Endogenous cholinergic system involved in peripheral analgesic control in mice is activated by TNF-α, CXCL-1 and IL-1 ß.

INTRODUCTION: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1ß, CXCL1, norepinephrine (NE) and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. METHODS: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. RESULTS: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-ß, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-ß injection; (3) The non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-ß; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. CONCLUSION: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-ß.

Investigation of the involvement of platelet-activating factor in the control of hypertension by aerobic training. A randomized controlled trial.

Although studies have demonstrated the effectiveness of exercise in controlling systemic arterial hypertension (SAH), the mechanisms involved in this effect are still poorly understood. Thus, this study investigated the impact of aerobic training on the relationship between platelet-activating factor (PAF) circulating levels and blood pressure in hypertensives. Seventy-seven hypertensive subjects were enrolled in this randomized controlled trial (age 66.51 ± 7.53 years, body mass 76.17 ± 14.19 kg). Participants were randomized to two groups: the intervention group (IG, n = 36), composed of hypertensive individuals submitted to an aerobic training protocol, and the control group (CG, n = 41), composed of non-exercised hypertensives. Body mass index, arterial blood pressure, quality of life, respiratory muscle strength, and functional capacity were assessed before and after 12 weeks. PAF and plasma cytokine levels were also evaluated respectively by liquid chromatography coupled with mass spectrometry and enzyme-linked immunosorbent assay. Aerobic training promoted a significant reduction in blood pressure while functional capacity, expiratory muscle strength, and quality of life, PAFC16:0 and PAFC18:1 plasma levels were increased in comparison to the CG (p < 0.05). In addition, multiple correlation analysis indicated a positive correlation [F (3.19) = 6.322; p = 0.001; R2adjusted = 0.499] between PAFC16:0 levels and expiratory muscle strength after aerobic training. Taken together, our findings indicate that PAF may be involved in the indirect mechanisms that control SAH, being mainly associated with increased respiratory muscle strength in hypertensive subjects undergoing aerobic training.

Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation.

Introduction: Chemotherapy-induced neuropathic pain (CINP) is one of the main adverse effects of chemotherapy treatment. At the spinal level, CINP modulation involves glial cells that upregulate Toll-like receptor 4 (TLR4) and signaling pathways, which can be activated by pro-inflammatory mediators as the high mobility group box-1 (HMGB1). Objective: To evaluate the spinal role of HMGB1 in the paclitaxel-induced neuropathic pain via receptor for advanced glycation end products (RAGE) and TLR4 activation expressed in glial cells. Methods: Male C57BL/6 Wild type and TLR4 deficient mice were used in the paclitaxel-induced neuropathic pain model. The nociceptive threshold was measured using the von Frey filament test. In addition, recombinant HMGB1 was intrathecally (i.t.) injected to confirm its nociceptive potential. To evaluate the spinal participation of RAGE, TLR4, NF-kB, microglia, astrocytes, and MAPK p38 in HMGB1-mediated nociceptive effect during neuropathic pain and recombinant HMGB1-induced nociception, the drugs FPS-ZM1, LPS-RS, PDTC, minocycline, fluorocitrate, and SML0543 were respectively administrated by i.t. rout. Microglia, astrocytes, glial cells, RAGE, and TLR4 protein expression were analyzed by Western blot. ELISA immunoassay was also used to assess HMGB1, IL-1ß, and TNF-α spinal levels. Results: The pharmacological experiments demonstrated that spinal RAGE, TLR4, microglia, astrocytes, as well as MAPK p38 and NF-kB signaling are involved with HMGB1-induced nociception and paclitaxel-induced neuropathic pain. Furthermore, HMGB1 spinal levels were increased during the early stages of neuropathic pain and associated with RAGE, TLR4 and microglial activation. RAGE and TLR4 blockade decreased spinal levels of pro-inflammatory cytokines during neuropathic pain. Conclusion: Taken together, our findings indicate that HMGB1 may be released during the early stages of paclitaxel-induced neuropathic pain. This molecule activates RAGE and TLR4 receptors in spinal microglia, upregulating pro-inflammatory cytokines that may contribute to neuropathic pain.

Efficacy of Respiratory Muscle Training in the Immediate Postoperative Period of Cardiac Surgery: A Systematic Review and Meta-Analysis.

INTRODUCTION: This study aimed to evaluate the efficacy of respiratory muscle training during the immediate postoperative period of cardiac surgery on respiratory muscle strength, pulmonary function, functional capacity, and length of hospital stay. METHODS: This is a systematic review and meta-analysis. A comprehensive search on PubMed®, Excerpta Medica Database (or Embase), Cumulative Index of Nursing and Allied Health Literature (or CINAHL), Latin American and Caribbean Health Sciences Literature (or LILACS), Scientific Electronic Library Online (or SciELO), Physiotherapy Evidence Database (or PEDro), and Cochrane Central Register of Controlled Trials databases was performed. A combination of free-text words and indexed terms referring to cardiac surgery, coronary artery bypass grafting, respiratory muscle training, and clinical trials was used. A total of 792 studies were identified; after careful selection, six studies were evaluated. RESULTS: The studies found significant improvement after inspiratory muscle training (IMT) (n = 165, 95% confidence interval [CI] 9.68, 21.99) and expiratory muscle training (EMT) (n = 135, 95% CI 8.59, 27.07) of maximal inspiratory pressure and maximal expiratory pressure, respectively. Also, IMT increased significantly (95% CI 19.59, 349.82, n = 85) the tidal volume. However, no differences were found in the peak expiratory flow, functional capacity, and length of hospital stay after EMT and IMT. CONCLUSION: IMT and EMT demonstrated efficacy in improving respiratory muscle strength during the immediate postoperative period of cardiac surgery. There was no evidence indicating the efficacy of IMT for pulmonary function and length of hospital stay and the efficacy of EMT for functional capacity.

A pilot observational study to identify reference values for the 6-minute walk test in Brazilian people with hypertension / Um estudo observacional piloto para identificar valores de referência para o teste de caminhada de 6 minutos em hipertensos brasileiros

Abstract Introduction Systemic arterial hypertension (SAH) is responsible for 9.5 million deaths in the global popu-lation. Lifestyle factors, including physical inactivity, are important modifiable risk factors in the development of SAH. Thus, physical exercise has been shown to be effective to control SAH and before the prescription, the six-minute walk test (6-MWT) has been commonly used to assess the physical capacity. Objective To propose reference values for the 6-MWT test in Brazilian people with SAH. Methods A cross-sectional observational study was conducted with 302 hypertensive subjects (62.61 + 10.93 years) admitted to a cardiac rehabilitation program. Participants were divided into different age quartiles and submitted to 6-MWT. The walking distance data was compared between the quartiles and adjusted by mul-tiple linear regression analysis. Results The hypertensive subjects walked 388.07 + 115.03 m during the 6-MWT. No significant difference between the genders was found. However, when the age quartiles were compared, for the 46-59 age group, the women walked less than the men. Intra-group comparisons showed that the distance walked in the 6-MWT decreased with the increase in age, in both men and women. Conclusion The present study provides reference values for the 6-MWT, both for Brazilian men and women of different age groups. This data may be an important parameter for future clinical studies, prevention strategies, and clinical intervention.

Resumo Introdução A hipertensão arterial sistêmica (HAS) é respon-sável por 9,5 milhões de mortes na população mundial. Con-dições do estilo de vida, incluindo a inatividade física, são importantes fatores de risco modificáveis no desenvolvimento da HAS. Desse modo, o exercício físico tem se mostrado eficaz no controle da HAS e, antes da prescrição, o teste de caminhada de seis minutos (TC6) tem sido comumente utilizado para ava-liar a capacidade física. Objetivo Propor valores de referência para o teste de TC6 em brasileiros com HAS. Métodos Realizou-se um estudo observacional transversal com 302 hipertensos (62,61 + 10,93 anos) admitidos em um programa de reabilitação cardíaca. Os participantes foram divididos em diferentes quartis de idade e submetidos ao TC6. Os dados de distância percorrida foram comparados entre os quartis e ajustados por análise de regressão linear múltipla. Resultados Os hipertensos caminharam 388,07 + 115,03 m durante o TC6. Não encontrou-se diferença significativa entre os gêneros. No entanto, quando comparados os quartis de idade, para a faixa etária de 46 a 59 anos, as mulheres caminharam menos do que os homens. As comparações intragrupo mostraram que a distância percorrida no TC6 diminuiu com o aumento da idade, tanto em homens quanto em mulheres. Conclusão O presente estudo fornece valores de referência para o TC6, tanto para homens quanto para mulheres brasileiras de diferentes faixas etárias. Esses dados podem ser um parâmetro importante para futuros estudos clínicos, estratégias de prevenção e intervenção clínica.

Efficacy of Respiratory Muscle Training in the Immediate Postoperative Period of Cardiac Surgery: A Systematic Review and Meta-Analysis

ABSTRACT Introduction: This study aimed to evaluate the efficacy of respiratory muscle training during the immediate postoperative period of cardiac surgery on respiratory muscle strength, pulmonary function, functional capacity, and length of hospital stay. Methods: This is a systematic review and meta-analysis. A comprehensive search on PubMed®, Excerpta Medica Database (or Embase), Cumulative Index of Nursing and Allied Health Literature (or CINAHL), Latin American and Caribbean Health Sciences Literature (or LILACS), Scientific Electronic Library Online (or SciELO), Physiotherapy Evidence Database (or PEDro), and Cochrane Central Register of Controlled Trials databases was performed. A combination of free-text words and indexed terms referring to cardiac surgery, coronary artery bypass grafting, respiratory muscle training, and clinical trials was used. A total of 792 studies were identified; after careful selection, six studies were evaluated. Results: The studies found significant improvement after inspiratory muscle training (IMT) (n = 165, 95% confidence interval [CI] 9.68, 21.99) and expiratory muscle training (EMT) (n = 135, 95% CI 8.59, 27.07) of maximal inspiratory pressure and maximal expiratory pressure, respectively. Also, IMT increased significantly (95% CI 19.59, 349.82, n = 85) the tidal volume. However, no differences were found in the peak expiratory flow, functional capacity, and length of hospital stay after EMT and IMT. Conclusion: IMT and EMT demonstrated efficacy in improving respiratory muscle strength during the immediate postoperative period of cardiac surgery. There was no evidence indicating the efficacy of IMT for pulmonary function and length of hospital stay and the efficacy of EMT for functional capacity.

Effect of a cardiac telerehabilitation program during COVID-19 associated social isolation.

This study aimed to compare the impact of a cardiac telerehabilitation (CTR) protocol aimed at patients with cardiovascular diseases (CVDs) during the period of coronavirus disease 2019 (COVID-19) associated with social isolation. This retrospective cohort study included 58 participants diagnosed with stable cardiovascular diseases (CVDs), which were divided into three groups: conventional cardiac rehabilitation (CCR) group (n â€‹= â€‹20), composed of patients undergoing conventional cardiac rehabilitation; cardiac telerehabilitation (CTR) group (n â€‹= â€‹18), composed of patients undergoing cardiac telerehabilitation and control group (n â€‹= â€‹20), composed of patients admitted for cardiac rehabilitation who had not started training programs. The results showed that body mass index was reduced (p â€‹= â€‹0.019) and quality of life was improved (e.g., limitations due to physical aspects [p â€‹= â€‹0.021), vitality [p â€‹= â€‹0.045] and limitations due to emotional aspects [p â€‹= â€‹0.024]) by CCR compared to baseline. These outcomes were not improved by CTR (p â€‹> â€‹0.05). However, this strategy prevented clinical deterioration in the investigated patients. Although CCR achieved a superior effect on clinical improvement and quality of life, CTR was relevant to stabilize the blood pressure and quality of life of patients with cardiovascular diseases during the period of COVID-19-associated social isolation.

IL-10/ß-Endorphin-Mediated Neuroimmune Modulation on Microglia during Antinociception.

Microglia are glial cells centrally related to pathophysiology and neuroimmunological regulation of pain through microglia-neuron crosstalk mechanisms. In contrast, anti-inflammatory mechanisms guided by immunological effectors such as IL-10 trigger the secretion of analgesic substances, culminating in the differential expression of genes encoding endogenous opioid peptides, especially ß-endorphin. Thus, when ß-endorphin binds to the µ-opioid receptor, it generates neuronal hyperpolarization, inhibiting nociceptive stimuli. This review aimed to summarize the recent advances in understanding the mechanism by which IL-10/ß-endorphin can reduce pain. For this, databases were searched for articles from their inception up until November 2022. Two independent reviewers extracted the data and assessed the methodological quality of the included studies, and seventeen studies were considered eligible for this review. Several studies have demonstrated the impact of IL-10/ß-endorphin in reducing pain, where IL-10 can stimulate GLP-1R, GRP40, and α7nAChR receptors, as well as intracellular signaling pathways, such as STAT3, resulting in increased ß-endorphin expression and secretion. In addition, molecules such as gabapentinoids, thalidomide, cynandione A, morroniside, lemairamin, and cinobufagin, as well as non-pharmacological treatments such as electroacupuncture, reduce pain through IL-10 mediated mechanisms, reflecting a microglia-dependent ß-endorphin differential increase. This process represents a cornerstone in pain neuroimmunology knowledge, and the results obtained by different studies about the theme are presented in this review.

Involvement of the Endocannabinoid System in the Control of Pain and Obesity by Exercise in Rodents: A Systematic Review.

Studies in recent years have shown that the endocannabinoid (eCB) system is activated by exercise and modulates several physiological processes. Thus, the present review aimed to summarize the literature about the involvement of the eCB system in the control of pain, obesity, and metabolism by exercise. MEDLINE, EMBASE, and Web of Science were searched for experimental studies that investigated the presence of the eCB system in animal models of pain and obesity, in which the animals were subjected to different exercise modalities. The primary outcomes were pain, obesity, and metabolism. The databases were searched for articles from their inception up until March 2020. Two independent reviewers extracted the data and assessed the methodological quality of the included studies. Thirteen studies were considered eligible for this review. The results indicated that there was increased expression and levels of cannabinoid receptors and eCBs, respectively, after aerobic and resistance exercise, and that this effect was associated with antinociception. The eCB system was modulated by exercise in obese rats, confirming that it may also be involved in the control of obesity and metabolism when these are modulated by aerobic training. Exercise can be effective in controlling pain, partly through the involvement of the eCB system. In addition, exercise can modulate the imbalance of the eCB system in obesity and metabolic disorders, thus also controlling these pathologies through this signaling system.

Cannabidiol reduces lipopolysaccharide-induced nociception via endocannabinoid system activation.

Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious aetiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception. Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg. The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process. CBD treatment prevented LPS-induced nociception and TLR4 expression. AM630 reversed antinociception and reduced CBD-induced endocannabinoids up-regulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice. Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.

Photobiomodulation Reduces the Cytokine Storm Syndrome Associated with COVID-19 in the Zebrafish Model.

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence.

Cannabidiol prevents chemotherapy-induced neuropathic pain by modulating spinal TLR4 via endocannabinoid system activation.

OBJECTIVES: This study aimed to investigate the effect of cannabidiol (CBD) on type 4 Toll-like receptors (TLR4), glial cells and pro-inflammatory cytokines during the neuropathic pain induced by the chemotherapy agent paclitaxel (PTX), as well as the involvement of the endocannabinoid system in this process. METHODS: Male C57BL6 mice were subjected to PTX-induced neuropathic pain. To evaluate the involvement of the TLR4, glial cells and cannabinoid CB2 receptor, specific inhibitors or antagonists were intrathecally administered. The western blotting and immunofluorescence assay was performed to evaluate the spinal expression of TLR4, microglia, astrocytes and cannabinoid CB2 receptor. The levels of spinal pro-inflammatory cytokines and endocannabinoids were determined by enzyme-linked immunosorbent assay and liquid chromatography-mass spectrometry analysis, respectively. KEY FINDINGS: CBD prevented PTX-induced neuropathic pain, and the cannabinoid CB2 receptor antagonist AM630 reversed this effect. In addition, CBD treatment inhibited the spinal expression of TLR4 and Iba1 in mice with neuropathic pain. CBD also increased spinal levels of endocannabinoids anandamide and 2-arachidonoylglycerol, and reduced levels of cytokines in mice with neuropathic pain. CONCLUSIONS: CBD was efficient in preventing PTX-induced neuropathic pain, and this effect may involve inhibition of the TLR4 on microglia spinal with activation of the endocannabinoid system.

Synergistic effect of cannabidiol and transcutaneous electrical nerve stimulation on neuropathic and inflammatory pain in mice.

OBJECTIVES: Pain is the most common cause of seeking healthcare and the leading cause of disability worldwide. Although cannabidiol and transcutaneous electrical nerve stimulation (TENS) are effective and safe strategies for treating chronic pain, the combined effect of these interventions remains overlooked. To compare the isolated and combined effect of cannabidiol and TENS in the treatment of experimental neuropathic and inflammatory pain. METHODS: Swiss mice were subjected to chronic constriction injury (CCI)-induced neuropathic or carrageenan-induced inflammatory pain models. Cannabidiol or TENS alone and the combination of these therapies were administered once. The nociceptive threshold was measured by the von Frey test. IL-1ß, TNF-α and IL-10 cytokine levels were measured by ELISA from spinal cord samples. RESULTS: Combined, cannabidiol and TENS potentiate antinociception only in neuropathic pain. IL-1ß and TNF-α levels were similarly reduced when TENS or cannabidiol were administered alone or in combination. However, only cannabidiol and TENS combined increased IL-10 levels. CONCLUSIONS: Our findings indicated TENS and cannabidiol combined were effective in potentiating antinociception in a neuropathic pain model, an effect potentially associated with spinal IL-10 upregulation.

Investigation of the effects of therapeutic ultrasound or photobiomodulation and the role of spinal glial cells in osteoarthritis-induced nociception in mice.

Pain is the most common symptom of osteoarthritis, and spinal glia is known to contribute to this symptom. Therapeutic ultrasound and laser therapy have been used to effectively treat osteoarthritis, with few adverse effects. Thus, this study aimed to investigate the effects of ultrasound and photobiomodulation on the symptoms and evaluate the participation of spinal glia in osteoarthritis-induced nociception in mice. Male Swiss mice were subjected to osteoarthritis induction with a 0.1-mg intra-articular injection of monosodium iodoacetate. Additionally, the mice received chronic ultrasound or photobiomodulation treatment for 21 days or a single treatment at day 14. Nociception was evaluated using von Frey filaments, and osteoarthritis symptoms were assessed by analysis of gait, joint temperature, and knee joint diameter. The role of spinal microglia and astrocytes on nociception was evaluated via an intrathecal injection of minocycline or fluorocitrate, and the spinal release of IL-1ß and TNF-α was assessed by ELISA after chronic treatment with ultrasound or photobiomodulation. Our data showed that both single and chronic treatment with ultrasound or photobiomodulation attenuated the osteoarthritis-induced nociception. No differences in gait, knee joint temperature, or knee joint diameter were found. The intrathecal injection of minocycline and fluorocitrate decreased the osteoarthritis-induced nociception. There was an increase in the spinal levels of TNF-α, which was reverted by chronic ultrasound and laser treatments. These results suggest that osteoarthritis induces nociception and glial activation via spinal release of TNF-α and that the chronic treatment with ultrasound or photobiomodulation decreased nociception and TNF-α release.

Resistance Exercise and Whey Protein Supplementation Reduce Mechanical Allodynia and Spinal Microglia Activation After Acute Muscle Trauma in Rats.

Muscle injury caused by direct trauma to the skeletal muscle is among the main musculoskeletal disorders. Non-pharmacological treatments have been effective in controlling muscle injury-induced pain; however, there are just a few studies in the literature investigating this response. Thus, the present study aimed to evaluate the effect of a resistance exercise training protocol combined or not with whey protein supplementation on mechanical allodynia induced by muscle injury. In addition, we also investigated the involvement of spinal glial cells in this process. For this purpose, male Wistar rats underwent a muscle injury model induced by direct trauma to the gastrocnemius muscle. Mechanical allodynia was measured by a digital von Frey algesimeter test. To evaluate the effect of exercise and/or supplementation on mechanical allodynia, the animals practiced exercises three times a week for 14 days and received supplementation daily for 14 days, respectively. Moreover, the effect of both the participation of spinal glial cells in the muscle injury and the resistance exercise training and/or whey protein supplementation on these cells was also investigated by the Western blot assay. The results demonstrated that resistance exercise training and whey protein supplementation, combined or alone, reduced mechanical allodynia. These treatments also reduced the number of interstitial cells and pro-inflammatory cytokine IL-6 levels in the injured muscle. It was also found that spinal microglia and astrocytes are involved in muscle injury, and that resistance exercise training combined with whey protein supplementation inhibits spinal microglia activation. The results suggest that both resistance exercise training and whey protein supplementation may be effective non-pharmacological treatments to control pain in the muscle after injury induced by acute trauma.

Preclinical Evaluation of Polymeric Nanocomposite Containing Pregabalin for Sustained Release as Potential Therapy for Neuropathic Pain.

This study offers a novel oral pregabalin (PG)-loaded drug delivery system based on chitosan and hypromellose phthalate-based polymeric nanocomposite in order to treat neuropathic pain (PG-PN). PG-PN has a particle size of 432 ± 20 nm, a polydispersity index of 0.238 ± 0.001, a zeta potential of +19.0 ± 0.9 mV, a pH of 5.7 ± 0.06, and a spherical shape. Thermal and infrared spectroscopy confirmed nanocomposite generation. PG-PN pharmacokinetics was studied after a single oral dose in male Wistar rats. PG-PN showed greater distribution and clearance than free PG. The antinociceptive effect of PG-PN in neuropathic pain rats was tested by using the chronic constriction injury model. The parameter investigated was the mechanical nociceptive threshold measured by the von Frey filaments test; PG-PN showed a longer antinociceptive effect than free PG. The rota-rod and barbiturate sleep induction procedures were used to determine adverse effects; the criteria included motor deficit and sedative effects. PG-PN and free PG had plenty of motors. PG-PN exhibited a less sedative effect than free PG. By prolonging the antinociceptive effect and decreasing the unfavorable effects, polymeric nanocomposites with pregabalin have shown promise in treating neuropathic pain.

Cytokines and chemokines systemic levels are related to dialysis adequacy and creatinine clearance in patients with end-stage renal disease undergoing hemodialysis.

Although the clearance of low-molecular weight toxins is modulated by dialysis dose, the relationship between dialysis adequacy and middle systemic inflammatory mediators is often overlooked. Thus, the relationship between dialysis adequacy, pro- and anti-inflammatory cytokines and chemokines in hemodialysis (HD) patients was investigated. Forty-eight HD patients (19 women and 25 men) were investigated. Age, body mass index, time in HD, nutritional status, Kt/V and blood biochemical parameters was similar in patients of both sexes (P > 0.05). Thus, patients were stratified by dialysis adequacy measured by Kt/V method (adequate Kt/V ≥ 1.2). Post-HD urea, creatinine, cytokines (IFN-γ, IL-4 and IL-10) and chemokines (CCL-2, CCL-5, CXCL-8 and CXCL-10) were higher in patients with Kt/V < 1.2 (P < 0.05). Kt/V exhibited significant correlation with CXCL-10/IP-10 serum levels. Positive correlation between creatinine with IFN-γ, CCL-2/MCP-1, and CXCL-10/IP-10, and negative correlation with IL-10 was identified in patients with Kt/V < 1.2 (P < 0.05). In patients with Kt/V ≥ 1.2, only IL-10 was positively and CXCL-10/IP-10 negatively correlated with creatinine levels (P < 0.05). Kt/V and creatinine levels exhibited variable predictive value (Kt/V = 27% to 37%, creatinine = 29% to 47%) to explain cytokines and chemokines circulating levels in patients with adequate and inadequate dialysis dose. Taken together, our findings provide evidence that in addition to modulating uremic toxins levels, such as urea and creatinine, dialysis dose is associated with circulating levels of inflammatory mediators. Thus, low Kt/V results and creatinine accumulation are potential indicators of the systemic inflammatory stress determined by up-regulation of proinflammatory cytokines and chemokines, and downregulation of anti-inflammatory cytokines.

Investigation of the Combination of Pregabalin with Duloxetine or Amitriptyline on the Pharmacokinetics and Antiallodynic Effect During Neuropathic Pain in Rats.

BACKGROUND: Amitriptyline, duloxetine, and pregabalin are among the most pharmacotherapeutic, effective treatments for neuropathic pain control. However, the evaluation of synergism by combining these treatments is still poorly investigated. OBJECTIVES: To evaluate the pharmacokinetics of the combination of pregabalin plus duloxetine and pregabalin plus amitriptyline, as well as the effect of these on neuropathic pain on rodent model. STUDY DESIGN: The experimental study. SETTING: The research took place in the research laboratories at the Federal University of Alfenas after ethics committee approval. METHODS: This study used male Wistar rats weighing between 220 and 250 g. The animals were randomly divided into the following groups: monotherapy (pregabalin, amitriptyline, duloxetine), combined therapy (pregabalin + amitriptyline, pregabalin + duloxetine), and vehicle (ultrapure water). Pharmacokinetic analysis of pregabalin or combination (pregabalin + amitriptyline or pregabalin + duloxetine) in the plasma were performed by ultraperformance liquid chromatography tandem mass spectrometry. Neuropathic pain was induced by sciatic nerve constriction (chronic constriction injury [CCI]) model, and nociceptive threshold was measured by von Frey filaments test. In addition, to evaluate the influence of the treatments on the motor coordination, the rotarod test was used. RESULTS: The pharmacokinetic disposition of pregabalin was changed in the association with amitriptyline, presenting a clearance reduction and consequently an increase in bioavailability. Furthermore, after the 14th day of CCI, pregabalin was administered orally and induced antiallodynic effect after 1, 2:15, 4, and 8 hours of its administration and showed the greatest antiallodynic effect after 4 hours of its administration. Moreover, this effect was prolonged (up to 8 hours) by combination with amitriptyline. Additionally, pregabalin and pregabalin + duloxetine showed a hypoalgesic effect in sham rats. In addition, the rotarod test results showed that drugs did not influence the motor coordination of the rats. LIMITATIONS: Potential competition mechanisms during the excretion of pregabalin, when pregabalin was combined with amitriptyline, were not investigated in this study. CONCLUSIONS: The data demonstrated that combined therapy of pregabalin plus amitriptyline improved the bioavailability of pregabalin and potentiated the efficacy of the antiallodynic effect of pregabalin alone, proving to be advantageous for the treatment of sciatic neuropathic pain.

Toxicological insights of Spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

The Spike protein (S protein) is a critical component in the infection of the new coronavirus (SARS-CoV-2). The objective of this work was to evaluate whether peptides from S protein could cause negative impact in the aquatic animals. The aquatic toxicity of SARS-CoV-2 Spike protein peptides derivatives has been evaluated in tadpoles (n = 50 tadpoles/5 replicates of 10 animals) from species Physalaemus cuvieri (Leptodactylidae). After synthesis, purification, and characterization of peptides (PSDP2001, PSDP2002, PSDP2003) an aquatic contamination has been simulated with these peptides during 24 h of exposure in two concentrations (100 and 500 ng/mL). The control group ("C") was composed of tadpoles kept in polyethylene containers containing de-chlorinated water. Oxidative stress, antioxidant biomarkers and AChE activity were assessed. In both concentrations, PSPD2002 and PSPD2003 increased catalase and superoxide dismutase antioxidants enzymes activities, as well as oxidative stress (nitrite levels, hydrogen peroxide and reactive oxygen species). All three peptides also increased acetylcholinesterase activity in the highest concentration. These peptides showed molecular interactions in silico with acetylcholinesterase and antioxidant enzymes. Aquatic particle contamination of SARS-CoV-2 has cholinesterasic effect in P. cuvieri tadpoles. These findings indicate that the COVID-19 can constitute environmental impact or biological damage potential.