Melanin-Like Nanomedicine Functions as a Novel RPE Ferroptosis Inhibitor to Ameliorate Retinal Degeneration and Visual Impairment in Dry Age-Related Macular Degeneration.

Ferrous ion accumulation and lethal oxidative stress mediate irreversible retinal pigment epithelial (RPE) cell ferroptosis and subsequent photoreceptor degeneration, a potential key pathogenic factor in the onset of dry age-related macular degeneration (dAMD), causing irreversible vision loss in the global elderly population. However, currently, no effective interventional treatment strategy exists in clinical practice. Herein, lesion site-targeted melanin-like nanoparticles, named ConA-MelNPs, are designed as a novel ferroptosis inhibitor for retinal degenerative diseases. ConA-MelNPs possessed chelating iron ion characteristics, alleviating severe mitochondrial damage caused by oxidative stress and protecting RPE cells from ferroptosis induced by sodium iodate (NaIO3). In a preclinical dAMD mouse model, a single intravitreal injection of ConA-MelNPs yielded significant responses in electroretinograms and visually-driven optomotor responses in visually impaired mice, resisting the challenge posed by secondary NaIO3-induced injuries, with the long-term sustainability of its therapeutic effect. Mechanistically, ConA-MelNPs achieve a therapeutic effect by interrupting the detrimental cascade involving "RPE cell ferroptosis, lethal oxidative stress, and microglial proinflammatory activation," affording the restoration of retinal homeostasis. The synthesized ConA-MelNPs demonstrated good biosafety, with no detected ophthalmic or systemic side effects. Collectively, ConA-MelNPs are proposed as a promising therapeutic option for atrophic retinal diseases such as dAMD.

The Salinity Survival Strategy of Chenopodium quinoa: Investigating Microbial Community Shifts and Nitrogen Cycling in Saline Soils.

Quinoa is extensively cultivated for its nutritional value, and its exceptional capacity to endure elevated salt levels presents a promising resolution to the agricultural quandaries posed by salinity stress. However, limited research has been dedicated to elucidating the correlation between alterations in the salinity soil microbial community and nitrogen transformations. To scrutinize the underlying mechanisms behind quinoa's salt tolerance, we assessed the changes in microbial community structure and the abundance of nitrogen transformation genes across three distinct salinity thresholds (1 g·kg-1, 3 g·kg-1, and 6 g·kg-1) at two distinct time points (35 and 70 days). The results showed the positive effect of quinoa on the soil microbial community structure, including changes in key populations and its regulatory role in soil nitrogen cycling under salt stress. Choroflexi, Acidobacteriota, and Myxococcota were inhibited by increased salinity, while the relative abundance of Bacteroidota increased. Proteobacteria and Actinobacteria showed relatively stable abundances across time and salinity levels. Quinoa possesses the ability to synthesize or modify the composition of keystone species or promote the establishment of highly complex microbial networks (modularity index > 0.4) to cope with fluctuations in external salt stress environments. Furthermore, quinoa exhibited nitrogen (N) cycling by downregulating denitrification genes (nirS, nosZ), upregulating nitrification genes (Archaeal amoA (AOA), Bacterial amoA (AOB)), and stabilizing nitrogen fixation genes (nifH) to absorb nitrate-nitrogen (NO3-_N). This study paves the way for future research on regulating quinoa, promoting soil microbial communities, and nitrogen transformation in saline environments.

Predictors of rapidly progressive interstitial lung disease and prognosis in Chinese patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis.

Background: Rapidly progressive interstitial lung disease (RP-ILD) is the most serious complication of anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM). This study was performed to assess the prognostic factors of patients with anti-MDA5+ DM and the clinical characteristics and predictors of anti-MDA5+ DM in combination with RP-ILD. Methods: In total, 73 MDA5+ DM patients were enrolled in this study from March 2017 to December 2021. They were divided into survival and non-survival subgroups and non-RP-ILD and RP-ILD subgroups. Results: The lactate dehydrogenase (LDH) concentration and prognostic nutritional index (PNI) were independent prognostic factors in patients with anti-MDA5+ DM: the elevated LDH was associated with increased mortality (p = 0.01), whereas the elevated PNI was associated with reduced mortality (p < 0.001). The elevated LDH was independent risk prognostic factor for patients with anti-MDA5+ DM (HR 2.42, 95% CI: 1.02-4.83, p = 0.039), and the elevated PNI was independent protective prognostic factor (HR, 0.27; 95% CI, 0.08 - 0.94; p = 0.039). Patients who had anti-MDA5+ DM with RP-ILD had a significantly higher white blood cell count and LDH concentration than those without RP-ILD (p = 0.007 and p = 0.019, respectively). In contrast, PNI was significantly lower in patients with RP-ILD than those without RP-ILD (p < 0.001). The white blood cell count and elevated LDH were independent and significant risk factors for RP-ILD (OR 1.54, 95% CI: 1.12 - 2.13, p = 0.009 and OR 8.68, 95% CI: 1.28 - 58.83, p = 0.027, respectively), whereas the lymphocyte was an independent protective factor (OR, 0.11; 95% CI, 0.01 - 0.81; p = 0.03). Conclusion: The elevated LDH and elevated PNI were independent prognostic factors for patients with anti-MDA5+ DM. The elevated LDH was independent risk factor for RP-ILD. Patients with anti-MDA5+ DM could benefit from the measurement of LDH and PNI, which are inexpensive and simple parameters that could be used for diagnosis as well as prediction of the extent of lung involvement and prognosis.

Prognostic Evaluation of Vitrectomy Assisted by Lucentis in Diabetic Retinopathy and Neovascular Glaucoma.

For verifying the prognosis of Lucentis-assisted vitrectomy (PPV) in diabetic retinopathy (DR) and neovascular glaucoma (NVG), a retrospective analysis of DR and NVG patients who were admitted to our hospital from July 2019 to December 2020 was conducted. According to the treatment protocol, subjects who had PPV intervention were in the control group (CG; n = 38) and those receiving Lucentis adjunctive PPV were included in the intervention group (RG; n = 40). The indicators between groups were listed: treatment success rate, postoperative complication rate, surgical outcome indicators, BCVA, intraocular pressure (IOP) change, foveal thickness, and VEGF level in aqueous humor. Indicators in RG were obviously higher than in CG, such as treatment success rate and surgical outcome indicators. Conversely, lower postoperative complication rate, postoperative BCVA, IOP, retinal fovea thickness, and VEGF level in aqueous humor were found in RG than in CG. Therefore, the study reached the following conclusions about vitrectomy assisted by Lucentis: (1) it effectively increases the success rate of treatment, decreases postoperative complications as well as surgical risks, and improves patients' vision; (2) it promotes the recovery of IOP, reduces macular edema and VEGF levels in aqueous humor, and inhibits the neonatal formation of blood vessels. It is finally confirmed that Lucentis adjuvant PPV in the treatment of DR complicated with NVG is safe and feasible.

Confirmation of the pathogenicity of a mutation p.G337C in the COL1A2 gene associated with osteogenesis imperfecta.

Mutation analysis as the gold standard is particularly important in diagnosis of osteogenesis imperfecta (OI) and it may be preventable upon early diagnosis. In this study, we aimed to analyze the clinical and genetic materials of an OI pedigree as well as to confirm the deleterious property of the mutation.A pedigree with OI was identified. All family members received careful clinical examinations and blood was drawn for genetic analyses. Genes implicated in OI were screened for mutation. The function and structure of the mutant protein were predicted using bioinformatics analysis.The proband, a 9-month fetus, showed abnormal sonographic images. Disproportionately short and triangular face with blue sclera was noticed at birth. She can barely walk and suffered multiple fractures till 2-year old. Her mother appeared small stature, frequent fractures, blue sclera, and deformity of extremities. A heterozygous missense mutation c.1009G>T (p.G337C) in the COL1A2 gene was identified in her mother and her. Bioinformatics analysis showed p.G337 was well-conserved among multiple species and the mutation probably changed the structure and damaged the function of collagen.We suggest that the mutation p.G337C in the COL1A2 gene is pathogenic for OI by affecting the protein structure and the function of collagen.

Selective phosphodiesterase-2A inhibitor alleviates radicular inflammation and mechanical allodynia in non-compressive lumbar disc herniation rats.

PURPOSE: Phosphodiesterase inhibitors possess anti-inflammatory properties. In addition, some studies report that phosphodiesterase 2A (PDE2A) are highly expressed in the dorsal horn of the spinal cord. The present study aimed to investigate whether intrathecal administration of Bay 60-7550, a specific PDE2A inhibitor, could alleviate mechanical allodynia in non-compressive lumbar disc herniation (NCLDH) rats. METHODS: Rat NCLDH models by autologous nucleus pulposus implantation to dorsal root ganglion were established. Vehicle or Bay 60-7550 (0.1, 1.0 mg/kg) was injected by intrathecal catheter at day 1 post-operation. The ipsilateral mechanical withdrawal thresholds were analyzed from the day before surgery to day 7 after surgery. At day 7 post-operation, the ipsilateral lumbar (L4-L6) segments of the spinal dorsal horns were removed, and tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) expressions were measured by ELISA. Furthermore, PDE2A mRNA and protein expressions in spinal cord were measured by Real-Time PCR and Western blot. RESULTS: Intrathecal administration of the PDE2A inhibitor Bay 60-7550, significantly attenuated mechanical allodynia, down-regulated spinal TNF-α, IL-1ß and IL-6 over-expressions, increased the expression of spinal cAMP, as well as cGMP in a more remarkable manner, and decreased the spinal PDE2A expression in NCLDH rats in a dose-dependent manner. CONCLUSIONS: Bay 60-7550 alleviated mechanical allodynia and inflammation in NCLDH rats, which might be associated with increased cAMP and especially cGMP increase. Thus, spinal PDE2A inhibition might represent a potential analgesic strategy for radiculopathy treatment in non-compressive lumbar disc herniation.

Fluoroscopy-guided Bipolar Radiofrequency Thermocoagulation Treatment for Discogenic Low Back Pain.

BACKGROUND: The efficacy of percutaneous intradiscal radiofrequency thermocoagulation (PIRFT) for the treatment of discogenic low back pain (LBP) remains controversial. However, all the PIRFT studies utilized monopolar radiofrequency thermocoagulation (RFTC). The aim of this study was to investigate the safety and efficacy of bipolar RFTC for the treatment of discogenic LBP. METHODS: A total of 23 patients with discogenic LBP were treated with single-level bipolar RFTC. The patients were assessed before the procedure and at 1 week, 1 month, 3 months, 6 months, and 1 year after the procedure. The primary outcome included the visual analog scale (VAS) score and the Oswestry Disability Index (ODI) score. The secondary outcome included pain relief, reduction of analgesic dose, and patient satisfaction. RESULTS: The VAS and ODI scores were significantly decreased after bipolar RFTC treatment at all time points of follow-up (P < 0.05). Bipolar RFTC treatment also resulted in a significant change in all secondary measures, such as pain relief, reduction of analgesic dose, and patient satisfaction. No serious complications or neurological sequelae were observed in any of the patients. CONCLUSIONS: Bipolar RFTC treatment can significantly attenuate pain and improve the function of patients with discogenic LBP.

Treatment of trigeminal neuralgia by radiofrequency of the Gasserian ganglion.

Trigeminal neuralgia (TN) is a neuropathic pain disorder that affects the trigeminal nerve distribution area. Pharmacological therapy has remained the first-line treatment for TN. If pharmacological intervention is not effective, surgical treatments including radiosurgery (mainly gamma knife therapy), radiofrequency (RF) of the Gasserian ganglion, and microvascular decompression have been utilized. RF is one of the most common procedures used to treat TN. Two RF approaches are commonly utilized: conventional radiofrequency (CRF) and pulsed radiofrequency (PRF). Both methods have been used to successfully treat TN; however, each procedure has distinct advantages and disadvantages. This article summarizes the current relevant literature to compare the treatment of TN with CRF vs. PRF. We discuss the treatment indications, operative methods, and complications of each treatment strategy. Most of the patients treated with CRF had a satisfactory outcome, whereas most PRF patients still had significant pain after the procedure. The application of a higher voltage can improve the curative effect of PRF, and its complications are less than CRF. Both CRF and PRF can be used to treat TN, and the former was more effective. Although the complications of CRF are more than those of PRF, most of them were short-lived and lacked sequelae. The pain relief rate in PRF-treated patients was significantly lower compared to CRF-treated patients. Furthermore, recurring pain was more commonly observed in PRF-treated patients. Therefore, CRF may be the preferred treatment option for TN, whereas treatment with PRF requires further study.

PAR2-mediated epigenetic upregulation of α-synuclein contributes to the pathogenesis of Parkinson׳s disease.

Parkinson׳s disease (PD) is a common neurodegenerative disorder characterized by the selective degeneration of projecting dopaminergic neurons in the substantia nigra and diminished dopamine levels in the striatum. Accumulating evidences demonstrate that the aggregation of extracellular α-synuclein contributes to the neuroinflammation and neuronal injury in the substantia nigra in the brain of patients with PD. Proteinase-activated receptor 2 (PAR2), a G-protein coupled receptor, is expressed throughout the peripheral and central nerve system. The present study aims to investigate the involvement of PAR2-NF-κB signaling in the upregulation of α-synuclein and motor dysfunction in the rodent model of PD. Significantly increased expression of α-synuclein was observed in the substantia nigra of the rats injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In these rats, significantly increased nigral PAR2 was observed, and blockade of PAR2 signaling reduced the α-synuclein synthesis in substantia nigra and recovered the motor dysfunction in the rats injected with MPTP. Furthermore, significantly increased phosphorylation of NF-κB subunit p65 was detected in these rats, which was abolished by the inhibition of PAR2 signaling. Blockade of NF-κB signaling significantly decreased histone H3 acetylation in Snca promoter region and α-synuclein expression in substantia nigra. It also decreased the synthesis of cytokine IL-1ß and TNF-α in substantia nigra and recovered the motor dysfunction in the rats injected with MPTP. These results indicated the critical involvement of PAR2-NF-κB signaling in the upregulation of α-synuclein and motor dysfunction in the rodent model of PD, and shed light on the development of novel approaches for the treatment of patients with PD.

Activation of spinal NF-κB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis.

OBJECTIVE: It is known that noxious stimuli from inflamed tissue may increase the excitability of spinal dorsal horn neurons (a process known as central sensitization), which can signal back and contribute to peripheral inflammation. However, the underlying mechanisms have yet to be fully defined. A number of recent studies have indicated that spinal NF-κB/p65 is involved in central sensitization, as well as pain-related behavior. Thus, the aim of this study was to determine whether NF-κB/p65 can facilitate a peripheral inflammatory response in rat adjuvant-induced arthritis (AIA). METHODS: Lentiviral vectors encoding short hairpin RNAs that target NF-κB/p65 (LV-shNF-κB/p65) were constructed for gene silencing. The spines of rats with AIA were injected with LV-shNF-κB/p65 on day 3 or day 10 after treatment with Freund's complete adjuvant (CFA). During an observation period of 20 days, pain-related behavior, paw swelling, and joint histopathologic changes were evaluated. Moreover, the expression levels of spinal tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and cyclooxygenase 2 (COX-2) were assessed on day 14 after CFA treatment. RESULTS: The presence of peripheral inflammation in rats with AIA induced an increase in NF-κB/p65 expression in the spinal cord, mainly in the dorsal horn neurons and astrocytes. Delivery of LV-shNF-κB/p65 to the spinal cord knocked down the expression of NF-κB/p65 and significantly attenuated hyperalgesia, paw edema, and joint destruction. In addition, spinal delivery of LV-shNF-κB/p65 reduced the overexpression of spinal TNFα, IL-1ß, and COX-2. CONCLUSION: These findings indicate that spinal NF-κB/p65 plays an important role in the initiation and development of both peripheral inflammation and hyperalgesia. Thus, inhibition of spinal NF-κB/p65 expression may provide a potential treatment to manage painful inflammatory disorders.

WW domain containing E3 ubiquitin protein ligase 1 (WWP1) negatively regulates TLR4-mediated TNF-α and IL-6 production by proteasomal degradation of TNF receptor associated factor 6 (TRAF6).

BACKGROUND: Toll-like receptors (TLRs) play a pivotal role in the defense against invading pathogens by detecting pathogen-associated molecular patterns (PAMPs). TLR4 recognizes lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, resulting in the induction and secretion of proinflammatory cytokines such as TNF-α and IL-6. The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) regulates a variety of cellular biological processes. Here, we investigated whether WWP1 acts as an E3 ubiquitin ligase in TLR-mediated inflammation. METHODOLOGY/RESULTS: Knocking down WWP1 enhanced the TNF-α and IL-6 production induced by LPS, and over-expression of WWP1 inhibited the TNF-α and IL-6 production induced by LPS, but not by TNF-α. WWP1 also inhibited the IκB-α, NF-κB, and MAPK activation stimulated by LPS. Additionally, WWP1 could degrade TRAF6, but not IRAK1, in the proteasome pathway, and knocking down WWP1 reduced the LPS-induced K48-linked, but not K63-linked, polyubiquitination of endogenous TRAF6. CONCLUSIONS/SIGNIFICANCE: We identified WWP1 as an important negative regulator of TLR4-mediated TNF-α and IL-6 production. We also showed that WWP1 functions as an E3 ligase when cells are stimulated with LPS by binding to TRAF6 and promoting K48-linked polyubiquitination. This results in the proteasomal degradation of TRAF6.

Hypoxia-inducible factor: a potential therapeutic target for rheumatoid arthritis.

The hypoxic microenvironment is a clinicopathological characteristic of many diseases, such as rheumatoid arthritis (RA). As a transcription factor activating the gene expression involved in processes such as cell metabolism and angiogenesis, hypoxia-inducible factor (HIF) has a central function in adaption to altered oxygen tension and even contributes to the progression of related diseases. In RA, HIF induces angiogenesis, cell migration, and cartilage destruction, inhibits the apoptosis of synovial cells and inflammatory cells and initiates glycolysis for energy supply by upregulating specific protein levels. HIF expression in RA can be regulated in both oxygen-dependent and independent fashions, leading to the aggravation of this disease. Therefore, HIF is one of the vital RA mediators. Based on the application of HIF-targeted drug research and development in tumors, HIF is a potential therapeutic target for treating RA.

Dual effects of isoflurane on proliferation, differentiation, and survival in human neuroprogenitor cells.

BACKGROUND: Previous studies have demonstrated that isoflurane can provide both neuroprotection and neurotoxicity in various tissue culture models and in rodent developing brains. The cellular and molecular mechanisms mediating these dual effects are not clear, but the exposure level and duration of isoflurane appear to be determinant factors. METHODS: Using the ReNcell CX (Millipore, Billerica, MA) human neural progenitor cell line, the authors investigated the impact of prolonged exposure to varying isoflurane concentrations on cell survival and neurogenesis. In addition, the authors assessed the impact of short isoflurane preconditioning on elevation of cytosolic Ca concentration and cytotoxic effects mediated by prolonged isoflurane exposures and the contribution of inositol-1,4,5-trisphosphate or ryanodine receptor activation to these processes. RESULTS: Short exposures to low isoflurane concentrations promote proliferation and differentiation of ReNcell CX cells, with no cell damage. However, prolonged exposures to high isoflurane concentrations induced significant ReNcell CX cell damage and inhibited cell proliferation. These prolonged exposures suppressed neuronal cell fate and promoted glial cell fate. Preconditioning of ReNcell CX cultures with short exposures to low concentrations of isoflurane ameliorated the effects of prolonged exposures to isoflurane. Pretreatment of ReNcell cultures with inositol-1,4,5-trisphosphate or ryanodine receptor antagonists mostly prevented isoflurane-mediated effects on survival, proliferation, and differentiation. Finally, isoflurane-preconditioned cultures showed significantly less isoflurane-evoked changes in calcium concentration. CONCLUSION: The commonly used general anesthetic isoflurane exerts dual effects on neuronal stem cell survival, proliferation, and differentiation, which may be attributed to differential regulation of calcium release through activation of endoplasmic reticulum localized inositol-1,4,5-trisphosphate and/or ryanodine receptors.

Treatment of lumbar intervertebral disc herniation using C-arm fluoroscopy guided target percutaneous laser disc decompression.

OBJECTIVE: To evaluate the safety and therapeutic efficacy of target percutaneous laser disc decompression (T-PLDD) for the treatment of lumbar disc herniation. BACKGROUND DATA: PLDD using the Nd:YAG laser has been regarded as an effective alternative treatment for disc herniation. However, all the previous studies were concentrated on vaporizing the nucleus pulposus in the intervertebral space. We hypothesize that insertion of the needle into the extruded part of the nucleus pulposus will decrease its volume and provide superior clinical effects compared to therapies that decrease the volume of the intradiscal nucleus pulposus. MATERIALS AND METHODS: A total of 25 patients suffering from posterolateral extruded but nonsequestered lumbar intervertebral disc herniation were treated with T-PLDD. After treatment, the patients were followed up and the therapeutic effect was assessed at 1, 3, 6, and 12 months using the modified MacNab criteria. RESULTS: The success rate was 80.0% (18 of 25), 88.0% (22 of 25), 92.0% (23 of 25), and 92.0% (23 of 25) at 1, 3, 6, and 12 months respectively. No serious complications occurred in any of the patients. Furthermore, we did not observe any neurological sequelae. CONCLUSIONS: T-PLDD can significantly decrease pain and improve function of patients who have extruded but nonsequestered lumbar intervertebral disc herniation.

[Expression of NF-kappaB and TNF-alpha in spinal dorsal horn in a rat model of neuropathic pain].

OBJECTIVE: To investigate the expressions of NF-kappaB and TNF-alpha in lumbar spinal cord in a rat model of chronic constrictive injury (CCI). METHODS: Seventy-six male SD rats were randomly divided into 2 groups (n = 38 each): CCI group receiving chronic constriction injury and sham group receiving sham operation as control. The mechanical and thermal nociceptive thresholds were assessed with paw withdrawal latency (PWL) to von Frey filaments and radiant heat at different time points. Five animals were sacrificed at each time point for real-time polymerase chain reaction (real-time PCR) and another three animals sacrificed at 7 d post-operation for double-immunofluorescence histochemical staining. Lumbar segments of spinal cord were removed. The expressions of NF-kappaB and TNF-alpha in spinal cord were examined by real-time PCR and double-immunofluorescence histochemical technique. RESULTS: The post-operative thresholds to mechanical and thermal stimuli decreased obviously. As compared with contralateral side and sham group, the expressions of NF-kappaB and TNF-alpha mRNA increased significantly in ipsilateral spinal dorsal horn. Their expressions began to increase at 4 d post-operation and peaked at 7 d. Then TNF-alpha began to decrease while NF-kappaB maintained at a high level throughout the experiment. Double-immunofluorescence histochemical staining revealed extensive co-localization of NF-kappaB with TNF-alpha on ipsilateral side of dorsal horn. CONCLUSION: The activation of NF-kappaB and its downstream inflammatory mediators may be involved in the regulation of neuropathic pain.