Protein phosphorylation modification is one of the key regulatory mechanisms in cellular signaling transduction and metabolic processes. The phosphorylation state of target proteins is regulated by specific protein kinases and phosphatases, which add or remove phosphate groups. Histidine phosphorylation (pHis) plays a crucial role in both prokaryotes and eukaryotes life activities and is linked to various pathological processes. Unlike the stable phosphorylation of proteins via phosphate ester bonds, histidine phosphorylation is linked through phosphoramide bonds, making it highly sensitive to high temperatures and low pH. This sensitivity has historically impeded progress in identifying and studying histidine phosphorylation. In recent years, the development of new techniques in phosphoproteomics and the emergence of pHis-specific antibodies have promoted the identification and functional research of pHis-modified substrates. For the first time, more than 700 pHis-modified proteins have been identified in mammalian cells, and pHis-modified substrates such as focal adhesion kinase (FAK) and phosphoglycerate mutase 1 (PGAM1) have been found to promote tumor development. This article mainly reviewed the key mechanisms and functions of histidine kinases and histidine phosphatases in regulating the histidine phosphorylation of specific substrates, and highlights their significant roles in human physiological and pathological processes, aiming to provide guidance for further research into the biological functions of histidine phosphorylation.

Aim To observe the effect of Astragalus membranaceus and Angelica sinensis on the apoptosis of chondrocytes,and to investigate the effect of Astrag-alus membranaceus and Angelica sinensis on the sur-vival of fresh ostecartilage allograft.Methods Forty-eight 4-month-old New Zealand white rabbits,half male and half female,were randomly divided into sham operation group,model group,positive group and As-tragalus and Angelica 5∶1 group.In addition to the sham operation group,the other groups were both male and female donors and recipients for knee joint osteo-cartilage cross transplantation modeling.After 8 weeks of drug intervention,samples were taken for general observation,HE staining,saffrane-O staining,immu-nohistochemical staining,qPCR and Western blot de-tection.Results Compared with model group,As-tragalus and Angelica 5∶1 group and positive group,the repair site healed better,the morphology of osteo-chondrocytes tended to be normal,and the division and proliferation were obvious.Proteoglycan deposition in-creased and type Ⅱ collagen content was higher,the differences were statistically significant(P＜0.05).qPCR and Western blot results showed that compared with model group,the mRNA and protein expressions of Bax,caspase-3 and caspase-9 in other groups were significantly decreased(P＜0.05).Conclusion As-tragalus and Angelica can promote the survival of fresh osteochondral allograft,and its mechanism may be re-lated to promoting collagen production,promoting chondrocyte proliferation and inhibiting chondrocyte apoptosis.

Previous studies have shown that high blood glucose-induced chronic microinflammation can cause inflammatory podocyte injury in patients with diabetic kidney disease(DKD). Therein, necroptosis is a new form of podocyte death that is closely associated with renal fibrosis(RF). To explore the effects and mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese herbal medicine Abelmoschus manihot for treating kidney diseases, on podocyte necroptosis and RF in DKD, and to further reveal its scientific connotation with multi-pathway and multi-target, the authors randomly divided all rats into four groups: a namely normal group, a model group, a TFA group and a rapamycin(RAP) group. After the modified DKD rat models were successfully established, four group rats were given double-distilled water, TFA suspension and RAP suspension, respectively by gavage every day. At the end of the 4th week of drug treatment, all rats were sacrificed, and the samples of their urine, blood and kidneys were collected. And then, the various indicators related to podocyte necroptosis and RF in the DKD model rats were observed, detected and analyzed, respectively. The results indicated that, general condition, body weight(BW), serum creatinine(Scr), urinary albumin(UAlb), and kidney hypertrophy index(KHI) in these modified DKD model rats were both improved by TFA and RAP. Indicators of RF, including glomerular histomorphological characteristics, fibronectin(FN) and collagen type Ⅰ(collagen Ⅰ) staining extent in glomeruli, as well as the protein expression levels of FN, collagen Ⅰ, transforming growth factor-β1(TGF-β1) and Smad2/3 in the kidneys were improved respectively by TFA and RAP. Podocyte damage, including foot process form and the protein expression levels of podocin and CD2AP in the kidneys was improved by TFA and RAP. In addition, tumor necrosis factor-α(TNF-α)-mediated podocyte necroptosis in the kidneys, including the morphological characteristics of podocyte necroptosis, the extent and levels of the protein expression of TNF-α and phosphorylated mixed lineage kinase domain like pseudokinase(p-MLKL) was improved respectively by TFA and RAP. Among them, RAP had the better effect on p-MLKL. More importantly, the activation of the receptor interacting serine/threonine protein kinase 1(RIPK1)/RIPK3/MLKL signaling axis in the kidneys, including the expression levels of its key signaling molecules, such as phosphorylated receptor interacting serine/threonine protein kinase 1(p-RIPK1), p-RIPK3, p-MLKL and cysteinyl aspartate specific proteinase-8(caspase-8) was improved respectively by TFA and RAP. Among them, the effect of TFA on p-RIPK1 was superior. On the whole, in this study, the authors demonstrated that TFA alleviates podocyte necroptosis and RF in DKD through inhibiting the activation of the TNF-α-mediated RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. The authors' findings provide new pharmacological evidence to reveal the scientific connotation of TFA in treating RF in DKD in more depth.
Humans ; Rats ; Animals ; Diabetic Nephropathies/drug therapy* ; Abelmoschus ; Flavones/pharmacology* ; Podocytes ; Tumor Necrosis Factor-alpha/metabolism* ; Necroptosis ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Fibrosis ; Threonine/pharmacology* ; Collagen/metabolism* ; Serine/pharmacology* ; Diabetes Mellitus/drug therapy*

Breast cancer has become the most prevalent malignant tumor among women, putting the health of women at serious risk. Screening for lead compounds in the active ingredients of plant that are effective and less toxic continues to be an important strategy for treating breast cancer. Gerbeloid J, a coumarin isolated from Gerbera piloselloides (L.) Cass., showed significant anti-cancer activity. But there is no report on the effect and mechanism of gerbeloid J on cycle and apoptosis of breast cancer. By using the CCK-8, clone formation, and PI staining assays, the effects of gerbeloid J on the proliferation of MCF-7 and MDA-MB-231 cells were assessed in this study. The effects of gerbeloid J on the apoptosis and mitochondrial function of MCF-7 and MDA-MB-231 cells were assessed using DAPI, Annexin V/TO-PRO-3, Rhod-2 AM, TMRM, DCFDA staining assays, and Western blot. The results demonstrated that gerbeloid J regulated the P21/CDC25C/CDK-1/cyclin B1 pathway and arrested the cell cycle at G2/M phase to suppressed the proliferation of MCF-7 and MDA-MB-231 cells. Additionally, gerbeloid J induced apoptosis through the stimulation of mitochondrial calcium excess, reduction of mitochondrial membrane potential, and promotion of ROS generation, and its mechanism was related to the activation of mitochondrial apoptotic pathway. In conclusion, by regulating the P21/CDC25C/CDK-1/cyclin B1 pathway and activating the mitochondrial apoptosis pathway, gerbeloid J could cause breast cancer cell cycle arrest and apoptosis, which might offer a promising candidate for the creation of new drugs against breast cancer.

Objective: To measure and analyze the shoulder circumferences of adults' permanent teeth crown preparations based on data collected through the intraoral scanning, so as to provide dental anatomy data for clinical diagnosis and analysis. Methods: Intraoral scanning data of 840 complete crown preparations were collected, and were entrusted to the World Dental Laboratory Co., Ltd. in Fuzhou between March 2021 and June 2022. Except the data of the third molar, the rest data were categorized in terms of 14 tooth positions in the upper and lower jaw (each category involved 30 samples from male group and 30 samples from female group). Image measurement software was used to measure the shoulder circumferences of permanent teeth crown preparations. And analysis was conducted to reveal the difference of shoulder circumference diameters between male and female groups. And then they were grouped according to the mean value at each tooth position, on the premise that the difference between the maximum and minimum values and the mean value of the entire group was≤±1.00 mm. Analysis were further conducted to determine the differences of shoulder circumference diameters between each dental position and the differences between male and female in the same groups. Results: Bivariate analysis of variance showed that gender had no effect on the shoulder circumference of full crown preparations (F=0.55, P=1.457), while tooth position had a significant impact on the shoulder circumference of full crown preparations (F=273.15, P<0.001). The samples were classified into 5 groups according to the mean values of shoulder circumference diameters relating to each tooth position. Statistical analysis showed that Group 1, covering maxillary lateral incisor, mandibular central incisor and mandibular lateral incisor, had shoulder circumference with diameters of (16.62±2.21) mm; Group 2, consisting of maxillary central incisor, maxillary cusp, mandibular cusp, mandibular first premolar and mandibular second premolar, had diameters of (20.78±2.48) mm; Group 3, consisting of maxillary first premolar and maxillary second premolar, had diamerters of (22.09±2.72) mm; Group 4, covering maxillary first molar, maxillary second molar and mandibular first molar, had diamerters of (30.21±2.67) mm; while group 5, with mandibular second molar alone its member, had diamerters of (31.34±3.18) mm. The difference among the 5 groups was statistically significant (P<0.05). Conclusions: Significant differences of shoulder circumference diameters could be found between different tooth positions, while at the same tooth position, the differences between male and female are not significant. The 14 tooth positions could be grouped into 5 groups according to their shoulder circumference diameters. Future research could take the grouping as reference.

OBJECTIVE: To analyze the characteristics of gene mutation and overexpression in newly diagnosed multiple myeloma (NDMM) patients. METHODS: Bone marrow cells from 208 NDMM patients were collected and analyzed. The gene mutation of 28 genes and overexpression of 6 genes was detected by DNA sequencing. Chromosome structure abnormalities were detected by fluorescence in situ hybridization (FISH). RESULTS: Gene mutations were detected in 61 (29.33%) NDMM patients. Some mutations occurred in 5 or more cases, such as NRAS, PRDM1, FAM46C, MYC, CCND1, LTB, DIS3, KRAS, and CRBN. Overexpression of six genes (CCND1, CCND3, BCL-2, CCND2, FGFR3, and MYC) were detected in 83 (39.9%) patients, and cell cycle regulation gene was the most common. Single nucleotide polymorphisms (SNP) changes were detected in 169 (81.25%) patients, the TP53 P72R gene SNP (70.17%) was the most common. Abnormality in chromosome structure was correlated to gene overexpression. Compared to the patients with normal chromosome structure, patients with 14q32 deletion showed higher proportion of CCND1 overexpression. Similarly, patients with 13q14 deletion showed higher proportion of FGFR3 overexpression, whereas patients with 1q21 amplification showed higher proportion of CCND2, BCL-2 and FGFR3 overexpression. CONCLUSION There are multiple gene mutations and overexpression in NDMM. However, there is no dominated single mutation or overexpression of genes. The most common gene mutations are those in the RAS/MAPK pathway and the genes of cyclin family CCND are overexpression.
Chromosome Aberrations ; Humans ; In Situ Hybridization, Fluorescence ; Multiple Myeloma/genetics* ; Mutation

Objective: To describe the clinical characteristics of Mycoplasma pneumoniae infection and analyze the factors associated with co-infections with other pathogens in children, and provide evidence for improvement of community acquired pneumonia (CAP) prevention and control in children. Methods: Based on the surveillance of hospitalized acute respiratory infections cases conducted in Soochow University Affiliated Children's Hospital (SCH), the CAP cases aged <16 years hospitalized in SCH between 2018 and 2021 were screened. The pathogenic test results of the cases were obtained through the laboratory information system, and their basic information, underlying conditions, and clinical characteristics were collected using a standardized questionnaire. The differences in clinical characteristics between M. pneumoniae infection and bacterial or viral infection and the effect of the co-infection of M. pneumoniae with other pathogens on clinical severity in the cases were analyzed; logistic regression was used to analyze the factors associated with the co-infections with other pathogens. Results: A total of 8 274 hospitalized CAP cases met the inclusion criteria. Among them, 2 184 were positive for M. pneumoniae (26.4%). The M. pneumoniae positivity rate increased with age (P<0.001), and it was higher in girls (P<0.001) and in summer and autumn (P<0.001). There were statistically significant differences in the incidence of wheezing, shortness of breath, wheezing sounds and visible lamellar faint shadow on chest radiographs, as well as fever and hospitalization days among M. pneumoniae, bacterial, and viral infection cases (all P<0.05). In the cases aged <60 months years, co-infection cases had higher rates of wheezing, gurgling with sputum and stridor; and in the cases aged ≥60 months, co-infection cases had a higher rate of shortness of breath (all P<0.05). Multifactorial logistic regression analysis showed that being boys (aOR=1.38,95%CI:1.15-1.67), being aged <6 months (aOR=3.30,95%CI:2.25-4.89), 6-23 months (aOR=3.44,95%CI:2.63-4.51), 24-47 months (aOR=2.50,95%CI:1.90-3.30) and 48-71 months (aOR=1.77,95%CI:1.32-2.37), and history of respiratory infection within 3 months (aOR=1.28,95%CI:1.06-1.55) were factors associated with co-infections of M. pneumoniae with other pathogens. Conclusions: M. pneumoniae was the leading pathogen in children hospitalized due to CAP. M. pneumoniae infections could cause fever for longer days compared with bacterial or viral infections; M. pneumoniae was often co-detected with virus or bacteria. Being boys, being aged <72 months and history of respiratory infection within 3 months were associated factors for co-infections.
Bacteria ; Child ; Coinfection/epidemiology* ; Community-Acquired Infections/epidemiology* ; Dyspnea ; Female ; Humans ; Male ; Mycoplasma pneumoniae ; Pneumonia, Mycoplasma/microbiology* ; Respiratory Sounds ; Respiratory Tract Infections/epidemiology* ; Virus Diseases

Transforming growth factor-β1 (TGF-β1) acts as a tumor promoter in advanced prostate cancer (PCa). We speculated that microRNAs (miRNAs) that are inhibited by TGF-β1 might exert anti-tumor effects. To assess this, we identified several miRNAs downregulated by TGF-β1 in PCa cell lines and selected miR-3691-3p for detailed analysis as a candidate anti-oncogene miRNA. miR-3691-3p was expressed at significantly lower levels in human PCa tissue compared with paired benign prostatic hyperplasia tissue, and its expression level correlated inversely with aggressive clinical pathological features. Overexpression of miR-3691-3p in PCa cell lines inhibited proliferation, migration, and invasion, and promoted apoptosis. The miR-3691-3p target genes E2F transcription factor 3 (E2F3) and PR domain containing 1, with ZNF domain (PRDM1) were upregulated in miR-3691-3p-overexpressing PCa cells, and silencing of E2F3 or PRDM1 suppressed PCa cell proliferation, migration, and invasion. Treatment of mice bearing PCa xenografts with a miR-3691-3p agomir inhibited tumor growth and promoted tumor cell apoptosis. Consistent with the negative regulation of E2F3 and PRDM1 by miR-3691-3p, both proteins were overexpressed in clinical PCa specimens compared with noncancerous prostate tissue. Our results indicate that TGF-β1-regulated miR-3691-3p acts as an anti-oncogene in PCa by downregulating E2F3 and PRDM1. These results provide novel insights into the mechanisms by which TGF-β1 contributes to the progression of PCa.