Systematic review and meta-analysis of randomized controlled trials on the effects of exercise interventions on amyloid beta levels in humans.

Alzheimer's disease (AD) represents the most common type of dementia. A crucial mechanism attributed to its development is amyloid beta (Aß) dynamics dysregulation. The extent to which exercise can modulate this phenomenon is uncertain. The aim of this study was to summarize the existing literature evaluating this issue. A comprehensive systematic search was performed in Pubmed, Scopus, Embase, Web of Science, and SciELO databases and completed in August 2023, aiming to identify randomized controlled trials investigating the effect of exercise upon Aß-related pathology. The keywords "exercise" and "amyloid beta", as well as all their equivalents and similar terms, were used. For the analysis, the negative or positive dementia status of the subjects was initially considered and then the soluble amyloid precursor protein (sAPP) components and Aß fragments separately. A meta-analysis was performed and involved eight studies (moderate-to-high quality) and 644 assessments, which were 297 for control and 347 for exercise. No overall effect favoring exercise interventions was observed for both negative (SMD95%=0,286 [-0,131; 0,704]; p = 0,179) or positive AD dementia status (SMD95%=0,110 [-0,155; 0,375]; p = 0,416). The absence of an overall effect favoring exercise interventions was also found for Aß peptides (SMD95%=0,226 [-0,028; 0,480]; p = 0,081) and for sAPP components (SMD95%=-0,038 50 [-0,472; 0,396]; p = 0,863) levels. Our findings suggest that exercise interventions do not improve Aß-related pathology in both healthy individuals and individuals with dementia (SMD95%=0,157 [-0,059; 0,373]; p = 0,155), indicating that the beneficial effects of exercise for AD reported in previous studies are related to other mechanistic effects rather than direct amyloid effects (PROSPERO registration number: CRD42023426912).

Evaluation of a preemptive intervention regimen with hesperidin methyl chalcone in delayed-onset muscle soreness in young adults: a randomized, double-blinded, and placebo-controlled trial study.

PURPOSE: Delayed-onset muscle soreness (DOMS) describes an entity characterized by ultrastructural muscle damage. Hesperidin methyl chalcone (HMC) is a synthetic flavonoid presenting analgesic, anti-inflammatory, and antioxidant properties. We evaluated the effects of HMC upon DOMS. METHOD: In a preventive paradigm, 31 sedentary young men were submitted to a randomized, double-blinded parallel trial and received HMC 500 mg or one placebo capsule × 3 days before an intense dynamic exercise protocol (concentric/eccentric actions) applied for lower limbs for inducing muscle damage. Assessments were conducted at baseline, and 24 and 48 h after, comprising physical performance, and post-muscle soreness and damage, inflammation, recovery of muscle strength, and postural balance associated with DOMS. HMC safety was also evaluated. Thirty participants completed the study. RESULTS: HMC improved the performance of participants during exercise (40.3 vs 51.3 repetitions to failure, p = 0.0187) and inhibited CPK levels (90.5 vs 57.9 U/L, p = 0.0391) and muscle soreness during passive quadriceps palpation (2.6 vs 1.4 VAS cm, p = 0.0439), but not during active actions, nor did it inhibit IL-1ß or IL-10 levels. HMC improved muscle strength recovery, and satisfactorily refined postural balance, without inducing injury to kidneys or liver. CONCLUSIONS: Preemptive HMC supplementation may be beneficial for boosting physical performance and for the amelioration of clinical parameters related to DOMS, including pain on muscle palpation, increased blood CPK levels, and muscle strength and proprioceptive deficits, without causing adverse effects. These data advance the understanding of the benefits provided by HMC for DOMS treatment, which supports its usefulness for such purpose.

Resolvin D5 (RvD5) Reduces Renal Damage Caused by LPS Endotoxemia in Female Mice.

In self-revolving gram-negative Escherichia coli infection, Resolvin D5 (RvD5) was found to enhance bacteria phagocytosis and reduce the production of inflammatory mediators, contributing to the resolution of infection. LPS (lipopolysaccharide) is a gram-negative bacterial structure product which activates the immune system and, at high doses, leads to endotoxemia. To our knowledge, the effect of RvD5 against LPS endotoxemia has not been investigated to date. Female Swiss mice received an i.p. treatment with RvD5 (0.1, 1 or 10 ng/animal). After 1 h, they were stimulated with LPS (10 mg/kg, i.v.), and samples were collected after additional 6 h. The resulting data demonstrated that RvD5 protected the kidneys (urea and creatinine serum levels) from tissue injury. These effects were related to an improvement in histopathological parameters and a reduction of enzymatic markers of leukocyte infiltration, pro-inflammatory cytokine (IL-1ß, TNF-α, and IL-6) production, and oxidative stress. Antioxidant markers were also increased by RvD5, but IL-10 (an anti-inflammatory cytokine) levels were unaltered. We also observed that RvD5 reduced the infiltration of CD45+ hematopoietic cells into the kidneys, reduced the activation of NFκB and promoted the Nrf2 pathway by reducing Keap-1 levels. Our data indicate that RvD5 may be a therapeutic possibility to reduce kidney lesions in LPS endotoxemia.

Association between IL-10 systemic low level and highest pain score in patients during symptomatic SARS-CoV-2 infection.

BACKGROUND: Despite the wide variety of Covid-19 symptoms, pain and the related mechanisms underlying unsettled nociceptive status are still under-prioritized. Understanding the complex network of Covid-19-related pain may result in new lines of study. It is unknown whether patient's immunological background influences pain in the acute phase of Covid-19, including musculoskeletal pain. Thus, we evaluated the blood levels of selected molecules that are upregulated in SARS-CoV-2 infection and analyzed a possible correlation with pain during Covid-19. METHODS: A cohort of 20 hospitalized patients with confirmed diagnoses for Covid-19 were evaluated in the context of pain. Visual analogic scale (VAS) was applied to quantitate pain level. Blood tests were used to determine the systemic levels of cytokines (IL-10 and IL-1ß), substance P, and leptin. The data were correlated when appropriate to determine the association between pain-related markers and assessed pain intensity. RESULTS: Our findings show that systemic levels of IL-10 have strong negative correlation with pain intensity on Covid-19 patients. Additionally, we also show that leptin systemic levels were increased in Covid-19 patients with pain, however, with moderate positive correlation between these events. IL-1ß and SP levels did not differ between Covid-19 patients with or without pain. Men reported less pain compared to women. No differences were found between genders in the levels of the molecules evaluated in patients with pain. CONCLUSION: IL-10 has been described over the years as an anti-inflammatory and analgesic cytokine. The present data support that low IL-10 levels might contribute to Covid-19-associated pain.

Diosmin Treats Lipopolysaccharide-Induced Inflammatory Pain and Peritonitis by Blocking NF-κB Activation in Mice.

Gram-negative bacterial infections induce inflammation and pain. Lipopolysaccharide (LPS) is a pathogen-associated molecular pattern and the major constituent of Gram-negative bacterial cell walls. Diosmin is a citrus flavonoid with antioxidant and anti-inflammatory activities. Here we investigated the efficacy of diosmin in a nonsterile model of inflammatory pain and peritonitis induced by LPS. Diosmin reduced in a dose-dependent manner LPS-induced inflammatory mechanical hyperalgesia, thermal hyperalgesia, and neutrophil recruitment to the paw (myeloperoxidase activity). Diosmin also normalized changes in paw weight distribution assessed by static weight bearing as a nonreflexive method of pain measurement. Moreover, treatment with diosmin inhibited LPS-induced peritonitis as observed by a reduction of leukocyte recruitment and oxidative stress. Diosmin reduced LPS-induced total ROS production (DCFDA assay) and superoxide anion production (NBT assay and NBT-positive cells). We also observed a reduction of LPS-induced oxidative stress and cytokine production (IL-1ß, TNF-α, and IL-6) in the paw. Furthermore, we demonstrated that diosmin inhibited LPS-induced NF-κB activation in peritoneal exudate. Thus, we demonstrated, using a model of nonsterile inflammation induced by LPS, that diosmin is a promising molecule for the treatment of inflammation and pain.

Contribution of spinal cord glial cells to L. amazonensis experimental infection-induced pain in BALB/c mice.

BACKGROUND: The cellular and molecular pathophysiological mecha\nisms of pain processing in neglected parasitic infections such as leishmaniasis remain unknown. The present study evaluated the participation of spinal cord glial cells in the pathophysiology of pain induced by Leishmania amazonensis infection in BALB/c mice. METHODS: Mice received intra-plantar (i.pl.) injection of L. amazonensis (1 × 105) and hyperalgesia, and paw edema were evaluated bilaterally for 40 days. The levels of TNF-α and IL-1ß, MPO activity, and histopathology were assessed on the 40th day. ATF3 mRNA expression was assessed in DRG cells at the 30th day post-infection. Blood TNF-α and IL-1ß levels and systemic parasite burden were evaluated 5-40 days after the infection. At the 30th day post-infection L. amazonensis, the effects of intrathecal (i.t.) treatments with neutralizing antibody anti-CX3CL1, etanercept (soluble TNFR2 receptor), and interleukin-1 receptor antagonist (IL-1ra) on infection-induced hyperalgesia and paw edema were assessed. In another set of experiments, we performed a time course analysis of spinal cord GFAP and Iba-1 (astrocytes and microglia markers, respectively) and used confocal immunofluorescence and Western blot to confirm the expression at the protein level. Selective astrocyte (α-aminoadipate) and microglia (minocycline) inhibitors were injected i.t. to determine the contribution of these cells to hyperalgesia and paw edema. The effects of i.t. treatments with glial and NFκB (PDTC) inhibitors on spinal glial activation, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation were also evaluated. Finally, the contribution of TNF-α and IL-1ß to CX3CL1 mRNA expression was investigated. RESULTS: L. amazonensis infection induced chronic mechanical and thermal hyperalgesia and paw edema in the infected paw. Mechanical hyperalgesia was also observed in the contralateral paw. TNF-α, IL-1ß, MPO activity, and epidermal/dermal thickness increased in the infected paw, which confirmed the peripheral inflammation at the primary foci of this infection. ATF3 mRNA expression at the ipsilateral DRG of the infected paw was unaltered 30 days post-infection. TNF-α and IL-1ß blood levels were not changed over the time course of disease, and parasitism increased in a time-dependent manner in the ipsilateral draining lymph node. Treatments targeting CX3CL1, TNF-α, and IL-1ß inhibited L. amazonensis-induced ongoing mechanical and thermal hyperalgesia, but not paw edema. A time course of GFAP, Iba-1, and CX3CR1 mRNA expression indicated spinal activation of astrocytes and microglia, which was confirmed at the GFAP and Iba-1 protein level at the peak of mRNA expression (30th day). Selective astrocyte and microglia inhibition diminished infection-induced ipsilateral mechanical hyperalgesia and thermal hyperalgesia, and contralateral mechanical hyperalgesia, but not ipsilateral paw edema. Targeting astrocytes, microglia and NFκB diminished L. amazonensis-induced GFAP, Iba-1, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation in the spinal cord at the peak of spinal cord glial cells activation. CX3CL1 mRNA expression was also detected in the ipsilateral DRG of infected mice at the 30th day post-infection, and the i.t. injection of TNF-α or IL-1ß in naïve animals induced CX3CL1 mRNA expression in the spinal cord and ipsilateral DRG. CONCLUSIONS: L. amazonensis skin infection produces chronic pain by central mechanisms involving spinal cord astrocytes and microglia-related production of cytokines and chemokines, and NFκB activation contributes to L. amazonensis infection-induced hyperalgesia and neuroinflammation.

Repurposing of the Nootropic Drug Vinpocetine as an Analgesic and Anti-Inflammatory Agent: Evidence in a Mouse Model of Superoxide Anion-Triggered Inflammation.

Clinically active drugs for the treatment of acute pain have their prescription limited due to the significant side effects they induce. An increase in reactive oxygen species (ROS) has been linked to several conditions, including inflammation and pain processing. Therefore, new or repurposed drugs with the ability of reducing ROS-triggered responses are promising candidates for analgesic drugs. Vinpocetine is a clinically used nootropic drug with antioxidant, anti-inflammatory, and analgesic properties. However, the effects of vinpocetine have not been investigated in a model with a direct relationship between ROS, inflammation, and pain. Based on that, we aimed to investigate the effects of vinpocetine in a model of superoxide anion-induced pain and inflammation using potassium superoxide (KO2) as a superoxide anion donor to trigger inflammation and pain. In the KO2 model, vinpocetine dose-dependently reduced pain-like behaviors (spontaneous pain and hyperalgesia), paw edema, and neutrophil and mononuclear cell recruitment to the paw skin (assessed by H&E staining, fluorescence, and enzymatic assays) and to the peritoneal cavity. Vinpocetine also restored tissue endogenous antioxidant ability and Nrf2 and Ho-1 mRNA expression and reduced superoxide anion production and gp91phox mRNA expression. We also observed the inhibition of IκBα degradation by vinpocetine, which demonstrates a reduction in the activation of NF-κB explaining the diminished production of IL-33, IL-1ß, and TNF-α. Collectively, our data show that vinpocetine alleviates pain and inflammation induced by KO2, which is a mouse model with a direct role of ROS in triggering pain and other inflammatory phenomena. Thus, the results suggest the repurposing of vinpocetine as an anti-inflammatory and analgesic drug.

The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin.

Rutin is a glycone form of the flavonol quercetin and it reduces inflammatory pain in animal models. Therapy with granulocyte colony-stimulating factor (G-CSF) is known by the pain caused as its main side effect. The effect of rutin and its mechanisms of action were evaluated in a model of hyperalgesia induced by G-CSF in mice. The mechanical hyperalgesia induced by G-CSF was reduced by treatment with rutin in a dose-dependent manner. Treatment with both rutin + morphine or rutin + indomethacin, at doses that are ineffectual per se, significantly reduced the pain caused by G-CSF. The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-ATP-sensitive potassium channel (KATP) signaling pathway activation is one of the analgesic mechanisms of rutin. Rutin also reduced the pro-hyperalgesic and increased anti-hyperalgesic cytokine production induced by G-CSF. Furthermore, rutin inhibited the activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NFκB), which might explain the inhibition of the cytokine production. Treatment with rutin upregulated the decreased mRNA expression of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) combined with enhancement of the mRNA expression of the Nrf2 downstream target heme oxygenase (HO-1). Intraperitoneal (i.p.) treatment with rutin did not alter the mobilization of neutrophils induced by G-CSF. The analgesia by rutin can be explained by: NO-cGMP-PKG-KATP channel signaling activation, inhibition of NFκB and triggering the Nrf2/HO-1 pathway. The present study demonstrates rutin as a promising pharmacological approach to treat the pain induced by G-CSF without impairing its primary therapeutic benefit of mobilizing hematopoietic progenitor cells into the blood.

The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells.

BACKGROUND: Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored. METHODS: The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7-150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated. RESULTS: Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1ß mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression). CONCLUSIONS: Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.

Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice.

Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately, 19-33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although, considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In this study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI.

Leishmania infection: painful or painless?

The complex life cycle and immunopathological features underpinning the interaction of Leishmania parasites and their mammalian hosts poses frequent poorly explored and inconclusively resolved questions. The altered nociceptive signals over the course of leishmaniasis remain an intriguing issue for nociceptive and parasitology researchers. Experimental investigations have utilized behavioral, morphological, and neuro-immune approaches in the study of experimental cutaneous leishmaniasis (CL). The data generated indicates new venues for the study of the pathological characteristics of nociceptive processing in this parasitic disease. Leishmania-induced pain may be easily observed in mice and rats. However, nociceptive data is more complex in human investigations, including the occurrence of painless lesions in mucocutaneous and cutaneous leishmaniasis. Data from recent decades indicate that humans can also be affected by pain-related symptoms, often distinct from the region of body infection. The molecular and cellular mechanisms underlying such variable nociceptive states in humans during the course of leishmaniasis are an active area of research. The present article reviews nociception in leishmaniasis, including in experimental models of CL and clinical reports.

Pyrrolidine dithiocarbamate inhibits superoxide anion-induced pain and inflammation in the paw skin and spinal cord by targeting NF-κB and oxidative stress.

We evaluated the effect of pyrrolidine dithiocarbamate (PDTC) in superoxide anion-induced inflammatory pain. Male Swiss mice were treated with PDTC and stimulated with an intraplantar or intraperitoneal injection of potassium superoxide, a superoxide anion donor. Subcutaneous PDTC treatment attenuated mechanical hyperalgesia, thermal hyperalgesia, paw oedema and leukocyte recruitment (neutrophils and macrophages). Intraplantar injection of superoxide anion activated NF-κB and increased cytokine production (IL-1ß, TNF-α and IL-10) and oxidative stress (nitrite and lipid peroxidation levels) at the primary inflammatory foci and in the spinal cord (L4-L6). PDTC treatment inhibited superoxide anion-induced NF-κB activation, cytokine production and oxidative stress in the paw and spinal cord. Furthermore, intrathecal administration of PDTC successfully inhibited superoxide anion-induced mechanical hyperalgesia, thermal hyperalgesia and inflammatory response in peripheral foci (paw). These results suggest that peripheral stimulus with superoxide anion activates the local and spinal cord oxidative- and NF-κB-dependent inflammatory nociceptive mechanisms. PDTC targets these events, therefore, inhibiting superoxide anion-induced inflammatory pain in mice.

Interleukin-10 limits intense acute swimming-induced muscle mechanical hyperalgesia in mice.

NEW FINDINGS: What is the central question of this study? This study investigated the role of the endogenous anti-inflammatory cytokine interleukin-10 in intense acute swimming-induced muscle mechanical hyperalgesia in mice. What is the main finding and its importance? Endogenous interleukin-10 has a key role in limiting exercise-induced muscle pain in a model presenting similarities to delayed-onset muscle soreness in mice. Interleukin-10 reduced muscle pain by diminishing leucocyte recruitment, hyperalgesic cytokine production, oxidative stress and myocyte damage. Interleukin-10 (IL-10) is an antihyperalgesic cytokine. In this study, IL-10-deficient (IL-10(-/-) ) mice were used to investigate the role of endogenous IL-10 in intense acute swimming-induced muscle mechanical hyperalgesia, which presents similarities with delayed-onset muscle soreness. An intense acute swimming session of 1 or 2 h induced significant muscle mechanical hyperalgesia in a time-dependent manner in wild-type mice compared with the sham group 24 h after the session, which was further increased in IL-10(-/-) mice (P Ë‚ 0.05). Intraperitoneal treatment of wild-type mice with IL-10 (1-10 ng) reduced muscle mechanical hyperalgesia in a dose-dependent manner and reversed the enhanced muscle hyperalgesia in IL-10(-/-) mice (P Ë‚ 0.05). The 2 h swimming session induced increases in tumour necrosis factor-α, interleukin-1ß and IL-10 production in the soleus muscle. However, tumour necrosis factor-α and interleukin-1ß production in the soleus muscle were even higher in IL-10(-/-) mice between 2 and 6 h after the stimulus (P Ë‚ 0.05). There was no statistical difference in the levels of the antihyperalgesic cytokines interleukin-4, interleukin-5, interleukin-13 and transforming growth factor-ß between wild-type and IL-10(-/-) mice (P Ëƒ 0.05). Interleukin-10 deficiency also resulted in increased myeloperoxidase activity, greater depletion of reduced glutathione levels, increased superoxide anion production and the maintenance of high plasma concentrations of creatine kinase (until 24 h after the swimming session) in soleus muscle (P Ë‚ 0.05). These results demonstrate that endogenous IL-10 controls intense acute swimming-induced muscle mechanical hyperalgesia by limiting oxidative stress and cytokine production.

Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF-κB activation.

OBJECTIVE: This study aimed at evaluating the activity of curcumin in superoxide anion-induced pain-like behavior and leukocyte recruitment in mice. TREATMENT: Administration of curcumin 10 mg/kg subcutaneously 1 h before stimulus. METHODS: KO2 was used as superoxide anion donor. Overt pain-like behaviors were determined by the number of abdominal writhings, paw flinches and time spent licking the paw. Mechanical and thermal hyperalgesia were determined using an electronic anesthesiometer and hot plate, respectively. Cytokine concentration and NF-κB activity were determined by ELISA, antioxidant effect by nitrobluetretrazolium assay and ABTS radical scavenging ability. Myeloperoxidase activity was measured by colorimetric assay. The Nrf2, heme oxygenase-1 (HO-1) and gp91phox mRNA expression was determined by quantitative PCR. Data were analyzed by ANOVA followed by Tukey's post hoc and considered significant when p<0.05. RESULTS: Curcumin inhibited superoxide anion-induced overt pain-like behaviors as well as mechanical and thermal hyperalgesia. Curcumin also inhibited superoxide anion-induced leukocyte recruitment in the peritoneal cavity and in the paw skin inhibited myeloperoxidase activity, oxidative stress, IL-1ß and TNF-α production and NF-κB activation as well as enhanced IL-10 production, and HO-1 and Nrf2 mRNA expression. CONCLUSION: Curcumin inhibits superoxide anion-induced inflammatory pain-like behaviors and leukocyte recruitment by targeting inflammatory molecules and oxidative stress; and inducing antioxidant and anti-inflammatory pathways.

Acute Effects of Citrulline Malate Supplementation on Nocturnal Blood Pressure Dipping After Exercise in Hypertensive Patients: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Citrulline malate (CM), especially when used in conjunction with physical exercise, has demonstrated potential as a non-pharmacological adjunct in the management of hypertension. Nevertheless, its impact on nocturnal blood pressure dipping remains unexplored. OBJECTIVE: Evaluate the impact of a single dose of CM on nocturnal blood pressure dipping after exercise in hypertensive individuals. METHODS: In a double-blind, placebo-controlled, parallel-group clinical trial, twenty hypertensive adults (55 ± 16 years) were randomly assigned to either a CM (6 g) or placebo (6 g of corn starch) group (PLA). Resting blood pressure was measured after a 20-min period of comfortable seating in a calm environment. Both groups underwent 40 min of treadmill running/walking at an intensity of 60-70% of their reserve heart rate, 120 min after ingesting the substances. Ambulatory blood pressure monitoring was employed to measure blood pressure over 24 h. RESULTS: No significant differences in systolic blood pressure values were observed between the CM and PLA groups at rest, during wakefulness, sleep, or over a 24-h period. However, CM exhibited a significant reduction in diastolic blood pressure in several metrics: delta 24 h (-14 mmHg vs -6 mmHg, p = 0.047), delta wakefulness (-12 mmHg vs -4 mmHg, p = 0.024), percent delta 24 h (-16% vs -6%, p = 0.024), and percent delta wakefulness (-14% vs -4%, p = 0.013). No significant differences were found between CM and PLA in terms of systolic and diastolic nocturnal absolute reductions (-13 mmHg vs -12 mmHg, p = 0.808, and -13 mmHg vs -8 mmHg, p = 0.273, respectively) or nocturnal percentage decrease (-9.9% vs -9.4%, p = 0.844, and -15.3% vs -11.7%, p = 0.399, respectively). CONCLUSIONS: The study found no significant changes in the post-exercise nocturnal blood pressure dip following a single dose of CM supplementation. However, a notable reduction in diastolic blood pressure was observed during the waking period and over the average 24-h monitoring period. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ClinicalTrials.gov platform (NCT03378596).

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain.

Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.

Leishmania spp. amastigotes surrounding sensory nerve fibers in human painless skin ulcers: Evidence of pathogen-neuron proximity and absence of neuronal apoptosis.

In this present study, carried out between November 2020 and July 2023 at Londrina's University Hospital, patients with active lesions of cutaneous leishmaniasis (CL) were analyzed regarding pain perception and anatomopathological aspects of the ulcers. Pain was assessed using a numerical rating scale (NRS) to compare five patients diagnosed with CL with four control patients diagnosed with vascular skin ulcers. Histopathological evaluations were used to investigate the nociceptor neuron-Leishmania interface. Patients with CL ulcers reported less pain compared to patients with vascular ulcers (2.60 ± 2.30 and 7.25 ± 0.95, respectively, p = 0.0072). Histopathology evidenced Leishmania spp. amastigote forms nearby sensory nerve fibers in profound dermis. Schwann cells marker (S100 protein) was detected, and caspase-3 activation was not evidenced in the in the nerve fibers of CL patients' samples, suggesting absence of apoptotic activity in nerve endings. Additionally, samples taken from the active edge of the lesion were negative for bacilli acid-alcohol resistant (BAAR), which excludes concomitant leprosy, in which painless lesions are also observed. Thus, the present data unveil for the first time anatomopathological and microbiological details of painless ulcers in CL patients, which has important clinical implications for a better understanding on the intriguing painless clinical characteristic of CL.

Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines.

The flavonoid vitexin (1) is a flavone C-glycoside (apigenin-8-C-ß-D-glucopyranoside) present in several medicinal and other plants. Plant extracts containing 1 are reported to possess antinociceptive, anti-inflammatory, and antioxidant activities. However, the only evidence that 1 exhibits antinociceptive activity was demonstrated in the acetic acid-induced writhing model. Therefore, the analgesic effects and mechanisms of 1 were evaluated. In the present investigation, intraperitoneal treatment with 1 dose-dependently inhibited acetic acid-induced writhing. Furthermore, treatment with 1 also inhibited pain-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), capsaicin (an agonist of transient receptor potential vanilloid 1, TRPV1), and both phases of the formalin test. It was also observed that inhibition of carrageenan-, capsaicin-, and chronic CFA-induced mechanical and thermal hyperalgesia occurred. Regarding the antinociceptive mechanisms of 1, it prevented the decrease of reduced glutathione levels, ferric-reducing ability potential, and free-radical scavenger ability, inhibited the production of hyperalgesic cytokines such as TNF-α, IL-1ß, IL-6, and IL-33, and up-regulated the levels of the anti-hyperalgesic cytokine IL-10. These results demonstrate that 1 exhibits an analgesic effect in a variety of inflammatory pain models by targeting TRPV1 and oxidative stress and by modulating cytokine production.

Antioxidant Compounds and Health Benefits of Citrus Fruits.

Recent evidence emanating from epidemiological prospective studies shows that increased intakes of antioxidant-rich fruits, vegetables, and legumes are associated with a lower risk of developing chronic oxidative stress-related diseases like cardiovascular diseases and cancer, as well as with a lower risk of cardiovascular, cancer, and all-cause mortality rates [...].