Mendelian randomization analysis reveals causal relationships between gut microbiome and optic neuritis.

BACKGROUND: It is unclear whether gut microbiota (GM) affects the risk of optic neuritis (ON) through the "gut-brain" axis and the "gut-retina" axis. To examine the causal relationship between GM and ON, we conducted Mendelian randomization (MR) study. METHODS: Up to 18,340 samples of 24 population-based cohorts were included in genome-wide association study (GWAS) of 196 GM taxa. ON outcomes were selected from the FinnGen GWAS (951 ON cases and 307,092 controls). In addition, the GWAS based on UK Biobank (UKB) (105 ON cases and 456,243 controls) was used for further exploration. Inverse variance weighted (IVW) was carried out to estimate their effects on ON risk and the MR assumptions were evaluated in sensitivity analyses. RESULTS: Among the 196 GM taxa, the IVW results confirmed that Family -Peptococcaceae (P = 2.17 × 10-3), Genus- Hungatella (P = 4.57 × 10-3) and genus-Eubacterium_rectale_group (P = 0.02) were correlated with the risk of ON based on Finngen GWAS. Based on data from UKB, Genus- Eubacterium_hallii_group (P = 1.50 × 10-3) and Genus- Ruminococcaceae_UCG_002 (P = 0.02) were correlated with the risk of ON. At the phylum, class and order levels, no GM taxa were causally related to ON (P > 0.05). Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analysis confirmed the robustness of the MR results. CONCLUSION: Our MR findings support the causal effect of specific GM taxa on ON. GM may affect the risk of ON through the "gut-brain" axis and the "gut-retina" axis. However, further research is needed to confirm the relevant mechanism of the relationship between GM and ON.

Neochamaejasmin B extracted from Stellera chamaejasme L. induces apoptosis through caspase-10-dependent way in insect neuronal cells.

To explore the toxicity mechanisms of neochamaejasmin B (NCB) extracted from Stellera chamaejasme L., we first evaluated its cytotoxicity in neuronal cells of Helicoverpa zea (AW1 cells). NCB inhibited cell growth and was cytotoxic to AW1 cells in a dose-dependent manner. Further, transmission electron microscopy (TEM) was used to analyze the microstructure, and typical apoptotic characteristics were observed in AW1 cells treated with NCB. Moreover, the NCB-induced apoptosis was dose dependent. Subsequently, we explored the mechanism of apoptosis. A decline in the mitochondrial membrane potential (MMP) was found. Also, the levels of Bax were increased with increases in drug concentration, but there was no statistical difference in Bcl-2 levels at different NCB doses. Caspase-3 and caspase-10 activity was increased. These findings confirmed that NCB induced apoptosis in AW1 cells through a caspase-10-dependent mechanism. The results provide the basic information needed for understanding the toxicity and mechanisms of action of NCB, which could potentially be used to develop NCB as a new insecticide.

The role of aldosterone in the pathogenesis of diabetic retinopathy.

Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.

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.

Causal effects of gut microbiota on diabetic retinopathy: A Mendelian randomization study.

Background: Previous researches have implicated a vital association between gut microbiota (GM) and diabetic retinopathy (DR) based on the association of the "gut-retina" axis. But their causal relationship has not been elucidated. Methods: Instrumental variables of 211 GM taxa were obtained from genome wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on DR risk from FinnGen GWAS (14,584 DR cases and 202,082 controls). Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses. Results: As for 211 GM taxa, IVW results confirmed that family-Christensenellaceae (P = 1.36×10-2) and family-Peptococcaceae (P = 3.13×10-2) were protective factors for DR. Genus-Ruminococcaceae_UCG_011 (P = 4.83×10-3), genus-Eubacterium_rectale_group (P = 3.44×10-2) and genus-Adlercreutzia (P = 4.82×10-2) were correlated with the risk of DR. At the phylum, class and order levels, we found no GM taxa that were causally related to DR (P>0.05). Heterogeneity (P>0.05) and pleiotropy (P>0.05) analysis confirmed the robustness of MR results. Conclusion: We confirmed that there was a potential causal relationship between some GM taxa and DR, which highlights the association of the "gut-retina" axis and offered new insights into the GM-mediated mechanism of DR. Further explorations of their association are required and will lead to find new biomarkers for targeted prevention strategies of DR.

Genetic variation reveals the influence of steroid hormones on the risk of retinal neurodegenerative diseases.

It is difficult to get evidence from randomized trials of a causal relationship between steroid hormones produced by the adrenal gland and gonad and retinal neurodegenerative disorders (RND). In this study, genetic variations of aldosterone (Aldo), androstenedione (A4), progesterone (P4), hydroxyprogesterone (17-OHP), and testosterone/17ß-estradiol (T/E2) were obtained from genome-wide association studies as instrumental variables. Mendelian randomization (MR) analysis was used to assess the impact on the risk of RND, including glaucoma (8,591 cases and 210,201 controls), diabetic retinopathy (DR, 14,584 cases and 202,082 controls) and age-related macular degeneration (AMD, 14,034 cases and 91,214 controls). As the main method, inverse variance weighted results suggest that the increased glaucoma risk was affected by T/E2 (OR = 1.11, 95% CI, 1.01-1.22, P = 0.03), which was further validated by other methods (PWM = 0.03, PMLE = 0.03, PMR-RAPS = 0.03). In the replicated stage, the causal relationship between T/E2 and glaucoma was verified based on the MRC-IEU consortium (P = 0.04). No impact of Aldo, A4, P4, 17-OHP, and T/E2 was observed for the risk of DR (P > 0.05) and AMD (P > 0.05). The heterogeneity test (P > 0.05) and pleiotropy test (P > 0.05) verified the robustness of the results. Our results suggest that T/E2 has a suggestive effect on the glaucoma risk. However, the genetic evidence based on a large sample does not support the effect of steroid hormones on DR and AMD risk. Further studies are vital to assess the possibility of steroid hormones as targets for prevention and treatment.

Isolation, Identification and Insecticidal Activity of the Secondary Metabolites of Talaromyces purpureogenus BS5.

The fungal strain BS5 was isolated from a soil sample collected in the Tibetan Plateau, which displayed good insecticidal activity and was identified as Talaromyces purpureogenus based on morphological and molecular analysis. This study aimed to evaluate the insecticidal activity and identify the active compound of the strain BS5 against the locust Locusta migratoria manilensis. The insecticidal activity of the fermented broth of BS5 was at 100% after 7 days against locusts. We extracted the fermented broth of BS5 and then evaluated the insecticidal activity of the extracts against locusts. The ethyl acetate extract exhibited promising activity levels with an LC50 value of 1077.94 µg/mL and was separated through silica gel column chromatography. The UPLC-Q-Exactive Orbitrap/MS system was employed to analyze the active fraction Fr2.2.2 (with an LC50 value of 674.87 µg/mL), and two compounds were identified: phellamurin and rubratoxin B.

miR-7 Reduces High Glucose Induced-damage Via HoxB3 and PI3K/AKT/mTOR Signaling Pathways in Retinal Pigment Epithelial Cells.

BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes. This study investigated the effect of miR-7 in the regulation of cell proliferation via the HoxB3 gene and PI3K/AKT/mTOR signaling pathways in DR. METHODS: Human retinal pigment epithelial cell line (ARPE-19) cultured in normal medium (Control) and high glucose medium (25mM glucose, HG) was transfected with mimics NC (HG+ mimics NC), miR-7 mimics (HG+miR-7 mimics), inhibitor NC (HG+ inhibitor NC), and miR-inhibitor (HG+miR-7 inhibitor). The cells were assayed for viability, apoptosis, and expression of genes. RESULTS: HG reduced cell viability and increased apoptosis. However, miR-7 mimics reduced the apoptosis. PCR results showed that miR-7 was significantly upregulated after transfection with miR-7 mimics. The expression of Hoxb3, mTOR, p-PI3K, and p- AKT was significantly downregulated at mRNA and protein levels after miR-7 mimics transfection, while no difference was observed for PI3K and AKT expression. CONCLUSION: Our findings demonstrate that miR-7 regulates the growth of retinal epithelial cells through various pathways and is a potential therapeutic target for the prevention and treatment of diabetic retinopathy.

Targeting long non-coding RNA MALAT1 alleviates retinal neurodegeneration in diabetic mice.

AIM: To observe the effect of inhibiting long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on diabetic neurodegeneration. METHODS: Thirty-six 8-week-old C57BL/6 mice were randomly divided into normal control, diabetic control, diabetic scrambled small interfering RNAs (siRNAs) and diabetic MALAT1-siRNA groups. After diabetic induction with streptozocin intraperitoneally-injection, the diabetic MALAT1-siRNA group was intravitreally injected with 1 µL 20 µmol/L MALAT1 siRNA, and the diabetic scrambled siRNA group was injected with the same amount of scrambled siRNA. Electroretinography was performed to examine photoreceptor functions 16wk after diabetes induction. MALAT1 expression was detected via real time polymerase chain reaction. Cone morphological changes were examined using immunofluorescence. Rod morphological changes were examined by determining outer nuclear layer (ONL) thickness. RESULTS: The upregulation of retinal MALAT1 expression was detected in the diabetic control mice, while MALAT1 expression in the diabetic MALAT1-siRNA mice was decreased by 91.48% compared to diabetic control mice. The diabetic MALAT1-siRNA and diabetic control mice showed lower a-wave and b-wave amplitudes than did the normal control mice in scotopic and photopic electroretinogram, while the diabetic MALAT1-siRNA mice showed higher amplitudes than diabetic control mice. Morphological examination revealed that ONL thickness in the diabetic MALAT1-siRNA and diabetic control mice was lower than normal control mice. However, ONL thickness was greater in the diabetic MALAT1-siRNA mice than diabetic control mice. Moreover, the diabetic control mice performed a sparser cone cell arrangement and shorter outer segment morphology than diabetic MALAT1-siRNA mice. CONCLUSION: Inhibiting retinal MALAT1 results in mitigative effects on the retinal photoreceptors, thus alleviating diabetic neurodegeneration.