Research Progress of Baihe Gujin Decoction in the Treatment of Lung Cancer.

Baihe Gujin decoction is one of the most commonly used decoction in traditional Chinese medicine for the treatment of lung cancer. It can nourish yin and moisten the lung as well as prevent phlegm from forming and stop coughing. On the one hand, Baihe Gujin decoction is characterized with extensive application, proven efficacy, a long history, and high safety. On the other hand, Baihe Gujin decoction can induce apoptosis of tumor cells, improve immune function and inhibit inflammation. The main anti-tumor components of this include kaempferol, quercetin, isorhamnetin, glycyrrhizin and ß-sitosterol. Clinically, Baihe Gujin decoction can improve the adverse reactions caused by radiotherapy, chemotherapy and immunotherapy for lung cancer, enhance the quality of life of patients, and prolong their survival time. At present, there are a large number of clinical and basic researches on the treatment of lung cancer with Baihe Gujin decoction. In this paper, we mainly discussed the treatment of lung cancer with Baihe Gujin decoction through analyzing basic and clinical researches at home and abroad in the past 20 years. Through the discussion, we aimed to probe deeper into Baihe Gujin decoction for the treatment of lung cancer, thereby providing a broader idea for clinical diagnosis and treatment of lung cancer.

Association of nirmatrelvir-ritonavir with post-acute sequelae and mortality in patients admitted to hospital with COVID-19: a retrospective cohort study.

BACKGROUND: Studies have established the short-term efficacy of nirmatrelvir-ritonavir in managing COVID-19, yet its effect on post-COVID-19 condition, especially in patients admitted to hospital, remains understudied. This study aimed to examine the effect of nirmatrelvir-ritonavir on post-COVID-19 condition among patients admitted to hospital in Hong Kong. METHODS: This retrospective cohort study used real-world, territory-wide inpatient records, vaccination records, and confirmed COVID-19 case data from the Hong Kong Hospital Authority and Department of Health, The Government of the Hong Kong Special Administrative Region. Patients aged 18 years and older who tested positive for SARS-CoV-2 between March 11, 2022, and Oct 10, 2023, and who were admitted to hospital with COVID-19 were included. The treatment group included patients prescribed nirmatrelvir-ritonavir within 5 days of symptom onset, excluding those prescribed molnupiravir within 21 days, and the control group had no exposure to either nirmatrelvir-ritonavir or molnupiravir. The outcomes were post-acute inpatient death and 13 sequelae (congestive heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, seizure, anxiety, post-traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were evaluated starting at 21 days after the positive RT-PCR date in each respective cohort constructed for the outcome. Standardised mortality ratio weights were applied to balance covariates, and Cox proportional hazards regression was used to investigate the relationship between nirmatrelvir-ritonavir and outcomes. FINDINGS: 136 973 patients were screened for inclusion, among whom 50 055 were eligible and included in the analysis (24 873 [49·7%] were female and 25 182 [50·3%] were male). 15 242 patients were prescribed nirmatrelvir-ritonavir during acute COVID-19 and 23 756 patients were included in the control group; 11 057 patients did not meet our definition for the exposed and unexposed groups. Patients were followed up for a median of 393 days (IQR 317-489). In the nirmatrelvir-ritonavir group compared with the control group, there was a significantly lower hazard of post-acute inpatient death (hazard ratio 0·62 [95% CI 0·57-0·68]; p<0·0001), congestive heart failure (0·70 [0·58-0·85]; p=0·0002), atrial fibrillation (0·63 [0·52-0·76]; p<0·0001), coronary artery disease (0·71 [0·59-0·85]; p=0·0002), chronic pulmonary disease (0·68 [0·54-0·86]; p=0·0011), acute respiratory distress syndrome (0·71 [0·58-0·86]; p=0·0007), interstitial lung disease (0·17 [0·04-0·75]; p=0·020), and end-stage renal disease (0·37 [0·18-0·74]; p=0·0049). There was no evidence indicating difference between the groups in deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis. INTERPRETATION: This study showed extended benefits of nirmatrelvir-ritonavir for reducing the risk of post-acute inpatient death as well as cardiovascular and respiratory complications among patients admitted to hospital with COVID-19. Further research is essential to uncover the underlying mechanisms responsible for these observed negative associations and to devise effective strategies for preventing the onset of post-acute sequelae. FUNDING: Health and Medical Research Fund, Research Grants Council theme-based research schemes, and Research Grants Council Collaborative Research Fund.

Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children With Myopia: A Randomized Clinical Trial.

Importance: Treatments are needed to slow progression of or reduce incidence of myopia. Objective: To evaluate the efficacy and safety of daily 650-nm low-level red light (LLRL) for myopia treatment. Design, Setting, and Participants: Single-masked, randomized clinical trial at 1 site in China. Baseline measurements were completed from August to September 2021. Participants were children aged 6 to 12 years with spherical equivalent error (SER) of -6 diopters (D) to 3 D. Data were analyzed from March to July 2023. Interventions: Irradiation daily with 650-nm LLRL for 3 minutes twice daily 4 or more hours apart or no intervention. Main Outcomes and Measures: Primary outcomes were changes in cycloplegia SER and axial length (AL) at 6- and 12-month follow-up visits. Safety was assessed on masked fundus photograph evaluations. Results: A total of 336 children were randomly allocated into the LLRL group or control group in a 1:1 ratio. The control group contained 86 female patients (51.2%), and the treatment group contained 90 female patients (53.6%). The mean (SD) age, SER, and AL were 9.0 (1.9) years, -1.3 (1.5) D, and 23.8 (1.0) mm for all patients. A total of 161 (95.8%) in the LLRL group and 159 (94.6%) in the control group returned for the 6-month follow-up. A total of 157 (93.5%) in the LLRL group and 152 (90.5%) in the control group returned for the 12-month follow-up. Mean (SD) changes in SER were 0.15 (0.16) D and -0.26 (0.21) D for the LLRL group and the control group, respectively (difference, -0.41 D; 95% CI, -0.48 to -0.34 D; P < .001), at 6 months and 0.24 (0.27) D and -0.65 (0.33) D for the LLRL group and the control group, respectively (difference, -0.89 D; 95% CI, -0.95 to -0.83 D; P < .001), at 12 months. Mean (SD) changes in AL were -0.06 (0.08) mm and 0.13 (0.12) mm for the LLRL group and control group, respectively (difference, 0.19 mm; 95% CI, 0.16 to 0.22 mm; P < .001), at 6 months and -0.11 (0.10) mm and 0.26 (0.16) mm for the LLRL group and control group, respectively (difference, 0.37 mm; 95% CI, 0.34 to 0.40 mm; P < .001). Masked fundus photograph review did not identify retinal changes in either group. Conclusions and relevance: These findings suggest daily use of 650-nm LLRL for 1 year can slow progression of SER and AL without safety concerns identified. Confirmation of these findings at independent sites seems warranted, as well as determining whether these effects can be sustained with or without continued treatment and whether LLRL has any effect on pathological myopia. Trial Registration: ChiCTR2200058963.

Evaluating the spike in the symptomatic proportion of SARS-CoV-2 in China in 2022 with variolation effects: a modeling analysis.

Despite most COVID-19 infections being asymptomatic, mainland China had a high increase in symptomatic cases at the end of 2022. In this study, we examine China's sudden COVID-19 symptomatic surge using a conceptual SIR-based model. Our model considers the epidemiological characteristics of SARS-CoV-2, particularly variolation, from non-pharmaceutical intervention (facial masking and social distance), demography, and disease mortality in mainland China. The increase in symptomatic proportions in China may be attributable to (1) higher sensitivity and vulnerability during winter and (2) enhanced viral inhalation due to spikes in SARS-CoV-2 infections (high transmissibility). These two reasons could explain China's high symptomatic proportion of COVID-19 in December 2022. Our study, therefore, can serve as a decision-support tool to enhance SARS-CoV-2 prevention and control efforts. Thus, we highlight that facemask-induced variolation could potentially reduces transmissibility rather than severity in infected individuals. However, further investigation is required to understand the variolation effect on disease severity.

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis­related genes.

Ischemic cardiomyopathy (ICM) is a serious cardiac disease with a very high mortality rate worldwide, which causes myocardial ischemia and hypoxia as the main damage. Further understanding of the underlying pathological processes of cardiomyocyte injury is key to the development of cardioprotective strategies. Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid hydroperoxides to lethal levels, resulting in oxidative damage to the cell membrane. The current understanding of the role and regulation of ferroptosis in ICM is still limited, especially in the absence of evidence from large-scale transcriptomic data. Through comprehensive bioinformatics analysis of human ICM transcriptome data obtained from the Gene Expression Omnibus database, the present study identified differentially expressed ferroptosis-related genes (DEFRGs) in ICM. Subsequently, their potential biological mechanisms and cross-talk were analyzed, and hub genes were identified by constructing protein-protein interaction networks. Ferroptosis features such as reactive oxygen species generation, changes in ferroptosis marker proteins, iron ion aggregation and lipid oxidation, were identified in the H9c2 anoxic reoxygenation injury model. Finally, the diagnostic ability of Gap junction alpha-1 (GJA1), Solute carrier family 40 member 1 (SLC40A1), Alpha-synuclein (SNCA) were identified through receiver operating characteristic curves and the expression of DEFRGs was verified in an in vitro model. Furthermore, potential drugs (retinoic acid) that could regulate ICM ferroptosis were predicted based on key DEFRGs. The present article presents new insights into the role of ferroptosis in ICM, investigating the regulatory role of ferroptosis in the pathological process of ICM and advocating for ferroptosis as a potential novel therapeutic target for ICM based on evidence from the ICM transcriptome.

Soybean steroids improve crop abiotic stress tolerance and increase yield.

Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF-YC9-mediated CCAAT-box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate-limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF-YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF-YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress-induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF-YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.

Association of glycogen synthase kinase-3ß with cognitive impairment in type 2 diabetes patients: a six-year follow-up study.

Background: Our previous multicenter case-control study showed that aging, up-regulation of platelet glycogen synthase kinase-3ß (GSK-3ß), impaired olfactory function, and ApoE ϵ4 genotype were associated with cognitive decline in type 2 diabetes mellitus (T2DM) patients. However, the causal relationship between these biomarkers and the development of cognitive decline in T2DM patients remains unclear. Methods: To further investigate this potential relationship, we designed a 6-year follow-up study in 273 T2DM patients with normal cognitive in our previous study. Baseline characteristics of the study population were compared between T2DM patients with and without incident mild cognitive impairment (MCI). We utilized Cox proportional hazard regression models to assess the risk of cognitive impairment associated with various baseline biomarkers. Receiver operating characteristic curves (ROC) were performed to evaluate the diagnostic accuracy of these biomarkers in predicting cognitive impairment. Results: During a median follow-up time of 6 years (with a range of 4 to 9 years), 40 patients (16.13%) with T2DM developed MCI. Participants who developed incident MCI were more likely to be older, have a lower education level, have more diabetic complications, a higher percentage of ApoE ϵ4 allele and a higher level of platelet GSK-3ß activity (rGSK-3ß) at baseline (P<0.05). In the longitudinal follow-up, individuals with higher levels of rGSK-3ß were more likely to develop incident MCI, with an adjusted hazard ratio (HR) of 1.60 (95% confidence interval [CI] 1.05, 2.46), even after controlling for potential confounders. The AUC of the combination of age, rGSK-3ß and ApoEϵ4 allele predicted for incident MCI was 0.71. Conclusion: Platelet GSK-3ß activity could be a useful biomarker to predict cognitive decline, suggesting the feasibility of identifying vulnerable population and implementing early prevention for dementia.

Projection of dengue fever transmissibility under climate change in South and Southeast Asian countries.

Vector-borne infectious disease such as dengue fever (DF) has spread rapidly due to more suitable living environments. Considering the limited studies investigating the disease spread under climate change in South and Southeast Asia, this study aimed to project the DF transmission potential in 30 locations across four South and Southeast Asian countries. In this study, weekly DF incidence data, daily mean temperature, and rainfall data in 30 locations in Singapore, Sri Lanka, Malaysia, and Thailand from 2012 to 2020 were collected. The effects of temperature and rainfall on the time-varying reproduction number (Rt) of DF transmission were examined using generalized additive models. Projections of location-specific Rt from 2030s to 2090s were determined using projected temperature and rainfall under three Shared Socioeconomic Pathways (SSP126, SSP245, and SSP585), and the peak DF transmissibility and epidemic duration in the future were estimated. According to the results, the projected changes in the peak Rt and epidemic duration varied across locations, and the most significant change was observed under middle-to-high greenhouse gas emission scenarios. Under SSP585, the country-specific peak Rt was projected to decrease from 1.63 (95% confidence interval: 1.39-1.91), 2.60 (1.89-3.57), and 1.41 (1.22-1.64) in 2030s to 1.22 (0.98-1.51), 2.09 (1.26-3.47), and 1.37 (0.83-2.27) in 2090s in Singapore, Thailand, and Malaysia, respectively. Yet, the peak Rt in Sri Lanka changed slightly from 2030s to 2090s under SSP585. The epidemic duration in Singapore and Malaysia was projected to decline under SSP585. In conclusion, the change of peak DF transmission potential and disease outbreak duration would vary across locations, particularly under middle-to-high greenhouse gas emission scenarios. Interventions should be considered to slow down global warming as well as the potential increase in DF transmissibility in some locations of South and Southeast Asia.

Predictive evolutionary modelling for influenza virus by site-based dynamics of mutations.

Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. Therefore, influenza vaccine strains need to be updated annually for the upcoming flu season to ensure vaccine effectiveness. We develop a computational approach, beth-1, to forecast virus evolution and select representative virus for influenza vaccine. The method involves modelling site-wise mutation fitness. Informed by virus genome and population sero-positivity, we calibrate transition time of mutations and project the fitness landscape to future time, based on which beth-1 selects the optimal vaccine strain. In season-to-season prediction in historical data for the influenza A pH1N1 and H3N2 viruses, beth-1 demonstrates superior genetic matching compared to existing approaches. In prospective validations, the model shows superior or non-inferior genetic matching and neutralization against circulating virus in mice immunization experiments compared to the current vaccine. The method offers a promising and ready-to-use tool to facilitate vaccine strain selection for the influenza virus through capturing heterogeneous evolutionary dynamics over genome space-time and linking molecular variants to population immune response.

The impact of the physical activity intervention on sleep in children and adolescents with autism spectrum disorder: A systematic review and meta-analysis.

Pharmacological treatments (i.e., melatonin) and non-pharmacological therapies (e.g., parent-based sleep education programs and behavioural interventions) have been found to result in improved sleep in children and adolescents with autism spectrum disorder (ASD). However, there are several limitations to these treatment approaches, including concerns about the possible side-effects and safety, high-cost and uncertainties of long-term effects. Physical activity (PA) intervention is a promising behavioural intervention that has received increasing attention. However, the effects of PA intervention on sleep are still unclear in this clinical group. This study aimed to synthesize available empirical studies concerning the effects of PA interventions on sleep in children and adolescents with ASD. Following PRISMA guidelines, seven electronic databases: APA PsychInfo, CINAHL Ultimate, ERIC, MEDLINE, PubMed, SPORTDiscus, and Web of Science, were searched from inception to March 2023. Randomized controlled trials/quasi-experimental designs with comparison groups were included. Initially, 444 articles were identified, 13 articles underwent systematic review, and 8 studies with control groups and sufficient statistical data were selected for meta-analysis. Compared to no-treatment control groups, PA interventions had a large positive effect on parent-reported general sleep problems, night awakenings, sleep resistance, sleep duration and actigraphy-assessed sleep efficiency in children and adolescents with ASD.

Multiregion WES of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns.

Pancreatic neuroendocrine tumors (PanNETs), though uncommon, have a high likelihood of spreading to other body parts. Previously, the genetic diversity and evolutionary patterns in metastatic PanNETs were not well understood. To investigate this, we performed multiregion sampling whole-exome sequencing (MRS-WES) on samples from 10 patients who had not received prior treatment for metastatic PanNETs. This included 29 primary tumor samples, 31 lymph node metastases, and 15 liver metastases. We used the MSK-MET dataset for survival analysis and validation of our findings. Our research indicates that mutations in the MEN1/DAXX genes might trigger the early stages of PanNET development. We categorized the patients based on the presence (MEN1/DAXXmut, n = 7) or absence (MEN1/DAXXwild, n = 3) of these mutations. Notable differences were observed between the two groups in terms of genetic alterations and clinically relevant mutations, confirmed using the MSK-MET dataset. Notably, patients with mutations in MEN1/DAXX/ATRX genes had a significantly longer median overall survival compared to those without these mutations (median not reached vs. 43.63 months, p = 0.047). Multiplex immunohistochemistry (mIHC) analysis showed a more prominent immunosuppressive environment in metastatic tumors, especially in patients with MEN1/DAXX mutations. These findings imply that MEN1/DAXX mutations lead PanNETs through a unique evolutionary path. The disease's progression pattern indicates that PanNETs can spread early, even before clinical detection, highlighting the importance of identifying biomarkers related to metastasis to guide personalized treatment strategies.

[A multi-center epidemiological study on pneumococcal meningitis in children from 2019 to 2020]. / 2019­2020å¹´160ä¾‹å„¿ç«¥è‚ºç‚Žé“¾çƒèŒè„‘è†œç‚Žä¸´åºŠæµè¡Œç— å­¦å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the clinical characteristics and prognosis of pneumococcal meningitis (PM), and drug sensitivity of Streptococcus pneumoniae (SP) isolates in Chinese children. METHODS: A retrospective analysis was conducted on clinical information, laboratory data, and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country. RESULTS: Among the 160 children with PM, there were 103 males and 57 females. The age ranged from 15 days to 15 years, with 109 cases (68.1%) aged 3 months to under 3 years. SP strains were isolated from 95 cases (59.4%) in cerebrospinal fluid cultures and from 57 cases (35.6%) in blood cultures. The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87) and 27% (21/78), respectively. Fifty-five cases (34.4%) had one or more risk factors for purulent meningitis, 113 cases (70.6%) had one or more extra-cranial infectious foci, and 18 cases (11.3%) had underlying diseases. The most common clinical symptoms were fever (147 cases, 91.9%), followed by lethargy (98 cases, 61.3%) and vomiting (61 cases, 38.1%). Sixty-nine cases (43.1%) experienced intracranial complications during hospitalization, with subdural effusion and/or empyema being the most common complication [43 cases (26.9%)], followed by hydrocephalus in 24 cases (15.0%), brain abscess in 23 cases (14.4%), and cerebral hemorrhage in 8 cases (5.0%). Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old, with rates of 91% (39/43) and 83% (20/24), respectively. SP strains exhibited complete sensitivity to vancomycin (100%, 75/75), linezolid (100%, 56/56), and meropenem (100%, 6/6). High sensitivity rates were also observed for levofloxacin (81%, 22/27), moxifloxacin (82%, 14/17), rifampicin (96%, 25/26), and chloramphenicol (91%, 21/23). However, low sensitivity rates were found for penicillin (16%, 11/68) and clindamycin (6%, 1/17), and SP strains were completely resistant to erythromycin (100%, 31/31). The rates of discharge with cure and improvement were 22.5% (36/160) and 66.2% (106/160), respectively, while 18 cases (11.3%) had adverse outcomes. CONCLUSIONS: Pediatric PM is more common in children aged 3 months to under 3 years. Intracranial complications are more frequently observed in children under 1 year old. Fever is the most common clinical manifestation of PM, and subdural effusion/emphysema and hydrocephalus are the most frequent complications. Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates. Adverse outcomes can be noted in more than 10% of PM cases. SP strains are high sensitivity to vancomycin, linezolid, meropenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.

All cause and cause specific mortality associated with transition to daylight saving time in US: nationwide, time series, observational study.

Objectives: To estimate the association between the transition to daylight saving time and the risks of all cause and cause specific mortality in the US. Design: Nationwide time series observational study based on weekly data. Setting: US state level mortality data from the National Center for Health Statistics, with death counts from 50 US states and the District of Columbia, from the start of 2015 to the end of 2019. Population: 13 912 837 reported deaths in the US. Main outcome measures: Weekly counts of mortality for any cause, and for Alzheimer's disease, dementia, circulatory diseases, malignant neoplasms, and respiratory diseases. Results: During the study period, 13 912 837 deaths were reported. The analysis found no evidence of an association between the transition to spring daylight saving time (when clocks are set forward by one hour on the second Sunday of March) and the risk of all cause mortality during the first eight weeks after the transition (rate ratio 1.003, 95% confidence interval 0.987 to 1.020). Autumn daylight saving time is defined in this study as the time when the clocks are set back by one hour (ie, return to standard time) on the first Sunday of November. Evidence indicating a substantial decrease in the risk of all cause mortality during the first eight weeks after the transition to autumn daylight saving time (0.974, 0.958 to 0.990). Overall, when considering the transition to both spring and autumn daylight saving time, no evidence of any effect of daylight saving time on all cause mortality was found (0.988, 0.972 to 1.005). These patterns of changes in mortality rates associated with transition to daylight saving time were consistent for Alzheimer's disease, dementia, circulatory diseases, malignant neoplasms, and respiratory diseases. The protective effect of the transition to autumn daylight saving time on the risk of mortality was more pronounced in elderly people aged ≥75 years, in the non-Hispanic white population, and in those residing in the eastern time zone. Conclusions: In this study, transition to daylight saving time was found to affect mortality patterns in the US, but an association with additional deaths overall was not found. These findings might inform the ongoing debate on the policy of shifting daylight saving time.

DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins.

Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. One subtype of HSP, known as SPG54, is caused by biallelic mutations in the DDHD2 gene. The primary pathological feature observed in patients with SPG54 is the massive accumulation of lipid droplets (LDs) in the brain. However, the precise mechanisms and roles of DDHD2 in regulating lipid homeostasis are not yet fully understood. Through Affinity Purification-Mass Spectroscopy (AP-MS) analysis, we identify that DDHD2 interacts with multiple members of the ATG8 family proteins (LC3, GABARAPs), which play crucial roles in lipophagy. Mutational analysis reveals the presence of two authentic LIR motifs in DDHD2 protein that are essential for its binding to LC3/GABARAPs. We show that DDHD2 deficiency leads to LD accumulation, while enhanced DDHD2 expression reduces LD formation. The LC3/GABARAP-binding capacity of DDHD2 and the canonical autophagy pathway both contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a small molecule that tethers LC3 to LDs to enhance their autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide valuable insights into the regulatory roles of DDHD2 in LD catabolism and offer a potential therapeutic approach for treating SPG54 patients.

Design, synthesis and biological evaluation of CDC20 inhibitors for treatment of triple-negative breast cancer.

The involvement of CDC20 in promoting tumor growth in different types of human cancers and it disturbs the process of cell division and impedes tumor proliferation. In this work, a novel of Apcin derivatives targeting CDC20 were designed and synthesized to evaluate for their biological activities. The inhibitory effect on the proliferation of four human tumor cell lines (MCF-7, MDA-MB-231, MDA-MB-468 and A549) was observed. Among them, compound E1 exhibited the strongest inhibitory effect on the proliferation of MDA-MB-231 cells with an IC50 value of 1.43 µM, which was significantly superior to that of Apcin. Further biological studies demonstrated that compound E1 inhibited cancer cell migration and colony formation. Furthermore, compound E1 specifically targeted CDC20 and exhibited a higher binding affinity to CDC20 compared to that of Apcin, thereby inducing cell cycle arrest in the G2/M phase of cancer cells. Moreover, it has been observed that compound E1 induces autophagy in cancer cells. In 4T1 Xenograft Models compound E1 exhibited the potential antitumor activity without obvious toxicity. These findings suggest that E1 could be regarded as a CDC20 inhibitor deserved further investigation.

Pharmacodynamics and mechanism of Erigeron breviscapus granules in the treatment of ischemic stroke in mice by regulating sphingolipid metabolism based on metabolomics.

AIM: Erigeron breviscapus (Vant.) Hand.-Mazz. (EB) granules is the extract preparation of EB, with clear curative effect and unclear mechanism. This study intends to systematically explore the specific mechanism of EB granules in the treatment of IS from the metabolic perspective. METHODS: The model of transient middle cerebral artery occlusion (tMCAO) in mice was established by the suture-occluded method. The therapeutic effect of EB granules on tMCAO mice was evaluated by behavioral evaluation, brain water content determination, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and levels of lactate dehydrogenase (LDH) and neuron specific enolase (NSE) in serum. In order to screen differential metabolites, non-targeted metabolomics technology was used to detect the metabolites in serum before and after administration. Univariate statistics, multivariate statistics and bioinformatics were used to analyze the changes of metabolites in serum of tMCAO mice. The possible related mechanism of EB granules in treating IS was screened by pathway enrichment analysis, and the preliminary verification was carried out at animal level by enzyme linked immunosorbent assay (ELISA) and western blot (WB). RESULTS: EB granules could significantly improve behavior of tMCAO mice, reduce brain water content and cerebral infarction volume, improve morphology of brain tissue, reduce the levels of LDH and NSE in serum. A total of 232 differential metabolites were screened, which were mainly enriched in many biological processes such as sphingolipid metabolism. The differential metabolite S1P and its receptors S1PR1 and S1PR2 in sphingolipid metabolism were verified. The results showed that the level of S1P in brain tissue increased and the protein expression of S1PR1 decreased significantly after modeling, and reversed after administration, but there was no significant difference in the protein expression of S1PR2. CONCLUSION: The therapeutic effects of EB granules may be related to affecting sphingolipid metabolism through regulating S1P/S1PR1.

Pharmacodynamics and Mechanism of Astragali Radix and Anemarrhenae Rhizoma in Treating Chronic Heart Failure by Inhibiting Complement Activation.

Astragali radix (AR) and anemarrhenae rhizoma (AAR) are used clinically in Chinese medicine for the treatment of chronic heart failure (CHF), but the exact therapeutic mechanism is unclear. In this study, a total of 60 male C57BL/6 mice were divided into 5 groups, namely sham, model, AR, AAR, and AR-AAR. In the sham group, the chest was opened without ligation. In the other groups, the chest was opened and the transverse aorta was ligated to construct the transverse aortic constriction model. After 8 weeks of feeding, mice were given medicines by gavage for 4 weeks. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were detected by echocardiography. Heart weight index (HWI) and wheat germ agglutinin staining were used to evaluate cardiac hypertrophy. Hematoxylin-eosin staining was used to observe the pathological morphology of myocardial tissue. Masson staining was used to evaluate myocardial fibrosis. The content of serum brain natriuretic peptide (BNP) was detected by enzyme-linked immunosorbent assay kit. The content of serum immunoglobulin G (IgG) was detected by immunoturbidimetry. The mechanism of AR-AAR in the treatment of CHF was explored by proteomics. Western blot was used to detect the protein expressions of complement component 1s (C1s), complement component 9 (C9), and terminal complement complex 5b-9 (C5b-9). The results show that AR-AAR inhibits the expression of complement proteins C1s, C9, and C5b-9 by inhibiting the production of IgG antibodies from B cell activation, which further inhibits the complement activation, attenuates myocardial fibrosis, reduces HWI and cardiomyocyte cross-sectional area, improves cardiomyocyte injury, reduces serum BNP release, elevates LVEF and LVFS, improves cardiac function, and exerts myocardial protection.