The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases, metabolic disorders, inflammatory conditions, and other related diseases, closely influencing their onset and progression. Therefore, restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management. In this review, we will introduce the lysosomal biogenesis, structure, and function, as well as the biological process of the autophagy-lysosome system. Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed, emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment. Finally, we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system, and summarize different strategies and methods for achieving this goal. This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.
Humans ; Lysosomes/physiology* ; Autophagy/physiology* ; Nanomedicine/methods* ; Neurodegenerative Diseases/therapy* ; Animals ; Nanostructures ; Lysosomal Storage Diseases/therapy*

[This corrects the article DOI: 10.1016/j.apsb.2024.03.030.].

OBJECTIVE To explore the effects of levosimendan on cardiac function， hemodynamics and prognosis of patients with septic shock complicated with myocardial depression， and evaluate the safety of levosimendan. METHODS Patients with septic shock complicated with myocardial depression who were admitted to the Department of Critical Care Medicine of Chongqing University Three Gorges Hospital from April 2021 to August 2023， underwent adequate fluid resuscitation， had a mean arterial pressure （MAP） ≥65 mmHg， and received pulse indicator continuous cardiac output （PiCCO） monitoring were enrolled. The patients were randomly divided into dobutamine group and levosimendan group according to a random number table， with 20 patients in each group. Both groups received intravenous infusion of Norepinephrine bitartrate injection at a dose of 0.1-2.0 μg/（kg·min）. On this basis， the dobutamine group additionally received intravenous infusion of Dobutamine hydrochloride injection at a dose of 5- 10 μg/（kg·min） for 3 to 7 days， while the levosimendan group additionally received intravenous infusion of Levosimendan injection at a dose of 0.1-0.2 μg/（kg·min） for 24 hours. Heart rate （HR） and hemodynamic parameters [systolic blood pressure， diastolic blood pressure， MAP， central venous pressure （CVP）]， PiCCO monitoring parameters [cardiac function index （CFI）， cardiac index （CI）， stroke volume index （SVI）， extravascular lung water index， global end-diastolic volume index， pulmonary vascular permeability index （PVPI）， global ejection fraction （GEF）， systemic vascular resistance index， left ventricular contractility index]， and prognosis indicators [death within 3 days after administration， mechanical ventilation time，intensive care unit （ICU） stay time， 28-day mortality rate] were compared between the two groups before treatment and at 24 and 72 hours after treatment. Adverse reactions were E-mail：recorded for both groups. RESULTS Compared with before treatment in the same group， CFI， CI and GEF at 24 hours after treatment， CI and GEF at 72 hours after treatment in the dobutamine group， as well as SVI at 24 hours after treatment and SVI and GEF at 72 hours after treatment in the levosimendan group were significantly increased； PVPI at 72 hours after treatment in the dobutamine group was significantly decreased （P＜0.05）. Compared with the dobutamine group during the same period， patients in the levosimendan group had significantly lower HR and significantly higher CVP at 24 hours after treatment （P＜0.05）. Within 3 days after administration， there were no deaths in either group； there were no statistically significant differences in mechanical ventilation time， ICU stay time， 28-day mortality rate， or the incidence of adverse reactions between the two groups （P＞0.05）. CONCLUSIONS For patients with septic shock complicated with myocardial depression who have undergone adequate fluid resuscitation and have a MAP of ≥65 mmHg， levosimendan is comparable to dobutamine in improving cardiac function and hemodynamic parameters， without affecting patients’ prognosis or increasing the risk of adverse reactions such as hypotension.

Background::Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown.Methods::GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice ( Grk2?SM22), and littermate controls ( Grk2flox/flox) were grouped into control and hypoxia mice ( n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein ( YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays. Results::The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2?SM22 mice compared with littermate controls. The amelioration of PH in Grk2?SM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions. Conclusion::Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.

Objective To investigate the impact of exosomal miRNAs derived from endoplasmic reticulum-stressed(ERS)head and neck squamous cell carcinoma(HNSCC)cells on macrophages.Methods This study was reviewed and approved by the Ethics Committee.The expression levels of ERS-associated proteins,including protein kinase R-like endoplasmic reticulum kinase(PERK)and glucose-regulated protein 78(GRP78),in HNSCC tissues and para-tumor tissues were detected by Western blot(WB)and quantitative real-time PCR(RT-qPCR).HN4 human laryngeal squamous cell carcinoma cells were treated with 500 U/mL interferon-γ(IFN-γ)for 48 h to induce ER stress,and exo-somes secreted by ER-stressed HN4 cells were collected and identified.The types of miRNAs in exosomes were identi-fied through bioinformatics analysis,and the target genes of miRNAs were predicted.Macrophages were transfected with miRNA,co cultured with collected exosomes,and the expression of PTEN in macrophages was knocked down.The downstream signaling pathway regulated by exosomal miRNAs was studied by WB and RT-qPCR.Results Compared with that in para-tumor tissues,the expression level of ER stress-associated proteins in HNSCC tissues was increased(P＜0.05).RNA-seq analysis revealed that miR-26a-5p was highly upregulated in ER-stressed HN4 cell-derived exo-somes(P＜0.05).PTEN is the target gene for miR-26a-5p.miR-26a-5p increased the expression level of PD-L1 in mac-rophages and downregulated the expression of PTEN(P＜0.05).Macrophages co cultured with ERS extracellular vesi-cles showed an increase in miR-26a-5p and PD-L1 expression,a decrease in PTEN expression,and an increase in p-AKT expression(P＜0.05).Knock down the expression of PTEN in macrophages and increase the expression of PD-L1(P＜0.01).Conclusion ERS HNSCC cell-derived exosomal miR-26a-5p promotes the expression of PD-L1 in macro-phages through the PTEN/AKT signaling pathway.

The Menghe Medical School is a highly influential academic school of Chinese medicine in China.Its academic features are mainly learning from others'strengths,openness and tolerance;integrity as the foundation,communication as the strength;harmo-ny as the way,and agility as the technique.The Menghe Medical School originated in Menghe,developed in Shanghai,spread all over the country,and spread around the world.The reasons for the prosperity and development of the Menghe Medical School are analyzed.Among them,imperial doctors being rewarded and supported,the stars having their roots in Menghe,inheritance from teach-ers by blood,help from in-laws,and the establishment of education and leadership in development are the main factors.On the basis of inheriting the scholarship of Menghe Medical School,Professor Tong Xiaolin innovatively proposed academic ideas such as the train-ing path of Xiang thinking,state-target differentiation and treatment,and dosage and effectiveness of prescriptions and medicines,pushing the academic thought of Menghe Medical School to a new theoretical peak in the new era.Based on the majestic development path of the Menghe Medical School,the implications for the inheritance,innovation and development of modern Chinese medicine are analyzed.

Objective:To observe any effect of ankle dorsiflexion angle on the gait of children with cerebral palsy (CP) after Achilles tendon lengthening surgery.Methods:Nine children with CP and equinus foot deformity were given Achilles tendon lengthening surgery. Reconstruction images of their pelvises and lower limbs were collected before the surgery and used to construct OpenSim simulations. Gait analysis data were also recorded before the surgery. The curve of changes to the Achilles tendon insertion was simulated in the software to determine the optimum angle of ankle dorsiflexion, and that guided the Achilles tendon extension surgery. The 3D gait analysis was repeated 12 months after the surgery to compare the spatiotemporal, kinematic and dynamic parameters (especially maximum ground reaction force on the affected side). The maximum dorsiflexion angles of the ankle joint before and after surgery were also recorded.Results:Before the surgery the dorsiflexion angles ranged from 8 to 12°, with an average of (10.1±1.2)°. After the surgery, significant changes were observed in the stride length, rhythm, speed and stride time of the affected side, as well as the maximum forward angle of the supported pelvis, the maximum dorsiflexion angle of the supported ankle and the maximum plantar flexion angle of the swinging ankle. Twelve months after the surgery, no recurrence of horseshoe malformation or over-correction complications were found in any of the 9 patients.Conclusions:3D gait analysis technology combined with OpenSim software can simulate the changes in Achilles tendon length needed by children with cerebral palsy. The optimum ankle dorsiflexion angle can be predicted pre-operatively and the simulation can also guide the operation. This technique also offers pre-and post-operative quantitative evaluation to provide references for subsequent rehabilitation treatment.

Essential oils (EOs) are natural, volatile substances derived from aromatic plants. They exhibit multiple pharmacological effects, including antibacterial, anticancer, anti-inflammatory, and antioxidant properties, with broad application prospects in health care, food, and agriculture. However, the instability of volatile components, which are susceptible to deterioration under light, heat, and oxygen exposure, as well as limited water solubility, have significantly impeded the development and application of EOs. Porous nanoclays are natural clay minerals with a layered structure. They possess unique structural characteristics such as large pore size, regular distribution, and tunable particle size, which are extensively utilized in drug delivery, adsorption separation, reaction catalysis, and other fields. Natural-derived porous nanoclays have garnered considerable attention for the encapsulation and delivery of EOs. This review comprehensively summarizes the structure, types, and properties of natural-derived porous nanoclays, focusing on the structural characteristics of porous nanoclays such as montmorillonite, palygorskite, halloysite, kaolinite, vermiculite, and natural zeolite. It also examines research advances in their delivery of EOs and explores engineering strategies to enhance the delivery of EOs by natural-derived porous nanoclays. Finally, various applications of natural-derived porous nanoclays for EOs in antibacterial, food preservation, repellent, and insecticide aspects are presented, providing a reference for the development and application of EOs.
Humans ; Nanoparticles/chemistry* ; Oils, Volatile/administration & dosage* ; Porosity ; Nanoparticle Drug Delivery System/chemistry*

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has been widely used for genome engineering and transcriptional regulation in many different organisms. Current CRISPR-activation (CRISPRa) platforms often require multiple components because of inefficient transcriptional activation. Here, we fused different phase-separation proteins to dCas9-VPR (dCas9-VP64-P65-RTA) and observed robust increases in transcriptional activation efficiency. Notably, human NUP98 (nucleoporin 98) and FUS (fused in sarcoma) IDR domains were best at enhancing dCas9-VPR activity, with dCas9-VPR-FUS IDR (VPRF) outperforming the other CRISPRa systems tested in this study in both activation efficiency and system simplicity. dCas9-VPRF overcomes the target strand bias and widens gRNA designing windows without affecting the off-target effect of dCas9-VPR. These findings demonstrate the feasibility of using phase-separation proteins to assist in the regulation of gene expression and support the broad appeal of the dCas9-VPRF system in basic and clinical applications.
Humans ; Transcriptional Activation ; RNA, Guide, CRISPR-Cas Systems ; Gene Expression Regulation ; CRISPR-Cas Systems/genetics*

Objective:The purpose of this study was to investigate the effect of voice therapy via telepractice on voice function in laryngopharyngeal reflux disease (LPRD) patients.Methods:The prospective study included 120 patients from January 2021 to July 2022 with dyspnea and LPRD diagnosed at the department of otolaryngology head and neck surgery of the First Hospital of Shanxi Medical University. These patients were then randomly divided into standard treatment group (group A), combined face-to-face voice therapy group (group B) and combined telepractice voice therapy group (group C). We collected and compared data on curative effect in patients with LPRD at the 8th week(Stage 1) and the 12th week of treatment(Stage 2) and the 6th week post-treatment(Stage 3). Statistical analysis was performed using SPSS 22.0.Results:One hundred and twenty patients with LPRD and dyspnea were included in the study (63 men, 57 women, 18-65 years old). At stage 1, there were statistically significant differences among the three groups in Voice Handicap Index(VHI), Reflux Symptom Index (RSI) and Reflux Finding Score(RFS) ( F=13.72, P<0.05; F=62.50, P<0.05; F=3.78, P<0.05). VHI and RSI in group B and C were significantly smaller than those in group A, VHI and RSI in group C were significantly smaller than those in group B, and RFS in group C was significantly smaller than that in group A and B. At stage 2, there were statistically significant differences between the three groups in Maximum Phonation Time(MPT), Dysphonia Severity Index(DSI), VHI, RSI and RFS( F=8.49, P<0.05; F=3.24, P<0.05; F=8.55, P<0.05; F=19.92, P<0.05; F=12.19, P<0.05). MPT and DSI in group B and C were significantly larger than those in group A. The scores of VHI, RSI and RFS in group B and C were significantly smaller than those in group A, and RFS in group C was significantly smaller than that in group B. At stage 3, there were statistically significant differences among the three groups in Jitter, MPT, DSI, VHI( F=3.19, P<0.05; F=19.37, P<0.05; F=43.56, P<0.05; F=11.05, P<0.05), and there were statistically significant differences among the three groups in RSI and RFS( F=25.58, P<0.05; F=11.82, P<0.05). MPT and DSI in group B and C were significantly larger than those in group A. The scores of VHI and RSI in group B and C were significantly smaller than those in group A, and RFS in group C was significantly smaller than those in group A and B. Conclusion:Telepractice can be used in patients with LPRD and dyspnea as an alternative to face-to-face voice therapy with better long-term outcomes.