BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

The high prevalence of major depressive disorder (MDD) frequently imposes severe constraints on psychosocial functioning and detrimentally impacts overall well-being. Despite the growing interest in the hypothesis of mitochondrial dysfunction, the precise mechanistic underpinnings and therapeutic strategies remain unclear and require further investigation. In this study, an MDD model was established in mice using lipopolysaccharide (LPS). Our research findings demonstrated that LPS exposure induced depressive-like behaviors and disrupted mitophagy by diminishing the mitochondrial levels of PINK1/Parkin in the brains of mice. Furthermore, LPS exposure evoked the activation of the NLRP3 inflammasome, accompanied by a notable elevation in the concentrations of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6). Additionally, neuronal apoptosis was stimulated through the JNK/p38 pathway. The administration of BGP-15 effectively nullified the impact of LPS, corresponding to the amelioration of depressive-like phenotypes and restoration of mitophagy, prevention of neuronal injury and inflammation, and suppression of reactive oxygen species (ROS)-mediated NLRP3 inflammasome activation. Furthermore, we elucidated the involvement of mitophagy in BGP-15-attenuated depressive-like behaviors using the inhibitors targeting autophagy (3-MA) and mitophagy (Mdivi-1). Notably, these inhibitors notably counteracted the antidepressant and anti-inflammatory effects exerted by BGP-15. Based on the research findings, it can be inferred that the antidepressant properties of BGP-15 in LPS-induced depressive-like behaviors could potentially be attributed to the involvement of the mitophagy pathway. These findings offer a potential novel therapeutic strategy for managing MDD.

Acetylated tau exacerbates learning and memory impairment by disturbing with mitochondrial homeostasis.

Increased tau acetylation at K274 and K281 has been observed in the brains of Alzheimer's disease (AD) patients and animal models, and mitochondrial dysfunction are noticeable and early features of AD. However, the effect of acetylated tau on mitochondria has been unclear until now. Here, we constructed three type of tau forms, acetylated tau mutant by mutating its K274/K281 into Glutamine (TauKQ) to mimic disease-associated lysine acetylation, the non-acetylation tau mutant by mutating its K274/K281 into Arginine (TauKR) and the wild-type human full-length tau (TauWT). By overexpression of these tau forms in vivo and in vitro, we found that, TauKQ induced more severe cognitive deficits with neuronal loss, dendritic plasticity damage and mitochondrial dysfunctions than TauWT. Unlike TauWT induced mitochondria fusion, TauKQ not only induced mitochondria fission by decreasing mitofusion proteins, but also inhibited mitochondrial biogenesis via reduction of PGC-1a/Nrf1/Tfam levels. TauKR had no significant difference in the cognitive and mitochondrial abnormalities compared with TauWT. Treatment with BGP-15 rescued impaired learning and memory by attenuation of mitochondrial dysfunction, neuronal loss and dendritic complexity damage, which caused by TauKQ. Our data suggested that, acetylation at K274/281 was an important post translational modification site for tau neurotoxicity, and BGP-15 is a potential therapeutic drug for AD.

Soil microbiomes divergently respond to heavy metals and polycyclic aromatic hydrocarbons in contaminated industrial sites.

Contaminated sites from electronic waste (e-waste) dismantling and coking plants feature high concentrations of heavy metals (HMs) and/or polycyclic aromatic hydrocarbons (PAHs) in soil. Mixed contamination (HMs + PAHs) hinders land reclamation and affects the microbial diversity and function of soil microbiomes. In this study, we analyzed HM and PAH contamination from an e-waste dismantling plant and a coking plant and evaluated the influences of HM and PAH contamination on soil microbiomes. It was noticed that HMs and PAHs were found in all sites, although the major contaminants of the e-waste dismantling plant site were HMs (such as Cu at 5,947.58 ± 433.44 mg kg-1, Zn at 4,961.38 ± 436.51 mg kg-1, and Mn at 2,379.07 ± 227.46 mg kg-1), and the major contaminants of the coking plant site were PAHs (such as fluorene at 11,740.06 ± 620.1 mg kg-1, acenaphthylene at 211.69 ± 7.04 mg kg-1, and pyrene at 183.14 ± 18.89 mg kg-1). The microbiomes (diversity and abundance) of all sites were determined via high-throughput sequencing of 16S rRNA genes, and redundancy analysis was conducted to investigate the relations between soil microbiomes and contaminants. The results showed that the microbiomes of the contaminated sites divergently responded to HMs and PAHs. The abundances of the bacterial genera Sulfuritalea, Pseudomonas, and Sphingobium were positively related to PAHs, while the abundances of the bacterial genera Bryobacter, Nitrospira, and Steroidobacter were positively related to HMs. This study promotes an understanding of how soil microbiomes respond to single and mixed contamination with HMs and PAHs.

STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model.

Background: Abnormal tau accumulation in the brain has a positively correlation with neurodegeneration and memory deterioration, but the mechanism underlying tau-associated synaptic and cognitive impairments remains unclear. Our previous work has found that human full length tau (hTau) accumulation activated signal transducer and activator of transcription-1 (STAT1) to suppress N-methyl-D-aspartate receptors (NMDARs) expression, followed by memory deficits. STAT3 also belongs to STAT protein family and is reported to involve in regulation of synaptic plasticity and cognition. Here, we investigated the role of STAT3 in the cognitive deficits induced by hTau accumulation. Methods:In vitro studies HEK293 cells were used. EMSA, Luciferase reporter assay, and Immunoprecipitation were applied to detect STAT3 activity. In vivo studies, AAV virus were injected into the hippocampal CA3 region of C57 mice. Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence were applied to examine the level of synaptic proteins. Electrophysiological analysis, behavioral testing and Golgi impregnation were used to determine synaptic plasticity and memory ability recovery after overexpressing STAT3 or non-acetylated STAT1. Results: Our results showed that hTau accumulation acetylated STAT1 to retain STAT3 in the cytoplasm by increasing the binding of STAT1 with STAT3, and thus inactivated STAT3. Overexpressing STAT3 or non-acetylated STAT1 ameliorated hTau-induced synaptic loss and memory deficits by increasing the expression of NMDARs. Conclusions: Taken together, our study indicates that hTau accumulation impaired synaptic plasticity through STAT3 inactivation induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.

In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of synaptic N-methyl-D-aspartate receptors (NMDARs). Here, overexpressing human P301L mutant tau (P301L-hTau) increased the phosphorylated level of Signal Transduction and Activator of Transcription-3 (STAT3) at Tyr705 by JAK2, which would promote STAT3 translocate into the nucleus and activate STAT3. However, STAT3 was found mainly located in the cytoplasm. Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm, and thus inhibited the nuclear translocation and inactivation of STAT3. Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression, synaptic and memory impairments. Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression. Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters. These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression, revealed a novel mechanism for tau-associated synapse and cognition deficits, and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.

Clinical effect of internal fixation of Hoffa fracture / 中华创伤杂志

Objective To approach the methods and effects of internal fixation for Hoffa fracture. Methods A total of 26 patients with 26 condylar Hoffa fractures ( medial condylar fractures in 13patients and lateral condylar fractures in 13) treated from August 1993 to February 2010 were retrospectively analyzed.According to the Letenneur classification,there were 16 patients with type Ⅰ fractures,four with type Ⅱ fractures and six with type Ⅲ fractures.Among them,two patients were with open fractures and 24 with closed fractures.Surgical approaches including screw fixation in 21 patients and lateral support plate fixation in five were selected based on the fracture types and affected sides. Results All patients were followed up for 12.5-48 months (average 18 months),which showed fracture healing in all the patients within 3-4 months (average 3.5 months).Two patients had slight shift together with knee joint pain,ie,one patient had ROM of knee for 95 °,and one failed the functional exercise because of pain and had ROM of knee for 60° during follow up.No complications including infection,delayed union or bone necrosis occurred.According to Letenneur' s functional assessment system,the postoperative outcomes were excellent and good in 24 condyles,fair in one and poor in one. Conclusions Surgical treatment for Hoffa fractures is safe and effective,but the key point is to choose correct screw fixation position and orientation according to the fracture types and fracture fragment size.

Construction, expression and immunogenicity analysis of a Tat N-terminus-deleted mutant fusion protein of human immunodeficiency virus type 1 / 病毒学报

In the study, a gene encoding Tat protein N terminal 1- 21 amino acid residues-deleted mutant (Tat22-101) was amplified by PCR from a full length Tat gene of human immunodeficiency virus type 1, and the prokaryotic expression plasmid pET32a-Tat22-101 was constructed. After identification by digestion with endonucleases and sequencing, the recombinant plasmid pET32a-Tat22-101 was transformed into E. coli BL21(DE3) and expressed with IPTG induction. The mutant fusion protein with deleted Tat N terminal was purified by an affinity chromatography column Ni(2+)-NTA and subsequently identified by SDS-PAGE and Western blotting. The results showed that the molecular weight of the mutant protein was approximately 26.9kD. Furthermore, BALB/c mice were immunized with the mutant protein and the anti-sera were collected. ELISA results showed that the mutant protein preserved its immunogenicity, particularly it could improve the production of antibodies to other epitopes in addition to the N terminal epitope of Tat protein, which might provide some valuable information for the study of Tat functions as well as for development of potential novel HIV Tat vaccine.

Shear bond strength of anterior teeth fragment reattachment using two different adhesive materials / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To compare the shear bond strength of the fractured anterior teeth reattached by two different adhesive materials.</p><p><b>METHODS</b>Forty crown fractured anterior modes were divided into two groups randomly, with 20 in each group. Group A were reattached by Clearfil SE Bond and Clearfil AP-X, while group B were reattached by Clearfil S3 Bond and Clearfil AP-X. Then the specimens were submitted to an axial compression test in a universal testing machine until tooth fractured. The strength was recorded.</p><p><b>RESULTS</b>The mean shear bond strength of group A and group B was (324.32 +/- 65.91) N and (263.08 +/- 55.88) N, separately. The mean shear bond strength of group A was statistically higher than group B(t = 3.17, P = 0.000).</p><p><b>CONCLUSION</b>The shear bond strength of two-step adhesive Clearfil SE Bond is higher than one-step adhesive Clearfil S3 Bond for the reattachment of fractured anterior teeth.</p>

Inhibiting effects of GW2974 on DMBA-induced hamster buccal pouch carcinogenesis / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To evaluate the inhibiting effects of GW2974, a tyrosine kinase inhibitors, on dimethyl-benzanthracene (DMBA)-induced Syrian golden hamster buccal pouch carcinogenesis.</p><p><b>METHODS</b>Ninety hamsters were painted with 0.5% DMBA in the left buccal pouches three times a week for 6 weeks, which were then divided into 3 groups: low-concentration, high-concentration and positive control groups. Positive control group received no further treatment. Ten hamsters served as negative control. The two treated groups were topically painted with GW2974 (4 mmol/L) and GW2974 (8 mmol/L) three times a week, respectively. Tissue samples of the left cheek pouch were obtained at 24 th week. The average number, average volume and burden of tumor, incidence of tumor and the pathological changes of each group were recorded.</p><p><b>RESULTS</b>After GW2974 (4 mmol/L and 8 mmol/L) was applied topically, tumor incidence decreased from 80.0% (24/30) to 43.3% (13/30, P < 0.01) and 36.7% (11/30, P < 0.01) respectively, the average number of tumors decreased from 1.00 +/- 0.87 to 0.47 +/- 0.82 (P < 0.05) and 0.37 +/- 0.62 (P < 0.05), the average volume and burden of tumors also declined, tumor incidence decreased from 70.0% (21/30) to 40.0% (12/30, P < 0.05) and 33.3% (10/30, P < 0.01), the number of tumors declined from 1.83 +/- 1.91 to 0.67 +/- 0.99 (P < 0.05) and 0.43 +/- 0.68 (P < 0.01).</p><p><b>CONCLUSIONS</b>Topical application of GW2974 could significantly inhibit hamster buccal pouch carcinogenesis, which suggests that GW2974 may have a major impact in chemoprevention and treatment of oral cancer.</p>