Nitenpyram in tea: Eco-friendly detection methodology and residue behavior.

Studies on nitenpyram determination and behavior within tea remain limited despite its widespread use as a neonicotinoid. An organic-saving analytical approach tailored for the detection of nitenpyram in tea was established. Nitenpyram was extracted by boiling water and cleaned up by Cleanert PCX solid-phase. The average recoveries were 75.1-94.5 %, with relative standard deviations (RSDs) of 0.7-8.6 % for saving 34.5-88.6 % organic solvent. The limits of quantification (LOQs) were 0.002 mg·kg-1 in fresh tea shoots, 0.005 mg·kg-1 in made tea, and 0.001 mg·L-1 in tea brew, satisfying the current minimum Maximum Residue Limit (MRL). Nitenpyram dissipated rapidly with half-lives of 1.2-1.4 days at the recommended dosage (27 g a.i. ha-1) in two locations. Remarkably, 20-110 % of nitenpyram was leached out from made tea in different brewing modes. This work provides insights into nitenpyram's rational application in tea cultivation and offers considerations to institutions tasked with unestablished MRLs in tea.

USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation.

The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3 mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.

Assessing Risk Factors for Cognitive Decline Using Electronic Health Record Data: A Scoping Review.

Background: The data and information contained within electronic health records (EHR) provide a rich, diverse, longitudinal view of real-world patient histories, offering valuable opportunities to study antecedent risk factors for cognitive decline. However, the extent to which such records' data have been utilized to elucidate the risk factors of cognitive decline remains unclear. Methods: A scoping review was conducted following the PRISMA guideline, examining articles published between January 2010 and April 2023, from PubMed, Web of Science, and CINAHL. Inclusion criteria focused on studies using EHR to investigate risk factors for cognitive decline. Each article was screened by at least two reviewers. Data elements were manually extracted based on a predefined schema. The studied risk factors were classified into categories, and a research gap was identified. Results: From 1,593 articles identified, 80 were selected. The majority (87.5%) were retrospective cohort studies, with 66.3% using datasets of over 10,000 patients, predominantly from the US or UK. Analysis showed that 48.8% of studies addressed medical conditions, 31.3% focused on medical interventions, and 17.5% on lifestyle, socioeconomic status, and environmental factors. Most studies on medical conditions were linked to an increased risk of cognitive decline, whereas medical interventions addressing these conditions often reduced the risk. Conclusions: EHR data significantly enhanced our understanding of medical conditions, interventions, lifestyle, socioeconomic status, and environmental factors related to the risk of cognitive decline.

Research Progress on Detection of New Psychoactive Substance Piperazines in vivo.

Piperazines are a class of new psychoactive substances with hallucinogenic effects that affect the central nervous system by affecting the level of monoamine neurotransmitters. Abuse of piperazines will produce stimulating and hallucinogenic effects, accompanied by headache, dizziness, anxiety, insomnia, vomiting, chest pain, tachycardia, hypertension and other adverse reactions, and may even cause cardiovascular diseases and multiple organ failure and lead to death, seriously affecting human physical and mental health and public safety. The abuse of new psychoactive substance piperazines has attracted extensive attention from the international community. The study of its pharmacological toxicology and analytical methods has become a research hotspot in the field of forensic medicine. This paper reviews the in vivo processes, sample treatment and analytical methods of existing piperazines, in order to provide reference for forensic identification.

[Determination of five veterinary drug residues in milk by ultra-high performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry based on modified chitosan membrane purification].

Milk is an important consumer product with high nutritional value. The presence of veterinary drug residues in milk owing to the indiscriminate use of veterinary drugs may affect consumer health. In the mass spectrometric analysis of trace compounds, chromatographic co-eluting components easily interfere with the mass spectral signals obtained, affecting the accuracy of qualitative and quantitative analyses. Matrix purification is a promising method to reduce the matrix effect. Chitosan is a natural biopolymer with numerous active functional groups such as amino, acetyl, and hydroxyl groups; these groups can adsorb lipids through hydrophobic and electrostatic interactions. Chitosan also has the advantages of low production cost, stable chemical properties, and convenient modification. Novel chitosan-based materials are promising candidates for lipid purification. In this study, a chitosan membrane was modified with trimethoxyoctadecylsilane (C18-CSM). C18-CSM was prepared through one-step hydrolysis and used as a dispersive solid phase extraction (DSPE) adsorbent to purify the matrix during milk pretreatment. We combined C18-CSM with ultra-high performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry (UHPLC-Q/Exactive Orbitrap MS) to develop an effective method for the extraction and determination of ofloxacin, enrofloxacin, ciprofloxacin, diazepam, and metronidazole in milk. C18-CSM was characterized using scanning electron microscopy, Fourier transform infrared spectroscopy, and water contact angle testing. The results indicated that the material has a rough surface and uniformly dense cross-section. The water contact angle of C18-CSM was 104°, indicating its good hydrophobicity. The pretreatment conditions (extraction solvent, dosage of NaCl, extraction frequency, and dosage of C18-CSM) that influenced the recoveries of the five veterinary drugs were investigated in detail. The optimal conditions were established as follows: 5% formic acid in acetonitrile, 1 g NaCl, extraction 1 time, 20 mg C18-CSM. Separation was performed on a Hypersil GOLD VANQUISH column (100 mm×2.1 mm, 1.9 µm). The mobile phase consisted of 0.1% formic acid aqueous solution and 0.1% formic acid in acetonitrile, and was flowed at a rate of 0.3 mL/min. The sample injection volume was 1 µL, and the column temperature was maintained at 25 ℃. Mass spectrometric analysis was performed in positive electrospray ionization mode. To verify the necessity of the purification material, the matrix effect was investigated using the matrix-matched standard curve method. The use of C18-CSM reduced the matrix effects of the five necessity drugs from the range of -22%-8.8% to the range of -13%-3.6%, indicating that C18-CSM is a highly efficient DSPE material. Under optimal conditions, the developed method showed good linearities within the range of 0.5-100 µg/L, with correlation coefficients (r2)≥0.9970. The limits of detection(LODs) and quantification (LOQs) were 0.2 µg/L and 0.5 µg/L, respectively. To assess the accuracy and precision of the method, we prepared milk samples with three spiked levels (low, medium, and high). The recoveries of the five veterinary drugs were ranged from 79.5% to 115%, and the intra-day and inter-day relative standard deviations were 7.0%-13% (n=6) and 1.3%-11% (n=3), respectively. This study provides a simple, accurate, and reliable method for the rapid and simultaneous determination of the five veterinary drug residues in milk.

The impact of chronic obstructive pulmonary disease on the risk of immune-related pneumonitis in lung cancer patients undergoing immunotherapy: a systematic review and meta-analysis.

BACKGROUND: Lung cancer, a leading cause of cancer mortality, poses significant treatment challenges. The use of immune checkpoint inhibitors (ICIs) has revolutionized therapy, but it is associated with immune-related pneumonitis (IRP). This study systematically reviews and analyzes the impact of Chronic Obstructive Pulmonary Disease (COPD) on the risk of IRP in lung cancer patients undergoing immunotherapy. METHODS: Adhering to PRISMA guidelines and using the PICO framework, a comprehensive search across PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Inclusion criteria encompassed peer-reviewed studies involving lung cancer patients treated with ICIs, comparing those with and without COPD. The primary outcome was the incidence and risk of IRP. The Newcastle-Ottawa Scale evaluated study quality. The effect size was calculated using random or fixed-effects models based on the observed heterogeneity. We assessed the heterogeneity between studies and conducted a sensitivity analysis. RESULTS: The search identified 1026 articles, with six meeting the criteria for inclusion. Studies varied in design and geography, predominantly retrospective cohort studies. Patients with COPD had an increased risk of IRP (OR = 1.54, 95% CI [1.24, 1.92, P < 0.01). Subgroup analysis based on radiation therapy exposure (< 40% and ≥ 40%) also indicated a heightened IRP risk in COPD patients. Sensitivity analysis affirmed the robustness of the results, and publication bias was not significant. CONCLUSIONS: Lung cancer patients with COPD undergoing immunotherapy have a significantly increased risk of developing IRP. This highlights the necessity for vigilant monitoring and individualized treatment strategies to improve the safety and effectiveness of immunotherapy in this group.

Transcriptomic responses and evolutionary insights of deep-sea and shallow-water mussels under high hydrostatic pressure condition.

Marine mussels inhabit a wide range of ocean depths, necessitating unique adaptations to cope with varying hydrostatic pressures. This study investigates the transcriptomic responses and evolutionary adaptations of the deep-sea mussel Gigantidas platifrons and the shallow-water mussel Mytilus galloprovincialis to high hydrostatic pressure (HHP) conditions. By exposing atmospheric pressure (AP) acclimated G. platifrons and M. galloprovincialis to HHP, we aim to simulate extreme environmental challenges and assess their adaptive mechanisms. Through comparative transcriptomic analysis, we identified both conserved and species-specific mechanisms of adaptation, with a notable change in gene expression associated with immune system, substance transport, protein ubiquitination, apoptosis, lipid metabolism and antioxidant processes in both species. G. platifrons demonstrated an augmented lipid metabolism, whereas M. galloprovincialis exhibited a dampened immune function. Additionally, the expressed pattern of deep-sea mussel G. platifrons were more consistent than shallow-water mussel M. galloprovincialis under hydrostatic pressures changed conditions which corresponding the long-term living stable deep-sea environment. Moreover, evolutionary analysis pinpointed positively selected genes in G. platifrons that are linked to transmembrane transporters, DNA repair and replication, apoptosis, ubiquitination which are important to cell structural integrity, substances transport, and cellular growth regulation. This indicates a specialized adaptation strategy in G. platifrons to cope with the persistent HHP conditions of the deep sea. These results offer significant insights into the molecular underpinnings of mussel adaptation to varied hydrostatic conditions and enhance our comprehension of the evolutionary forces driving their depth-specific adaptations.

Nitrogen removal performance and mechanism in constructed wetlands under saline conditions: Role of Canna indica inoculated with Piriformospora indica.

The phytopromotional root endophytic fungus Piriformospora indica was introduced into the wetland plant Canna indica L. to explore its impact on nitrogen (N) removal in constructed wetlands (CWs) to treat normal and saline (0.9 % NaCl) wastewater. P. indica colonization increased total nitrogen, NH4+-N, and NO3--N removal efficiencies under normal and saline conditions, with NO3--N removal rates significantly increasing by 17.5 % under saline conditions (P<0.05). N removal by plant uptake improved by 26.1 % and 27.7 % under normal and saline conditions due to P. indica-mediated growth-promoting effects. Salt-tolerant denitrifiers and nitrifiers guaranteed the dominant role of microbial degradation in N removal under saline conditions. P. indica inoculation considerably improved the contribution of Nocardioides and Nitrosomnas to dissimilatory/assimilatory nitrate reduction and nitrification genes, respectively. These findings elucidate the mechanisms and potential applications of P. indica-mediated phytoremediation in practical wastewater treatment under varying salty conditions.

[Retracted] Cognitive improvements and reduction in amyloid plaque deposition by saikosaponin D treatment in a murine model of Alzheimer's disease.

[This retracts the article DOI: 10.3892/etm.2020.8760.].

Predominance of hyperprogression in mucosal melanoma during anti-PD-1 monotherapy treatment.

BACKGROUND: A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. METHODS: Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. RESULTS: A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005). CONCLUSION: A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

Helical polyisocyanide-based macroporous organic catalysts for asymmetric Michael addition with high efficiency and stereoselectivity.

Porous materials have attracted interest due to their high specific surface area and rich functionality. Immobilizing organocatalysts onto porous polymers not only boosts enantioselectivity but also improves the reaction rates. In this work, a series of porous polymers C-poly-3ms with rigid polyisocyanide-carrying secondary amine pendants as building blocks were successfully prepared. And the pore size and optical activity of C-poly-3ms can be controlled by the length of the polyisocyanide blocks due to their rigid and helical backbone. C-poly-3150 demonstrated a preferred left-handed helix with a θ 364 value of -8.21 × 103. The pore size and S BET of C-poly-3150 were 17.52 nm and 7.98 m2 g-1, respectively. The porous C-poly-3150 catalyzes the asymmetric Michael addition reaction efficiently and generates the target products in satisfactory yield and excellent enantioselectivity. For 6ab, an enantiomeric excess (ee) and a diastereomeric ratio (dr) up to 99% and 99/1 could be achieved, respectively. The recovered catalyst can be recycled at least 6 times in the asymmetric Michael addition reaction while maintaining activity and stereoselectivity.

Deciphering deep-sea chemosynthetic symbiosis by single-nucleus RNA-sequencing.

Bathymodioline mussels dominate deep-sea methane seep and hydrothermal vent habitats and obtain nutrients and energy primarily through chemosynthetic endosymbiotic bacteria in the bacteriocytes of their gill. However, the molecular mechanisms that orchestrate mussel host-symbiont interactions remain unclear. Here, we constructed a comprehensive cell atlas of the gill in the mussel Gigantidas platifrons from the South China Sea methane seeps (1100 m depth) using single-nucleus RNA-sequencing (snRNA-seq) and whole-mount in situ hybridisation. We identified 13 types of cells, including three previously unknown ones, and uncovered unknown tissue heterogeneity. Every cell type has a designated function in supporting the gill's structure and function, creating an optimal environment for chemosynthesis, and effectively acquiring nutrients from the endosymbiotic bacteria. Analysis of snRNA-seq of in situ transplanted mussels clearly showed the shifts in cell state in response to environmental oscillations. Our findings provide insight into the principles of host-symbiont interaction and the bivalves' environmental adaption mechanisms.

The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by high heterogeneity, poor long-term survival, and a propensity for relapse. Exceptional efficacy in treating recurrent or refractory B-lymphoid malignancies has been demonstrated by Chimeric antigen receptor T cells (CAR-T cells). Given the therapeutic potential of targeting both CD33 and C-type lectin-like molecule-1 (CLL1) in AML, the development of a dual-targeting CD33-CLL1 CAR-T cells assumes significant importance. MATERIALS AND METHODS: The expressions of CD33 and CLL-1 antigens in peripheral blood cells and bone marrow cells from AML patients was assessed. Subsequently, a Chimeric Antigen Receptor (CAR) incorporating a dual-specific single-chain variable fragment targeting CLL1 and CD33 (CD33-CLL1-CAR-T) was engineered. The anti-tumor efficacy and potential side effects of CD33-CLL1-CAR-T cells were comprehensively investigated in both in vitro and in vivo settings. RESULTS: The constructed tandem CD33-CLL1 CAR-T exhibited potent cytotoxicity against leukemia cell lines and human primary AML cells in vitro. Co-cultivation of AML blasts with CD33-CLL1-CAR-T cells resulted in effective proliferation and the secretion of substantial quantities of GM-CSF and IFN-γ. Importantly, the impact of CD33-CLL1-CAR-T cells on normal hematopoietic stem cells was minimal, ensuring safety in vivo mouse models. Notably, significant anti-leukemic activity was observed in the mouse model, with CD33-CLL1-CAR-T cells leading to tumor eradication and prolonged survival. DISCUSSION: The tandem CD33-CLL1 CAR-T cells not only efficiently eliminated AML blasts but also exhibited low cytotoxicity toward normal hematopoietic stem cells (HSCs). These findings underscore the potential clinical applicability of the tandem CD33-CLL1 CAR-T cells as an effective and safe treatment strategy for AML, representing a noteworthy advancement in the field of CAR-T cells therapy.

Genomic anatomy of homozygous XX females and YY males reveals early evolutionary trajectory of sex-determining gene and sex chromosomes in Silurus fishes.

Sex chromosomes display remarkable diversity and variability among vertebrates. Compared with research on the X/Y and Z/W chromosomes, which have long evolutionary histories in mammals and birds, studies on the sex chromosomes at early evolutionary stages are limited. Here, we precisely assembled the genomes of homozygous XX female and YY male Lanzhou catfish (Silurus lanzhouensis) derived from an artificial gynogenetic family and a self-fertilized family, respectively. Chromosome 24 (Chr24) was identified as the sex chromosome based on resequencing data. Comparative analysis of the X and Y chromosomes showed an approximate 320 kb Y-specific region with a Y-specific duplicate of anti-Mullerian hormone type-II receptor (amhr2y), which is consistent with findings in two other Silurus species but on different chromosomes (Chr24 of S. meridionalis and Chr5 of S. asotus). Deficiency of amhr2y resulted in male-to-female sex reversal, indicating that amhr2y plays a male-determining role in S. lanzhouensis. Phylogenetic analysis and comparative genomics revealed that the common sex-determining gene amhr2y was initially translocated to Chr24 of the Silurus ancestor along with the expansion of transposable elements. Chr24 was maintained as the sex chromosome in S. meridionalis and S. lanzhouensis, whereas a sex-determining region transition triggered sex chromosome turnover from Chr24 to Chr5 in S. asotus. Additionally, gene duplication, translocation, and degeneration were observed in the Y-specific regions of Silurus species. These findings present a clear case for the early evolutionary trajectory of sex chromosomes, including sex-determining gene origin, repeat sequence expansion, gene gathering and degeneration in sex-determining region, and sex chromosome turnover.

Development of a Predictive Nomogram for Intra-Hospital Mortality in Acute Ischemic Stroke Patients Using LASSO Regression.

Background and Purpose: Ischemic stroke is a leading cause of mortality and disability globally, necessitating accurate prediction of intra-hospital mortality (IHM) for improved patient care. This study aimed to develop a practical nomogram for personalized IHM risk prediction in ischemic stroke patients. Methods: A retrospective study of 422 ischemic stroke patients (April 2020 - December 2021) from Chongqing Medical University's First Affiliated Hospital was conducted, with patients divided into training (n=295) and validation (n=127) groups. Data on demographics, comorbidities, stroke risk factors, and lab results were collected. Stroke severity was assessed using NIHSS, and stroke types were classified by TOAST criteria. Least absolute shrinkage and selection operator (LASSO) regression was employed for predictor selection and nomogram construction, with evaluation through ROC curves, calibration curves, and decision curve analysis. Results: LASSO regression and multivariate logistic regression identified four independent IHM predictors: age, admission NIHSS score, chronic obstructive pulmonary disease (COPD) diagnosis, and white blood cell count (WBC). A highly accurate nomogram based on these variables exhibited excellent predictive performance, with AUCs of 0.958 (training) and 0.962 (validation), sensitivities of 93.2% and 95.7%, and specificities of 93.1% and 90.9%, respectively. Calibration curves and decision curve analysis validated its clinical applicability. Conclusion: Age, admission NIHSS score, COPD history, and WBC were identified as independent IHM predictors in ischemic stroke patients. The developed nomogram demonstrated high predictive accuracy and practical utility for mortality risk estimation. External validation and prospective studies are warranted for further confirmation of its clinical efficacy.

Physicochemical properties and flavor substances analyses of refined beef tallow with dry fractionation treatment.

Dry fractionation represents a significant technique for separation of diverse fractions from beef tallow. The objective of this study was to undertake a systematic investigation of alterations in physicochemical properties, crystallization behavior, thermal properties, and flavor compounds that occur during the beef tallow dry fractionation process. The solid component yielded at 40, 30, and 15 °C were 44.88%, 33.72%, and 13.04% respectively, with an 8.36% liquid content at 15 °C, which was consistent with the characteristics of saturated fatty acids content. The ß - ß' transformation in the dry fractionation process was clearly revealed by X-ray diffraction. Differential scanning calorimetry curves exhibited alterations in exothermic and endothermic peak, as well as enthalpy. Electronic nose identified short-chain compounds, aldehydes, ketones, and nitrogen-containing substances as flavor compounds. Volatile compounds were quantified using HS-SPME-GC-MS. Overall, dry fractionation produces beef tallow fractionated compounds with diverse physicochemical properties and aromatic-active substances, thereby expanding its potential utilization.

A comprehensive review of new small molecule drugs approved by the FDA in 2022: Advance and prospect.

In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications. The successful cases provide valuable information for optimizing efficacy and enhancing pharmacokinetic properties through strategies like macrocyclization, bioequivalent group utilization, prodrug synthesis, and conformation restriction. Therefore, gaining an in-depth understanding of the design principles and strategies underlying these drugs will greatly facilitate the development of new therapeutic agents. This review focuses on the research and development process of these newly approved small molecule drugs including drug design, structural modification, and improvement of pharmacokinetic properties to inspire future research in this field.

Genome-Wide Mendelian Randomization Study Reveals Druggable Genes for Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD. METHODS: We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment. RESULTS: Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the ALDH2 and KLHL24 genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes ADRB1, BTN3A2, and EFEMP1 were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.