Lysosomes are the degradation centers and signaling hubs in the cell. Lysosomes undergo adaptation to maintain cell homeostasis in response to a wide variety of cues. Dysfunction of lysosomes leads to aging and severe diseases including lysosomal storage diseases (LSDs), neurodegenerative disorders, and cancer. To understand the complexity of lysosome biology, many research approaches and tools have been developed to investigate lysosomal functions and regulatory mechanisms in diverse experimental systems. This review summarizes the current approaches and tools adopted for studying lysosomes, and aims to provide a methodological overview of lysosomal research and related fields.

Background: MicroRNAs (miRNAs) have pivotal roles in gene regulation. Circulating miRNAs have been developed as novel candidate non-invasive biomarkers for diagnosis, prognosis, and treatment response for diseases. However, miRNAs that have causal effects on Parkinson’s Disease (PD) remain largely unknown. To investigate the causal relationships between miRNAs and PD, here we conduct a Mendelian randomization (MR) study.Methods: This study utilized the summary-level data of respective genome-wide association studies (GWAS) for 2083 miRNAs and seven PD-related outcomes to comprehensively reveal the causal associations between the circulating miRNAs and PD. Two-sample MR design was deployed and the causal effects were estimated with inverse variance weighted, MR-Egger, and weighted median. Comprehensively sensitive analyses were followed, including Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, to validate the robustness of our results. Finally, we investigated the potential role of the MR significant miRNAs by predicting their target genes and functional enrichment analysis.Results: Inverse variance weighted estimates suggested that two miRNAs, miR-205-5p (β = −0.46, 95%CI: −0.690 to −0.229, p = 9.3 × 10⁻⁵) and miR-6800-5p (β = −0.389, 95%CI: −0.575 to −0.202, p = 4.32 × 10⁻⁵), significantly decreased the rate of cognitive decline among PD patients. In addition, eight miRNAs were nominally associated with more than three PD-related outcomes each. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Gene Ontology (GO) analysis showed that the targets of these causal miRNAs were significantly enriched in cell cycle, apoptotic, and aging pathways.Conclusion: This MR study identified two miRNAs whose genetically regulated expression might have a causal role in the development of PD dementia. Our findings provided potential miRNA biomarkers to make better and early diagnoses and risk assessments of PD.

Background: Long coronavirus disease (COVID), characterized by persistent and sometimes debilitating symptoms following a severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, has garnered increasing attention as a potential public health crisis. Emerging evidence indicates a higher incidence of hearing loss in individuals who have had COVID 2019 (COVID‐19) compared to the general population. However, the conclusions were inconsistent, and the causal relationship between COVID‐19 and sensorineural hearing loss remains unknown.Methods: To addresses this outstanding issue, we performed Mendelian randomization analysis to detect the causal association between COVID‐19 and hearing loss using the largest genome‐wide association study data to date in the European population and confirmed the results in the East Asian population. Comprehensively sensitive analyses were followed, including Cochran's Q test, Mendelian randomization (MR)‐Egger intercept test, MR‐pleiotropy residual sum and outlier, and leave‐one‐out analysis, to validate the robustness of our results.Results: Our results suggested that there is no causal association between COVID‐19 and the risk of hearing loss in the European population. Neither the susceptibility, hospitalization, and severity of COVID‐19 on hearing loss (inverse variance weighted method: odds ratio (OR) = 1.046, 95% confidence interval (CI) = 0.907–1.205, p = .537; OR = 0.995, 95% CI = 0.956–1.036, p = .823; OR = 0.995, 95% CI = 0.967–1.025, p = .76). Replicated analyses in the East Asian population yielded consistent results. No pleiotropy and heterogeneity were found in our results.Conclusion: In conclusion, our MR results do not support a genetically predicted causal relationship between COVID‐19 and sensorineural hearing loss. Thus, the associations observed in prior observational studies may have been influenced by confounding factors rather than a direct cause‐and‐effect relationship. More clinical and mechanism research are needed to further understand this association in the future.

BackgroundHyperemesis gravidarum (HG), excessive vomiting in pregnancy, occurs in 0.3-10.8% of pregnancies and is associated with maternal and fetal morbidity. Despite the existence of several off-label treatment options that have shown clinical effectiveness in managing HG symptoms, the variability in treatment response highlights the need for more effective therapies. Our study aims to identify novel therapeutic targets that could lead to the development of additional, more effective treatment options.MethodsA two-sample Mendelian randomization (MR) analysis was performed to estimate the causal effects of blood-druggable genes on HG. Summary statistics for HG were obtained from the FinnGen study and UK Biobank. Cis-expression quantitative trait loci (cis-eQTL) for blood druggable genes were obtained from the eQTLGen Consortium and used as genetic instrumental variables. Another MR method, summary level mendelian randomization (SMR), was used to further confirm our results. We also used eQTL data of other vomiting-related tissues, brain regions, and esophagus, to validate our MR results. Finally, the potential side effects of the druggable genes for HG treatment were assessed using a phenome-wide MR.ResultsOverall, 2499 unique druggable genes were gathered. Two blood drug targets (OVGP1 and LGALS1) showed significant MR results in two independent datasets. No significant heterogeneity of instrumental variables or pleiotropy was detected. In addition, SMR analysis further confirmed the significance of these two prior druggable genes in the brain and esophagus tissues. Further phenome-wide MR analysis revealed no association between genetic proxies of OVGP1, and LGALS1 has been detected in increasing the risk of adverse pregnancy outcomes and other common diseases.ConclusionsThis study provides genetic evidence that targeting two druggable genes for HG has potential therapeutic advantages. This information is of considerable value in guiding and prioritizing the development of more effective therapies for HG.

Dysregulation of the autophagy–lysosome pathway is implicated in neurodegenerative disorders. To extend the chemical diversity of jatrophane diterpenoids from Euphorbia peplus and evaluate lysosome-associated phenotypes, phytochemical isolation and a LysoTracker Green assay in HeLa cells were performed. Five previously undescribed jatrophane diterpenoids, Euphjatrophanes M–Q (1–5), together with three known analogues (6–8), were isolated. The structures of 1–5 were assigned from one- and two-dimensional NMR, IR, and UV and the available HR-ESI-MS data, together with a comparison with reported compounds. At 10 and 40 μM, compounds 1, 2, and 4–8 produced higher LysoTracker-associated fluorescence than the DMSO vehicle control, whereas compound 3 showed a small numerical increase at 10 μM and a decrease at 40 μM. Compound 1 gave the largest numerical response (1.76-fold and 3.01-fold at 10 and 40 μM, respectively). These findings provide preliminary cell-based phenotypic evidence of lysosome-modulating activity and require orthogonal validation.