ObjectiveTo investigate the inhibitory effect of Biejiajian Pills （BJJW） on the growth of liver cancer， as well as its potential mechanism in mediating the AMP-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR） pathway through mitochondrial energy metabolism. MethodsHuman hepatoma Huh7 cells were used to establish a nude mouse model of subcutaneous xenograft tumor. A total of 18 tumor-bearing nude mice were randomly divided into model group， BJJW group （2.2 g/kg）， and metformin group （250 mg/kg）， and the corresponding drug was given by gavage for 14 consecutive days. Tumor volume and weight were monitored during the experiment； HE staining was used to observe histopathological changes； the levels of reactive oxygen species （ROS） and adenosine triphosphate （ATP） in tumor tissue were measured； immunohistochemistry and Western blotting were used to measure the expression levels of proteins associated with the AMPK/mTOR pathway. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the Tukey’s test was used for further comparison between two groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups， and the Dunn’s test was used for further comparison between two groups. ResultsCompared with the model group， the BJJW group had a tumor inhibition rate of 45.73%， with significant reductions in both tumor volume and weight （P<0.01）. Pathological examination showed that compared with the model group， the BJJW group had a significant reduction in the number of tumor cells and the presence of extensive necrosis. Mechanistic studies showed that compared with the model group， the BJJW group had a significant increase in ROS level （P<0.001） and a significant reduction in ATP level （P<0.001）， as well as significant increases in p-AMPK/AMPK ratio （0.81±0.20 vs 0.13±0.04， P<0.01） and p-ULK1/ULK1 ratio （0.69±0.17 vs 0.18±0.13， P<0.01） and a significant reduction in p-mTOR/mTOR ratio （1.34±0.16 vs 3.20±0.62， P<0.01）. ConclusionBJJW may inhibit the growth of liver cancer by inducing mitochondrial energy metabolism dysfunction， increasing the level of ROS， reducing the level of ATP， and activating the AMPK/mTOR signaling pathway.

OBJECTIVE To investigate the immunotoxicity and potential mechanism of Carthamus tinctorius extract on RBL-2H3 cells via direct induction and induction by sensitized serum prepared with an overdose of the extract. METHODS For direct induction by C. tinctorius extract， RBL-2H3 cells were divided into normal control group （no treatment） and C. tinctorius extract group （10 mg/mL）. For induction by sensitized serum prepared with an overdose of C. tinctorius extract， rats were divided into normal control group （no treatment）， adjuvant-treated group （1 mL adjuvant）， C. tinctorius extract-induced sensitization group （2.04 g/mL）， and ovalbumin （OVA）-induced sensitization group （50 mg/mL）. Sensitization was performed once every other day for a total of 3 times. Morphological changes of RBL-2H3 cells were observed， the degranulated rate of cells was counted， and histamine content was determined； the release rate of β -hexosaminidase （ β -Hex） was calculated， the levels of interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） and intracellular Ca²⁺ concentration were detected. RESULTS Under direct induction by C. tinctorius extract， compared with the normal control group， the volume of cells in the C. tinctorius extract group was significantly reduced and cell density decreased； the degranulation rate of cells， histamine content， β -Hex release rate， IL-6 and TNF-α levels， as well as intracellular Ca²⁺ concentration were all significantly increased （ P ＜0.01）. Under i nduction by sensitized serum prepared with an overdose of C. tinctorius extract， compared with the adjuvant-treated group， the above indicators in the C. tinctorius extract-induced sensitization group and the OVA-induced sensitization group showed consistent changes with those in the C. tinctorius extract group under direct induction， all being significantly elevated （ P ＜0.01）. CONCLUSIONS C. tinctorius extract may affect degranulation of RBL-2H3 cells and promote Ca²⁺ influx accompanied by the release of pro-inflammatory cytokines through two approaches： direct induction and induction by sensitized serum prepared under overdose administration. Its mechanism may be related to the activation of the calcium signaling pathway and the regulation of inflammatory pathways under the synergistic effect of multiple components.

BACKGROUND: Preclinical studies have indicated that Angong Niuhuang Pills (ANP) reduce cerebral infarct and edema volumes. This study aimed to investigate whether ANP safely reduces cerebral infarct and edema volumes in patients with moderate to severe acute ischemic stroke. METHODS: This randomized, double-blind, placebo-controlled pilot trial included patients with acute ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores ranging from 10 to 20 in 17 centers in China between April 2021 and July 2022. Patients were allocated within 36 h after onset via block randomization to receive ANP or placebo (3 g/day for 5 days). The primary outcomes were changes in cerebral infarct and edema volumes after 14 days of treatment. The primary safety outcome was severe adverse events (SAEs) for 90 days. RESULTS: There were 57 and 60 patients finally included in the ANP and placebo groups, respectively for modified intention-to-treat analysis. The median age was 66.0 years, and the median NIHSS score at baseline was 12.0. The changes in cerebral infarct volume at day 14 were 0.3 mL and 0.4 mL in the ANP and placebo groups, respectively (median difference: -7.1 mL; interquartile range [IQR]: -18.3 to 2.3 mL, P = 0.30). The changes in cerebral edema volume of the ANP and placebo groups on day 14 were 11.4 mL and 4.0 mL, respectively ( median difference: 3.0 mL, IQR: -1.3 to 9.9 mL, P = 0.15). The rates of SAE within 90 days were similar in the ANP (3/57, 5%) and placebo (7/60, 12%) groups ( P = 0.36). Changes in serum mercury and arsenic concentrations were comparable. In patients with large artery atherosclerosis, ANP reduced the cerebral infarct volume at 14 days (median difference: -12.3 mL; IQR: -27.7 to -0.3 mL, P = 0.03). CONCLUSIONS: ANP showed a similar safety profile to placebo and non-significant tendency to reduce cerebral infarct volume in patients with moderate-to-severe stroke. Further studies are warranted to assess the efficacy of ANP in reducing cerebral infarcts and improving clinical prognosis. TRAIL REGISTRATION Clinicaltrials.gov , No. NCT04475328.
Aged ; Female ; Humans ; Male ; Middle Aged ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Ischemic Stroke/drug therapy* ; Pilot Projects ; Stroke/drug therapy* ; Treatment Outcome

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

While multiple step saccades (MSS) are occasionally reported in the healthy population, they are more evident in patients with Parkinson's disease (PD). Therefore, MSS has been suggested as a biological marker for the diagnosis of PD. However, the lack of clarity on the neural mechanism underlying the generation of MSS largely impedes their application in the clinic. We have proposed recently that MSS are triggered by the discrepancy between desired and executed saccades. Accordingly, brain regions involved in saccadic planning and execution might play a role in the generation of MSS. To test this hypothesis, we explored the role of the prefrontal (PFC) and posterior parietal cortex (PPC) in generating MSS by conducting two experiments: electroencephalographic recording and single-pulse transcranial magnetic stimulation in the PFC or PPC of humans while participants were performing a gap saccade task. We found that the PFC and PPC are involved in the generation of MSS.
Humans ; Parietal Lobe/physiology* ; Saccades/physiology* ; Prefrontal Cortex/physiology* ; Male ; Transcranial Magnetic Stimulation ; Female ; Electroencephalography ; Adult ; Young Adult

Intentional tooth replantation (ITR) is an advanced treatment modality and the procedure of last resort for preserving teeth with inaccessible endodontic or resorptive lesions. ITR is defined as the deliberate extraction of a tooth; evaluation of the root surface, endodontic manipulation, and repair; and placement of the tooth back into its original socket. Case reports, case series, cohort studies, and randomized controlled trials have demonstrated the efficacy of ITR in the retention of natural teeth that are untreatable or difficult to manage with root canal treatment or endodontic microsurgery. However, variations in clinical protocols for ITR exist due to the empirical nature of the original protocols and rapid advancements in the field of oral biology and dental materials. This heterogeneity in protocols may cause confusion among dental practitioners; therefore, guidelines and considerations for ITR should be explicated. This expert consensus discusses the biological foundation of ITR, the available clinical protocols and current status of ITR in treating teeth with refractory apical periodontitis or anatomical aberration, and the main complications of this treatment, aiming to refine the clinical management of ITR in accordance with the progress of basic research and clinical studies; the findings suggest that ITR may become a more consistent evidence-based option in dental treatment.
Humans ; Tooth Replantation/methods* ; Consensus ; Periapical Periodontitis/surgery*

Objective To assess the exposure levels of heavy metals,including lead,arsenic,mercury,and cadmium,in the local population in Sichuan and Chongqing,China,to compare and analyze the differences in reference intervals(RIs)obtained from direct and indirect sampling methods,and to explore the interchangeability and limitations of these two sampling methods.Methods RIs were obtained by the direct sampling method and the indirect sampling method.In the direct sample method,the levels of blood arsenic,urinary cadmium,urinary mercury,and blood lead levels of 5562 healthy participants aged 22-50 years in Sichuan and Chongqing,China were measured by atomic absorption spectrometry and inductively coupled plasma-mass spectrometry.Using the human biomonitoring(HBM)data,we established RIs for the population by a nonparametric method.On the other hand,in the indirect sampling method,RIs were established via a nonparametric method based on data from the laboratory information system(LIS)of a local hospital after stratifying healthy individuals using a Gaussian mixture model(GMM).Comparative analysis of the RIs derived from the two sampling methods were then conducted.Results The RI for blood arsenic was 0.11-1.3 μmol/L.The RI for urinary cadmium was 0.51-2.80 μmol/mol creatine for adults aged 22 to under 43 years and 0.66-2.96 μmol/mol creatine for adults aged 43-50 years.The RI for urinary mercury was 0.12-1.10 μmol/mol creatine.The RI for blood lead was 14.00-47.00 pg/L for adults aged 22 to under 41 year,16.00-53.38 pg/L for males aged 41-50 year,and 15.00-51.02 pg/L for females aged 41-50 year.Most of the RIs established by the direct sampling method had a narrower range compared to those established by the indirect sampling method,and the RIs established by both sampling methods were partially biased.Conclusions The RIs for blood arsenic,urine cadmium,urine mercury,and blood lead in healthy individuals aged 22-50 years in Sichuan and Chongqing,China were established using both direct and indirect sampling methods,which contributes to a better understanding of environmental exposure to metals in the general population and provides a reference for metal poisoning.For data from the same lab,the GMM-based indirect sampling method demonstrated relatively consistent performance in establishing RIs compared with the direct sampling method.

Objective To explore the relationship between the duration of breastfeeding and re-fractive error in preschool children.Methods A cross-sectional survey was conducted to investigate the visual acuity of 2,915 preschool children aged 3 to 6 years using a questionnaire.Results After adjusting for potential confounding factors such as parental education level,premature birth,birth weight,family structure,only-child status,screen-watching,outdoor activity time,and sleep time u-sing a Logistic regression equation,compared with a breastfeeding duration of less than 6 months,a breastfeeding duration of 6 to 12 months(OR=0.683,95％CI:0.516 to 0.903)and＞12 months(OR=0.628,95％CI:0.451 to 0.874)were found to be protective factors against refractive error.Further stratified analysis revealed that a breastfeeding duration of 6 to 12 months(OR=0.640,95％CI:0.459 to 0.892)and＞12 months(OR=0.519,95％CI:0.347 to 0.777)had a protective effect on the visual acuity of preschool children aged 3 to 4 years.Conclusion The duration of breastfeed-ing is a protective factor against refractive error in preschool children aged 3 to 4 years,and prolonging the duration of breastfeeding is beneficial for reducing the occurrence of refractive error.

Objective To prepare a nano drug(PFOB@Lip-MMC)with liposome as the carrier,liquid perfluorooc-tyl bromide(PFOB)as core and mitomycin C(MMC)loading on the liposome shell and study its inhibitory effect on the proliferation of human pterygium fibroblasts(HPFs).Methods The thin film dispersion-hydration ultrasonic method was used to prepare PFOB@Lip-MMC and detect its physical and chemical properties.Cell Counting Kit-8,Cam-PI cell viability staining and flow cytometry were employed to detect the impact of different concentrations of PFOB@Lip-MMC on the via-bility of HPFs.DiI fluorescence labeled PFOB@Lip-MMC was used to observe the permeability of the nano drug to HPFs under a laser confocal microscope.After establishing HPF inflammatory cell models,they were divided into the control group(with sterile phosphate-buffered saline solution added),PFOB@Lip group(with PFOB@Lip added),MMC group(with MMC added),PFOB@Lip-MMC group(with PFOB@Lip-MMC added)and normal group(with fresh culture medi-um added)according to the experimental requirements.After co-incubation for 24 h,flow cytometer was used to detect the apoptosis rate of inflammatory cells,and the gene expression levels of interleukin(IL)-1β,prostaglandin E2(PGE2),tumor necrosis factor(TNF)-α and vascular endothelial growth factor(VEGF)in cells were analyzed by PCR.Results The average particle size and Zeta potential of PFOB@Lip-MMC were(103.45±2.17)nm and(27.34±1.03)mV,respec-tively,and its entrapped efficiency and drug loading rate were(72.85±3.28)％and(34.27±2.04)％,respectively.The sustained-release MMC of drug-loaded nanospheres reached(78.34±2.92)％in vitro in a 24-hour ocular surface environ-ment.The biological safety of PFOB@Lip-MMC significantly improved compared to MMC.In terms of the DiI fluorescence labeled PFOB@Lip-MMC,after co-incubation with inflammatory HPFs for 2 h,DiI fluorescence labeling was diffusely dis-tributed in the cytoplasm of inflammatory HPFs.The apoptosis rate of inflammatory HPFs in the PFOB@Lip-MMC group[(77.23±4.93)％]was significantly higher than that in the MMC group[(51.62±3.28)％].The PCR examination results showed that the gene transcription levels of IL-1 β,PGE2,TNF-α and VEGF in other groups were significantly reduced com-pared to the control group and PFOB@Lip group,with the most significant decrease in the PFOB@Lip-MMC group(all P＜0.05).Conclusion In this study,a novel nano drug(PFOB@LIP-MMC)that inhibited the proliferation of HPFs was successfully synthesized,and its cytotoxicity was significantly reduced compared to the original drugs.It has good bio-compatibility and anti-inflammatory effects,providing a new treatment approach for reducing the recurrence rate after pte-rygium surgery.