Microglial functions are linked to Ca²⁺ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer's disease (AD), but how ER Ca²⁺ receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca²⁺ transients in controls and normalized Ca²⁺ transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca²⁺ receptors in both homeostatic and AD microglia, providing insights into microglial Ca²⁺ malfunctions in AD.
Animals ; Microglia/pathology* ; Alzheimer Disease/pathology* ; Phagocytosis/drug effects* ; Ryanodine Receptor Calcium Release Channel/metabolism* ; Disease Models, Animal ; Mice ; Cell Movement/drug effects* ; Mice, Transgenic ; Calcium Signaling/physiology* ; Calcium/metabolism* ; Mice, Inbred C57BL ; Male ; Endoplasmic Reticulum/metabolism*

Polycyclic polyprenylated acylphloroglucinols (PPAPs) represent a distinct subclass of specialized metabolites predominantly found in the plant kingdom, particularly within the Guttiferae (Clusiaceae) family. These compounds exhibit remarkable structural diversity and a wide range of biological activities. Seco- and nor-PPAPs, two unique variants of PPAPs with diverse skeletal structures, have been extensively investigated. As of June 2023, 200 compounds have been isolated from four genera, with Hypericum being the primary source. Notably, 115 of these compounds were identified in the past four years, indicating a significant increase in research activity. Seco- and nor-PPAPs can be categorized into six main subgroups based on the original PPAP scaffolds. Biological studies have revealed their potential in various therapeutic applications, including anti-cancer, anti-inflammatory, hepatoprotective, anti-Alzheimer's disease (anti-AD), multidrug resistance (MDR) reversal, anti-depressant, neuroprotective, and immunosuppressive effects. This review provides a comprehensive overview of the occurrence, structures, and bioactivities of natural seco- and nor-PPAPs, offering valuable insights for the further development of PPAPs.
Phloroglucinol/analogs & derivatives* ; Humans ; Molecular Structure ; Animals ; Clusiaceae/chemistry* ; Plant Extracts/pharmacology* ; Biological Products/pharmacology*

Objective To explore the development and validation of a prediction model for severe communi-ty-acquired pneumonia in adults based on peripheral blood inflammatory indicators.Methods Venous blood samples of 204 community-acquired pneumonia in adults patients admitted to 7 hospitals in Chongqing area from April 2021 to August 2022 were collected to detect C-reactive protein(CRP),peripheral white blood cell count(WBC),neutrophil to lymphocyte ratio(NLR),cytokines,lymphocyte subgroups and neutrophil CD64 index.All of patients were divided into a training group and a validation group according to the time of admis-sion.Univariate and multivariate Logistic regression were used to analyze the data of the training group,the characteristic factors of severe progression for pneumonia were selected to construct the nomogram model,and the data of the validation group was used to verify the model.The receiver operating characteristic(ROC)curve,calibration curve and decision curve analysis(DCA)were used to evaluate the prediction ability of the model for severe community-acquired pneumonia in adults.Results Logistic regression analysis showed that age,CRP,WBC,interleukin(IL)-4/interferon gamma ratio and IL-6/IL-10 ratio were independent risk factors for severe community-acquired pneumonia in adults.The area under the ROC curve of the nomogram model in the training group and the validation group was 0.893 and 0.880,respectively.The calibration curve and DCA results shown that the model had a good prediction effect for severe community-acquired pneumonia in adults.Conclusion The inflammatory indicators included in this model are simple and easy to obtain clinically.This model with good differentiation and accuracy,it can be used as a practical tool to predict severe community-ac-quired pneumonia in adults,and has certain clinical application value.

BACKGROUND:Berberine has the potential to induce osteogenic differentiation of various mesenchymal stem cells under normal conditions and special conditions such as high glucose,infection and inflammation.It is a natural small molecule drug that can induce bone formation in seed cells instead of growth factors,and has great application prospect in bone tissue engineering. OBJECTIVE:To review and summarize the research progress in the osteogenic mechanism and efficacy of berberine,especially its osteogenic potential under high glucose,infection and inflammation conditions,and its biological safety,so as to provide theoretical basis for its development and application in bone tissue engineering. METHODS:PubMed,WanFang,and CNKI were searched for relevant literature using the keywords of"berberine,bone defects,bone repair,bone regeneration,osteoinductive,osteoporosis,osteoblast,osteoclast,bone tissue engineering,bone,high glucose,diabetes,inflam*,infect*"in English and Chinese,respectively.A total of 105 literatures were selected for review. RESULTS AND CONCLUSION:Berberine can be used to treat multiple diseases including bone diseases,and it has the ability to promote bone regeneration.This article systematically reviews the mechanism of berberine on bone regeneration and in vivo and in vitro studies.Studies have shown that it can play a role in bone repair by promoting osteogenesis,inhibiting osteoclast formation and activity,and preventing osteoporosis.It shows excellent osteogenic differentiation potential mainly via Wnt/β-catenin,PI3K/AKT,EGFR/MEK/p38MAPK,cAMP/PKA/CREB,ERK and other signaling pathways.Berberine can also relieve the inhibition of osteogenic differentiation caused by high glucose,infection and inflammation,which provides more possibilities for the treatment of bone defects in patients with diabetes or infection and inflammation in the bone defect site.Berberine also has the advantages of low toxicity,low price,easy access(currently it can be synthesized),which is a relatively ideal bone induction potential drug.In recent years,the application of berberine in the treatment of bone defect tends to be localized,mainly through the combination with bone tissue engineering technology to improve bioavailability,and has shown good bone repair effect and excellent biological safety in animal experiments.In addition,preclinical experiments have shown splendid bone regeneration potential in the conditions of diabetes,local infection and inflammation.In the future,more studies are needed to fully reveal the osteogenic mechanism and biological safety of berberine,and seek the most suitable controlled release loading system to make artificial bone replacement materials with good mechanical strength,efficacy and biological safety.

To investigate the therapeutic effect of open reduction and internal fixation (ORIF) on supination external rotation (SER) ankle fractures (AF) and its impact on ankle joint function and range of motion in patients.Methods:The observation group patients were treated with ORIF, while the control group patients were treated with manual reduction combined with plaster external fixation. Both groups of patients were followed up after 3 and 6 months of treatment. Compare the ankle joint function levels of two groups of patients before treatment and after 3 and 6 months of treatment (Kofood score, AOFAS score, Olerud Molander subjective ankle score (OMAS)). Compare the joint range of motion (relative peak force, torque acceleration energy, endurance) between two groups of patients after 3 and 6 months of treatment. Compare the clinical indicators and incidence of adverse events between two groups of patients after 6 months of treatment. T-test was used for comparison between two groups. Multiple group comparisons were conducted using analysis of variance, while pairwise comparisons were conducted using Dunnett-t test. Comparison of count data between groups using χ2 inspections or Fisher exact test. Results:Before treatment, there was no statistically significant difference in the Kofoed score, AOFAS score, and OMAS score between the two groups of patients (all P>0.05). The Kofoed scores of patients in the observation group before treatment and at 3 and 6 months of treatment were (53.78±6.40), (76.73±4.12), and (89.07±5.78) points, respectively. The control group was (52.22±7.08), (71.68±4.82), and (84.05±5.45) points, respectively. The Kofoed scores of patients in both groups were higher than before treatment at 3 and 6 months of treatment (all P<0.05), and the observation group was higher than the control group (all P<0.01).The AOFAS scores of patients in the observation group before treatment and at 3 and 6 months of treatment were (70.13±5.39), (81.62±4.25), and (92.05±4.15) points, respectively. The control group was (69.85±5.41), (79.08±4.60), and (88.92±4.43) points, respectively. The AOFAS scores of patients in both groups were higher than before treatment at 3 and 6 months of treatment (all P<0.05), and the observation group was significantly higher than the control group (all P<0.01).The OMAS scores of the observation group patients before treatment and at 3 and 6 months of treatment were (53.43±5.07), (76.14±4.52), and (85.68±4.14) points, respectively. The control group was (54.42±4.86), (71.39±3.94), and (81.78±4.15) points, respectively. The OMAS scores of the two groups of patients at 3 and 6 months of treatment were higher than before treatment (all P<0.05), and the observation group was higher than the control group (all P<0.01). The fracture healing time (38.85±4.50) days and complete weight-bearing time (66.62±7.14) days of the observation group patients were shorter than those of the control group patients (49.42±5.43) days and (74.39±6.75) days, and the differences between the two groups were statistically significant (t-values were 12.89 and 6.80, respectively, all P<0.01); There was no statistically significant difference in the incidence of adverse events between the two groups of patients (5.41% (4/74) and 9.46% (7/74)), χ2=0.88, P=0.347). Conclusion:ORIF has a good therapeutic effect on SER-AF patients, promotes ankle joint function recovery, and has a low incidence of adverse events, indicating good safety.

Objective:To study effect of STIL gene on proliferation and apoptosis of cervical cancer cells and its mechanism.Methods:Expressions of STIL mRNA and STIL protein in cervical cancer tissues,adjacent tissues,cervical cancer cell lines HeLa,SiHa,caski and human normal cervical epithelial cells HUCEC were calculated by RT-qPCR and Western blot.HeLa cells were divided into control(NC)group,si-NC group,si-STIL group,si-STIL+IL-6 group.CCK-8 and plate cloning assay were utilized to detect cell proliferation and cloning ability,and flow cytometry was used to analyze cell apoptosis rate.Western blot was used to detect IL-6,IL-6R and p-STAT3 proteins levels.sh-STIL stably transfected HeLa cells were subcutaneously inoculated into back of nude mice to investigate effect of inhibiting STIL expression on tumor formation.Results:STIL mRNA and protein expressions in cervical cancer tissues were significantly higher than adjacent tissues(P<0.05).STIL mRNA and protein expressions in HeLa,SiHa,and caski cells were significantly higher than HUCEC cells(P<0.05).Compared with si-NC group,cell absorbance,number of clones,and protein levels of IL-6,IL-6R and p-STAT3 in si-STIL group were significantly reduced(P<0.05),and apoptosis rate was significantly in-creased(P<0.05).Compared with si-STIL group,cell absorbance,number of clones and protein levels of IL-6,IL-6R and p-STAT3 in si-STIL+IL-6 group were significantly increased(P<0.05),and apoptotic rate was significantly reduced(P<0.05).Inhibiting STIL significantly inhibited tumor growth in vivo(P<0.05).Conclusion:STIL gene expression is up-regulated in cervical cancer,and inhi-biting STIL can inhibit proliferation and induce apoptosis of cervical cancer cells by inhibiting IL-6/STAT3 pathway.

Objective To explore the mechanism of Gualou Xiebai Baijiu Decoction(GXB)in improving atherosclerosis(AS)in mice by regulating the gut microbiota(GM)and its metabolites.Methods Thirty-two male ApoE-/-mice were divided randomly into a Blank group,Model group,atorvastatin(Ato)group,and GXB group(n=8 mice per group).AS was established in all mice,except the Blank group,and the respective treatments were administered by gavage.Aortic plaques were detected by Oil red O staining and pathological changes in aortic tissue were detected by hematoxylin and eosin staining.The GM was analyzed using 16S rRNA gene sequencing technology,and mouse GM metabolites,including trimethylamine oxide(TMAO),short-chain fatty acids(SCFA),and serum levels of triglycerides(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),and nitric oxide(NO)were determined.Results Compared with the Blank group,mice in the Model and Ato groups showed an increase in AS plaque area(P＜0.05).Serum levels of TG,TC,and LDL-C were increased(P＜0.001)while levels of HDL-C and NO were decreased(P＜0.01,P＜0.001)in the Model group compared with the Blank group.The plaque area was decreased(P＜0.05),serum levels of TG,TC,and LDL-C were decreased(P＜0.001),and NO levels were increased(P＜0.01)in the Ato and GXB groups,while HDL-C levels were increased in the GXB group(P＜0.05)compared with the Model group.Plaque area was decreased(P＜0.05)and the NO level was increased(P＜0.01)in the GXB group compared with the Ato group.A total of 6345 characteristic sequences were obtained from 16S rRNA analysis.α-Diversity analysis indicated that GXB reduced the richness of the GM in AS mice(P＜0.001)and improved its uniformity(P＜0.05).β-Diversity analysis suggested that the microbial community structure in the GXB group was similar to that in the Blank group.The abundance of microbial communities differed among the groups at the phylum and genus levels.At the phylum level,the abundance of Proteobacteria was increased(P＜0.01)in AS mice,while GXB intervention reduced the abundance of Proteobacteria(P＜0.01)and increased the abundance of Verrucomimicrobiota(P＜0.05).At the genus level,GXB effectively increased the abundance of Akkermansia(P＜0.05).SCFAs were significantly increased(P＜0.01)and TMAO levels were significantly decreased(P＜0.01)in the GXB group compared with the Model group.Conclusions GXB can regulate the intestinal flora and intestinal flora metabolites SCFA and TMAO to improve AS.Akkermansia may be a key bacterial genus of the gut microbiota through which GXB may improve AS.

OBJECTIVE: To explore the genetic basis for 4 patients with globozoospermia. METHODS: Semen and blood samples were collected from the patients for the determination of sperm concentration, viability, survival rate, morphology and acrosome antigen CD46. Meanwhile, DNA was extracted for whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing. RESULTS: All of the four patients were found to harbor variants of the DPY19L2 gene. Patients 1 ~ 3 had homozygous deletions of the DPY19L2 gene. Sanger sequencing confirmed that the DPY19L2 gene in patient 3 was disrupted at a recombination breakpoint area BP2, resulting in nonallelic homologous recombination and complete deletion of the DPY19L2 gene. Patients 2 and 3 respectively harbored novel homozygous deletions of exons 2 ~ 22 and exons 14 ~ 15. Patient 4 harbored heterozygous deletion of the DPY19L2 gene, in addition with a rare homozygous deletion of the 3' UTR region. CONCLUSION DPY19L2 gene variants probably underlay the globozoospermia in the four patients, which has fit an autosomal recessive pattern of inheritance and the characteristics of genomic diseases.
Male ; Humans ; Teratozoospermia/genetics* ; Homozygote ; Semen ; Sequence Deletion ; 3' Untranslated Regions ; Membrane Proteins

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with Mental retardation autosomal dominant 51 (MRD51). METHODS: A child with MRD51 who was hospitalized at Guangzhou Women and Children's Medical Center on March 4, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 5-year-and-3-month-old girl, had manifested autism spectrum disorder (ASD), mental retardation (MR), recurrent febrile convulsions and facial dysmorphism. WES revealed that she has harbored a novel heterozygous variant of c.142G>T (p.Glu48Ter) in the KMT5B gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. The variant has not been recorded in the ClinVar, OMIM and HGMD, ESP, ExAC and 1000 Genomes databases. Analysis with online software including Mutation Taster, GERP++ and CADD indicated it to be pathogenic. Prediction with SWISS-MODEL online software suggested that the variant may have a significant impact on the structure of KMT5B protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. CONCLUSION The c.142G>T (p.Glu48Ter) variant of the KMT5B gene probably underlay the MRD51 in this child. Above finding has expanded the spectrum of KMT5B gene mutations and provided a reference for clinical diagnosis and genetic counseling for this family.
Humans ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation

Microbial Engineering is a practical and applied course, it is therefore an indispensable part of teaching to let the students practice in the production line of an enterprise. However, lack of internship resources has always been a bottleneck hampering the high-level internship training during teaching the Microbial Engineering course. A virtual production line developed based on information technology enables students to learn the theoretical knowledge of the complex production system. Moreover, it enables students to perform complex virtual operations, thereby improving students' practicing and innovation abilities. In order to let the virtual simulation experiments project play a great role in undergraduate teaching, this article summarizes the progress, characteristics, and value of the virtual simulation experiments for Microbial Engineering. In addition, the main challenges that limit its shared application are also discussed, with potential solutions prospected.
Computer Simulation ; Curriculum ; Humans ; Learning ; Students