Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency.

HCV NS5B polymerase is an attractive and validated target for anti-HCV therapy. Starting from our previously identified 2-aryl quinolones as novel non-nucleoside NS5B polymerase inhibitors, structure-based optimization furnished 2-alkyl-N-benzyl quinolones with improved antiviral potency by employing privileged fragment hybridization strategy. The N-(4-chlorobenzyl)-2-(methoxymethyl)quinolone derivative 5f proved to be the best compound of this series, exhibiting a selective sub-micromolar antiviral effect (EC50=0.4µM, SI=10.8) in Huh7.5.1 cells carrying a HCV genotype 2a. Considering the undesirable pharmacokinetic property of the highly substituted quinolones, a novel chemotype of 1,6-naphthyridine-4,5-diones were evolved via scaffold hopping, affording brand new structure HCV inhibitors with compound 6h (EC50 (gt2a)=2.5µM, SI=7.2) as a promising hit. Molecular modeling studies suggest that both of 2-alkyl quinolones and 1,6-naphthyridine-4,5-diones function as HCV NS5B thumb pocket II inhibitors.

The role of foam cells in spinal cord injury: challenges and opportunities for intervention.

Spinal cord injury (SCI) results in a large amount of tissue cell debris in the lesion site, which interacts with various cytokines, including inflammatory factors, and the intrinsic glial environment of the central nervous system (CNS) to form an inhibitory microenvironment that impedes nerve regeneration. The efficient clearance of tissue debris is crucial for the resolution of the inhibitory microenvironment after SCI. Macrophages are the main cells responsible for tissue debris removal after SCI. However, the high lipid content in tissue debris and the dysregulation of lipid metabolism within macrophages lead to their transformation into foamy macrophages during the phagocytic process. This phenotypic shift is associated with a further pro-inflammatory polarization that may aggravate neurological deterioration and hamper nerve repair. In this review, we summarize the phenotype and metabolism of macrophages under inflammatory conditions, as well as the mechanisms and consequences of foam cell formation after SCI. Moreover, we discuss two strategies for foam cell modulation and several potential therapeutic targets that may enhance the treatment of SCI.

Impact of inflammation and Treg cell regulation on neuropathic pain in spinal cord injury: mechanisms and therapeutic prospects.

Spinal cord injury is a severe neurological trauma that can frequently lead to neuropathic pain. During the initial stages following spinal cord injury, inflammation plays a critical role; however, excessive inflammation can exacerbate pain. Regulatory T cells (Treg cells) have a crucial function in regulating inflammation and alleviating neuropathic pain. Treg cells release suppressor cytokines and modulate the function of other immune cells to suppress the inflammatory response. Simultaneously, inflammation impedes Treg cell activity, further intensifying neuropathic pain. Therefore, suppressing the inflammatory response while enhancing Treg cell regulatory function may provide novel therapeutic avenues for treating neuropathic pain resulting from spinal cord injury. This review comprehensively describes the mechanisms underlying the inflammatory response and Treg cell regulation subsequent to spinal cord injury, with a specific focus on exploring the potential mechanisms through which Treg cells regulate neuropathic pain following spinal cord injury. The insights gained from this review aim to provide new concepts and a rationale for the therapeutic prospects and direction of cell therapy in spinal cord injury-related conditions.

Central sensitization syndrome in patients with rotator cuff tear: prevalence and associated factors.

INTRODUCTION: A significant number of rotator cuff tear (RCT) patients developed chronic shoulder pain that did not correspond to physiological changes. Central sensitization syndrome (CSS) is a neurophysiological adaptation process that can result in hypersensitivity to peripheral stimuli. Although there is evidence of an association between CSS and musculoskeletal problems, no studies have focused on the association between CSS and RCT. The primary purpose of this study was to examine the prevalence of CSS in patients with RCT. The secondary purpose was to document the associated conditions and comorbidity that were associated with the CSS. METHODS: This was a cross-sectional study of patients with RCT who completed the Central Sensitization Inventory (CSI). Patients with score of ≥ 40/100 were considered positive for CSS. Demographic and clinical data and CSI results were collected to analyze the prevalence and associated factors of CSS in RCT patients. RESULTS: A total of 404 RCT patients were included, and the CSS prevalence was 39.4%. Compared to the non-CSS group, the CSS group had an odds ratio of 4.13 (95% CI, 2.70-6.32; p＜0.001) for ages 51-60, 3.07 (95% CI, 2.00-4.69; p＜0.001) for symptoms lasting more than 6 months, 6.08 (95% CI, 3.90-9.47; p＜0.001) for nonphysical laborers, 3.69 (95%CI, 2.42-5.61; p＜0.001) for long head of biceps (LHB) abnormality, 2.93 (95% CI, 1.93-4.45; p＜0.001) for concurrent shoulder stiffness, 4.82 (95% CI, 2.55-9.10; p＜0.001) for anxiety or panic episodes, and 2.11 (95% CI, 1.12, 4.00; p＜0.001) for depression. CONCLUSIONS: The prevalence of CSS in patients with RCT was relatively high at 39.4%. The CSS was associated with higher age, female gender, and clinical findings of symptoms lasting over six months, nonphysical laborers, abnormal LHB, concurrent shoulder stiffness, anxiety, and depression.

Changes in respiratory structure and function after traumatic cervical spinal cord injury: observations from spinal cord and brain.

Respiratory difficulties and mortality following severe cervical spinal cord injury (CSCI) result primarily from malfunctions of respiratory pathways and the paralyzed diaphragm. Nonetheless, individuals with CSCI can experience partial recovery of respiratory function through respiratory neuroplasticity. For decades, researchers have revealed the potential mechanism of respiratory nerve plasticity after CSCI, and have made progress in tissue healing and functional recovery. While most existing studies on respiratory plasticity after spinal cord injuries have focused on the cervical spinal cord, there is a paucity of research on respiratory-related brain structures following such injuries. Given the interconnectedness of the spinal cord and the brain, traumatic changes to the former can also impact the latter. Consequently, are there other potential therapeutic targets to consider? This review introduces the anatomy and physiology of typical respiratory centers, explores alterations in respiratory function following spinal cord injuries, and delves into the structural foundations of modified respiratory function in patients with CSCI. Additionally, we propose that magnetic resonance neuroimaging holds promise in the study of respiratory function post-CSCI. By studying respiratory plasticity in the brain and spinal cord after CSCI, we hope to guide future clinical work.

The Effect of Intra-articular Injection of Hyaluronic Acid in Frozen Shoulder: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Frozen shoulder (FS) is a common progressive disorder that causes restricted motion and refractory pain undermining quality of life. Intra-articular hyaluronic acid (HA) injection is a widely adopted conservative therapy relieving symptomatic FS, whereas the effect of which were contradictory and unclear in current literatures. The aim of the present study is to investigate whether intra-articular HA administration facilitates symptomatic pain relief and functional improvements in patients diagnosed with shoulder FS. METHODS: The PubMed, Embase, Cochrane Library electronic databases and Google scholar were searched, from inception to 15th Jan 2022. Randomized controlled trials (RCTs) comparing intra-articular HA administration with any other non-surgical treatment in patients with FS were included. Risk of bias was evaluated using the Cochrane risk-of-bias tool and meta-analyses were undertaken to pool the data of visual analog scale for pain, range of motion (ROM) in external rotation, abduction, and flexion, as well as Shoulder Pain and Disability Index (SPADI), Constant score and American Shoulder and Elbow Surgeons (ASES). RESULTS: The present study included 7 RCTs involving 504 patients. The results provided no support for superior pain control in patients undergoing HA injection compared with any other treatment (p = 0.75). Furthermore, HA group failed to exert superior improvements to other treatments in ROM concerning abduction (p = 0.69) and flexion (p = 0.33). However, HA injection was observed to facilitate functional recovery in external rotation (p = 0.003). In addition, the pooled data showed a significant higher SPADI score in control group than in HA group (p = 0.01), while no statistical significance between two groups was observed in Constant score (p = 0.36) and ASES (p = 0.76). CONCLUSIONS: The current meta-analysis suggested that HA is a beneficial treatment procedure in improving the ROM of the shoulder for patients with FS, whereas the effect in relieving pain may be equal to the existing therapy. In conclusion, Intra-articular HA injection is recommended for FS patients.

Intravitreal anti-VEGF injections for treating wet age-related macular degeneration: a systematic review and meta-analysis.

AIMS: Age-related macular degeneration (AMD) is the main cause of blindness. Anti-vascular endothelial growth factor is used to prevent further neovascularization due to wet AMD. The purpose of this systematic review was to investigate the effect and protocol of anti-vascular endothelial growth factor treatment on wet AMD. METHODS: A comprehensive literature search was performed in PubMed, Embase, the Cochrane Library, CNKI, and reference lists. Meta-analysis was performed using Stata12.0 software, best corrected visual acuity (BCVA), retinal thickness, and lesion size were evaluated. RESULTS: Twelve randomized controlled trials spanning from 2010 to 2014 and involving 5,225 patients were included. A significant difference was observed between the intravitreal ranibizumab (IVR) group and the intravitreal bevacizumab group (standard mean difference = -0.14, 95% confidence interval [CI] = -0.23 to -0.05). No significant differences were observed in best corrected VA, retinal thickness, or lesion size between IVR and the intravitreal aflibercept group. Compared to monthly injection, IVR as-needed injections (PRN) can raise VA by 1.97 letters (weighted mean difference = 1.97, 95% CI = 0.14-3.794). Combination therapy of IVR and photodynamic therapy can significantly raise VA by 2.74 letters when combined with IVR monotherapy (weighted mean difference = 2.74, 95% CI = 0.26-5.21). CONCLUSION: The superiority remains unclear between IVR and intravitreal bevacizumab in the treatment of neovascular AMD. Intravitreal aflibercept dosed every 2 months required fewer injection times, but produced similar efficacy as monthly IVR. IVR PRN could significantly increase VA. Combined with photodynamic therapy, IVR therapy could also increase VA effectively.