Growth arrest DNA damage-inducible protein 45 β (GADD45B) has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes. However, its precise role and mechanism of action in stress susceptibility remain elusive. In this study, we found a significant reduction in GADD45B expression specifically in the ventral, but not the dorsal hippocampal CA1 (dCA1) of stress-susceptible mice. Furthermore, we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation (LTP) in the ventral hippocampal CA1 (vCA1). Importantly, through pharmacological inhibition using the NMDA receptor antagonist MK801, we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP. Collectively, these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
Animals ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; CA1 Region, Hippocampal/drug effects* ; Male ; Stress, Psychological/physiopathology* ; Mice ; Neuronal Plasticity/drug effects* ; Long-Term Potentiation/drug effects* ; Mice, Inbred C57BL ; Antigens, Differentiation/metabolism* ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; GADD45 Proteins

Insufficient alveolar bone thickness increases the risk of periodontal dehiscence and fenestration, especially in orthodontic tooth movement. Abaloparatide (ABL), a synthetic analog of human PTHrP (1-34) and a clinical medication for treating osteoporosis, has recently demonstrated its potential in enhancing craniofacial bone formation. Herein, we show that intraoral submucosal injection of ABL, when combined with mechanical force, promotes in situ alveolar bone thickening. The newly formed bone is primarily located outside the original compact bone, implying its origin from the periosteum. RNA sequencing of the alveolar bone tissue revealed that the focal adhesion (FA) pathway potentially mediates this bioprocess. Local injection of ABL alone enhances cell proliferation, collagen synthesis, and phosphorylation of focal adhesion kinase (FAK) in the alveolar periosteum; when ABL is combined with mechanical force, the FAK expression is upregulated, in line with the accomplishment of the ossification. In vitro, ABL enhances proliferation, migration, and FAK phosphorylation in periosteal stem cells. Furthermore, the pro-osteogenic effects of ABL on alveolar bone are entirely blocked when FAK activity is inhibited by a specific inhibitor. In summary, abaloparatide combined with mechanical force promotes alveolar bone formation via FAK-mediated periosteal osteogenesis. Thus, we have introduced a promising therapeutic approach for drug-induced in situ alveolar bone augmentation, which may prevent or repair the detrimental periodontal dehiscence, holding significant potential in dentistry.
Osteogenesis/drug effects* ; Periosteum/cytology* ; Parathyroid Hormone-Related Protein/administration & dosage* ; Animals ; Focal Adhesion Protein-Tyrosine Kinases/metabolism* ; Alveolar Process/drug effects* ; Cell Proliferation/drug effects* ; Phosphorylation ; Rats ; Male ; Humans ; Focal Adhesion Kinase 1/metabolism* ; Cell Movement/drug effects*

Objective To reveal the mechanism by which the programmed death-ligand 1(PD-L1)-protein tyrosine phosphatase 1B(PTP1B)-focal adhesion kinase(FAK)signaling axis promotes the progression of hepatocellular carcinoma(HCC)and elucidate its effector functions in HCC.Methods GEPIA database was used to plot a 10-year survival curve for PD-L1 and FAK expression levels in HCC patients.Immunohistochemical(IHC)staining was utilized to analyze the relative expression levels of PD-L1 and FAK phosphorylated at the Y397 site[p-FAK(Y397)]in HCC tissues,and the results were compared to those in the adjacent non-tumor tissues.Subsequently,endogenous PD-L1 expression was detected with Western blotting in HCC cell lines with low(SNU-387)and high(Hep3B)PD-L1 expression levels.After lentivirus-transduced SNU-387PDL1+and Hep3BPDL1-cells were constructed,the effect of high and low expression of PD-L1 on the expression of p-FAK(Y397)with Western blotting.To elucidate the functional mechanism of FAK in HCC,functional rescue experiments were performed by administering a FAK inhibitor to SNU-387PDL1+cells and a FAK activator to Hep3BPDL1-cells,combined with wound healing scratch assay,Transwell invasion assay,EdU proliferation assay,and colony formation assay to evaluate tumor malignant effects.The GENEMANIA database predicted functional interactions between protein tyrosine phosphatase 1B(PTP1B),PD-L1,and FAK.IHC staining was performed to analyze the correlation among PD-L1,PTP1B,and p-FAK(Y397)expression.Co-immunoprecipitation(Co-IP)and indirect immunofluorescence(IF)were applied to validate the interaction between PD-L1 and PTP1B.Western blotting was utilized to confirm the regulatory relationship between PD-L1 and PTP1B.In vitro PTP1B phosphatase activity assay measured the changes in PTP1B activity.Subsequently,Western blotting was used to screen cell lines with high endogenous PTP1B expression(SNU-387)and low endogenous PTP1B expression(Hep3B).Furthermore,Hep3BPTP1B+and SNU-387PTP1B-cell lines were generated,and then p-FAK(Y397)levels were then detected in these modified cell lines,and the aforementioned functional effect assays(migration,invasion,proliferation and colony formation)and rescue experiments were repeated.Furthermore,Western blotting was employed to detect changes in downstream signaling pathways following enhancement or attenuation of p-FAK(Y397)in SNU-387 and Hep3B cells.Results IHC staining revealed a positive correlation between PD-L1 and p-FAK(Y397)expression in HCC tissues(95%CI:1.065～3.801,P<0.01).In SNU-387PDL1+cells,PD-L1 overexpression significantly enhanced phosphorylation at the FAK Y397 site(P<0.01)and increased cell migration,invasion,proliferation,and colony formation capabilities(P<0.01),and these effects could be reversed by FAK inhibitor treatment(P<0.05).Conversely,in Hep3BPDL1-cells,PD-L1 knockdown significantly reduced FAK Y397 phosphorylation(P<0.01)and decreased cell migration,invasion,proliferation,and colony formation abilities(P<0.01),and these effects were restored by FAK activator treatment(P<0.05).IHC staining further showed a negative correlation between PTP1B expression and both PD-L1 and p-FAK(Y397)in HCC tissues(95%CI:1.886～3.514,P<0.05).Co-IP and IF assays confirmed a direct interaction between PD-L1 and PTP1B,with PD-L1 suppressing PTP1B expression level and reducing its activity(P<0.01).In SNU-387PTP1B-cells,PTP1B knockdown significantly increased FAK Y397 phosphorylation(P<0.01)and enhanced cell migration,invasion,proliferation,and colony formation(P<0.01),and these effects were reversed by FAK inhibitor(P<0.05).While in Hep3BPTP1B+cells,PTP1B overexpression significantly decreased FAK Y397 phosphorylation(P<0.01)and reduced cell migration,invasion,proliferation,and colony formation(P<0.01),and those effects were restored by FAK activator treatment(P<0.05).Furthermore,enhanced phosphorylation at the FAK Y397 site in SNU-387 cells activated downstream PI3K/AKT and MEK/ERK signaling pathways(P<0.01),whereas inhibition of FAK(Y397)phosphorylation in Hep3B cells attenuated the activation of these signaling pathways(P<0.01).Conclusion PD-L1 activates FAK by suppressing PTP1B,thereby promoting migration,invasion,and proliferation in HCC.

Long non-coding RNA(lncRNA)play crucial roles in cell development,differentia-tion,and proliferation,serving as one of key molecules in regulating gene expression.Studies have shown that abnormal expression of lncRNAs is closely associated with the onset,malignant progression,and metastasis of various tumors.Prostate cancer associated transcript 1(PCAT1),as an important member of lncRNA,has been demonstrated to be highly expressed in multiple cancers and involved in multiple biological regulatory processes,thereby promoting cancer development.This article reviewed the roles,mechanisms,and regulatory targets of lncRNA PCAT1 in cancer initiation and progression,aiming to provide a reference for subsequent research.

Objective:To observe the effects of acupuncture and moxibustion on ubiquitin-like containing PHD and RING finger domains 1(UHRF1)and DNA methyltransferase 1(DNMT1)in ectopic endometrium of rats with endometriosis(EMS). Methods:Forty Sprague-Dawley rats were randomly divided into a sham operation group with 10 rats and a model-building group with 30 rats according to body mass.EMS rat models were established in the model-building group and then were divided into a model group,an acupuncture and moxibustion group,and a progesterone group,with 10 rats in each group.All rats were fixed by a fixator.The sham operation group and the model group were given normal saline by gavage.The acupuncture and moxibustion group received acupuncture at Xuehai(SP10)and Sanyinjiao(SP6),moxibustion at Guanyuan(CV4),and gavage of normal saline.The progesterone group was given the mixed liquid made of dydrogesterone and normal saline by gavage.After 28 d of treatments,the three diameters(length,width,and height)of EMS rats'ectopic cysts were measured,the cyst volumes were calculated,the volumes before intervention were subtracted,and the difference values were used to evaluate the growth of ectopic cysts.UHRF1 and DNMT1 mRNA and protein levels in normal endometrium,eutopic endometrium,and ectopic endometrium were detected by real-time polymerase chain reaction and immunohistochemistry. Results:There was no significant difference in the ectopic cyst volume difference between the acupuncture and moxibustion group and the progesterone group(P>0.05),but they were smaller than that of the model group(P<0.05).The levels of UHRF1 and DNMT1 mRNA and protein in the ectopic endometrium of the model group were lower than those in the normal endometrium(P<0.05).The levels of DNMT1 mRNA and UHRF1 protein in the eutopic endometrium of the model group were lower than those in the normal endometrium(P<0.05).The levels of UHRF1 mRNA and protein and the level of DNMT1 protein in the ectopic endometrium of the acupuncture and moxibustion group were higher than those in the model group(P<0.05),and the level of UHRF1 mRNA was higher than that in the progesterone group(P<0.05).The level of DNMT1 mRNA in the eutopic endometrium of the acupuncture and moxibustion group was higher than that in the model group(P<0.05).The levels of UHRF1 and DNMT1 mRNA and protein in the acupuncture and moxibustion group were insignificantly different from those in the normal endometrium(P>0.05). Conclusion:Acupuncture and moxibustion may up-regulate the levels of UHRF1 mRNA and UHRF1 and DNMT1 proteins in the ectopic endometrium to the normal level so as to reduce the volume of ectopic cysts and cure EMS in rats.

Objective This study aims to establish an approach to integrate autonomous maximal smile(AMS)3D facial image with digital 3D dental models to demonstrate the digital orthodontic set-up in the 3D facial context.Methods Using Geomagic Studio software,the AMS 3D facial image and pre-treatment dental model were manually and globally registered.Subsequently,the pre-treatment dental model was substituted with the predicted post-treatment dental model.The intraoral region of the AMS 3D facial image was removed,achieving a conjunctive display of the AMS 3D facial image and the post-treatment dental set-up.The distances between four groups of corresponding landmark pairs on the AMS 3D facial image and the pre-treatment dental set-up were calculated,and the accuracy of the registration operation was evaluated by paired t-test.Results The novel approach effectively facilitated the integration of AMS 3D facial images with the pre-treatment and predicted post-treatment 3D dental models.The average distances between the pairs of points were(1.19±0.55)mm and(1.55±0.59)mm for the two registrations,respectively.Notably,no statistically significant difference was observed be-tween the two measurements(P>0.05),indicating a high agreement(intraclass correlation coefficient=0.914).Conclu-sion This study established an approach to integrate AMS 3D facial images with digital 3D dental models.Through this approach,the digital orthodontic set-up design can be displayed in the context of a 3D facial image,which may help to improve the quality of outcome set-up in digital orthodontics,such as clear aligner therapy.

The wide use of ZnO and CuO nanoparticles in research, medicine, industry, and other fields has raised concerns about their biosafety. It is therefore unavoidable to be discharged into the sewage treatment system. Due to the unique physical and chemical properties of ZnO NPs and CuO NPs, it may be toxic to the members of the microbial community and their growth and metabolism, which in turn affects the stable operation of sewage nitrogen removal. This study summarizes the toxicity mechanism of two typical metal oxide nanoparticles (ZnO NPs and CuO NPs) to nitrogen removal microorganisms in sewage treatment systems. Furthermore, the factors affecting the cytotoxicity of metal oxide nanoparticles (MONPs) are summarized. This review aims to provide a theoretical basis and support for the future mitigating and emergent treatment of the adverse effects of nanoparticles on sewage treatment systems.
Wastewater/toxicity* ; Sewage/chemistry* ; Zinc Oxide/chemistry* ; Waste Disposal, Fluid ; Nanoparticles/chemistry* ; Metal Nanoparticles/chemistry* ; Nitrogen/metabolism* ; Water Purification

Objective : To investigate the achieved intrusion amount of the maxillary incisors and the influencing factors in clear aligner cases treated with extraction of premolars. Methods : This study has been reviewed and approved by the Ethics Committee, and informed consent has been obtained from patients. Thirty adult female patients who underwent extraction of the bilateral maxillary first premolars followed by clear aligner therapy were included. CBCT data before and after treatment were obtained, and three-dimensional reconstruction with registration alignment was performed. A spatial coordinate system was established, and the achieved intrusion amount was measured, followed by calculation of the intrusion efficacy. The factors related to the achieved intrusion amount were investigated through multiple linear regression analysis. Results : The overall efficacy of maxillary incisor intrusion was 54%, with the maxillary central incisors (48%) lower than the lateral incisors (59%), which was statistically significant (P<0.001). Regression analysis showed that the designed intrusion amount and the stepwise intrusion design were positively correlated with the achieved intrusion amount. The designed retroclination amount and use of class Ⅱ intermaxillary elastics were negatively correlated with the achieved intrusion amount. The initial overbite, overjet, crowding, upper central incisor inclination, amount of the first series of aligners, canine attachment type, posterior teeth attachment type and bite ramps had no significant correlation with the achieved intrusion amount. Conclusion In maxillary first premolar extraction cases treated with clear aligners, the upper central incisors have lower efficacy of intrusion movement than the lateral incisors. The achieved intrusion amount of maxillary incisors was influenced by multiple factors, which should be considered comprehensively for better vertical control in such cases.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Resource utilization is an effective way to cope with the rapid increase of kitchen waste and excess sludge, and volatile fatty acids produced by anaerobic fermentation is an important way of recycling organic waste. However, the single substrate limits the efficient production of volatile fatty acids. In recent years, volatile fatty acids produced by anaerobic co-fermentation using different substrates has been widely studied and applied. In this paper, we analyze the characteristics of fermentation to produce acid using kitchen waste and excess sludge alone or mixture. Influences of environmental factors and microbial community structure on the type and yield of volatile fatty acids in the anaerobic fermentation system are discussed in detail. Moreover, we propose future research directions, to provide a reference for recycling kitchen waste and excess sludge.
Anaerobiosis ; Bioreactors ; Fatty Acids, Volatile ; Fermentation ; Hydrogen-Ion Concentration ; Microbiota ; Organic Chemicals ; Sewage