Brazilian Journal of Medical and Biological Research最新文献

Cellular senescence is an important cause of age-related degenerative diseases, including osteoarthritis (OA). Chondrocyte senescence is crucial in OA onset and progression. As a non-invasive, safe, and widely used physical rehabilitation factor, the effect and mechanism of low intensity pulsed ultrasound (LIPUS) on chondrocyte senescence remain unclear. This study evaluated the inhibitory effect of LIPUS on OA chondrocyte senescence in vitro and in vivo. The effect of LIPUS on chondrocyte senescence was examined by RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. Changes in levels of reactive oxygen species (ROS) and γ-h2ax foci in senescent chondrocytes were detected using fluorescent staining. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. The PI3K inhibitor LY294002 and the PI3K agonist 740Y-P were used to investigate whether PI3K/AKT/mTOR signalling was involved in the effect of LIPUS in senescent chondrocytes. Chondrocyte senescence and cartilage degeneration were analyzed in a destabilization of the medial meniscal (DMM) mouse model by immunohistochemistry, hematoxylin and eosin staining, and safranin-O/fast green staining. LIPUS inhibited the expression of the senescence-associated secretory phenotype (SASP) factors CCL4 and CCL2 and the senescence phenotype in doxorubicin-treated chondrocytes by inhibiting the PI3K/AKT/mTOR pathway. LIPUS alleviated chondrocyte senescence and attenuated OA progression in the DMM mice. These results demonstrated a novel role for LIPUS in inhibiting chondrocyte senescence and the SASP by modulating PI3K/AKT/mTOR signalling. Our findings expanded the clinical application of LIPUS and provide a new, non-invasive, and safe treatment approach to prevent and treat age-related degenerative joint disorders.

Rapid dissemination of Klebsiella pneumoniae carbapenemase (KPC) is a leading cause of treatment failure, significantly increasing morbidity and mortality rates among inpatients, particularly in the intensive care unit (ICU). This study aimed to detect the occurrence of carbapenemase- and carbapenem-resistant-encoding genes in K. pneumoniae isolates from COVID-19 positive and negative patients, and to assess their impact on patient outcomes. A prospective analysis was conducted at a tertiary care hospital in Saudi Arabia, collecting 97 carbapenem-resistant K. pneumoniae (CRKP) isolates from patients with COVID-19 during 2020-2021. Isolates were obtained from various clinical specimens. Antimicrobial susceptibility assays were performed using the Automated Vitek-2 system, and data were analyzed using IBM SPSS Statistics. The predominant carbapenemases identified were Oxacillinase-48 (OXA-48), followed by KPC and New Delhi metallo-β-lactamase (NDM), with Imipenemase (IMP) and Verona integron-encoded metallo-β-lactamase (VIM) being the least prevalent. COVID-19 did not significantly affect the distribution of these genes (P>0.05); however, COVID-19 status and age over 60 years significantly impacted the outcomes of CRKP patients. Other factors such as gender, total ICU or ward stay, and comorbidities did not significantly affect CRKP infection outcomes. The most common carbapenem-resistant genes identified were blaKPC, blaNDM, and blaOXA-48; however, they were not significantly associated with increased mortality.

Low back pain (LBP) is a common type of pain that causes disability and impairs cognitive function. With over 80% of adults estimated to experience LBP during their lifetime, this type of pain not only has a significant impact on the individual, but also on public health systems and national economies. Unfortunately, there is no single standard of care for patients with LBP. N-acetylcysteine (NAC), which is used clinically to treat acetaminophen overdose, has recently been tested as a potential treatment for LBP. NAC is inexpensive and commercially available, and it has an established tolerance and safety profile. However, NAC's efficacy in LBP has not been established. This scoping review presents a summary of studies investigating the effects of NAC and the potential benefits in LBP treatment, and highlights its potential molecular mechanisms and side effects. A systematic literature search in Pubmed/MEDLINE, Embase, Scopus, Science Direct, Web of Science, Cinahl, and Lilacs databases was conducted. The PRISMA-ScR checklist was used to ensure integrity of the review. The scoping review protocol was registered in the Open Science Framework. No limit was set on study language and publication date. In total, 2357 articles were located, of which 16 were included. The studies show that NAC has potential for LBP treatment, but data are derived only from a few clinical trials and preclinical studies. Thus, there is much to learn and more clinical studies should be performed before NAC can be clinically recommended for the treatment of LBP.

The COVID-19 pandemic has caused a global crisis, overwhelming hospitals and intensive care units (ICU) and leading to an increase in nosocomial infections due to prolonged hospitalization and other risk factors. The present study evaluated the prevalence of secondary fungal infections in critically ill patients with COVID-19. This is a retrospective, single-center study conducted in a hospital in northeastern Brazil, which evaluated 1,364 medical records of patients admitted to a COVID-19 ICU during 2020 and 2021. A total of 327 pathogenic yeasts were isolated from 132 (40.4%) respiratory, 70 (21.4%) blood, 124 (37.9%) urine, and one (0.3%) surgical wound samples. Fungal infections were diagnosed in the intermediate (5 to 12 days) or late (≥12 days) stage of hospitalization. The most frequent yeast isolated from critically ill COVID-19 patients was Candida albicans [126 (67.7%) and 60 (42.6%)], followed by Candida tropicalis [25 (13.4%) and 39 (27.7%)]. Candida parapsilosis isolates increased 5.7-fold in 2021 [40 (28.4%)] compared to 2020 [7 (3.8%)]. The least frequently isolated in 2020 and 2021 were Nakaseomyces glabratus [4 (2.2%) and 1 (0.7%)], and Pichia kudriavzevii, which was isolated only in 2021 (1 (0.7%)). During the study period, a decrease in susceptibility to antifungals was observed: susceptibility to voriconazole reduced from 100 to 77.2%, to flucytosine from 99.4 to 78.8%, and to micafungin from 99.4 to 83.6%. The changes in the frequency of species causing secondary infections in critically ill COVID-19 patients and susceptibility to the antifungals indicate the need for early and adequate diagnosis to minimize negative outcomes.

Sprint interval training (SIT), which consists of vigorous-intensity exercise interspersed with periods of rest or low-intensity exercise, can improve human anaerobic performance. Probiotic strains, including yeasts (e.g. Saccharomyces boulardii; Sb), have beneficial effects on human health; however, evidence regarding the effects of probiotics on anaerobic performance is unavailable. The current study investigated whether Sb supplementation influences the SIT-induced changes to the following performance variables: peak (PPO) and mean (MPO) power output. Fifteen healthy individuals (twelve men and three women) were randomly divided into two groups: placebo (PLA; n=8) and Sb (n=7). The individuals performed six SIT sessions on a cycle ergometer (four to seven 30-s all-out sprints thrice weekly). During the training period, participants ingested a capsule containing PLA or at least 1×109 Sb cells daily for 14 days. Performance-related variables were compared between the first and last training sessions. Sb supplementation did not influence the changes in PPO and MPO across the two weeks of training (P>0.05); therefore, the data from both groups were analyzed collectively to assess performance changes induced by SIT. Training increased PPO, an index of anaerobic power, in the sixth session compared to the first session (by 8±11% in the first sprint; +1.0±1.2 W/kg; P=0.008) but did not change MPO. In conclusion, short-term SIT improved the participants' anaerobic performance (power), as evidenced by increased PPO. Sb supplementation did not affect the improved anaerobic power caused by SIT.

As limb muscle function is age- and sex-related, both elbow and knee isokinetic muscle functions and their main predictors, such as physical activity level and cardiovascular risk factors, should be determined. We aimed to describe the percentiles of normality of the isokinetic muscle function of the knee and elbow joints. Secondarily, we developed equations to predict muscle function in apparently healthy adults aged 20-80 years, including cardiovascular risk factors. We conducted a cross-sectional study with 1,334 adults. We collected sociodemographic data, self-reported cardiovascular risk, anthropometry, body composition (bioelectrical impedance), moderate-to-vigorous physical activity (MVPA) (triaxial accelerometry), and isokinetic muscle function. Multiple regression analysis was used to develop equations to predict isokinetic muscle function. Percentiles of normality for muscle function were described by sex and age (20-39, 40-59, and >60 years). The models accounted for 49.6-70.9% of the total variability of muscle function, but MVPA and cardiovascular risk slightly influenced the coefficient of determination (additional ΔR2=0.003-0.006). Demographic and anthropometric variables were more relevant predictors of isokinetic muscle function (R2=0.50-0.70) than MVPA and cardiovascular risk. Even though they correlated with muscle function, cardiovascular risk and MVPA failed to explain the variability of muscle function largely determined by anthropometric and sociodemographic data. The percentile values and equations developed will help in interpreting the isokinetic muscle function and improve its clinical use.

Age-related macular degeneration (AMD), particularly the wet form characterized by choroidal neovascularization, is a leading cause of vision loss. Dysregulation of regulatory T cells (Tregs), key modulators of inflammatory responses, may contribute to wet AMD pathogenesis. This study explored the involvement of Tregs and the Rac1 signaling pathway in modulating Treg-derived cytokine expression and their role in choroidal neovascularization during wet AMD progression. Peripheral blood samples from healthy controls, dry AMD patients, and wet AMD patients were collected. An in vitro transmembrane co-culture system of Tregs and human choroidal endothelial cells (HCECs) was employed to investigate the impact of Tregs (with or without Rac1 silencing) on the angiogenic phenotype of HCECs. A mouse model of AMD was established to evaluate the effects of a Rac1 inhibitor and IL-10/TGF-β neutralization on Tregs and choroidal neovascularization. An increased Treg percentage in the CD4+ T lymphocyte population was found in the peripheral blood samples of wet AMD patients. Tregs from wet AMD patients showed an increased expression of Rac1 and an elevated production of IL-10 and TGF-β1. Rac1 silencing suppressed Treg stability and differentiation, and impaired the pro-angiogenic effect of Tregs on HCECs. In the animal model of AMD, the administration of a Rac1 inhibitor or neutralizing antibodies against IL-10/TGF-β1 reduced Treg abundance and attenuated choroidal neovascularization. Rac1 upregulation in Tregs promoted IL-10 and TGF-β1 production to mediate choroidal neovascularization in wet AMD. Targeting Rac1 and Treg-derived IL-10/TGF-β1 production in Tregs may serve as a strategy to ameliorate AMD progression.

Neutrophil extracellular traps (NETs) are a novel regulatory mechanism of neutrophils, which can promote endothelial cell inflammation through direct or indirect pathways and play a crucial role in the occurrence and development of atherosclerosis (AS). This study aimed to explore the mechanism of NETs in AS progression using bioinformatics methods. We acquired datasets from Gene Expression Omnibus (GEO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and used Weighted Gene Co-expression Network Analysis (WGCNA) to identify communal genes shared by NET-related genes. Gene Ontology (GO) and KEGG enrichment analyses were conducted. Machine learning algorithms were used to identify hub genes, then protein-protein interaction (PPI), CO-expression network construction, nomogram model building and validation, and immune infiltration analysis were performed. Data were verified by qPCR. Four datasets related to AS progression were included. Module genes shared 27 genes with NRGs. Pathways related to immune regulation, leukocyte migration, and others were identified. Machine learning revealed SLC25A4 and C5AR1 as hub genes. SLC25A4 and C5AR1 were confirmed to have predictive value for intraplaque hemorrhage (IPH), advanced AS plaques, ruptured plaques, and unstable plaques. These pathologic changes are closely related to AS progression and are the main contents of AS progression. Immune infiltration analysis revealed 4 immune cells associated with IPH, among them resting dendritic cells, which were closely related to SLC25A4. In qPCR validation, SLC25A4 and C5AR1 were shown to be consistent with the bioinformatic analysis results. These findings provided novel insights into the molecular characteristics of NRGs and potential therapies for AS progression.

Osteonecrosis of the femoral head (ONFH) is a debilitating condition characterized by the death of bone cells in the hip joint, resulting in profound disability. This condition has a significant global prevalence. Glucocorticoid (GC)-induced apoptosis of bone cells serves as a crucial cellular mechanism underlying ONFH. The protein kinase C zeta (PKCζ) and c-Jun N-terminal kinase (JNK)/c-Jun cascades have been implicated in the progression of ONFH, yet their interrelationship and contributions to disease development remain unclear. The objective of this study was to investigate the combined impact of PKCζ and JNK/c-Jun signaling on dexamethasone (Dex)-induced apoptosis in osteoblasts in vitro and in GC-induced ONFH rat models in vivo. In vitro experiments were conducted using hFOB1.19 osteoblastic cells to scrutinize the effects of Dex-induced apoptosis. The role of the PKCζ/JNK/c-Jun signaling pathway in this process was examined using naringenin-7-O-β-D-Glucuronide (N7G), a PKC inhibitor, and anisomycin, a JNK activator. The findings were further validated using a rat model of ONFH in vivo. Our results revealed that PKCζ activation augmented JNK/c-Jun signaling and facilitated Dex-induced osteoblast apoptosis. Inhibition of PKCζ with N7G mitigated these effects, while JNK activation with anisomycin intensified them. Similar regulatory effects on osteoblast apoptosis and ONFH progression were observed in the in vivo rat models. Glucocorticoids can induce osteoblast apoptosis and contribute to the development of ONFH by activating the PKCζ/JNK/c-Jun signaling pathway. This study provides compelling evidence supporting the potential therapeutic value of comprehending the pathogenesis of ONFH and developing targeted treatments for this debilitating condition.

Prenatal care is of fundamental importance and must be carried out by a multidisciplinary healthcare team, including dental care, as several changes and complications affecting the oral cavity may occur during pregnancy. This was a cross-sectional study that aimed to analyze the hematological profile of pregnant women with and without periodontal disease (PD). Data were obtained by consulting medical and dental records, which were stratified into two subgroups: pregnant women with PD (n=107) and pregnant women without PD (n=42). Study variables were related to PD, sociodemographic, clinical, and laboratory characteristics. Data were collected from the complete blood count and the following indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), derived NLR (dNLR), systemic inflammation response index (SIRI), aggregate index of systemic inflammation (AISI), and systemic immune-inflammation index (SII). The mean age in both subgroups was 27 years. Pregnant women with less education had more PD. Mean corpuscular volume was significantly higher in pregnant women with PD, probably a reflection of folate deficiency. White blood cell and lymphocyte counts were significantly higher in pregnant women with periodontitis, possibly reflecting an inflammatory process caused by bacterial invasion of the periodontium with systemic repercussions. This study reinforces the need for a multidisciplinary team, including a dentist, in prenatal care, to lower the risk of complications for the mother and child.