). The maximum angle of the DEX (p < 0.05), ESK (p < 0.05), and DEX+ESK groups (p < 0.01) were higher than the SCI group, and the maximum angle of DEX+ESK group was higher than DEX and ESK groups (p < 0.05). The levels of IL-18, IL-1ß, and TNF-α in the DEX, ESK, and DEX+ESK groups were lower than the SCI group (p < 0.01), while the DEX+ESK group had significantly lower IL-18, IL-1ß, and TNF-α levels than the DEX and ESK groups (p < 0.01). The levels of SP (p < 0.01) and NK-1R (p < 0.05) were lower in the DEX, ESK, and DEX+ESK groups compared to the SCI group, and the levels of SP and NK-1R were lower in the DEX+ESK group compared to the DEX and ESK groups (p < 0.01). The DEX and ESK groups suppressed the activity of spinal astrocytes (p < 0.01), however, the DEX+ESK group had larger effects on spinal astrocytes than the ESK group (p < 0.05). CONCLUSIONS: Treatment using DEX combined with ESK improves the motor function, inhibits inflammation and astrocyte activity, and exerts analgesic effects on rats with SCI. These findings can serve as a reference for the selection of multi-modal analgesics.

Differences in Neuropathology between Nitroglycerin-Induced Mouse Models of Episodic and Chronic Migraine.

Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation.

Molecular pathway of pancreatic cancer-associated neuropathic pain.

The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1ß into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.

NK3R signalling in the posterodorsal medial amygdala is involved in stress-induced suppression of pulsatile LH secretion in female mice.

Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety. We investigate whether NK3R activation in the MePD is involved in mediating the inhibitory effect of psychosocial stress on LH pulsatility in ovariectomised female mice. First, we administered senktide, an NK3R agonist, into the MePD and monitored the effect on pulsatile LH secretion. We then delivered SB222200, a selective NK3R antagonist, intra-MePD in the presence of predator odour, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Senktide administration into the MePD dose-dependently suppresses pulsatile LH secretion. Moreover, NK3R signalling in the MePD mediates TMT-induced suppression of the GnRH pulse generator, which we verified using a mathematical model. The model verifies our experimental findings: (i) predator odour exposure inhibits LH pulses, (ii) activation of NK3R in the MePD inhibits LH pulses and (iii) NK3R antagonism in the MePD blocks stressor-induced inhibition of LH pulse frequency in the absence of ovarian steroids. These results demonstrate for the first time that NK3R neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator.

Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal.

During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.

Advances in the research and application of neurokinin-1 receptor antagonists. / 神经激肽1å—ä½“æ‹®æŠ—å‰‚çš„ç ”ç©¶ä¸Žåº”ç”¨è¿›å±•.

Recently, the substance P (SP)/neurokinin-1 receptor (NK-1R) system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019 (COVID-19). Besides, studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis. These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy. This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers, as well as the underlying mechanisms. Furthermore, the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized, such as solid dispersion systems, nanonization, and nanoencapsulation. As a radiopharmaceutical therapeutic, the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors. However, combining NK-1R antagonists with other drugs can produce a synergistic effect, thereby enhancing the therapeutic effect, alleviating the symptoms, and improving patients quality of life in several diseases and cancers.

Plasma levels of neurogenic inflammation related neuropeptides in pediatric patients with community-acquired pneumonia and their potential diagnostic value in distinguishing viral and bacterial pneumonia.

Neurogenic inflammation is involved in the development and progression of respiratory inflammatory diseases. However, its role in community-acquired pneumonia (CAP) remains unclear. We therefore aimed to investigate plasma levels of neurogenic inflammation-related neuropeptides, calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), and procalcitonin (PCT) in pediatric patients with CAP and to assess their diagnostic value in viral and bacterial/mixed pneumonia. A total of 124 pediatric patients with CAP (1 month-18 years old) and 56 healthy children of similar ages were prospectively enrolled. The patients were classified as viral (n = 99) and bacterial/mixed (n = 25) pneumonia. Plasma levels of the peptides were quantified by ELISA. ROC analysis was performed to evaluate possible diagnostic value of the peptides. While plasma levels of CGRP, VIP and PCT were significantly higher in patients with CAP than in the control group, respectively, NPY levels were significantly lower. Moreover, plasma levels of all neuropeptides and PCT were significantly higher in bacterial pneumonia patients compared to viral pneumonia patients. ROC analysis revealed that CGRP, SP and NPY had a diagnostic value in distinguishing viral and bacterial/mixed pneumonia. CONCLUSIONS: Our findings suggest that these neuropeptides may be implicated in pediatric CAP. CGRP, SP and NPY together may be a promising candidate in distinguishing viral and bacterial/mixed pneumonia, however, for this, further studies are needed. WHAT IS KNOWN: • Neurogenic inflammation contributes to the development and progression of respiratory inflammatory diseases such as chronic obstructive pulmonary disease and bronchial asthma. WHAT IS NEW: • Plasma levels of neurogenic inflammation related neuropeptides calcitonin gene-related peptide, substance P, vasoactive intestinal peptide and neuropeptide Y are changed in pediatric community-acquired pneumonia. Calcitonin gene-related peptide, substance P and neuropeptide Y are promising candidates in distinguishing viral and bacterial/mixed pneumonia.

Excimer light effect on neurogenic inflammation in active versus stable psoriasis lesions.

Neurogenic inflammation, mediated by T helper 17 cell (Th17) and neurons that release neuropeptides such as substance P (SP), is thought to play a role in the pathogenesis of psoriasis. Excimer light is used in the treatment of psoriasis via induction of T cell apoptosis. The objective of this study is to study the effect of excimer light on active versus stable psoriasis and investigate the levels of substance P and its receptor in both groups. The study included 27 stable and 27 active psoriatic patients as well as 10 matched healthy controls. Clinical examination (in the form of local psoriasis severity index (PSI) and visual analogue scale (VAS)) was done to determine disease severity, level of itching, and quality of life. Tissue levels of SP and neurokinin-1 receptor (NK-1R) were measured by ELISA before and after 9 excimer light sessions in 43 patients. A statistically significant lower levels of PSI and VAS were reached after therapy with no significant difference between the stable and active groups. The mean tissue levels of SP before therapy were significantly higher than the control group. Lower levels of SP and NK-1 receptor were found after treatment overall and in each group. Excimer therapy can be effective for both stable and active plaque psoriasis and this effect could be partly through its role on ameliorating the neurogenic inflammation.

Probiotic potential of Lacticaseibacillus rhamnosus VHProbi M15 on sucralfate-induced constipation in mice.

The main objective of this study was to investigate the potential probiotic properties of Lacticaseibacillus rhamnosus VHProbi®M15 (M15). This study examined the effects of M15 on sucralfate-induced constipation in a mouse model. The BALB/c mice were randomly divided into four groups: the normal group (NOR) was without any treatment, while the constipation (CON), phenolphthalein (PHE), and probiotic (PRO) treatment groups were fed with sucralfate until the appearance of constipation symptoms. Afterward, the NOR and CON groups were given 1 ml saline orally every day until the end of the experiment; the PHE and PRO groups were given phenolphthalein or M15 suspension in 1 ml orally, respectively. Compared with the CON group, the fecal water content and intestinal peristalsis improved in the PRO group. Here, intake of M15 effectively attenuated sucralfate-induced constipation, recuperated colonic epithelial integrity, and increased serum levels of gastrointestinal excitatory neurotransmitters (motilin, gastrin, substance P). Analysis of the intestinal microbiota of mice by 16S rRNA metagenomic revealed an increase in the relative abundance of Bacteroides and a decrease in Sclerotinia, Verrucosa and Proteus in the PRO group. Compared with the CON group, the constipation-induced intestinal microecological changes were partially recovered in the PHE and PRO groups. These results demonstrate that M15 enhanced gastrointestinal transit and alleviated in mice with sucralfate-induced constipation.

The vasoactive effects of bradykinin, vasoactive intestinal peptide, calcitonin gene-related peptide and neuropeptide Y depend on the perivascular tissue in porcine retinal arterioles in vitro.

PURPOSE: The retina contains a number of vasoactive neuropeptides and corresponding receptors, but the role of these neuropeptides for tone regulation of retinal arterioles has not been studied in detail. METHODS: Porcine arterioles with preserved perivascular retinal tissue were mounted in a wire myograph, and the tone was measured after the addition of increasing concentrations of bradykinin, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP). The experiments were performed during inhibition of the synthesis of nitric oxide (NO), prostaglandins and dopamine and were repeated after removal of the perivascular retinal tissue. RESULTS: Bradykinin, VIP and CGRP induced significant concentration-dependent dilatation and NPY significant concentration-dependent contraction of the arterioles in the presence of perivascular retinal tissue (p < 0.03 for all comparisons) but not on isolated arterioles. BNP and SP had no effect on vascular tone. The NOS inhibitor L-NAME reduced bradykinin- and VIP-induced relaxation (p < 0.001 for both comparisons), whereas none of the other inhibitors influenced the vasoactive effects of the studied neuropeptides. CONCLUSION: The effects of neuropeptides on the tone of retinal arterioles depend on the perivascular retinal tissue and may involve effects other than those mediated by nitric oxide, prostaglandins and adrenergic compounds. Investigation of the mechanisms underlying the vasoactive effect of neuropeptides may be important for understanding and treating retinal diseases where disturbances in retinal flow regulation are involved in the disease pathogenesis.

Substance P Increases STAT6-Mediated Transcription Activation of Lymphocyte Cytosolic Protein 2 to Sustain M2 Macrophage Predominance in Pediatric Asthma.

Substance P (SP) is a neuropeptide released by neurons and participates in various biological processes, including inflammation. M2 macrophages are major immune cells associated with type 2 inflammation in asthma. This study investigated the effect of SP on macrophage phenotype in pediatric asthma and the underpinning factors. Asthmatic children exhibited an increased level of SP, along with a higher proportion of M2 macrophages in their bronchoalveolar lavage fluid. Flow cytometry revealed that SP treatment enhanced the M2 polarization of 12-O-tetradecanoylphorbol 13-acetate-treated THP-1 cells (macrophages) in vitro. By contrast, the administration of a neutralizing antibody of SP reduced the M2 macrophage population, mitigated inflammatory cell infiltration in mouse lung tissues, and decreased the population of immune cells in the mouse bronchoalveolar lavage fluid. SP up-regulated the expression of STAT6, which, in turn, activated the transcription of lymphocyte cytosolic protein 2 (LCP2). The population of macrophages and allergic inflammatory responses in mice were reduced by STAT6 inhibition but restored by LCP2 overexpression. Collectively, the present study demonstrated that SP sustains M2 macrophage predominance and allergic inflammation in pediatric asthma by enhancing STAT6-dependent transcription activation of LCP2.

Investigation of the Therapeutic Effect of Salbutamol on Endometriosis in a Mouse Model.

Endometriosis is an immune chronic inflammatory disease, and there are currently no more effective drugs for treating endometriosis due to its unknown etiology. Salbutamol is a ß2-adrenergic receptor (ß2AR) agonist commonly used to treat asthma by selectively activating ß2 receptors on airway smooth muscle and leukocytes, exerting bronchial dilation and synergistic anti-inflammatory effects. In recent years, ß2AR agonists have been used in endometriosis studies, and we speculate that salbutamol may have a therapeutic effect on endometriosis. The purpose of this research was to explore the therapeutic effect of salbutamol on endometriosis mice. The mouse endometriosis model was established and treated with different doses of salbutamol. Endometrial lesions were harvested for pathological diagnosis, immunohistochemistry (IHC), Masson staining, and toluidine blue analysis. We found that the number and size of endometriotic lesions were all significantly decreased after 3 weeks of treatment with different doses of salbutamol on endometriosis model mice (P < 0.05). After Salbutamol treatment, the amount of mast cells (toluidine blue) and macrophages (F4/80) in the lesions as well as the expressions of interleukin (IL)-1ß, tumor necrosis factor (TNF)-ɑ, platelet-derived growth factor subunit B (PDGFB), CD31, transforming growth factor (TGF)-ß, Masson staining, BCL2, TUBB3, substance P (SP), and nerve growth factor (NGF) were significantly reduced (P < 0.05). These results suggested that salbutamol could effectively treat endometriosis in mice by reducing immune inflammatory cells and factors, angiogenesis, and fibrosis, increasing apoptosis of endometriotic lesions, and decreasing neurogenesis.

The effect of NK3-Saporin injection within the arcuate nucleus on puberty, the LH surge, and the response to Senktide in female sheep†.

The timing of puberty onset is reliant on increased gonadotropin-releasing hormone (GnRH). This elicits a corresponding increase in luteinizing hormone (LH) due to a lessening of sensitivity to the inhibitory actions of estradiol (E2). The mechanisms underlying the increase in GnRH release likely involve a subset of neurons within the arcuate (ARC) nucleus of the hypothalamus that contain kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons). We aimed to determine if KNDy neurons in female sheep are critical for: timely puberty onset; the LH surge; and the response to an intravenous injection of the neurokinin-3 receptor (NK3R) agonist, senktide. Prepubertal ewes received injections aimed at the ARC containing blank-saporin (control, n = 5) or NK3-saporin (NK3-SAP, n = 6) to ablate neurons expressing NK3R. Blood samples taken 3/week for 65 days following surgery were assessed for progesterone to determine onset of puberty. Control ewes exhibited onset of puberty at 33.2 ± 3.9 days post sampling initiation, whereas 5/6 NK3-SAP treated ewes didn't display an increase in progesterone. After an artificial LH surge protocol, surge amplitude was lower in NK3-SAP ewes. Finally, ewes were treated with senktide to determine if an LH response was elicited. LH pulses were evident in both groups in the absence of injections, but the response to senktide vs saline was similar between groups. These results show that KNDy cells are necessary for timely puberty onset and for full expresson of the LH surge. The occurrence of LH pulses in NK3-SAP treated ewes may indicate a recovery from an apulsatile state.

Distribution and Chemistry of Phoenixin-14, a Newly Discovered Sensory Transmission Molecule in Porcine Afferent Neurons.

Phoenixin-14 (PNX), initially discovered in the rat hypothalamus, was also detected in dorsal root ganglion (DRG) cells, where its involvement in the regulation of pain and/or itch sensation was suggested. However, there is a lack of data not only on its distribution in DRGs along individual segments of the spinal cord, but also on the pattern(s) of its co-occurrence with other sensory neurotransmitters. To fill the above-mentioned gap and expand our knowledge about the occurrence of PNX in mammalian species other than rodents, this study examined (i) the pattern(s) of PNX occurrence in DRG neurons of subsequent neuromeres along the porcine spinal cord, (ii) their intraganglionic distribution and (iii) the pattern(s) of PNX co-occurrence with other biologically active agents. PNX was found in approximately 20% of all nerve cells of each DRG examined; the largest subpopulation of PNX-positive (PNX+) cells were small-diameter neurons, accounting for 74% of all PNX-positive neurons found. PNX+ neurons also co-contained calcitonin gene-related peptide (CGRP; 96.1%), substance P (SP; 88.5%), nitric oxide synthase (nNOS; 52.1%), galanin (GAL; 20.7%), calretinin (CRT; 10%), pituitary adenylate cyclase-activating polypeptide (PACAP; 7.4%), cocaine and amphetamine related transcript (CART; 5.1%) or somatostatin (SOM; 4.7%). Although the exact function of PNX in DRGs is not yet known, the high degree of co-localization of this peptide with the main nociceptive transmitters SP and CGRP may suggests its function in modulation of pain transmission.

Long-Term Tumor Control Following Targeted Alpha Therapy (TAT) of Low-Grade Gliomas (LGGs): A New Treatment Paradigm?

The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [213Bi]Bi/[225Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [90Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG.

The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant.

The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration, angiogenesis, the Warburg effect, and the prevention of apoptosis. Tumor cells overexpress NK-1R, which influences their viability. A typical specific anticancer strategy using NK-1R antagonists, irrespective of the tumor type, is possible because these antagonists block all the effects mentioned above mediated by SP on cancer cells. This review will update the information regarding using NK-1R antagonists, particularly Aprepitant, as an anticancer drug. Aprepitant shows a broad-spectrum anticancer effect against many tumor types. Aprepitant alone or in combination therapy with radiotherapy or chemotherapy could reduce the sequelae and increase the cure rate and quality of life of patients with cancer. Current data open the door to new cancer research aimed at antitumor therapeutic strategies using Aprepitant. To achieve this goal, reprofiling the antiemetic Aprepitant as an anticancer drug is urgently needed.