Background the global burden of Parkinson’s disease (PD) is rising, yet its pathogenesis remains incompletely understood. Growing evidence implicates the microbiota-gut-brain axis, especially metabolites gut microbiota, as key modulators of PD pathogenesis, but their precise molecular actions remain unclear. Methods using Global Burden of Disease data (1990–2021), we first characterized global epidemiological trends of PD. We identified gut microbiota metabolites and their key targets involved in PD by integrating network pharmacology and molecular docking. Functional enrichment highlighted AKT1 related signaling as a central hub. Finally, Cell Counting Kit 8 (CCK8) assays assessed the neuroprotective effects of selected compounds in 1-methyl-4-phenylpyridinium induced HT-22 neuronal cells. Results global PD prevalence increased from 3,148,395 (1990) to 11,767,272 (2021). Integration of 1,518 gut microbiota metabolite targets with 8,679 PD genes yielded 63 shared targets, among which AKT1, IL6, JUN, TP53, and NFKB1 emerged as hubs. Enrichment analyses highlighted pathways related to inflammation, cellular stress, and apoptosis. Docking suggested favorable IPA-AKT1 binding (-7.553 kcal/mol), and IPA rescued viability in MPP⁺ treated HT‑22 cells (n = 6 per group, mean ± SD; P < 0.05 vs. MPP⁺ control), with significant gains versus MPP⁺ controls (P < 0.05). Conclusion this study integrates epidemiological analysis with computational and experimental approaches to reveal that gut microbiota metabolites, particularly IPA, may influence PD through AKT1 mediated regulation of neuroinflammatory and apoptotic pathways. The insight highlight gut microbiota metabolites as promising candidates for biomarker discovery and therapeutic exploration in PD.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Emerging evidence highlights the diet-gut-brain axis in neurological outcomes, yet the specific metabolic mediators remain elusive. This study integrated epidemiological, genetic, and experimental approaches to investigate the potential neuroprotective role of gut-derived metabolites in ICH. Utilizing Global Burden of Disease data and Mendelian randomization analysis, we explored the associations between dietary habits and ICH, and investigated putative causal relationships between specific gut microbiota and disease risk. Subsequent network pharmacology analysis predicted that 3-indolepropionic acid (3-IPA) might exert neuroprotective effects primarily through anti-apoptotic pathways. To evaluate these findings in vivo, we established a mouse model of ICH. Administration of 3-IPA significantly ameliorated neurological deficits and improved cognitive memory in the Morris water maze test. Furthermore, immunofluorescence and Western blot analyses indicated that 3-IPA treatment was associated with the upregulation of the anti-apoptotic protein BCL2 and the reduction of pro-apoptotic markers in the peri-hematomal region. In conclusion, our multidisciplinary study outlines a potential biological pathway linking dietary patterns, gut microbial metabolism, and brain injury recovery. Our findings suggest that the gut microbial metabolite 3-IPA protects against ICH-induced secondary brain injury, potentially by attenuating neuronal apoptosis, highlighting it as a promising metabolic intervention target for ICH therapy.

Postoperative delirium (POD) and Alzheimer's disease (AD) are increasingly recognized as related neurocognitive conditions, but the aging-associated cell states that may connect them remain poorly defined. Here, we integrated two brain transcriptomic discovery datasets analyzed at single-cell/single-nucleus resolution, including a POD-related cohort (GSE291019) and an AD cohort (GSE129308), together with two independent peripheral-blood bulk transcriptomic datasets (GSE163943 and GSE63060), to identify aging-associated cellular programs and prioritize convergent molecular candidates. Across 184,168 high-quality cells, inhibitory neurons showed the most consistent aging-associated perturbation across the POD- and AD-related datasets. Re-clustering further identified three inhibitory-neuron subtypes, Inh_Neurons2, Inh_Neurons3, and Inh_Neurons5, with relatively high aging-related gene activity and preferential localization to later pseudotime states. Cross-platform integration of aging-associated inhibitory-neuron genes with a shared bulk DEG set identified four convergent candidates: RGL2, AKT1, SYK, and TNFSF13B. Among them, RGL2 emerged as the leading candidate, with the strongest downstream support concentrated in AD-related analyses. In two-sample Mendelian randomization, genetically predicted higher RGL2 expression was associated with increased AD risk, whereas the estimate for the delirium genome-wide association study proxy used for POD-related analyses was not significant. Pathway analyses further linked higher RGL2 expression to complement/coagulation and innate immune-inflammatory programs in AD-related analyses. These findings suggest a model in which POD and AD may partially intersect through aging-vulnerable inhibitory-neuron states and identify RGL2 as a prioritized candidate for downstream mechanistic investigation.

AIMS:Intracerebral hemorrhage (ICH) frequently triggers acute lung injury (ALI) via sympathetic overactivation. We aimed to investigate the neuroinflammatory mechanisms driving this brain-lung crosstalk and evaluate targeted neuromodulatory interventions via the mechanosensor PIEZO2. METHODS:We utilized an ICH mouse model and norepinephrine (NE)-stimulated MLE12 cells. Pathological mechanisms were explored using transcriptomics, calcium imaging, and Vps35 knockdown. Therapeutic efficacies were assessed via central sympathetic blockade (stellate ganglion block, SGB) and peripheral PIEZO2 inhibition (D-GsMTx4). RESULTS:NE release exacerbated neurogenic ALI post-ICH. Mechanistically, NE upregulated VPS35, which simultaneously promoted PIEZO2 membrane trafficking and impaired ATP2A2-dependent endoplasmic reticulum (ER) calcium clearance. This induced massive intracellular calcium influx, triggering widespread ER stress and NLRP3/GSDMD-mediated pyroptosis in alveolar epithelial cells. Vps35 knockdown attenuated these effects in vitro. Crucially, targeted interventions with SGB or D-GsMTx4 successfully blocked this lethal central-peripheral cascade, alleviating pulmonary pyroptosis and improving in vivo outcomes. CONCLUSION:Sympathetic overactivation drives neurogenic ALI post-ICH via the VPS35/PIEZO2-ER stress-pyroptosis axis. Dual-node neuromodulation (SGB or PIEZO2 inhibition) offers a promising therapeutic strategy for secondary multiorgan complications following acute brain injury.

Secondary brain injury (SBI) following intracerebral hemorrhage (ICH) is heavily driven by the mechanical compression of the expanding hematoma, yet how neurons transduce this physical force into pathological intracellular signals remains poorly understood. This study investigates the role of the mechanosensitive ion channel Piezo2 in ICH-induced SBI and its underlying molecular mechanisms. Using a collagenase-induced ICH mouse model and single-cell RNA sequencing analysis, we identified a marked upregulation of Piezo2 in perihematomal neurons. To determine its functional significance, we employed both genetic knockdown (shRNA) and pharmacological modulation with D-GsMTx4 in vivo. Modulation of Piezo2 significantly alleviated acute neurological deficits, reduced brain edema, and improved long-term cognitive performance in ICH mice. Mechanistically, we observed that the neuroprotective effects of Piezo2 inhibition were associated with an attenuation of neuronal endoplasmic reticulum (ER) stress. Specifically, inhibition of Piezo2 preserved ER ultrastructure, which was accompanied by a robust downregulation of the PERK/ATF4/CHOP signaling cascade markers. Collectively, our findings suggest that Piezo2 contributes to neuronal damage following ICH and that its modulation impacts ER stress. Targeting Piezo2 represents a novel experimental concept to mitigate secondary neurodegeneration associated with hematoma-induced mechanical strain, though extensive preclinical optimization is required before considering its clinical viability.

Clopidogrel is usually discontinued 5–7 days before elective surgery to reduce the risk of bleeding. However, the perioperative safety of patients receiving low-molecular-weight heparin (LMWH) bridging therapy or continuing clopidogrel therapy remains unknown. We identified patients who received clopidogrel for cardiovascular diseases and underwent elective surgery at a large central hospital in China between June 2022 and January 2024. The primary endpoints were perioperative blood transfusion events and bleeding-related reoperations. A total of 62 patients who received clopidogrel and underwent abdominal surgery were included in this study. Based on the preoperative clopidogrel therapy strategy, patients were categorised into three groups: the LMWH bridging group (clopidogrel withdrawal followed by LMWH bridging therapy for 5-7 days; n = 22), the no-bridging group (clopidogrel withdrawal for 5-7 days; n = 26), and the continued group (clopidogrel therapy maintained; n = 24). Perioperative blood transfusion rates were higher in the LMWH bridging and continued groups. However, there was not a significant distinction ( P = .197). Additionally, hospital stay length, bleeding-related reoperation, and 3-month mortality were similar across the groups (P > .05). No patients experienced myocardial infarction or stroke within 3 months post-procedure. Patients who received preoperative LMWH bridging therapy or continued clopidogrel therapy had a slightly higher risk of perioperative bleeding. These findings need to be confirmed by further randomised controlled trials.

Thalamic hemorrhage (TH), a critical subtype of intracerebral hemorrhage, often leads to central post-stroke pain (CPSP) and neurological deficits, yet its molecular mechanisms remain poorly understood. This study investigated the role of Rip3 in TH pathophysiology by constructing Rip3-knockout (KO) mice and integrating behavioral assessments, transcriptomic sequencing, and molecular experiments. Results demonstrated that TH induced motor dysfunction, mechanical pain hypersensitivity, working memory impairment, and anxiety-like behaviors in wild-type (WT) mice, while Rip3 knockout significantly alleviated pain sensitivity and anxiety and reduced hemorrhage volume. Transcriptomic analysis identified 956 Rip3-related candidate genes, among which Tac1, Gal, and Pdyn were validated as key downstream genes through protein-protein interaction networks and experimental assays. RT-qPCR and Western blot revealed significant upregulation of these genes in WT mice post-TH, with reduced expression in KO mice. Functional enrichment analysis implicated these genes in pathways such as NEUREXINS_AND_NEUROLIGINS and DOPAMINERGIC_NEUROGENESIS. Drug prediction identified potential therapeutic candidates, including Nizatidine, Ginger Allergenic Extract, Paregoric, and Estradiol 3-Benzoate, with the latter showing promise in modulating synaptic plasticity and pain signaling. Inhibition of Pdyn and Tac1 alleviated mechanical allodynia, while all three inhibitors, including Gal's, exhibited significant anxiolytic effects in the TH-induced CPSP model. This study reveals, for the first time, a correlative link between Rip3 and post-TH neurological injury and CPSP, potentially mediated via Tac1, Gal, and Pdyn regulation, providing novel targets for therapeutic intervention. Future research should validate direct Rip3-gene interactions and the efficacy of predicted drugs.

OBJECTIVE:To investigate the mechanism underlying the effect of the Huanglian decoction (, HLD) on morphine tolerance (MT), using network pharmacology, and to verify these mechanisms in vitro and in vivo. METHODS:Available biological data on each drug in the HLD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target proteins of MT were retrieved from the GeneCards, PharmGkb, Therapeutic Target Database, DrugBank, and Online Mendelian Inheritance in Man databases. Information regarding MT and the drug targets was compared to obtain overlapping elements. This information was imported into the Search Tool for the Retrieval of Interacting Genes/Proteins platform to obtain a protein-protein interaction network diagram. Then, a "component-target" network diagram was constructed using screened drug components and target information, viaCytoscape (Institute for Systems Biology, Seattle, WA, USA). The database for annotation, visualization, and integrated discovery was used for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways analyses. Pathway information predicted by network pharmacology was verified using animal studies and cell experiments. RESULTS:Network pharmacology analysis identified 22 active compounds of HLD and revealed that HLD partially ameliorated MT by modulating inflammatory, apoptosis, and nuclear factor kappa B (NF-κB) signaling pathways. Berberine (BBR), one of the main components of HLD, inhibited the development of MT in mice. BBR reduced cell viability while increasing B-cell lymphoma 2 (Bcl-2) protein expression and decreasing CD86, NF-κB, Bax, and Caspase-3 protein expression in brain vascular 2 (BV2) mcroglia cells treated with morphine. Additionally, BBR contributed to a reduction in pro-inflammatory cytokine release and apoptotic cell number. CONCLUSIONS:BBR, a key component of HLD, effectively suppressed microglial activation and neuro-inflammation by regulating the NF-κB and apoptosis signaling pathways, thereby delaying MT. This study offers a novel approach to enhance the clinical analgesic efficacy of morphine.

Objectives:To analyze temporal trends in the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of intracerebral hemorrhage (ICH) in China from 1990 to 2021, and to evaluate risk factors and predict future trends. Methods:Data were extracted from the 2021 Global Burden of Disease Study. Join-point regression was used to estimate average annual percentage changes (AAPC) in ICH incidence and mortality. Age-period-cohort analysis assessed demographic effects, while the autoregressive integrated moving average (ARIMA) model projected ICH burden from 2020 to 2036. Results:In 2021, China reported 3.12 million ICH cases and 913,023 deaths (68.84 per 100,000). From 1990 to 2021, ICH incidence and mortality significantly declined, with AAPCs of -1.90 and -2.42, respectively. Males exhibited higher rates, and key risk factors included low vegetable intake, hypertension, and smoking. Projections suggest further declines in incidence and mortality to 50.37 and 35.01 per 100,000 by 2036. Conclusions:Despite declining trends, ICH remains a significant public health concern in China. Targeted preventive strategies focusing on dietary improvements, hypertension management, and air quality enhancement are essential to mitigate its burden.

BackgroundA mounting body of evidence suggests a strong connection between gut microbiota and the risk of frailty. However, the question of causality remains unanswered. In this study, we employed a Mendelian randomization (MR) approach to assess potential causal relationships between gut microbiota and the risk of frailty.Materials and methodsSummary statistics for the gut microbiome were obtained from a genome wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). Our primary analysis utilized the inverse variance weighted (IVW) method. To enhance the robustness of our results, we also applied weighted median methods, MR Egger regression, and MR pleiotropy residual sum and outlier test. Finally, we conducted reverse MR analysis to investigate the potential for reverse causality.ResultsIVW method identified 7 bacterial taxa nominally associated with the risk of FI. Class Bacteroidia (p = 0.033) and genus Eubacterium ruminantium group (p = 0.028) were protective against FI. In addition, class Betaproteobacteria (p = 0.042), genus Allisonella (p = 0.012), genus Bifidobacterium (p = 0.013), genus Clostridium innocuum group (p = 0.036) and genus Eubacterium coprostanoligenes group (p = 0.003) were associated with a higher risk of FI. No pleiotropy or heterogeneity were found.ConclusionThe MR analysis indicates a causal relationship between specific gut microbiota and FI, offering new insights into the mechanisms underlying FI mediated by gut microbiota.

BackgroundPrevious researches have suggested a significant connection between the gut microbiota/immune cells and morphine tolerance (MT), but there is still uncertainty regarding their causal relationship. Hence, our objective is to inverstigate this causal association and reveal the impact of gut microbiota/immune cells on the risk of developing MT using a two-sample Mendelian randomization (MR) study.MethodsWe conducted a comprehensive analysis using genome-wide association study (GWAS) summary statistics for gut microbiota, immune cells, and MT. The main approach employed was the inverse variance-weighted (IVW) method in MR. To assess horizontal pleiotropy and remove outlier single-nucleotide polymorphisms (SNPs), we utilized the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) technique as well as MR-Egger regression. Heterogeneity detection was performed using Cochran’s Q-test. Additionally, leave-one-out analysis was carried out to determine if any single SNP drove the causal association signals. Finally, we conducted a reverse MR to evaluate the potential of reverse causation.ResultsWe discovered that 6 gut microbial taxa and 16 immune cells were causally related to MT (p < 0.05). Among them, 2 bacterial features and 9 immunophenotypes retained a strong causal relationship with lower risk of MT: genus. Lachnospiraceae NK4A136group (OR: 0.962, 95% CI: 0.940–0.987, p = 0.030), genus. RuminococcaceaeUCG011 (OR: 0.960, 95% CI: 0.946–0.976, p = 0.003), BAFF-R on B cell (OR: 0.972, 95% CI: 0.947–0.998, p = 0.013). Furthermore, 4 bacterial features and 7 immunophenotypes were identified to be significantly associated with MT risk: genus. Flavonifractor (OR: 1.044, 95% CI: 1.017–1.069, p = 0.029), genus. Prevotella9 (OR: 1.054, 95% CI: 1.020–1.090, p = 0.037), B cell % CD3-lymphocyte (OR: 1.976, 95% CI: 1.027–1.129, p = 0.026). The Cochrane’s Q test revealed no heterogeneity (p > 0.05). Furthermore, the MR-Egger and MR-PRESSO analyses reveal no instances of horizontal pleiotropy (p > 0.05). Besides, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the gut microbial taxa and immune cells exposure-outcome effect were attenuated.ConclusionOur research confirm the potential link between gut microbiota and immune cells with MT, shedding light on the mechanism by which gut microbiota and immune cells may contribute to MT. These findings lay the groundwork for future investigations into targeted prevention strategies.

Morphine has a crucial role in treating both moderate to severe pain and chronic pain. However, prolonged administration of morphine can lead to tolerance of analgesia, resulting in increased doses and poor treatment of pain. Many patients, such as those with terminal cancer, require high doses of morphine for long periods. Addressing morphine tolerance can help this group of patients to escape pain, and the mechanisms behind this need to be investigated. Microglia are the key cells involved in morphine tolerance and chronic morphine administration leads to microglia activation, which in turn leads to activation of internal microglia signalling pathways and protein transcription, ultimately leading to the release of inflammatory factors. Inhibiting the activation of microglia internal signalling pathways can reduce morphine tolerance. However, the exact mechanism of how morphine acts on microglia and ultimately leads to tolerance is unknown. This article discusses the mechanisms of morphine induced microglia activation, reviews the signalling pathways within microglia and the associated therapeutic targets and possible drugs, and provides possible directions for clinical prevention or retardation of morphine induced analgesic tolerance.

Commentary: Case report: Chronic neutrophilic leukemia associated with monoclonal gammopathies. A case series and review of genetic characteristics and practical management

Objective To investigate the neuroprotective effect of curcumin on mice with 1-methyl-4-phenyl-1,2,3,6-tet-rahydropyridine(MPTP)-induced Parkinson's disease(PD)and its mechanism.Methods A total of 72 male C57BL/6J mice were randomly divided into control group(group A),MPTP group(group B),and MPTP+curcumin group(group C).For the 5 d before the experiment,the mice in groups B and C were given intraperitoneal injection of MPTP every day,and those in group A were given intraperitoneal injection of an equal volume of normal saline;since day 6,the mice in group C were given intraperito-neal injection of curcumin dissolved in DMSO at a dose of 50 mg/kg,and those in groups A and B were given intraperitoneal injec-tion of an equal volume of DMSO,every day for 7 consecutive days.After the end of administration,behavioral experiments were used to evaluate the motor,learning,and memory functions of mice in each group.On day 15 of the experiment,the samples of substantia nigra were collected from the mice in each group,and ELISA was used to measure the content of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and interleukin-6(IL-6);Western blotting was used to measure the relative content of CD86 and NF-κB;immunohistochemical staining was used to measure the number of TH-positive neurons.Results Compared with group B,groups A and C had a significant reduction in descending time,significant increases in drop latency and percentage of al-ternation(F=17.29-19.28,P＜0.05),significant reductions in the content of TNF-α,IL-1β,and IL-6(F=31.73-80.97,P＜0.05)and the expression of CD86 and NF-κB in the substantia nigra(F=24.93,55.61,P＜0.05),and a significant increase in the number of TH-positive neurons in the substantia nigra(F=47.64,P＜0.05).Conclusion Curcumin can effectively improve be-havior disorder and exert a neuroprotective effect in PD mice,possibly by inhibiting the NF-κB signaling pathway,thereby leading to the inhibition of microglial cell activation,the reduction in inflammatory response,and the alleviation of dopaminergic neuron de-generation.

Objective To establish and validate a drug in vitro absorption model of MDCK-MDR1 cells for research on the mechanism of oral drug absorption and transport. Methods MDCK-MDR1 cells with different concentrations (group L with 1.0×108/L, group M with 2.5×108/L, and group H with 5.0×108/L) were inoculated onto a 24-well Transwell plate and cultured for 1-7 d. Optical density (OD) was measured to plot the growth curve of MDCK-MDR1 cells, and cell morphology was observed at different time points of culture. Transepithelial electrical resistance (TEER) was measured at different time points to determine the optimal cell inoculation concentration and culture time for the formation of a monolayer structure. Lucifer yellow transfer assay was used to validate the monolayer structure formed at different concentrations and time points. Results The groups L, M, and H showed the formation of the monolayer structure on days 5, 3, and 1, respectively, after inoculation, and OD reached the peak value on days 5, 4, and 3, respectively, For group L, TEER reached 300 Ω·cm2 on day 5 of inoculation and tended to be stable on days 5-7. Therefore, 1.0×108/L was selected as the optimal cell inoculation concentration, with an optimal culture time of 5 d. Lucifer yellow transfer assay showed that the monolayer structure had a Lucifer yellow apparent permeability coefficient of 4.27×10-7 cm/s, which was lower than 5.0×10-7 cm/s determined by the permeability test. Conclusion The MDCK-MDR1 cell model established in this study has validated monolayer structural integrity and permeability and can be used as an in vitro model to simulate the absorption and transport mechanisms of oral drugs.

OBJECTIVE:To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia.METHODS:Morphine-induced acute tolerance model: mice received intraperitoneal berberine at doses of 2.5, 5.0, and 10 mg/kg; 30 min later, subcutaneous morphine 10 mg/kg was injected every hour for nine continuous h. Morphine 10 mg/kg alone was administered at 24 and 48 h. Morphine-induced chronic tolerance model: mice received intraperitoneal berberine 2.5, 5.0, and 10 mg/kg; 30 min later, 10 mg/kg morphine was injected subcutaneously for eight consecutive days. On the ninth day, morphine 10 mg/kg was given alone. Morphine-induced established tolerance model: mice were injected subcutaneously with morphine 10 mg/kg once a day for eight consecutive days. Berberine 2.5 mg/kg was administered on day one, four, and seven and morphine 10 mg/kg alone on day nine. The baseline latency (T0) and post-treatment latency (T1) were determined by the hot plate test, and the maximum possible analgesic effect (MPAE) was calculated. Nitric oxide synthase (NOS) activity and nitric oxide (NO) content in the spinal cord were measured by spectrophotometer. Verification of berberine analgesic effect by blocking N-methyl-D-aspartate (NMDA) receptor: HT-22 and HEK-293 cells transfected with NMDA plasmid were randomly divided into five groups: control group, NMDA group, berberine low-dose, medium-dose, and high-dose groups (5, 10, 20 μmol/L, respectively). Except for the control group, cells were treated with NMDA (HT-22 cells: 20 mmol/L; HEK-293 cells: 50 μmol/L). After 24 h, cell viability was detected by cell counting kit-8. The molecular mechanism between berberine and the NMDA receptor was studied by molecular docking.RESULTS:Berberine 2.5 and 5.0 mg/kg could prolong the analgesic time of morphine. In acute and chronic morphine tolerance models, berberine could inhibit the decrease of MPAE and baseline latency (0.05). In the established tolerance model, berberine could rapidly reverse the decreased MPAE (0.05). The combination of berberine and morphine on day one could effectively inhibit the morphine-induced increase of NOS activity and NO content in the spinal cord (0.05). Berberine significantly increased the cell viability of NMDA-induced nerve injury in HT-22 and HEK-293 cells (0.05). Molecular docking showed that berberine binds to the receptor pocket of NMDA.CONCLUSIONS:Berberine could effectively enhance and prolong the duration of morphine analgesia and inhibit the development of morphine-induced tolerance and hyperalgesia. Furthermore, berberine has a certain neuroprotective effect, which may be related to the inhibition of NMDA activity.

Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm (MPN). Due to its nonspecific clinical symptoms and lack of specific molecular markers, it was previously difficult to distinguish it from other diseases with increased neutrophils. However, the discovery of the CSF3R mutation in CNL 10 years ago and the update of the diagnostic criteria by the World Health Organization (WHO) in 2016 brought CNL into a new era of molecular diagnosis. Next-generation sequencing (NGS) technology has led to the identification of numerous mutant genes in CNL. While CSF3R is commonly recognized as the driver mutation of CNL, other mutations have also been detected in CNL using NGS, including mutations in other signaling pathway genes ( CBL , JAK2 , NARS , PTPN11 ) and chromatin modification genes ( ASXL1 , SETBP1 , EZH2 ), DNA methylation genes ( DNMT3A , TET2 ), myeloid-related transcription factor genes ( RUNX1 , GATA2 ), and splicing and RNA metabolism genes ( SRSF2 , U2AF1 ). The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients.

Objective To investigate the anesthetic effect of propofol combined with esketamine and sufentanil for intravenous anesthesia in hysteroscopic surgery. Methods A total of 90 patients who underwent elective hysteroscopic surgery were divided into sufentanil+propofol group (group A) and esketamine+sufentanil+propofol group (group B). Mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SpO2) were recorded before anesthesia (T0), when eyelash reflex disappeared (T1), at cervix dilation (T2), at the end of surgery (T3), and at the time of awaking from anesthesia (T4), and the amount of propofol used, time of operation, awakening time after surgery, Visual Analog Scale (VAS) score of postoperative pain, and Ramsay sedation score were recorded, as well as the incidence rate of perioperative adverse events. Results Compared with group A, group B had a significant increase in MAP at T1, T2, T3, and T4 (F=19.121-32.681,P<0.05) and significant increases in SpO2 and HR at T1 and T2 (F=6.868-18.551,P<0.05); in addition, group B had a significant reduction in the amount of propofol used during surgery, a significantly shorter postoperative awakening time, and a significant reduction in postoperative Ramsay sedation score (W=1 453.000,t=6.059,3.321,P<0.05), as well as significant reductions in the composition ratio of respiratory depression, body movement, hypotension, sinus bradycardia, and the degree of respiratory depression (χ2=4.464-11.072,W=1 669.500,P<0.05). There were no significant differences between the two groups in time of operation, postoperative VAS score, psychotomimetic symptoms, and adverse reactions including nausea and vomiting (P>0.05). Conclusion Propofol combined with esketamine and sufentanil for intravenous anesthesia in hysteroscopic surgery has a relatively satisfactory anesthetic effect and can effectively stabilize intraoperative blood pressure, HR, and blood oxygen saturation, with a significant reduction in the amount of propofol used during surgery, a significantly shortened awakening time, and few adverse reactions, and therefore, it holds promise for clinical application.