EXCLI Journal最新文献

Osteoarthritis (OA) is a degenerative joint disease that occurs with aging. In its late phases, it is determined by the loss of chondrocytes and the breakdown of the extracellular matrix, resulting in pain and functional impairment. Interleukin-1 beta (IL-1β) is increased in the injured joints and contributes to the OA pathobiology by inducing chondrocyte apoptosis and up-regulation of matrix metalloproteinases (MMPs). Here, we aimed to understand whether minocycline could protect chondrocytes against the IL-1β-induced effects. The human C28/I2 chondrocyte cell line was treated with IL-1β or IL-1β plus minocycline. Cell viability/toxicity, cell cycle progression, and apoptosis were assessed with MMT assay and flow cytometry. Expression of apoptotic genes and MMPs were evaluated with qRT-PCR and western blotting. IL-1β showed a significant cytotoxic effect on the C28/I2 chondrocyte cells. The minocycline effective concentration (EC₅₀) significantly protected the C28/I2 cells against the IL-1β-induced cytotoxic effect. Besides, minocycline effectively lowered IL-1β-induced sub-G1 cell population increase, indicating the minocycline anti-apoptotic effect. When assessed by real-time PCR and western blotting, the minocycline treatment group showed an elevated level of Bcl-2 and a significant decrease in the mRNA and protein expression of the apoptotic markers Bax and Caspase-3 and Matrix metalloproteinases (MMPs) such as MMP-3 and MMP-13. In conclusion, IL-1β promotes OA by inducing chondrocyte death and MMPs overexpression. Treatment with minocycline reduces these effects and decreases the production of apoptotic factors as well as the MMP-3 and MMP-13. Minocycline might be considered as an anti-IL-1β therapeutic supplement in the treatment of osteoarthritis. See also the graphical abstract(Fig. 1).

Celecoxib, a selective COX-2 inhibitor, and non-selective anti-inflammatory drug, is commonly prescribed as the first-line analgesic for osteoarthritis, rheumatoid arthritis, and certain acute pain cases. It is mainly preferred for its lower risk of gastrointestinal adverse effects. However, it also carries risks, including renal and liver toxicity, anaphylaxis, and Stevens-Johnson syndrome. A rare but severe cutaneous adverse reaction associated with celecoxib is Acute Generalized Exanthematous Pustulosis (AGEP), characterized by extensive nonfollicular sterile pustules on an erythematous background, fever, and neutrophilic leukocytosis. AGEP is a rare condition with an incidence rate of 1-5 cases per million per year in the general population. It is primarily triggered by drugs, with antibiotics accounting for over 90 % of cases. Here, we present the case of a 44-year-old female who presented with a sudden, rapidly progressive, painful, pruritic rash all over her body with associated leukocytosis. A skin biopsy confirmed the presence of a pustular rash. The patient reported taking Celebrex (celecoxib) for worsening arthritis two weeks prior to symptom onset. The patient was diagnosed with Celecoxib-induced AGEP based on clinical and histopathological features. Treatment involved steroid therapy and discontinuation of NSAIDs (non-steroidal anti-inflammatory drugs). Encouragingly, the patient's rash improved within three days. Our case report aims to raise awareness of AGEP as a side effect of NSAIDs. Although AGEP is not typically serious, it can be fatal in elderly patients. Therefore, prompt identification and immediate cessation of the culprit drug is crucial.

Swallowing problems are frequent in Parkinson's disease (PD). The aim of this study was to determine the effectiveness of combined transcranial Direct Current Stimulation (tDCS) and Conventional Dysphagia Therapy (CDT) on dysphagia in PD patients. Twenty PD patients with dysphagia were randomized into two groups: combination therapy (anodal tDCS plus CDT) and sham tDCS combined with CDT. Anodal or sham tDCS, bilaterally over the pharyngeal motor cortex, was applied with one mA during the first 20 min (real) or 30 s (sham) of CDT, which was delivered for 30 min. Both groups received twice-daily treatment sessions within two weeks. Swallowing functions were evaluated before, immediately, and one month after the intervention via the Penetration-Aspiration Scale (PAS), and the Swallowing Disorder Questionnaire (SDQ) as the primary outcome measures, and the Dysphagia Handicap Index (DHI) as the secondary outcome measure. The results showed a significant improvement of PAS scores from baseline to post-intervention and baseline to follow-up in both groups without significant differences between groups (t=0.03, p=0.973, and t=1.27, p=0.22 for post-intervention and follow-up time points, respectively). The results showed a significant reduction of SDQ and DHI scores in both groups after the intervention, but the magnitude of the change was significantly larger in the anodal tDCS group at the post-intervention (ta=2.58, pa=0.019 and tb=2.96, pb=0.008) and follow-up (ta=2.65, pa=0.016 and tb=2.97, pb=0.008) time points. This study provides preliminary evidence that bi-hemispheric anodal tDCS combined with CDT enhances swallowing functions in patients with Parkinson's disease more than CDT alone.

Drug-induced kidney injury (DIKI) is a cause of drug development failure. Dogs represent a common non-rodent animal model in pre-clinical safety studies; however, biomarker assays for detecting nephrotoxicity in dogs are limited. To identify novel proteins and gain insight into the molecular mechanisms involved in DIKI, we developed an assay to evaluate proteomic changes associated with DIKI in male beagle dogs that received nephrotoxic doses of tobramycin for 10 consecutive days. Label-free quantitative discovery proteomics analysis on representative kidney cortex tissues collected on Day 11 showed that the tobramycin-induced kidney injury led to a significant differential regulation of 94 proteins mostly associated with mechanisms of nephrotoxicity such as oxidative stress and proteasome degradation. For verification of the proteomic results, we developed a multiplex peptide-centric immunoaffinity liquid chromatography tandem mass spectrometry assay (IA LC-MS/MS) to evaluate the association of eight DIKI protein biomarker candidates using kidney cortices collected on Day 11 and urine samples collected on Days -4, 1, 3, 7 and 10. The results showed that most biomarkers evaluated were detected in the kidney cortices and their expression profile in tissue aligned with the label-free data. Cystatin C was the most consistent marker regardless of the magnitude of the renal injury while fatty acid-binding protein-4 (FABP4) and kidney injury molecule-1 (KIM-1) were the most affected biomarkers in response to moderate proximal tubular injury in absence of changes in serum-based concentrations of blood urea nitrogen or creatinine. In the urine, clusterin is considered the most consistent biomarker regardless of the magnitude and time of the renal injury. To our knowledge, this is the most comprehensive multiplex assay for the quantitative analysis of mechanism-based proximal tubular injury biomarkers in dogs.

In recent decades, significant progress has been made in understanding the molecular characteristics of cancer and its microenvironment, leading to the development of life-saving treatments. However, patients often experience side effects from standard therapies, highlighting the need for personalized medicine. Personalized medicine aims to customize drug therapy and preventive care based on individual patients' specific requirements. The heterogeneity within tumors and among patients necessitates personalized medicine approaches. Patient-derived organoids (PDOs), xenografts (PDXs), and explants (PDEs) have emerged as valuable models for studying tumor behaviour and drug response. This paper aims to summarize the latest advancements in patient-derived explants, focusing on their potential utility in the clinic. Different methods for culturing PDEs, including the free-floating approach, the grid method, and sponge scaffolds, are discussed. These approaches provide opportunities for long-term viability, oxygen and nutrient supply, and maintenance of tissue integrity. Additionally, various solid tumor models using PDEs are highlighted, together with assays to study PDE viability, characteristics, and response to drug treatment.

Addressing the formidable challenge posed by the development of effective and personalized interventions for major depressive disorder (MDD) necessitates a comprehensive comprehension of the intricate role that plasma amino acids play and their implications in MDD pathology and pharmacology. Amino acids, owing to their indispensable functions in neurotransmission, metabolism, and immune regulation, emerge as pivotal entities in this intricate disorder. Our primary objective entails unraveling the underlying mechanisms and unveiling tailored treatments through a meticulous investigation into the interplay between plasma amino acids, MDD, and pharmacological strategies. By conducting a thorough and exhaustive review of the existing literature, we have identified pertinent studies on plasma amino acids in MDD, thereby uncovering noteworthy disturbances in the profiles of amino acids among individuals afflicted by MDD when compared to their healthy counterparts. Specifically, disruptions in the metabolism of tryptophan, phenylalanine, and tyrosine, which serve as precursors to essential neurotransmitters, have emerged as prospective biomarkers and critical contributors to the pathophysiology of depression. Amnio acids play an essential role in MDD and could represent an attractive pharmacological target, more studies are further required to fully reveal their underlying mechanisms.

Early and reliable detection of infection is vital for successful treatment. Serum markers such as C-reactive protein (CRP) and procalcitonin (PCT) are known to increase with a time lag. Azurocidin 1 (AZU1) has emerged as a promising marker for septic patients, but its diagnostic value in orthopedic and trauma patients remains unexplored. Between July 2020 and August 2023, all patients necessitating inpatient treatment for periprosthetic joint infection (PJI), peri-implant infection (II), soft tissue infection, chronic osteomyelitis, septic arthrodesis, bone non-union with and without infection were enrolled. Patients undergoing elective total joint arthroplasty (TJA) served as the control group. Blood samples were collected and analyzed for CRP, white blood cell count (WBC), PCT, and AZU1. Based on the inclusion and exclusion criteria 222 patients were included in the study (trauma = 38, soft tissue infection = 75, TJA = 33, PJI/II = 39, others = 37). While sensitivity and specificity were comparably high for AZU1 (0.734/0.833), CRP and PCT had higher specificity (0.542/1 and 0.431/1, respectively), and WBC a slightly higher sensitivity (0.814/0.455) for septic conditions. Taken together, the area under the curve (AUC) showed the highest accuracy for AZU1 (0.790), followed by CRP (0.776), WBC (0.641), and PCT (0.656). The Youden-Index was 0.57 for AZU1, 0.54 for CRP, 0.27 for WBC, and 0.43 for PCT. Elevated AZU1 levels effectively distinguished patients with a healthy condition from those suffering from infection. However, there is evidence suggesting that trauma may influence the release of AZU1. Additional research is needed to validate the diagnostic value of this new biomarker and further explore its potential clinical applications.

This review delves into the pivotal role of the long non-coding RNA NEAT1 in cancer biology, particularly in lung cancer (LC). It emphasizes NEAT1's unique subcellular localization and active involvement in gene regulation and chromatin remodeling. The review highlights NEAT1's impact on LC development and progression, including cell processes such as proliferation, migration, invasion, and resistance to therapy, positioning it as a potential diagnostic marker and therapeutic target. The complex web of NEAT1's regulatory interactions with proteins and microRNAs is explored, alongside challenges in targeting it therapeutically. The review concludes optimistically, suggesting future avenues for research and personalized LC therapies, shedding light on NEAT1's crucial role in LC. See also the Graphical abstract(Fig. 1).