Rejected

Genetic and preclinical studies have implicated adenylyl cyclase 1 (AC1) as a potential target for the treatment of chronic inflammatory pain. AC1 activity is increased following inflammatory pain stimuli and AC1 knockout mice show a marked reduction in responses to inflammatory pain. Previous drug discovery efforts have centered around the inhibition of AC1 activity in cell-based assays. In the present study, we used an approach focused on inhibition of the protein-protein interaction (PPI) between Ca/calmodulin (CaM) and AC1, an interaction that is required for activation of AC1. We developed a novel fluorescence polarization (FP) assay focused on the PPI between an AC1 peptide and CaM and used this assay to screen over 23,000 compounds for inhibitors of the AC1-CaM PPI. Next, we used a cellular NanoBiT assay to validate 21 FP hits for inhibition of the AC1-CaM PPI in a cellular context with full-length proteins. Based on efficacy, potency, and selectivity for AC1, hits , , , , , and were prioritized. We then tested these compounds for inhibition of AC1 activity in cyclic AMP (cAMP) accumulation assays, using HEK293 cells stably expressing AC1. Hit contained a dithiophene scaffold and was of particular interest because it shared structural similarities with our recently reported benzamide series of AC1 inhibitors. We next tested a small set of 13 compounds containing the dithiophene scaffold for structure-activity relationship studies. Although many compounds were non-selective, we observed trends for tuning AC1/AC8 selectivity based on heterocycle type and substituents. Having an ethyl on the central thiophene caused the scaffold to be more selective for AC8. Cyclization of the alkyl substituent fused to the thiophene significantly reduced activity and also shifted selectivity toward AC8. Notably, combining the fused cyclohexane-thiophene ring system with a morpholine heterocycle significantly increased potency at both AC1 and AC8. Through designing a novel FP screen and NanoBiT assay, and evaluating hits in cAMP accumulation assays, we have discovered a novel, potent, dithiophene scaffold for inhibition of the AC1- and AC8-CaM PPI. We also report the most potent fully efficacious inhibitor of AC8 activity known to-date.

Chronic low back pain (CLBP) after percutaneous endoscopic transforaminal discectomy (PTED) surgery may be caused by preoperative lumbar microinstability (MI). However, there is a paucity of research on the relationship between lumbar microinstability and chronic low back pain. The purpose of this article is to assess the preoperative radiographic characteristics of patients and evaluate the effects of lumbar microinstability on patient-reported outcomes among single-level lumbar disc herniation (LDH) patients who underwent PTED.

Herein, we tested the hypothesis that Asymptomatic (Pv) infected individuals (Asym) feature different epidemiological, clinical and biochemical characteristics, as well as hematological parameters, potentially predictive of clinical immunity in comparison to symptomatic Pv infected individuals (Sym).

Opioid-free anesthesia (OFA) may improve postoperative outcomes by reducing opioid-related adverse effects. This study aims to evaluate the effects of OFA on postoperative nausea and vomiting (PONV), postoperative pain, and 30-day outcomes after thyroid and parathyroid surgery.

Viral infections can induce autoimmune diseases in susceptible patients. SARS-CoV-2 has been associated with the development of rheumatic disease, especially small vessel vasculitis and arthritis. Typically, onset occurs days to weeks after the antigenic challenge and in patients with mild COVID-19. We report a case of large vessel vasculitis (LVV) temporally related to SARS-CoV-2 infection.

Spinal cord injury causes permanent neurological deficits, which have devastating physical, social, and vocational consequences for patients and their families. Traditional Chinese medicine uses acupuncture to treat neuropathic pain and improve nerve conduction velocity. This treatment can also reduce peripheral nerve injury joint contracture and muscle atrophy in affected patients. And it's got a remarkable restoration when electrical stimulation therapy on impaired peripheral nerves in animal models and clinical trials.

To determine the distribution and diagnostic value of peripheral enthesitis detected by whole-body MRI (WBMRI) in axial spondyloarthritis (axSpA) diagnosis, and to determine the value of the peripheral enthesitis score in axSpA assessment.

Chronic pain is an enormous modern public health problem, with significant numbers of people debilitated by chronic pain from a variety of etiologies. Translocator protein 18 kDa (TSPO) was discovered in 1977 as a peripheral benzodiazepine receptor. It is a five transmembrane domain protein, mainly localized in the outer mitochondrial membrane. Recent and increasing studies have found changes in TSPO and its ligands in various chronic pain models. Reversing their expressions has been shown to alleviate chronic pain in these models, illustrating the effects of TSPO and its ligands. Herein, we review recent evidence and the mechanisms of TSPO in the development of chronic pain associated with peripheral nerve injury, spinal cord injury, cancer, and inflammatory responses. The cumulative evidence indicates that TSPO-based therapy may become an alternative strategy for treating chronic pain.

The median effective analgesic concentration (MEAC) of ropivacaine in interscalene brachial plexus block (ISBPB) for postoperative analgesia after arthroscopic rotator cuff repair (ARCR) has not been determined. Therefore, this study aimed to evaluate the MEAC after ARCR using 10 ml ropivacaine. This study was conducted on 40 patients with American Society of Anesthesiologists grade I or II who had selective ARCR. The 10 ml ropivacaine was administered for determined, with an initial concentration of 0.3% using up-and-down sequential allocation. After successful or unsuccessful postoperative analgesia, the concentration of ropivacaine was decreased or increased by 0.05% in the next patient. We defined successful postoperative analgesia as a visual analog scale score of <4 at rest within the initial 8 h after ISBPB. The analytic techniques of linear, linear-logarithmic, exponential regressions and centered isotonic regression were used for calculating MEAC. The secondary outcomes was sufentanil consumption, time to 1st rescue analgesic, onset time of sensory block and motor block. The concentration of ropivacaine administered ranged from 0.1% to 0.35%. The MEAC from the four different methods (linear, linear-logarithmic, exponential regressions and centered isotonic regression) were 0.207% (95% CI, 0.168-0.355%), 0.182% (95% CI, 0.165-0.353%), 0.196% (95% CI, 0.154-0.356%), and 0.163%, respectively. Of the four models, exponential regression had the least residual standard error (0.0990). The MEAC derived from the four statistical models for 10 ml ropivacaine in ultrasound-guided ISBPB for postoperative analgesia was distributed within a narrow range of 0.163%-0.207%. The exponential regression model calculated by the goodness-of-fit test at a concentration of 0.196% best fits the study data. http://www.chictr.org.cn/showproj.aspx?proj=127449, identifier ChiCTR2100047978.

Magnetic resonance imaging (MRI) is important in the management of axial spondyloarthritis (SpA). However, many MRI lesions are not exclusive to axial SpA. Further characterization of these lesions may lead to better clinical decisions.