PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 µM) significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3ß/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect.

Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H+, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway.

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke currently. Caffeic acid is a phenolic acid that widely exists in a number of plant species. Previous studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/reperfusion. In this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral ischemia. Ischemia stroke was induced on rats by permanent middle cerebral artery occlusion (pMCAO). Caffeic acid (0.4, 2, 10 mg·kg-1·d-1, i.g.) was administered to the rats for 3 consecutive days before or after the surgery. We showed that either pre-pMCAO or post-pMCAO administration of caffeic acid (2 mg·kg-1·d-1) effectively reduced the infarct volume and improved neurological outcome. The therapeutic time window could last to 2 h after pMCAO. We found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation, and enhanced antioxidant capacity in pMCAO rat brain. We further demonstrated that caffeic acid down-regulated TFR1 and ACSL4, and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation (OGD/R)-treated SK-N-SH cells in vitro. Application of ML385, an Nrf2 inhibitor, blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models, evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense system. In conclusion, caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling pathway. Caffeic acid might serve as a potential treatment to relieve brain injury after cerebral ischemia. Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. The effects of caffeic acid on neuroinflammation and ferroptosis in cerebral ischemia were explored in a primary microglia-neuron coculture system. Caffeic acid played a role in reducing neuroinflammation and resisting ferroptosis through the Nrf2 signaling pathway, which further suggested that caffeic acid might be a potential therapeutic method for alleviating brain injury after cerebral ischemia.

TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization.

Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting MMP activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice; they also inhibited junctional protein degradation and translocation to reduce paracellular permeability in human brain microvascular endothelial cells (ECs) exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with α3ß1 integrin on ECs, inhibiting Src activation-dependent VE-cadherin phosphorylation, VE-cadherin/catenin complex destabilization, and subsequent VE-cadherin internalization. Notably, localization of VE-cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. All together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.

Design, synthesis and biological evaluation of novel indanones derivatives as potent acetylcholinesterase/monoamine oxidase B inhibitors.

Aim: Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Results: These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound A1 possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC50 = 0.054 ± 0.004 µM; MAO-B: IC50 = 3.25 ± 0.20 µM), moderate inhibitory effects on self-mediated amyloid-ß (Aß) aggregation and antioxidant activity. In addition, compound A1 exhibited low neurotoxicity. More importantly, compound A1 showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. Conclusion: All results suggest that compound A1 may become a promising lead of anti-AD drug for further development.

Subclinical damage to the contralateral eye in unilateral optic neuritis: A longitudinal study.

BACKGROUND: Early detection of subclinical injuries can lead to a correct diagnosis and help control the advancement of the condition. This study aims to investigate the presence of subclinical damage and silent progression to the contralateral eye's visual function and structure in patients experiencing their first episode of unilateral optic neuritis (ON). METHODS: Fifty patients with first-onset unilateral ON were enrolled in this study. Based on etiology, they were classified as having neuromyelitis optica spectrum disorder-related ON (NMOSD-ON), myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON), idiopathic ON (IDON), or multiple sclerosis-related ON (MS-ON). These cases were followed up for one year to determine whether there was any silent progression of visual function and structure in the contralateral non-ON (NON) eye. A gender- and age-matched healthy control (HC) group was included to compare the differences in visual function and structure between the patients with NON eyes and the HC group. RESULTS: Within two weeks of onset, best-corrected visual acuity (BCVA; P = 0.008), mean deviation (MD) of the visual field (VF) (P = 0.001), and peripapillary retinal nerve fiber layer (pRNFL; P = 0.019) thickness were significantly worse in the NMOSD-NON patients than those in the HC group, while there were no differences in the pRNFL and the ganglion cell-inner plexiform layer (GCIPL) thicknesses and quadrant thicknesses (P > 0.05) of the groups. IDON-NON only showed subclinical damage in VF (P = 0.001) and temporal pRNFL (P = 0.042), while the BCVA, VF, and optic nerve structure (pRNFL, GCIPL) of the MOG-NON patients showed no subclinical damage (P > 0.05). In addition, the one-year follow-up of each NON eye type showed that there was no silent progression in NMOSD-NON, MOG-NON, or IDON-NON. A pairwise comparison of the different types of NON eyes revealed no statistical differences (P > 0.05). CONCLUSION: Among the patients with unilateral ON, NMOSD-NON and IDON-NON resulted in subclinical damage to the visual function and structure of the contralateral eye within two weeks of onset, whereas MOG-NON did not show any subclinical damage to visual function or structure. Furthermore, these subclinical damages did not show any silent progression during the one-year follow-up period.

Deep learning system for distinguishing optic neuritis from non-arteritic anterior ischemic optic neuropathy at acute phase based on fundus photographs.

Purpose: To develop a deep learning system to differentiate demyelinating optic neuritis (ON) and non-arteritic anterior ischemic optic neuropathy (NAION) with overlapping clinical profiles at the acute phase. Methods: We developed a deep learning system (ONION) to distinguish ON from NAION at the acute phase. Color fundus photographs (CFPs) from 871 eyes of 547 patients were included, including 396 ON from 232 patients and 475 NAION from 315 patients. Efficientnet-B0 was used to train the model, and the performance was measured by calculating the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Also, Cohen's kappa coefficients were obtained to compare the system's performance to that of different ophthalmologists. Results: In the validation data set, the ONION system distinguished between acute ON and NAION achieved the following mean performance: time-consuming (23 s), AUC 0.903 (95% CI 0.827-0.947), sensitivity 0.796 (95% CI 0.704-0.864), and specificity 0.865 (95% CI 0.783-0.920). Testing data set: time-consuming (17 s), AUC 0.902 (95% CI 0.832-0.944), sensitivity 0.814 (95% CI 0.732-0.875), and specificity 0.841 (95% CI 0.762-0.897). The performance (κ = 0.805) was comparable to that of a retinal expert (κ = 0.749) and was better than the other four ophthalmologists (κ = 0.309-0.609). Conclusion: The ONION system performed satisfactorily distinguishing ON from NAION at the acute phase. It might greatly benefit the challenging differentiation between ON and NAION.

Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent.

Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.

Antidepressant effect of 4-Butyl-alpha-agarofuran via HPA axis and serotonin system.

Depression is a leading cause of disability worldwide and the psychiatric diagnosis most commonly associated with suicide. 4-Butyl-alpha-agarofuran (AF-5), a derivative of agarwood furan, is currently in phase III clinical trials for generalized anxiety disorder. Herein, we explored the antidepressant effect and its possible neurobiological mechanisms in animal models. In present study, AF-5 administration markedly decreased the immobility time in mouse forced swim test and tail suspension test. In the sub-chronic reserpine-induced depressive rats, AF-5 treatment markedly increased the rectal temperature and decreased the immobility time of model rats. In addition, chronic AF-5 treatment markedly reversed the depressive-like behaviors in chronic unpredictable mild stress (CUMS) rats by reducing immobility time of forced swim test. Single treatment with AF-5 also potentiated the mouse head-twitch response induced by 5-hydroxytryptophan (5-HTP, a metabolic precursor to serotonin), and antagonized the ptosis and motor ability triggered by reserpine. However, AF-5 had no effect on yohimbine toxicity in mice. These results indicated that acute treatment with AF-5 produced serotonergic, but not noradrenergic activation. Furthermore, AF-5 reduced adrenocorticotropic hormone (ACTH) level in serum and normalized the neurotransmitter changes, including the decreased serotonin (5-HT) in hippocampus of CUMS rats. Moreover, AF-5 affected the expressions of CRFR1 and 5-HT2C receptor in CUMS rats. These findings confirm the antidepressant effect of AF-5 in animal models, which may be primarily related to CRFR1 and 5-HT2C receptor. AF-5 appears to be promising as a novel dual target drug for depression treatment.

Discovery of a Novel, Potent, Orally Active, and Safe Inhibitor Targeting Human Mitochondrial RNA Polymerase.

High oxidative phosphorylation (OXPHOS) happens in some tumors, which depends on OXPHOS for energy supply, particularly in slow-cycling tumor cells. Therefore, targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression emerges as a potential therapeutic strategy to eradicate tumor cells. In this work, exploration and optimization of the first-in-class POLRMT inhibitor IMT1B and its SAR led to the identification of a novel compound D26, which exerted a strong antiproliferative effect on several cancer cells and decreased mitochondrial-related genes expression. In addition, mechanism studies demonstrated that D26 arrested cell cycle at the G1 phase and had no effect on apoptosis, depolarized mitochondria, or reactive oxidative stress generation in A2780 cells. Importantly, D26 exhibited more potent anticancer activity than the lead IMT1B in A2780 xenograft nude mice and had no observable toxic effect. All results suggest that D26 deserves to be further investigated as a potent and safe antitumor candidate.

The value of convolutional neural networks-based deep learning model in differential diagnosis of space-occupying brain diseases.

Objectives: It is still a challenge to differentiate space-occupying brain lesions such as tumefactive demyelinating lesions (TDLs), tumefactive primary angiitis of the central nervous system (TPACNS), primary central nervous system lymphoma (PCNSL), and brain gliomas. Convolutional neural networks (CNNs) have been used to analyze complex medical data and have proven transformative for image-based applications. It can quickly acquire diseases' radiographic features and correct doctors' diagnostic bias to improve diagnostic efficiency and accuracy. The study aimed to assess the value of CNN-based deep learning model in the differential diagnosis of space-occupying brain diseases on MRI. Methods: We retrospectively analyzed clinical and MRI data from 480 patients with TDLs (n = 116), TPACNS (n = 64), PCNSL (n = 150), and brain gliomas (n = 150). The patients were randomly assigned to training (n = 240), testing (n = 73), calibration (n = 96), and validation (n = 71) groups. And a CNN-implemented deep learning model guided by clinical experts was developed to identify the contrast-enhanced T1-weighted sequence lesions of these four diseases. We utilized accuracy, sensitivity, specificity, and area under the curve (AUC) to evaluate the performance of the CNN model. The model's performance was then compared to the neuroradiologists' diagnosis. Results: The CNN model had a total accuracy of 87% which was higher than senior neuroradiologists (74%), and the AUC of TDLs, PCNSL, TPACNS and gliomas were 0.92, 0.92, 0.89 and 0.88, respectively. Conclusion: The CNN model can accurately identify specific radiographic features of TDLs, TPACNS, PCNSL, and gliomas. It has the potential to be an effective auxiliary diagnostic tool in the clinic, assisting inexperienced clinicians in reducing diagnostic bias and improving diagnostic efficiency.

Influence of obstructive sleep apnea syndrome on the contralateral optic nerve in patients with unilateral nonarteritic anterior ischemic optic neuropathy.

STUDY OBJECTIVES: The aim was to quantitatively evaluate the influence of obstructive sleep apnea syndrome (OSAS) on the morphology and function of the contralateral optic nerve in patients with unilateral nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: Fifty patients with unilateral NAION were divided into non-OSAS (n = 16), mild OSAS (n = 15), and moderate-severe OSAS (n = 19) groups based on their apnea-hypopnea index (AHI) scores. Systemic and ocular characteristics were compared between these groups. Spearman correlation and multiple linear regression analyses were used to determine the independent factors that most influenced the thickness of the peripapillary retinal nerve fiber layer (pRNFL). RESULTS: Body mass index and hypertension occurrence were higher in the moderate-severe OSAS group than in the non-OSAS group. Temporal pRNFL was thinner in the moderate-severe group than in the mild and non-OSAS groups, whereas no difference was found between the mild and non-OSAS groups. Spearman correlation showed that the AHI (r = -.469, P = .001) and the percentage of total sleep time with oxygen saturation < 90% (T90%; r = -.477, P = .001) correlated with temporal pRNFL thickness. Multiple linear regression showed that the AHI was negatively associated with temporal pRNFL thickness (ß = -0.573, P = .003). CONCLUSIONS: OSAS may cause subclinical temporal pRNFL thinning in the contralateral optic nerve among patients with unilateral NAION without any significant change in visual function. Advanced optic nerve observation and intervention may be warranted in patients with moderate-severe OSAS. CITATION: Li X, Zhang Y, Guo T, et al. Influence of obstructive sleep apnea syndrome on the contralateral optic nerve in patients with unilateral nonarteritic anterior ischemic optic neuropathy. J Clin Sleep Med. 2023;19(2):347-353.

A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells.

Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.

Brain Temperature as an Indicator of Cognitive Function in Traumatic Brain Injury Patients.

Whether brain temperature noninvasively extracted by magnetic resonance imaging has a role in identifying brain changes in the later phases of mild to moderate traumatic brain injury (TBI) is not known. This prospective study aimed to evaluate if TBI patients in subacute and chronic phases had altered brain temperature measured by whole-brain magnetic resonance spectroscopic imaging (WB-MRSI) and if the measurable brain temperature had any relationship with cognitive function scores. WB-MRSI was performed on eight TBI patients and fifteen age- and sex-matched control subjects. Brain temperature (T) was extracted from the brain's major metabolites and compared between the two groups. The T of the patients was tested for correlation with cognitive function test scores. The results showed significantly lower brain temperature in the TBI patients (p < 0.05). Brain temperature derived from N-acetylaspartate (TNAA) strongly correlated with the 2 s paced auditory serial addition test (PASAT-2s) score (p < 0.05). The observation of lower brain temperature in TBI patients may be due to decreased metabolic activity resulting from glucose and oxygen depletion. The correlation of brain temperature with PASAT-2s may imply that noninvasive brain temperature may become a noninvasive index reflecting cognitive performance.

Central nervous system tumefactive demyelinating lesions: Risk factors of relapse and follow-up observations.

Objective: To track the clinical outcomes in patients who initially presented with tumefactive demyelinating lesions (TDLs), we summarized the clinical characteristics of various etiologies, and identified possible relapse risk factors for TDLs. Methods: Between 2001 and 2021, 116 patients initially presented with TDLs in our hospital were retrospectively evaluated. Patients were followed for relapse and clinical outcomes, and grouped according to various etiologies. Demographic information, clinical data, imaging data, and laboratory results of patients were obtained and analyzed. The risk factors of relapse were analyzed by the Log-Rank test and the Cox proportional hazard model in multivariate analysis. Result: During a median follow-up period of 72 months, 33 patients were diagnosed with multiple sclerosis (MS), 6 patients with Balo, 6 patients with neuromyelitis optica spectrum disorders (NMOSD), 10 patients with myelin oligodendrocyte glycoprotein antibody-associated demyelination (MOGAD), 1 patient with acute disseminated encephalomyelitis (ADEM), and the remaining 60 patients still have no clear etiology. These individuals with an unknown etiology were categorized independently and placed to the other etiology group. In the other etiology group, 13 patients had recurrent demyelinating phases, while 47 patients did not suffer any more clinical events. Approximately 46.6% of TDLs had relapses which were associated with multiple functional system involvement, first-phase Expanded Disability Status Scale score, lesions morphology, number of lesions, and lesions location (P<0.05). And diffuse infiltrative lesions (P=0.003, HR=6.045, 95%CI:1.860-19.652), multiple lesions (P=0.001, HR=3.262, 95%CI:1.654-6.435) and infratentorial involvement (P=0.006, HR=2.289, 95%CI:1.064-3.853) may be independent risk factors for recurrence. Relapse free survival was assessed to be 36 months. Conclusions: In clinical practice, around 46.6% of TDLs relapsed, with the MS group showing the highest recurrence rate, and lesions location, diffuse infiltrative lesions, and multiple lesions might be independent risk factors for relapse. Nevertheless, despite extensive diagnostic work and long-term follow-up, the etiology of TDLs in some patients was still unclear. And these patients tend to have monophase course and a low rate of relapse.

Risk Factors for Fellow Eye Involvement in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy.

INTRODUCTION: To investigate the possible risk factors for fellow eye involvement in patients with nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: A total of 113 patients with unilateral NAION attack were included and divided into two groups according to whether fellow eye involvement was present over a mean follow-up period of 2.70 years (P25-P75: 0.77-3.54 years). General characteristics (including age, sex, diabetes, hypertension, hyperlipidemia and obstructive sleep apnea syndrome) and ocular characteristics (including initial best corrected visual acuity, initial visual field damage of the first eye and the presence/absence of a crowded disc) were analyzed and compared between the two groups. Cox regression was used to assess the risk factors for fellow eye involvement. RESULTS: During the follow-up period, 40 patients developed fellow eye involvement. The initial best corrected visual acuity (P = 0.048) and mean deviation (MD) of the visual field (VF) (P = 0.039) of the first eye in patients with fellow eye involvement were worse than those in patients without it. Diabetes (HR = 3.06, 95% CI: 1. 50, 6.26, P = 0.002) and increased VF damage (moderate vs. mild, HR = 2.92, 95% CI: 1.03, 8.25, P = 0.043; severe vs. mild, HR = 5.01, 95% CI: 1.65, 15.20, P = 0.004) were associated with a significantly increased risk of fellow eye involvement. In 57 patients with apnea hypopnea index (AHI) data for further study, an AHI score≥ 23.2 was also found to be a risk factor (HR = 3.36, 95% CI: 1.17, 9.69, P = 0.025). CONCLUSION: Diabetes, severer initial VF damage, and more severe obstructive sleep apnea syndrome (OSAS) were risk factors for fellow eye involvement in NAION. For patients with these risk factors, more intensive follow-ups might be warranted.

Targeting SOST using a small-molecule compound retards breast cancer bone metastasis.

BACKGROUND: Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis. METHODS: SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo. RESULTS: We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-ß/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice. CONCLUSIONS: Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC50 = 0.58 ± 0.05 µM; MAO-B: IC50 = 0.41 ± 0.04 µM). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.

Nalbuphine 20 mg combined with sufentanil 2 µg/kg exerts a better postoperative analgesia effect in patients undergoing a second cesarean section: a randomised trial.

BACKGROUND: Pain management following cesarean section remains a challenge, with many puerpera suffering from severe acute postoperative pain. And for a second cesarean section the degree of uterine contraction pain is more severe and frequent than that of a primipara. This study investigated the effect of different doses of nalbuphine combined with sufentanil for postoperative analgesia in patients undergoing a second cesarean section. METHODS: We prospectively recruited 168 women with a scarred uterus undergoing elective second cesarean section and they were randomly divided into 4 groups by random number extraction. A single intravenous injection of different doses of nalbuphine was given before the intravenous drip of oxytocin, and visual analogue scale (VAS) scores of uterine contraction pain were recorded 10 minutes before intravenous infusion of oxytocin (T1) and 10 minutes (T2), 30 minutes (T3), and 60 minutes (T4) after intravenous infusion of oxytocin. At 4, 8, 12, 24, and 48 hours after patient-controlled intravenous analgesia (PCIA), pain intensity was reassessed using the VAS score. RESULTS: One hundred and sixty patients underwent elective second cesarean section in between December 2020 and May 2021 completed the study. The VAS scores of uterine contractions at T1 and T4 were 3 (1.0), while the VAS scores at T2 and T3 were 7 (1.0), 6 (1.0), 5 (1.0), 5 (1.0) and 8 (1.0), 5 (2.0), 3 (1.0), 3 (0.75). The VAS scores at 12 hours after surgery of nalbuphine10mg and sufentanil (NS1), nalbuphine 10 mg and sufentanil 20 mg (NS2) and nalbuphine 30 mg and sufentanil 20 mg (NS3) were lower than sufentanil (S) group (P<0.001). Compared with the S group, total amount of sufentanil and PCIA compression numbers in the NS1, NS2, and NS3 groups at 4-8 and 8-12 hours after surgery decreased (P<0.001), with a more significant decrease in the NS2 and NS3 groups than in the NS1 group (P<0.001). The NS3 group had a significantly higher incidence of dizziness and sleepiness (P=0.02, P=0.001). Compared with the NS2 and NS3 groups, the incidence of respiratory depression in the S group was significantly higher (P=0.001). CONCLUSIONS: A single intravenous injection of nalbuphine 20 mg 10 minutes before the infusion of oxytocin combined with sufentanil 2 µg/kg could be safely used for postoperative analgesia in patients undergoing a second cesarean section and could effectively inhibit uterine contractions induced by oxytocin and reduce adverse reactions. TRIAL REGISTRATION: Clinical Trial Registry ChiCTR2100042382.

The impact of tubeless anesthesia versus intubated anesthesia on cerebral oxygen saturation and postoperative cognitive function in patients undergoing video-assisted thoracoscopic surgery: a randomized trial.

Background: In video-assisted thoracoscopic surgery (VATS), intubated anesthesia may affect cerebral oxygen balance and postoperative cognitive dysfunction (POCD). To avoid complications associated with intubated anesthesia, tubeless strategies have been proposed in recent years, but its effect on cerebral oxygen balance and POCD is still unclear. This prospective study compared the cerebral oxygen saturation and the incidence of POCD in patients undergoing VATS anesthetized with tubeless anesthesia vs. intubated anesthesia. Methods: A total of 60 patients with American Society of Anesthesiologists Standard (ASA) grade I-II who planned to undergo VATS at The First People's Hospital of Yunnan Province between May and October 2021 were selected and divided into non-intubated spontaneous ventilation group (SV group) or intubated mechanical ventilation group (MV group) by random number method. The primary outcome included the incidence of POCD and Mini-Mental State Examination (MMSE) on the 1st before operation and the 4th, 7th, 14th, and 30th day postoperatively, and cerebral oxygen saturation during surgery. Other outcomes of interest include respiratory and hemodynamic parameters, serum concentration of cognitive function related proteins [S100ß, interleukin (IL)-6, IL-1ß, and tumor necrosis factor α (TNF-α)], inflammatory cell counts, perioperative adverse events (arrhythmia, hypoxemia, asphyxia, etc.), postoperative pain scores, etc. Results: The incidence of hypercapnia in the SV group was significantly higher than in the MV group (P<0.001). Cerebral oxygen saturation at intraoperative was significantly higher than that in MV group (P<0.01). There was no significant difference in the incidence of POCD and the expression of cognitive function related proteins between the two groups (P>0.05). Leukocyte and neutrophil counts were significantly higher in the MV group after operation (P<0.05), whilst compared to the MV group, the SV group showed shorter postoperative recovery time, rest time before the first out of bed activity, chest tube duration, as well as less drainage volume of the chest tube and postoperative sore throat rarely occurred (P<0.05). Conclusions: Tubeless VATS can increase the incidence of hypercapnia and intraoperative cerebral oxygen saturation, but has no statistically significant difference in the incidence of POCD. In addition, tubeless anesthesia reduces systemic inflammatory, promotes the early postoperative mobilization, and accelerates the postoperative rehabilitation of patients. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100042381.