New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity.

Depression is highly prevalent globally, however, currently available medications face challenges such as low response rates and short duration of efficacy. Additionally, depression mostly accompany other psychiatric disorders, further progressing to major depressive disorder without long-term effective management. Thus, sustained antidepressant strategies are urgently needed. Recently, ketamine and psilocybin gained attention as potential sustained antidepressants. Review of recent studies highlights that synaptic plasticity changes as key events of downstream long-lasting changes in sustained antidepressant effect. This underscores the significance of synaptic plasticity in sustained antidepressant effect. Moreover, neurexins, key molecules involved in the regulation of synaptic plasticity, act as critical links between synaptic plasticity and sustained antidepressant effects, involving mechanisms including protein level, selective splicing, epigenetics, astrocytes, positional redistribution and protein structure. Based on the regulation of synaptic plasticity by neurexins, several drugs with potential for sustained antidepressant effect are also discussed. Focusing on neurexins in regulating synaptic plasticity promises much for further understanding underlying mechanisms of sustained antidepressant and the next step in new drug development. This research represents a highly promising future research direction.

Clarifying the effect of gut microbiota on allergic conjunctivitis risk is instrumental for predictive, preventive, and personalized medicine: a Mendelian randomization analysis.

Background: Allergic conjunctivitis is an ocular immune disease which affects the conjunctiva, eyelids, and cornea. Growing evidence implicates the gut microbiota in balancing and modulating immunity response, and in the pathogenesis of allergic disease. As a result, gut microbial imbalance could be a useful indicator for allergic conjunctivitis. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of gut microbial imbalance in the development of allergic conjunctivitis could provide a window of opportunity for primary prediction, targeted prevention, and personalized treatment of the disease. Working hypothesis and methodology: In our study, we hypothesized that individuals with microbial dysbiosis may be more susceptible to allergic conjunctivitis due to an increased inflammatory response. To verify the working hypothesis, our analysis selected genetic variants linked with gut microbiota features (N = 18,340) and allergic conjunctivitis (4513 cases, 649,376 controls) from genome-wide association studies. The inverse-variance weighted (IVW) estimate, Mendelian randomization (MR)-Egger, weighted median estimator, maximum likelihood estimator (MLE), and MR robust adjusted profile score (MR.RAPS) were employed to analyze the impact of gut microbiota on the risk of allergic conjunctivitis and identify allergic conjunctivitis-related gut microbes. Ultimately, these findings may enable the identification of individuals at risk of allergic conjunctivitis through screening of gut microbial imbalances, and allow for new targeted prevention and personalized treatment strategies. Results: Genetic liability to Ruminococcaceae_UCG_002 (OR, 0.83; 95% CI, 0.70-0.99; P = 4.04×10-2), Holdemanella (OR, 0.78; 95% CI, 0.64-0.96; P = 2.04×10-2), Catenibacterium (OR, 0.69; 95% CI, 0.56-0.86; P = 1.09×10-3), Senegalimassilia (OR, 0.71; 95% CI, 0.55-0.93; P = 1.23×10-2) genus were associated with a low risk of allergic conjunctivitis with IVW. Besides, we found suggestive associations of a genetic-driven increase in the Oscillospira (OR, 1.41; 95% CI, 1.00-2.00; P = 4.63×10-2) genus with a higher risk of allergic conjunctivitis. Moreover, MLE and MR.RAPS show consistent results with IVW after further validation and strengthened confidence in the true causal associations. No heterogeneity and pleiotropy was detected. Conclusions: Our study suggests that gut microbiota may play a causal role in the development of allergic conjunctivitis and provides new insights into the microbiota-mediated mechanism of the disease. Gut microbiota may serve as a target for future predictive diagnostics, targeted prevention, and individualized therapy in allergic conjunctivitis, facilitating the transition from reactive medical services to PPPM in the management of the disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00321-9.

Exploring the Effect of the Gut Microbiome on the Risk of Age-Related Macular Degeneration From the Perspective of Causality.

Purpose: To explore the mechanisms relating the gut microbiome (GM) to age-related macular degeneration (AMD), as they remain unclear. GM taxa that appear to act within the gut-retina axis may affect the risk of AMD. Methods: Single-nucleotide polymorphisms (SNPs) of 196 GM taxa were obtained from the MiBioGen consortium, and a Mendelian randomization (MR) study was carried out to estimate the causality between GM taxa and AMD (defined as an endpoint based on ICD-9 and ICD-10). Using the data from the FinnGen consortium (6157 patients and 288,237 controls), we explored the GM taxa for causality and verified the results at the replication stage based on the MRC-IEU consortium (3553 cases and 147,089 controls). Inverse variance weighting (IVW) was the main method used to analyze causality, and the MR results were verified using heterogeneity tests and pleiotropy tests. Results: According to the MR results, order Rhodospirillales (P = 3.38 × 10-2), family Victivallaceae (P = 3.14 × 10-2), family Rikenellaceae (P = 3.58 × 10-2), genus Slackia (P = 3.15 × 10-2), genus Faecalibacterium (P = 3.01 × 10-2), genus Bilophila (P = 1.11 × 10-2), and genus Candidatus Soleaferrea (P = 2.45 × 10-2) were suggestively associated with AMD. In the replication stage, only order Rhodospirillales (P = 0.03) passed validation. The heterogeneity (P > 0.05) and pleiotropy (P > 0.05) tests in two stages confirmed the robustness of the MR results. Conclusions: We confirmed that order Rhodospirillales influenced the risk of AMD based on the gut-retina axis, providing new impetus for the development of the GM as an intervention to prevent the occurrence and development of AMD.

Alterations in Macular Microvasculature in Pterygium Patients Measured by OCT Angiography.

Previous studies have reported an association between pterygia and maculopathy, yet the underlying mechanisms and alterations to the macular microvasculature in pterygium patients have yet to be fully elucidated. Our study conducted an analysis of macular superficial vessel length density (VLD) and vessel perfusion density (VPD) to establish associations between the conjunctival and macular microvasculature in patients with unilateral and bilateral pterygia. We revealed a loss of macular microvasculature in the outer nasal (ON) region in both unilateral and bilateral pterygium patients. VLD was significantly decreased in both pterygium groups in the ON region, and VPD was notably lower in bilateral pterygium patients in the same area. Furthermore, in unilateral pterygium patients, the vessel percent pixel coverage (PPC) of the pterygium and the area of the pterygium exhibited a negative correlation with VLD in the ON region. Multiple stepwise linear regression models indicated that the PPC could best predict VLP in the ON region. Taken together, our findings suggest that patients with pterygia may be more susceptible to macular diseases, and this may be due to a compensatory increase in blood perfusion via the anterior ciliary artery. These results underscore the importance of managing maculopathy in patients with pterygia.

Financial compensation for natural forest logging ban: Standard calculation based on willingness to accept.

To alleviate the deteriorating environment and protect biodiversity, China has implemented a natural forest protection system, demonstrating the importance of sustainable forest management for ecological conservation and socio-economic development, including the complete cessation of commercial logging of natural forests. Financial compensation is adopted to increase farmers' enthusiasm within the commercial Logging Ban of Natural Forests framework. This study used the contingent valuation method and the Heckman two-stage model to explore farmers' willingness to participate in the Logging Ban of Natural Forests and the willingness to accept by survey data on 486 farming households. 72% of farmers are willing to join the Logging Ban of Natural Forests. Their willingness to accept is 517.95 yuan/ha per year, higher than the current state subsidy standard (225 yuan/ha per year). The key factors influencing willingness to accept include the education and degree of fragmentation of woodland and village collective willingness to accept. The age of the rural household head, the fragmentation of the forest, and the evaluation of the Logging Ban of Natural Forests policies have inhibited the increase of farmers' compensation. Farmers' assessment of the Logging Ban of Natural Forests policy only impacts the medium level of compensation. The age and the degree of forest fragmentation would affect the higher compensation amount. The results from this study suggest more financial sources and increased compensation standards are needed. The government should also strengthen ecological awareness and adopt different compensation standards for other groups to achieve sustainable forestry.

Body shape and risk of glaucoma: A Mendelian randomization.

Background: Body size (BS) is one of the risk factors for the development of many clinical diseases, but the relationship between BS and glaucoma is controversial. Herein, we try to use Mendelian randomization (MR) method to study BS causal association with glaucoma risk from the genetic level. Methods: The Body Size was determined through anthropometric traits (ATs), such as body mass index (BMI), waist-to-hip ratio adjusted by body mass index (WHRadjBMI), waist-to-hip ratio (WHR), and waist circumference (WC). Association of single nucleotide polymorphisms (SNPs) with each AT and glaucoma were determined individually from the aggregated data of the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the FinnGen study summary data (8,591 cases with glaucoma and 210,201 controls). To explore the role of BS and glaucoma, a two-sample MR analysis was performed on genome-wide association study (GWAS) data. Besides, three MR methods [inverse variance weighted (IVW), Weighted median, and MR-Egger regression] were used to get the whole causal estimate for multiple instrumental SNPs. Results: BMI (OR = 1.20; 95% CI = 1.02-1.41; P = 0.03) and WC (OR = 1.32; 95% CI =1.04-1.69; P = 0.03) were associated with a risk of glaucoma. Besides, genetically predicted WHRadjBMI (OR = 1.10; 95% CI = 0.88-1.35; P = 0.43) and WHR (OR = 1.22; 95% CI = 0.93-1,572; P = 0.14) were not associated with glaucoma. No heterogeneity and directional pleiotropy were detected. Conclusion: The data of this study revealed that increased BMI and WC are potential risk factors for glaucoma, and WHRadjBMI and WHR are not associated with the occurrence of glaucoma.

Association of mTORC1­dependent circulating protein levels with cataract formation: a mendelian randomization study.

BACKGROUND: The mechanistic target of rapamycin (mTOR) signal pathway plays a critical regulating role in the occurrence and development of cataract. However, the role of mTORC1 downstream proteins, including ribosomal protein S6K (RP-S6K), eukaryotic initiation factor 4E-binding protein (EIF4EBP), eukaryotic initiation factor 4G (EIF-4G), eukaryotic initiation factor 4E (EIF-4E), and eukaryotic initiation factor 4A (EIF-4A), in regulating cataract development is still unknown. Herein, we conducted a mendelian randomization (MR) study to understand the function of mTORC1 signaling in the process of cataract development. RESULTS: The causal estimate was evaluated with inverse-variance weighted (IVW) estimate, weighted median estimator, MR-Egger and MR robust adjusted profile score (MR. RAPS). The single-nucleotide polymorphisms (SNPs), P<5 × 10- 6 and r2<0.05, were selected to genetically predict the RP-S6K, EIF4EBP, EIF-4E, EIF-4A, and EIF-4G. We included a total of 26,758 cases and 189,604 controls in this MR study. The study revealed causal association between circulating EIF4EBP (OR 1.09, 95% confidence interval 1.03,1.16, P = 0.004), RP-S6K (OR 1.04, 95% confidence interval 1.01, 1.08, P = 0.02) and cataract formation with IVW estimate. Whereas after correcting outliers, MR robust adjusted profile score (MR. RAPS) shows consistent result with IVW for EIF4EBP (OR = 1.08, 95%CI:1.05-1.11, P = 0.007). The observation strengthened the confidence in the true causal associations. However, no association was found for circulating EIF-4E (OR 1.03, 95% confidence interval 0.97, 1.09, P = 0.31), EIF-4A (OR 1.02, 95% confidence interval 0.98, 1.07, P = 0.34), and EIF-4G (OR 1.02, 95% confidence interval 0.94, 1.01, P = 0.64) levels with cataract formation. No evidence of heterogeneity and unbalanced horizontal pleiotropy was detected. CONCLUSION: The MR study suggests that EIF4EBP is a high-risk factor for cataract development. There may be a potential causal association between the mTORC1/EIF4EBP axis and cataract. This research highlights the potential mechanism for cataract development and a genetic target to prevent as well as treat cataracts.

Targeting autophagy in atherosclerosis: Advances and therapeutic potential of natural bioactive compounds from herbal medicines and natural products.

Atherosclerosis (AS) is the most common causes of cardiovascular disease characterized by the formation of atherosclerotic plaques in the arterial wall, and it has become a dominant public health problem that seriously threaten people worldwide. Autophagy is a cellular self-catabolism process, which is critical to protect cellular homeostasis against harmful conditions. Emerging evidence suggest that dysregulated autophagy is involved in the development of AS. Therefore, pharmacological interventions have been developed to inhibit the AS via autophagy induction. Among various AS treating methods, herbal medicines and natural products have been applied as effective complementary and alternative medicines to ameliorate AS and its associated cardiovascular disease. Recently, mounting evidence revealed that natural bioactive compounds from herbs and natural products could induce autophagy to suppress the occurrence and development of AS, by promoting cholesterol efflux, reducing plaque inflammation, and inhibiting apoptosis or senescence. In the present review, we highlight recent findings regarding possible effects and molecular mechanism of natural compounds in autophagy-targeted mitigation of atherosclerosis, aiming to provide new potential therapeutic strategies for the atherosclerosis treatment preclinically and clinically.

Implicating Causal Brain Magnetic Resonance Imaging in Glaucoma Using Mendelian Randomization.

Background: Glaucoma is hypothesized to originate in the brain but manifests as an eye disease as it possesses the common features of neurodegeneration diseases. But there is no evidence to demonstrate the primary brain changes in glaucoma patients. In the present study, we have used Mendelian randomization (MR) to understand the causal effect of brain alterations on glaucoma. Methods: Our MR study was carried out using summary statistics from genome-wide associations for 110 diffusion tensor imaging (DTI) measurements of white matter (WM) tracts (17,706 individuals), 101 brain region-of-interest (ROI) volumes (19,629 individuals), and glaucoma (8,591 cases, 210,201 control subjects). The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method and verified by two other MR methods, including MR Egger, weighted median, and extensive sensitivity analyses. Results: Genetic liability to fornix fractional anisotropy (FX.FA) (OR = 0.71, 95%CI = 0.56-0.88, P = 2.44 × 10-3), and uncinate fasciculus UNC.FA (OR = 0.65, 95%CI = 0.48-0.88, P = 5.57 × 10-3) was associated with a low risk of glaucoma. Besides, the right ventral diencephalon (OR = 1.72, 95%CI = 1.17-2.52, P = 5.64 × 10-3) and brain stem (OR = 1.35, 95%CI = 1.08-1.69, P = 8.94 × 10-3) were associated with the increased risk of glaucoma. No heterogeneity and pleiotropy were detected. Conclusion: Our study suggests that the fornix and uncinate fasciculus degenerations and injures of the right ventral diencephalon and brain stem potentially increase the occurrence of glaucoma and reveal the existence of the brain-eye axis.

Improved Dry Eye Symptoms and Signs of Patients With Meibomian Gland Dysfunction by a Dietary Supplement.

Purpose: To explore the therapeutic effect of a dietary supplement on dry eye with meibomian gland dysfunction (MGD). Methods: Sixty patients with MGD-related dry eye were included in this prospective and randomized, placebo-controlled study. All the subjects were treated with eye hot compress, artificial tears, and antibiotic ointment. After that, the patients received dietary supplementary or placebo daily for 12 weeks. The dry eye signs, function of MG, and visual quality of the patients were assessed at 4, 8, and 12 weeks after the treatment. Results: Twelve weeks after the treatment, patients who received dietary supplement had a significantly better improvement of dry eye symptoms, in terms of ocular surface diseases index and tear breaking-up time (TBUT), than those who received placebo (P < 0.05). The functions of MG, in terms of meibum quality and MG exclusion and MG obstruction scores, were significantly improved in both dietary supplement and placebo groups (P < 0.05). Patients who received dietary supplement had a significantly better improvement in the MG structure, in terms of acinar diameter and acinar density, than those who received placebo (P < 0.05). The number of inflammatory cells near MG was significantly lower in the dietary supplement group when compared with the placebo group (P < 0.05). The objective visual quality was significantly improved in the dietary supplement group, but not in the placebo group (P < 0.05). Conclusion: The dietary supplement can effectively improve the symptoms and signs of MGD-related dry eye, reduce the inflammatory reaction of MG, restore the gland structure, and indirectly improve the visual quality.

Mitochondrial Targeting Therapeutics: Promising Role of Natural Products in Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide, and its prevalence is still growing rapidly. However, the efficient therapies for this liver disease are still limited. Mitochondrial dysfunction has been proven to be closely associated with NAFLD. The mitochondrial injury caused reactive oxygen species (ROS) production, and oxidative stress can aggravate the hepatic lipid accumulation, inflammation, and fibrosis. which contribute to the pathogenesis and progression of NAFLD. Therefore, pharmacological therapies that target mitochondria could be a promising way for the NAFLD intervention. Recently, natural products targeting mitochondria have been extensively studied and have shown promising pharmacological activity. In this review, the recent research progress on therapeutic effects of natural-product-derived compounds that target mitochondria and combat NAFLD was summarized, aiming to provide new potential therapeutic lead compounds and reference for the innovative drug development and clinical treatment of NAFLD.