RESUMO
PRESTO was established in 2022 and is a concerted effort by leading European experts in the field of P2XRs and extracellular ATP to promote and advance the transition to the clinic of P2XR-targeting therapies. Following the inaugural meeting in Ferrara which set the foundations of the action and generated interest from many groups and institutes, the second meeting covered the preclinical and clinical aspects of P2XRs as a common route in different diseases, recognising the multidisciplinary and collaborative approach required for a number of medical conditions.
RESUMO
BACKGROUND OBJECTIVES: Malaria, a vector-borne diseases caused by Plasmodium species and transmitted by Anopheles species. Among them, Anopheles subpictus has emerged as a potent malarial vector in coastal areas of India. Numerous studies highlighted that bacterial communities within mosquito influence vector competence. The present study was designed to isolate and characterize bacterial microbiota from A. subpictus larvae. METHODS: Isolation and purification of the predominant bacterial strain (AL1). Morphological, biochemical, antibiotic susceptibility and molecular characterization of the isolated bacteria. RESULTS: Bacterial isolate (AL1) was found to be rod, gram negative, catalase positive and oxidase negative. AL1 was identified as Leclercia adecarboxylata (Accession number: OR649235) through 16S rRNA ribotyping. Further, leaf extract of Nyctanthes arbortristis showed inhibitory effect against AL1. INTERPRETATION CONCLUSION: This is the first report on isolation of symbiotic bacteria (L. adecarboxylata) from A. subpictus and its control by leaf extract of Nyctanthes arbortristis. Isolated gram-negative bacterial strain might inhibit the development of mosquito vector and might use for various biological control strategies to combat malaria transmission.
RESUMO
The inaugural meeting of the EU COST Action CA21130 PRESTO was held in February 2023, at the University of Ferrara, Italy. Our meeting report provides an overview of PRESTO, a tribute to Professor Jim Wiley, overviews of the talk, and a speaker synopsis that discusses the resources, models, equipment, and techniques available in different lab groups throughout Europe, increasing the prospect of collaborative research.
Assuntos
Trifosfato de Adenosina , Receptores Purinérgicos P2X , ItáliaRESUMO
PURPOSE OF REVIEW: This review aims at providing updates on selected post-stroke complications. We examined recent advances in diagnosing and treating the following post-stroke complications: cognitive impairment, epilepsy, depression, fatigue, tremors, dysphagia, and pain. RECENT FINDINGS: Advances in understanding the mechanisms of post-stroke complications, in general, are needed despite advances made in understanding, treating, and preventing these complications. There are growing progresses in integrating new tools to diagnose post-stroke cognitive impairment. The potential role of acute stroke reperfusion treatment in post-stroke epilepsy and its impact on other stroke complications is getting more transparent. Post-stroke depression remains underestimated and new tools to diagnose depression after stroke are being developed. New promising pharmacological approaches to treating post-stroke pain are emerging. Tremors related to stroke are poorly understood and under-evaluated, while treatment towards post-stroke dysphagia has benefited from new non-pharmacological to pharmacological approaches. CONCLUSIONS: An integrative approach to stroke complications and collaborations between providers across specialties are more likely to improve stroke outcomes.
Assuntos
Transtornos de Deglutição , Epilepsia , Acidente Vascular Cerebral , Humanos , Depressão/terapia , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Tremor , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/psicologia , Dor/complicaçõesRESUMO
Skeletal muscle is an endocrine organ secreting exercise-induced factors (exerkines), which play a pivotal role in interorgan cross talk. Using mass spectrometry (MS)-based proteomics, we characterized the secretome and identified thymosin ß4 (TMSB4X) as the most upregulated secreted protein in the media of contracting C2C12 myotubes. TMSB4X was also acutely increased in the plasma of exercising humans irrespective of the insulin resistance condition or exercise mode. Treatment of mice with TMSB4X did not ameliorate the metabolic disruptions associated with diet induced-obesity, nor did it enhance muscle regeneration in vivo. However, TMSB4X increased osteoblast proliferation and neurite outgrowth, consistent with its WADA classification as a prohibited growth factor. Therefore, we report TMSB4X as a human exerkine with a potential role in cellular cross talk.
Assuntos
Proliferação de Células/efeitos dos fármacos , Contração Muscular , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Timosina/metabolismo , Timosina/farmacologia , Animais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Humanos , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Osteoblastos/patologia , Resistência Física , Proteômica , Transdução de Sinais , Espectrometria de Massas em TandemRESUMO
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.
Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Metástase Neoplásica , Proteína-Lisina 6-Oxidase/metabolismo , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/prevenção & controle , Neoplasias da Mama/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Camundongos , Fatores de Transcrição NFATC/metabolismo , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Receptores de Estrogênio/deficiência , Receptores de Estrogênio/genéticaRESUMO
BACKGROUND: COVID-19 pandemic has created unprecedented health and economic impact. Psychological stress, anxiety and depression are affecting not only COVID-19 patients but also health professionals, and general population. Fear of contracting COVID-19, forced restrictive social measures, and economic hardship are causing mental trauma. Nepal is a developing country from South Asia where the COVID-19 pandemic is still evolving. This online survey has been carried out to understand impact of COVID- 19 on mental health of Nepalese community dwellers. METHODS: The COVID-19 Peritraumatic Distress Index (CPDI) questionnaire adapted from the Shanghai Mental Health Centre was used for online data collection from 11 April-17 May 2020. Collected data were extracted to Microsoft excel-13 and imported and analyzed using SPSS (Statistical Package for Social Sciences) version-22. An initial univariate analysis was conducted for all variables to assess the distribution. Logistic regression analyses were done to estimate the odds ratios of relevant predicting variables. RESULTS: A total of 410 participants completed the self-rated questionnaires. Mean age of study participants was 34.8 ± 11.7 years with male preponderance. 88.5% of the respondents were not in distress (score less than 28) while, 11% had mild to moderate distress and 0.5% had severe distress. The prevalence of distress is higher among age group > 45 years, female gender, and post-secondary education group. Health professional were more likely to get distressed. Respondents with post-secondary education had higher odds (OR = 3.32; p = 0.020) of developing distress as compared to respondents with secondary education or lower. CONCLUSION: There is lower rate of psychological distress in city dwellers and people with low education. Adequate intervention and evaluation into mental health awareness, and psychosocial support focused primarily on health care workers, female and elderly individuals is necessary.
Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Angústia Psicológica , Estresse Psicológico/epidemiologia , Adulto , COVID-19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nepal/epidemiologia , Prevalência , SARS-CoV-2 , Fatores Socioeconômicos , Estresse Psicológico/psicologia , Inquéritos e QuestionáriosRESUMO
It is now widely recognized that purinergic signaling plays an important role in the regulation of bone remodeling. One receptor subtype, which has been suggested to be involved in this regulation, is the P2Y2 receptor (P2Y2R). In the present study, we investigated the effect of P2Y2R overexpression on bone status and bone cell function using a transgenic rat. Three-month-old female transgenic Sprague Dawley rats overexpressing P2Y2R (P2Y2R-Tg) showed higher bone strength of the femoral neck. Histomorphometry showed increase in resorptive surfaces and reduction in mineralizing surfaces. Both mineral apposition rate and thickness of the endocortical osteoid layer were higher in the P2Y2R-Tg rats. µCT analysis showed reduced trabecular thickness and structural model index in P2Y2R-Tg rats. Femoral length was increased in the P2Y2R-Tg rats compared to Wt rats. In vitro, there was an increased formation of osteoclasts, but no change in total resorption in cultures from P2Y2R-Tg rats. The formation of mineralized nodules was significantly reduced in the osteoblastic cultures from P2Y2R-Tg rats. In conclusion, our study suggests that P2Y2R is involved in regulation of bone turnover, due to the effects on both osteoblasts and osteoclasts and that these effects might be relevant in the regulation of bone growth.
Assuntos
Remodelação Óssea/fisiologia , Receptores Purinérgicos P2Y2/metabolismo , Animais , Feminino , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos TransgênicosRESUMO
INTRODUCTION: The use of locally administered medication (LAM) agents such as minocycline, metronidazole, and tetracycline as antimicrobials has drawbacks, including the development of microorganism resistance, exorbitant pricing, and limited accessibility. Thus, there is a need for safer and more affordable alternatives. Numerous natural therapies have been found to be superior in this situation. In this study, the efficacy of tulsi extract as a LAM agent was assessed and it was compared with curcumin, which is currently used for the treatment of periodontal pockets. METHODS AND MATERIALS: There were three categories: each category had 30 sites. Category 1 sites underwent scaling along with root planing (SRP) solely, Category 2 sites received curcumin extract as LAM in the periodontal pocket in addition to SRP, and Category 3 sites received tulsi extract as LAM in the periodontal pocket in addition to SRP. The stent was used to ensure consistent and unbiased measurements on the 30th day after treatment. Clinical attachment level (CAL) and probing pocket depth (PPD) were measured at six points around each tooth. Results: The reduction in values of periodontal parameters such as BAPNA (Nα-benzoyl-DL-arginine-p-nitroanilide) assays, modified sulcus bleeding index (mSBI), gingival index (GI), plaque index (PI), CAL, and PPD in sites within Category 1, Category 2, and Category 3 was statistically significant. The decrease in BAPNA assay results indicates that tulsi extract is more effective than curcumin gel at eradicating red-complex bacteria. Although not significantly different, the decrease in PI and GI was observed to be greater when curcumin jelly was used. This suggests that curcumin jelly has a stronger impact on reducing plaque, which in turn decreases gingival inflammation. CONCLUSION: Based on the overall results of the study, it can be said that both tulsi and curcumin have similar effectiveness in reducing periodontal markers.
RESUMO
BACKGROUND: A spinal discectomy surgery (SDS) is a common surgical procedure performed to treat lumbosacral radiculopathy. AIM: To evaluate postoperative patterns of pain and disability in patients undergoing spinal discectomy. METHODS AND MATERIALS: This investigation was a retrospective longitudinal review of prospective information gathered from 543 enrolled patients for lumbar radiculoplasty. The study participants were divided into two categories: Category 1 (SDS) comprising patients of lumbar radiculoplasty managed with SDS (n=270) and Category 2 (non-SDS) comprising patients of lumbar radiculoplasty managed with therapy other than SDS (n=273). It included study participants taking medication for pain control including opioids and non-opioids and physiotherapy for strengthening lower back muscles. At baseline, three months, 12 months, and 24 months after surgery, patient-reported information was gathered. Leg pain magnitude, back pain magnitude, and pain-related impairment were the key outcome metrics of interest. RESULTS: The mean postoperative visual analog scale (VAS) score for leg pain at three-month follow-up was 4.3±1.2 in study participants in SDS and 8.1±1.3 in the non-SDS category. The VAS score was lower in the SDS category showing greater reduction in postoperative pain with statistically meaningful results (p<0.001). The mean postoperative VAS score at 12-month follow-up was 2.8±1.1 in study participants in SDS and 7.9±1.5 in the non-SDS category. The VAS score was lower in the SDS category showing greater reduction in postoperative pain with statistically meaningful results (p<0.001). The mean postoperative VAS score at 24-month follow-up was 1.7±1.2 in study participants in SDS and 7.1±1.1 in the non-SDS category. The VAS score was lower in the SDS category showing greater reduction in postoperative pain with statistically meaningful results (p<0.001). CONCLUSION: It was observed that after discectomy, patients suffering from lumbar radiculopathy have significant pain and disability recovery. According to these results, only a small percentage of individuals exhibit negative results at the level of impairment.
RESUMO
Background Gingivitis is a common oral health condition characterized by inflammation of the gingiva, which, if left untreated, can progress to more severe forms of periodontal disease. Effective oral hygiene practices play a crucial role in managing gingivitis, but the comparative efficacy of different oral hygiene aids remains unclear. This study aimed to evaluate and compare the efficacy of various oral hygiene aids in maintaining periodontal health in patients with gingivitis, considering gender and the degree of gingivitis as potential influencing factors. Methods A total of 120 participants with gingivitis were enrolled in this study. The participants were randomly assigned to one of four groups, each utilizing a different oral hygiene aid: Group A (toothbrush), Group B (electric toothbrush), Group C (brushing along with the use of an interdental brush), and Group D (brushing along with the use of a water flosser). All participants received toothpaste for use with their respective oral hygiene aids. Periodontal health parameters, including plaque index (PI), gingival index (GI), and bleeding on probing (BOP) score, were assessed at baseline and after a specified duration of oral hygiene intervention. Also, the microbial count for Streptococcus, Actinomyces, Porphyromonas, Fusobacterium, and Veillonella species was evaluated. Results No significant differences in periodontal health outcomes were observed between males and females in any of the oral hygiene aid groups. Similarly, no significant differences were found among the mild, moderate, and severe gingivitis groups within each oral hygiene aid group. The microbial count also has no statistical significance except for streptococcus species. These findings indicate that the efficacy of the tested oral hygiene aids was comparable across genders and different degrees of gingivitis. Conclusion The findings of this study suggest that the tested oral hygiene aids were effective in maintaining periodontal health in patients with gingivitis, irrespective of gender and the degree of gingivitis. These results have implications for oral healthcare professionals in their recommendations to patients regarding oral hygiene practices. However, it is important to consider the limitations of this study, including the relatively small sample size and the specific oral hygiene aids tested.
RESUMO
BACKGROUND: Craniotomy is associated with significant postoperative discomfort. Standardized pain management and enhanced recovery after surgery (ERAS) protocol could improve patient-reported outcomes and lower medical expenses. AIM: The aim of this study is to prospectively assess the effectiveness of an ERAS protocol for neurosurgery in the treatment of postoperative pain following elective craniotomies. METHODS AND MATERIALS: A total of 128 patients were assigned to the ERAS group and received care in accordance with the neurosurgical ERAS regulations, while 130 other participants were assigned to the control group and received traditional postoperative assistance. The participants' postoperative pain ratings using the numerical rating scale (NRS) were this study's main outcome of interest. The verbal NRS uses the numbers 0 to 10, with 0 indicating no sensation of pain and 10 indicating the most severe pain. On postoperative day (POD) 1, the patients' postoperative pain level at the surgical site was evaluated using the NRS. This was repeated every day until the patient either reported feeling no sensation of pain or was discharged home. RESULTS: The mean value of pain on the day of surgery was 4.43 ± 0.43 and 4.72 ± 0.68 for patients in the ERAS and control groups, respectively. The pain values were higher in the control group compared to the ERAS group. However, the difference was not statistically significant (p = 0.478). The mean value of pain on POD1 was 3.13 ± 0.21 and 4.45 ± 0.95 for patients in the ERAS and control groups, respectively. These pain values were higher in the control group compared to the ERAS group, and the difference was statistically significant (p = 0.011). The mean value of pain on POD2 was 2.86 ± 0.3 and 4.33 ± 0.37 for patients in the ERAS and control groups, respectively. The values of pain were higher in the control group compared to the ERAS group, and the difference was statistically significant (p = 0.003). The mean value of pain on POD3 was 2.33 ± 0.52 and 4.04 ± 0.15 for patients in the ERAS and control groups, respectively. The pain values were higher in the control group compared to the ERAS group. The difference was meaningful statistically (p < 0.001). The mean value of pain on POD4 was 2.26 ± 0.9 and 2.84 ± 0.13 for the ERAS and control groups, respectively. However, the difference was not statistically significant (p = 0.274). The ERAS group had a significantly higher proportion of participants rating their pain between 1 and 3 (68.9%) and a lower proportion rating their pain between 4 and 7 (28.2%), compared to the control group (p < 0.001). Differences in the highest pain ratings (8-10) between the groups were not statistically significant. The duration of hospital stay, beginning from surgery to discharge, was lesser among study participants in the ERAS group, and this finding was statistically significant (p < 0.001). CONCLUSION: The findings of this study imply that the ERAS protocol may aid pain management following elective craniotomies. Additionally, the ERAS protocol decreased the overall expense of medical care and the cumulative/postoperative length of hospital stay.
RESUMO
The use of herbal mouthrinse is gaining momentum in recent years. Therefore, it is of interest to evaluate the effect of 2 herbal mouthrinse (curcumin, cinnamon) in comparison with2 conventional mouthrinse (povidone iodine, chlorhexidine) when used as coolant in dental ultrasonic scalers. Hence, 200 participants were included in this study. Analysis of gingival index, periodontal index at baseline and one month follow up was completed. The inhibitory effects of both conventional and herbal mouth rinse in gingival health are similar. However, cinnamon and curcumin owing to its minimal adverse effects and low cost is useful as an alternative to chlorhexidine for reducing bacterial load in dental aerosols produced due to ultrasonic scalers.
RESUMO
OBJECTIVES: In preparation of a definitive randomized clinical trial (RCT), the current parallel-grouped triple-blind pilot RCT assessed the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) with polylactic acid/polyglycolic acid (PLA/PGA) membrane for improvement of periodontal tissue regeneration in Class II furcation type defects. METHOD AND MATERIALS: With the present single-center investigation, 24 patients/24 mandibular molars revealing Class II furcation lesions with involved buccal surfaces were randomly allocated and treated surgically, using either a PLA/PGA membrane alone (control, n = 12) or in combination with rhBMP-2 (n = 12). Assessors, participants, and the statistician were blinded to the treatment groups. Clinical parameters including Plaque Index (PI), Papillary Bleeding Index (PBI), clinical attachment level, vertical probing depth, horizontal probing depth, and gingival recession were assessed at baseline and 6 months postsurgery. RESULTS: Baseline values concerning the investigated parameters were comparable between both groups (P > .05). After 6 months, clinical attachment level gain was similar (P = .76), while greater reductions in vertical probing depth (P = .01) and horizontal probing depth (P = .05), along with less gingival recession (P = .03) were observed in the PLA/PGA + rhBMP-2 group (compared to the controls). An increased number of completely closed furcation type defects was observed in the PLA/PGA + rhBMP-2 group (with no adverse effects). CONCLUSIONS: When treating Class II furcation lesions, the use of rhBMP-2 (combined with PLA/PGA membranes) seems advantageous. The presented set-up seems feasible with regards to recruitment, randomization, acceptance, retention, and adherence to the study protocol. (Quintessence Int 2023;54:112-124; doi: 10.3290/j.qi.b3631815).
Assuntos
Defeitos da Furca , Retração Gengival , Humanos , Retração Gengival/cirurgia , Defeitos da Furca/cirurgia , Implantes Absorvíveis , Projetos Piloto , Perda da Inserção Periodontal/cirurgia , Poliésteres , Dente Molar/cirurgia , Regeneração Tecidual Guiada Periodontal/métodos , Membranas Artificiais , Resultado do TratamentoRESUMO
BACKGROUND: Postoperative pain is a common concern in root canal treatment, and the choice of instrumentation technique can significantly impact patient comfort. This study aimed to evaluate the impact of different instrumentation techniques on the incidence of postoperative pain in patients undergoing root canal treatment. METHODS: A randomized controlled trial was conducted on 208 patients randomly assigned to four groups: step-back preparation, crown-down preparation, hybrid technique, and conventional instrumentation. Pain intensity was assessed using a verbal rating scale (VRS) at six, 12, 24, 48, and 72 hours postoperatively. Data were analyzed using appropriate statistical methods. RESULTS: The mean pain scores and standard deviations (SDs) were calculated for each instrumentation technique at different time intervals. At six hours, the step-back preparation group reported a mean pain score of 2.3 (SD = 0.8), the crown-down preparation group had a score of 2.8 (SD = 0.9), the hybrid technique group had a score of 2.5 (SD = 0.7), and the conventional instrumentation group had a score of 3.1 (SD = 0.1). The differences in pain scores between the groups were statistically significant at all time intervals (p < 0.05). CONCLUSION: The choice of instrumentation technique significantly influenced the incidence of postoperative pain in root canal treatment. The step-back preparation technique was associated with lower pain intensity than the crown-down preparation, hybrid technique, and conventional instrumentation. These findings highlight the importance of considering the instrumentation technique to optimize patient comfort during and after root canal treatment.
RESUMO
The effect of chlorhexidine (CHX) digluconate, Betadine (BET), curcumin (CUR) on gingival wound healing is of interest to dental practitioners. Hence, we studied the average fibroblast viability % for each of the concentrations of CUR, BET and CHX over various time durations. It was found that mean percentage of viability of fibroblasts is high in CUR and low in CHX at all time periods while the mean percentage of viability of fibroblasts in BET 1% was greater than CHX but lower than CUR at all time periods. Thus, curcumin at a concentration of 0.003% demonstrates the least cytotoxicity for fibroblasts. Hence, it is the most effective bacterial suppression, and the best wound healing.
RESUMO
Ocrelizumab is a recombinant humanized antibody targeted against CD-20 molecule, which was approved for the treatment of relapsing and primary progressive multiple sclerosis. Common adverse events of ocrelizumab include infusion-related reactions like rash, pruritus, and flushing. Late-onset neutropenia (LON) is a rarely reported complication of ocrelizumab therapy. We report a case of severe late-onset neutropenia in a patient with primary progressive multiple sclerosis treated with ocrelizumab with neutropenia occurring 3 months after the last dose received treated with empirical broad-spectrum intravenous antibiotics and filgrastim. Severe late-onset neutropenia is a rare unpredictable adverse event and outlines the importance of regular routine blood workup for detecting severe neutropenia early in its course.
RESUMO
Increased incidence of bone fractures in the elderly is associated with gradual sarcopenia. Similar deterioration of bone quality is seen with prolonged bed rest, spinal cord injuries or in astronauts exposed to microgravity and, preceded by loss of muscle mass. Signaling mechanisms involving uridine-5'-triphosphate (UTP) regulate bone homeostasis via P2Y2 receptors on osteoblasts and osteoclasts, whilst dictating the bone cells' response to mechanical loading. We hypothesized that muscle paralysis-induced loss of bone quality would be prevented in P2Y2 receptor knockout (KO) mice. Female mice injected with botulinum toxin (BTX) in the hind limb developed muscle paralysis and femoral DXA analysis showed reduction in bone mineral density (<10%), bone mineral content (<16%) and bone area (<6%) in wildtype (WT) compared to KO littermates (with <13%, <21%, <9% respectively). The femoral metaphyseal strength was reduced equally in both WT and KO (<37%) and <11% in diaphysis region of KO, compared to the saline injected controls. Tibial micro-CT showed reduced cortical thickness (12% in WT vs. 9% in KO), trabecular bone volume (38% in both WT and KO), trabecular thickness (22% in WT vs. 27% in KO) and increased SMI (26% in WT vs. 19% in KO) after BTX. Tibial histomorphometry showed reduced formation in KO (16%) but unchanged resorption in both WT and KO. Furthermore, analyses of DXA and bone strength after regaining the muscle function showed partial bone recovery in the KO but no difference in the bone recovery in WT mice. Primary osteoblasts from KO mice displayed increased viability and alkaline phosphatase activity but, impaired bone nodule formation. Significantly more TRAP-positive osteoclasts were generated from KO mice but displayed reduced resorptive function. Our data showed that hind limb paralysis with a single dose of BTX caused profound bone loss after 3 weeks, and an incomplete reversal of bone loss by week 19. Our findings indicate no role of the P2Y2 receptor in the bone loss after a period of skeletal unloading in mice or, in the bone recovery after restoration of muscle function.
Assuntos
Doenças Ósseas Metabólicas , Animais , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/prevenção & controle , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Knockout , Músculos , ParalisiaRESUMO
Maintenance of a healthy skeleton is highly dependent on an intricate regulation of bone metabolism, as changes in the balance between bone formation and bone resorption leads to bone loss, bone fragility and ultimately bone fractures. During the last three decades it has become increasingly evident that physiological release of purines in the extracellular space is imperative for bone homeostasis and is orchestrated via the network of purinoceptors. Adenosine derivatives are released locally in the skeleton either by the bone forming osteoblasts or the bone degrading osteoclasts actioned directly by processes like mechanical loading and indirectly by systemic hormones. Adenosine derivatives directly affect the bone cells by their action on the membranal receptors or have co-stimulatory actions with bone active hormones such as parathyroid hormone or the gut hormones. Any deviations leading to increased levels of extracellular adenosine derivatives in the bone tissue such as in pathologic situations, trigger complex pathways with opposing effects on tissue health as presented by studies involving a range of model organisms. Pathological conditions where skeletal purinergic signaling is affected are following tissue injury like microdamage and macroscopic fractures; and during inflammatory processes where nucleotides and nucleosides play an important part in the pathophysiological skeletal response. Moreover, adenosine derivatives also play an important role in the interaction between malignant cells and bone cells in several types of cancers involving the skeleton, such as but not limited to multiple myeloma and bone osteolysis. Much knowledge has been gained over the last decades. The net- resulting phenotype of adenosine derivatives in bone (including the ratio of ATP to Adenosine) is highly dependent on CD39 and CD73 enzymes together with the expression and activity of the specific receptors. Thus, each component is important in the physiological and pathophysiological processes in bone. Promising perspectives await in the future in treating skeletal disorders with medications targeting the individual components of the purinergic signaling pathway.