Instant Cascara (IC) is a sustainable beverage made from dried coffee cherry pulp, a by-product of coffee processing. It is rich in nutrients and bioactive compounds and has a high concentration of antioxidants. This study explored the impact of regular IC consumption on colonic motor function and innervation. Over a period of 4 weeks, male and female healthy rats were given drinking water containing 10 mg/mL of IC. Thereafter, colon samples were obtained to evaluate the longitudinal (LM) and circular (CM) smooth muscle contractile response to acetylcholine (ACh) and electrical field stimulation (EFS) in an organ bath, before and after atropine administration (10-6 M). Histological and immunohistochemical analyses assessed colon damage, muscle thickness, and immunoreactivity to substance P (SP) and neuronal nitric oxide synthase (nNOS). ACh and EFS induced similar responses across groups, but the CM response to EFS was greater in females compared with males, despite their lower body weight. Atropine completely blocked the response to ACh but only partially antagonized the neural response to EFS, particularly that of CM in females treated with IC, which had a greater liquid intake than those exposed to water. However, in the myenteric ganglia, no statistically significant differences were observed in SP or nNOS. Our results suggest that regular IC exposure may enhance specific neural pathway functions, particularly in females, possibly due to their increased IC consumption.

A significant quantity of substance P (SP) and its receptor, the neurokinin 1 (NK1) receptors are found in the brain. SP is a neuropeptide distributed in the central nervous system and functions as a neurotransmitter, neuromodulator, and neurotrophic factor. The concentrations of SP in the brain and cerebrospinal fluid fluctuate in individuals with Alzheimer\'s disease (AD). SP is an endogenous ligand for NK1 receptor, enhancing the expression of toll-like receptors (TLR) and vice versa. So, both pathways are interconnected, where activation of one pathway activates the second pathway. Researchers have observed the interaction of TLR with SP in the pathophysiology of AD. Thus, this review discusses various TLRs involved in regulating amyloid processing and its interaction with SP in AD. Further, in AD pathology, SP can regulate the non-amyloidogenic pathway. Recent studies have also demonstrated the capacity of SP in regulating voltage-gated potassium channel currents, emphasizing SP\'s neuroprotective ability. Therefore, we corroborate the findings linking the SP, NK1R, and TLRs in AD.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect related to activation of substance P (SP). SP activation can result from dysregulation of the gut-brain axis, and also from activation of protein kinase A signaling (PKA) signaling. In this study, we connected these factors in an attempt to unveil the mechanisms underlying CINV and develop new therapeutic strategies. Female rats were injected with cisplatin to induce pica. Fecal samples were collected before/after injection, and subjected to lipid metabolomics analysis. In another portion of pica rats, the PKA inhibitor KT5720 was applied to investigate the involvement of PKA signaling in CINV, while fecal microbiota transplantation (FMT) was implemented to verify the therapeutic effect of the lipid metabolite 14(15)-EpETE. Pica symptoms were recorded, followed by ileal histological examination. The targeting relationship between 14(15)-EpETE and glucagon was determined by bioinformatics. SP and glucagon/PKA signaling in rat ileum, serum, and/or brain substantia nigra were detected by immunohistochemistry, enzyme-linked immunosorbent assay, and/or western blot. The results showed a significantly lower level of 14(15)-EpETE in rat feces after cisplatin injection. KT5720 treatment alleviated cisplatin-induced pica symptoms, ileal injury, SP content increase in the ileum, serum, and brain substantia nigra, and ileal PKA activation in rats. The ileal level of glucagon was elevated by cisplatin in rats. FMT exerted an effect similar to that of KT5720 treatment, relieving the cisplatin-induced changes, including ileal glucagon/PKA activation in rats. Our findings demonstrate that FMT restores 14(15)-EpETE production, which inhibits SP release by targeting GCG/PKA signaling, ultimately mitigating CINV.

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.

The objectives of this prospective, randomized, blinded, crossover, experimental study were to detect the potential anaesthetic- and analgesic-sparing effects of classical music provided to dogs undergoing skin surgery, and to investigate the role of substance P as an intraoperative pain indicator. Twenty dogs were included, each subjected to three different treatments: Chopin music, Mozart music and no music. They were premedicated with acepromazine, butorphanol and meloxicam and anaesthetized with propofol and isoflurane. Fentanyl was used as rescue analgesia. The anaesthetic depth was monitored by using the bispectral index along with standard anaesthetic monitoring, and autonomic nervous system responses were used to monitor the adequacy of analgesia. Furthermore, measurements of substance P serum concentration were carried out. Dogs exposed to music required less isoflurane and fentanyl. Furthermore, a statistically significant effect of time on substance P concentration was observed regardless of exposure to music, and there was a significant interaction effect between different timepoints and the type of acoustic stimulus. Classical music seems to have an isoflurane and fentanyl sparing effect on dogs undergoing minor surgery. Following surgical stimulation, the serum substance P concentration increases rapidly, and thus appears to be a potentially useful pain indicator.

OBJECTIVE: To investigate tear neuropeptide Y (NPY) and substance P concentrations in individuals with type 1 diabetes, comparing those with and without both diabetic retinopathy (DR) and peripheral neuropathy.
METHODS: This cross-sectional study involved 41 participants with type 1 diabetes and none to moderate DR, and 22 healthy controls. Assessments included clinical ocular surface parameters, quantification of corneal nerve attributes (based on in vivo confocal microscopy imaging), DR grading, and evaluation for small and large fibre neuropathy. Concentrations of NPY and substance P in tear samples were measured using enzyme-linked immunosorbent assay.
RESULTS: Mean (± standard deviation) tear NPY concentrations in participants with type 1 diabetes and length-dependent small fibre neuropathy (SFN) was lower than in controls (10.84 ± 4.10 ng/mL vs 14.72 ± 3.12 ng/mL; p=0.004), but not significantly different from type 1 diabetes participants without SFN (13.39 ± 4.66 ng/mL; p=0.11). Tear NPY levels were lower in individuals with type 1 diabetes and mild/moderate non-proliferative DR (10.44 ± 3.46 ng/mL) compared to none/minimal DR (13.79 ± 4.76 ng/mL; p=0.0005) and controls. In separate linear regression models, both the presence of SFN (β = -0.75, p=0.02) and the presence of mild/moderate DR (β = -0.84, p=0.009) were significantly associated with tear NPY levels relative to controls, after adjusting for participant age, sex, and dry eye disease. There were no inter-group differences for tear substance P concentrations.
CONCLUSIONS: Tear NPY has potential utility as an indicator of peripheral microvascular complications associated with type 1 diabetes.

<b>Introduction:</b> Previous studies indicate a significant role of the inflammatory response in the etiopathogenesis of peripheral artery disease (PAD) and chronic pain (CP).<b>Aim:</b> The aim of the study was to determine the relationship between the concentration of SP and the level/concentration of inflammatory mediators (pro-inflammatory cytokines, positive and negative acute phase protein, anti-inflammatory cytokines) and pain intensity in people suffering from chronic pain (CP) in the course of PAD.<b>Material and methods:</b> We examined 187 patients of the Department of Vascular Surgery. As many as 92 patients with PAD and CP (study group) were compared to 95 patients with PAD without CP (control group). The relationship between SP and the level/concentration of fibrinogen, C-reactive protein (CRP), antithrombin III (AT), serum albumin, interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α) and pain intensity (Numeric Rating Scale; NRS) was analyzed. Statistical analysis was performed using the R program, assuming the level of statistical significance of α = 0.05.<b>Results:</b> Patients with CP had significantly higher levels of fibrinogen (P < 0.001), CRP (P < 0.001), SP (P < 0.001), IL-10 (P < 0.001), and lower serum albumin levels (P < 0.023). Higher SP concentration was associated with higher levels of IL-10, CRP, and pain intensity. In both groups, SP concentration correlated negatively with the level of fibrinogen (P < 0.001) as well as with albumin in the control group (P < 0.001).<b>Conclusions:</b> Thus, there is a relationship between the concentration of SP and fibrinogen, along with CRP, IL-10, and the intensity of pain in people suffering from CP in the course of PAD, and the level of albumin in the group without CP.

Tumour innervation is associated with worse patient outcomes in multiple cancers1,2, which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1high cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis.

Hyperglycemia and hyperinsulinemia in type 2 diabetes result in complications exacerbated by oxidative stress, leading to cardiovascular, nephropathic, neuropathic, and retinopathic problems. Substance P(SP), a natural neuropeptide, inhibits cell death and enhances cell growth during oxidative or inflammatory stress, suggesting a potential role in reducing diabetic complications. Objective -investigate serum levels of SP, total antioxidant status (TAS), glycemic measures, and lipid profiles in non-obese type 2 diabetic patients and evaluate the relationships involving these biomarkers.
METHODS: A case-control study involved 85 adult subjects (46males & 39females), aged (30-60) year, included two groups; diabetic group:53(males & females) non-obese type 2 diabetic patients, healthy group: Apparently healthy subjects of 32 individuals chosen from the general population and matched with patients age, sex and BMI.
RESULTS: The results showed that patients\' glucose levels increased as percentage increase of (˃141%),mild elevated insulin levels (˃50%), higher insulin resistance (˃250%), the lipid parameters exhibited disruption in comparison to the control group, in diabetic group, the serum levels of TAS, SP decreased considerably in comparison to the control group.
CONCLUSIONS: As evidenced by the outcomes; the TAS showed significant negative correlations with fasting serum glucose and low-density lipoprotein, and positive correlations with high-density lipoprotein. Neither the glycemic indices nor the lipid profiles or TAS demonstrated any notable associations with SP levels. This suggests that while SP levels are reduced in type 2 diabetes, they do not appear to be directly linked with the measured biomarkers.

BACKGROUND: Inflammation affects labor by influencing contractions and dilation. Pain, often linked to tissue ischemia, involves mediators like nitric oxide (NO), TNF-α, and substance P (SP). Neuraxial analgesia, including combined spinal epidural analgesia (SEA) with levobupivacaine, is preferred for its effectiveness and minimal side effects in painless labor. Understanding the impact of painless labor techniques on biomolecular processes such as NO, TNF-α, and substance P levels is crucial for improving pain management strategies. This study investigates these effects in parturients undergoing SEA with levobupivacaine, contributing to the development of novel pain medications and enhancing obstetric care.
METHODS: This experimental study, conducted at a General Hospital in Indonesia, involved 60 expectant mothers in labor or in the third trimester, expected to give birth vaginally at Permata Hati Metro Hospital. Blood serum was used for analysis, and serum NO, TNF-α, and SP levels were assessed using ELISA kit.
RESULTS: There\'s a significant decrease in NO levels before and post-treatment in the SEA group compared to the control group (p < 0.05). However, no significant difference in TNF-α levels was observed between groups before and after treatment (p > 0.05). Additionally, there was no significant difference in SP levels between groups before treatment, but a significant difference was seen after treatment (p < 0.05). SEA significantly reduced labor pain compared to the control group (P < 0.05), with notable improvements in vital signs and APGAR scores, while also shortening labor duration (P < 0.001).
CONCLUSIONS: In conclusion, SEA with levobupivacaine during painless labor reduces NO levels significantly and shows a trend of decreasing TNF-α and substance P levels, although not statistically significant, with clinical benefits for both patients and babies.