Pyroptosis in neurodegenerative diseases: from bench to bedside.

The central nervous system regulates all aspects of physiology to some extent. Neurodegenerative diseases (NDDs) lead to the progressive loss and dysfunction of neurons, which are particularly evident in Alzheimer's disease, Parkinson's disease, and many other conditions. NDDs are multifactorial diseases with complex pathogeneses, and there has been a rapid increase in the prevalence of NDDs. However, none of these diseases can be cured, making the development of novel treatment strategies an urgent necessity. Numerous studies have indicated how pyroptosis induces inflammation and affects many aspects of NDD. Therefore, components related to pyroptosis are potential therapeutic candidates and are attracting increasing attention. Here, we review the role of pyroptosis in the pathogenesis of NDDs and potential treatment options. Additionally, several of the current drugs and relevant inhibitors are discussed. Through this article, we provide theoretical support for exploring new therapeutic targets and updating clinical treatment strategies for NDDs. Notably, pyroptosis, a recently widely studied mode of cell death, is still under-researched compared to other traditional forms of cell death. Moreover, the focus of research has been on the onset and progression of NDDs, and the lack of organ-specific target discovery and drug development is a common problem for many basic studies. This urgent problem requires scientists and companies worldwide to collaborate in order to develop more effective drugs against NDDs.

[Mid-frequency transcutaneous electrical acupoint stimulation combined with tamoxifen for the treatment of oligoasthenozoospermia].

OBJECTIVE: To explore the feasibility, safety and clinical effect of mid-frequency transcutaneous electrical acupoint stimulation (TEAS) combined with oral tamoxifen (TAM) in the treatment of oligoasthenozoospermia. METHODS: We randomly and equally assigned 120 patients with idiopathic oligoasthenozoospermia to receive oral TAM, mid-frequency TEAS, or TAM+TEAS, all for 8 weeks. Before and after treatment, we recorded the semen volume, total sperm count, sperm concentration, sperm motility, percentage of progressively motile sperm (PMS), and the levels of follicle-stimulating hormone (FSH), luteotrophic hormone (LH) and testosterone (T) in the peripheral serum and compared these parameters among the three groups of patients. RESULTS: Compared with the baseline, none of the patients showed significant improvement in the semen volume (P >0.05) but all exhibited remarkably elevated levels of serum FSH, LH and T after treatment (P <0.05); TAM significantly improved the total sperm count (ï¼»25.16 ± 2.05ï¼½ vs ï¼»42.65 ± 5.78ï¼½ ×106, P <0.05) and sperm concentration (ï¼»12.15 ± 2.51ï¼½ vs ï¼»24.31 ± 2.59ï¼½ ×106/ml, P <0.05), but not total sperm motility (ï¼»21.78 ± 8.81ï¼½ vs ï¼»22.61 ± 5.75ï¼½ %, P >0.05) or PMS (ï¼»15.87 ± 7.81ï¼½ vs ï¼»16.76 ± 5.86ï¼½ %, P >0.05); TEAS markedly increased total sperm motility (ï¼»24.81 ± 8.27ï¼½ vs ï¼»32.43 ± 4.97ï¼½ %, P <0.05) and PMS (ï¼»19.71 ± 9.15ï¼½ vs ï¼»27.17 ± 5.09ï¼½%, P <0.05), but not the total sperm count (ï¼»23.23 ± 3.14ï¼½ vs ï¼»25.87 ± 4.96ï¼½ ×106, P >0.05) or sperm concentration (ï¼»11.27 ± 2.24ï¼½ vs ï¼»14.12 ± 2.47ï¼½ ×106/ml, P >0.05); TAM+TEAS, however, improved not only the total sperm count (ï¼»26.17 ± 5.05ï¼½ vs ï¼» 51.14 ± 3.69ï¼½×106, P <0.05) and sperm concentration (ï¼»12.78 ± 2.41ï¼½ vs ï¼»27.28 ± 1.98ï¼½ ×106/ml, P <0.05), but also total sperm motility (ï¼»23.89 ± 9.05ï¼½ vs ï¼»37.12 ± 5.33ï¼½%, P <0.05) and PMS (ï¼»17.14 ± 8.04ï¼½ vs ï¼»31.09 ± 7.12ï¼½%, P <0.05). The total effectiveness rate was significantly higher in the TAM+TEAS group than in the TAM and TEAS groups (97.5% vs 72.5% and 75.0%, P <0.05). CONCLUSIONS: Mid-frequency TEAS combined with tamoxifen can significantly improve semen quality and increase sex hormone levels in patients with idiopathic oligoasthenozoospermia.

[Intravaginal ejaculatory latency time: Advances in studies].

Although premature ejaculation (PE) is a common type of male sexual dysfunction, to date we lack a unified definition of PE. The multidimensional definition of PE has been accepted by more and more clinicians. Intravaginal ejaculatory latency time (IELT) is one of the three important dimensions (time to ejaculation, inability to control or delay ejaculation, and negative consequences) for defining PE. Rapid ejaculation is one of the core symptoms of PE and IELT is an objective measurement as well as an important tool for the evaluation of PE. This article reviews estimated IELT, stopwatch-measured IELT, the correlation between estimated and stopwatch-measured IELT, and the factors affecting IELT in the general male population, PE patients, and those complaining of PE.

[Clinical efficacy of Paroxetine combined with mid-frequency electrical pulse acupoint stimulation for premature ejaculation].

OBJECTIVE: To investigate the clinical value of Paroxetine combined with mid-frequency electrical pulse acupoint stimulation (EPAS) in the treatment of premature ejaculation (PE). METHODS: Totally 69 PE patients were equally assigned to receive oral Paroxetine 20 mg/d, mid-frequency EPAS, or oral Paroxetine 10 mg/d combined with mid-frequency EPAS (P + EPAS) , all for 8 weeks. We obtained the intravaginal ejaculation latency time (IELT) and Chinese Index of Premature Ejaculation (CIPE-5) scores of the patients before and after treatment, and compared adverse reactions among the three groups of patients. RESULTS: One patient of the Paroxetine group gave up treatment because of abdominal pain and nausea. Compared with the baseline, the patients in the Paroxetine, EPAS, and P + EPAS groups all showed markedly increased IELT ([0.92 ± 0.11] vs [4.07 ± 0.11] min, P < 0.01; [0.92 ± 0.12] VS [2.78 ± 0.17] min P < 0.05; [0.91 ± 0.09] vs [5.31 ± 0.13], P < 0.01) and decreased CIPE-5 scores (12.5 ± 3.0 vs 22.0 ± 2.1, P < 0.01; 12.8 ± 2.9 vs 19.5 ± 1.9, P > 0.05; 13.1 ± 2.8 vs 25.2 ± 2.1, P 0.01), with statistically significant differences between the P + EPAS group and the other two (P < 0.05). The total effectiveness rate was 95.7% in the P + EPAS group, remarkably higher than in the Paroxetine (72.7%, P < 0.05) and the EPAS group (47.8, P < 0.01). CONCLUSION: Oral Paroxetine combined with mid-frequency EPAS has a higher safety and efficacy than either Paroxetine or EPAS alone in the treatment of PE.

Novel Digital Mouth Preparation Technique for Fabricating Implant-Retained Removable Partial Dentures with Distal Extension: a Case Report.

Implant-retained removable partial dentures (RPDs) are commonly used to resolve the complications associated with traditional distal extension RPDs; however, this technology does not consider the necessity and importance of parallelism between the path of RPD insertion and the long axis of the implant. This clinical report presents a novel digital preparation technique that involves the preparation of parallel guiding planes on abutment teeth and implant insertion in the distal extension area using a computer-aided design and manufacturing template. This clinical case of implant-retained RPDs illustrates the fabrication and application of the digital template. Using this technique, the path of RPD insertion is parallel to the long axis of the implant. As a result, the components of the implant-retained RPD, including the abutment teeth, implants and attachments, can demonstrate greater longevity.

Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders.

Different fates of neural stem/progenitor cells (NSPCs) and their progeny are determined by the gene regulatory network, where a chromatin-remodeling complex affects synergy with other regulators. Here, we review recent research progress indicating that the BRG1/BRM-associated factor (BAF) complex plays an important role in NSPCs during neural development and neural developmental disorders. Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation, which can also lead to various diseases in humans. We discussed BAF complex subunits and their main characteristics in NSPCs. With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs, we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs. Considering recent progress in these research areas, we suggest that three approaches should be used in investigations in the near future. Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders. More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.

Manifestation and Mechanisms of Abnormal Mineralization in Teeth.

Tooth biomineralization is a dynamic and complicated process influenced by local and systemic factors. Abnormal mineralization in teeth occurs when factors related to physiologic mineralization are altered during tooth formation and after tooth maturation, resulting in microscopic and macroscopic manifestations. The present Review provides timely information on the mechanisms and structural alterations of different forms of pathological tooth mineralization. A comprehensive study of these alterations benefits diagnosis and biomimetic treatment of abnormal mineralization in patients.

Optimization of Lactoferrin-Derived Amyloid Coating for Enhancing Soft Tissue Seal and Antibacterial Activity of Titanium Implants.

A poor seal of the titanium implant-soft tissue interface provokes bacterial invasion, aggravates inflammation, and ultimately results in implant failure. To ensure the long-term success of titanium implants, lactoferrin-derived amyloid is coated on the titanium surface to increase the expression of cell integrins and hemidesmosomes, with the goal of promoting soft tissue seal and imparting antibacterial activity to the implants. The lactoferrin-derived amyloid coated titanium structures contain a large number of amino and carboxyl groups on their surfaces, and promote proliferation and adhesion of epithelial cells and fibroblasts via the PI3K/AKT pathway. The amyloid coating also has a strong positive charge and possesses potent antibacterial activities against Staphylococcus aureus and Porphyromonas gingivalis. In a rat immediate implantation model, the amyloid-coated titanium implants form gingival junctional epithelium at the transmucosal region that resembles the junctional epithelium in natural teeth. This provides a strong soft tissue seal to wall off infection. Taken together, lactoferrin-derived amyloid is a dual-function transparent coating that promotes soft tissue seal and possesses antibacterial activity. These unique properties enable the synthesized amyloid to be used as potential biological implant coatings.

A biomaterial-based therapy using a sodium hyaluronate/bioglass composite hydrogel for the treatment of oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic, inflammatory and potentially malignant oral disorder. Its pathophysiology is extremely complex, including excessive collagen deposition, massive inflammatory infiltration, and capillary atrophy. However, the existing clinical treatment methods do not fully take into account all the pathophysiological processes of OSF, so they are generally low effective and have many side effects. In the present study, we developed an injectable sodium hyaluronate/45S5 bioglass composite hydrogel (BG/HA), which significantly relieved mucosal pallor and restricted mouth opening in OSF rats without any obvious side effects. The core mechanism of BG/HA in the treatment of OSF is the release of biologically active silicate ions, which inhibit collagen deposition and inflammation, and promote angiogenesis and epithelial regeneration. Most interestingly, silicate ions can overall regulate the physiological environment of OSF by down-regulating α-smooth muscle actin (α-SMA) and CD68 and up-regulating CD31 expression, as well as regulating the expression of pro-fibrotic factors [transforming growth factor-ß1 (TGF-ß1), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α) and tissue inhibitors of metalloproteinase-1 (TIMP-1)] and anti-fibrotic factors [interleukin-1ß (IL-1ß)] in macrophage. In conclusion, our study shows that BG/HA has great potential in the clinical treatment of OSF, which provides an important theoretical basis for the subsequent development of new anti-fibrotic clinical preparations. STATEMENT OF SIGNIFICANCE: : Oral submucous fibrosis (OSF) is a chronic, inflammatory and potentially malignant mucosal disease with significant impact on the quality of patients' life. However, the existing clinical treatments have limited efficacy and many side effects. There is an urgent need for development of specific drugs for OSF treatment. In the present study, bioglass (BG) composited with sodium hyaluronate solution (HA) was used to treat OSF in an arecoline-induced rat model. BG/HA can significantly inhibit collagen deposition, regulate inflammatory response, promote angiogenesis and repair damaged mucosal epithelial cells, and thereby mitigate the development of fibrosis in vivo.

[Effects of down-regulation of CC chemokine ligand 5 (CCL5) on proliferation of human breast cancer cells in vitro].

OBJECTIVE: To investigate the effect of suppression of CCL5 ligand gene on the proliferation of human breast cancer cells. METHODS: A lentiviral vector carrying a short interfering RNA (siRNA) targeting CCL5 was transfected into human breast cancer cell line MCF-7 and MDA-MB-231 cells. The expression of CCL5 mRNA in the cells was detected by real-time PCR. The proliferation of MCF-7 and MDA-MB-231 cells was assessed by MTT assay and FACS assay, and the colony formation ability of both cell lines were measured, respectively. RESULTS: Real time PCR showed a good knockdown effect of CCL5 in both cell-lines. Colony-forming assay showed that the ability of colony formation of MCF-7/CCL5-siRNA and MDA-MB-231/CCL5-siRNA was decreased markedly. The colony number of MCF-7/CCL5-siRNA group was (0.34 ± 0.08), significantly lower than 0.81 ± 0.12 in the MCF-7/CCL5-N group and 0.92 ± 0.12 in the MCF-7 group (P < 0.05). The colony number of MDA-MB-231/CCL5-siRNA group was 0.33 ± 0.10, significantly lower than 0.97 ± 0.09 in the MDA-MB-231/CCL5-N group and 1.04 ± 0.07 in the MDA-MB-231 group (P < 0.05). However, MTT assay revealed that the proliferation of MCF-7/CCL5-siRNA cells was not significantly different from that of MCF-7/CCL5-N or MCF-7 cells, respectively (P > 0.05), and the same result was found in MDA-MB-231 cells. FACS assay showed that the proliferation index (PI) of groups MCF-7/CCL5-siRNA, MCF-7/CCL5-N and MCF-7 were 0.48 ± 0.03, 0.43 ± 0.01 and 0.45 ± 0.02. The PI of groups MDA-MB-231/CCL5-siRNA, MDA-MB-231/CCL5-N and MDA-MB-231 cells were 0.48 ± 0.02, 0.44 ± 0.05 and 0.47 ± 0.02. There was no statistical difference among them (P > 0.05). CONCLUSION: The down-regulation of CCL5 gene in human breast cancer cells may significantly suppress their colony formation ability, rather than affecting their population doubling time to some extent.

White Blood Cell Counts to High-Density Lipoprotein Cholesterol Ratio, as a Novel Predictor of Long-Term Adverse Outcomes in Patients After Percutaneous Coronary Intervention: A Retrospective Cohort Study.

Background: White blood cell (WBC) counts and high-density lipoprotein cholesterol (HDL-C) are widely available in clinical practice. However, the predictive value for cardiovascular disease (CVD) is uncertain. In the present study, we firstly assessed the prognostic value of WBC to HDL-C ratio (WHR) in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI). Methods: Six thousand and fifty patients with CAD after PCI from a retrospective cohort study (identifier: ChiCTR-INR-16010153) were evaluated initially. Three hundred and seventy-one patients were excluded due to HDL cholesterol data not available, malignancy, dementia, psoriasis or eczema, systemic connective tissue disorders, multiple sclerosis, chronic liver disease, and chronic obstructive pulmonary disorder. Finally, 5,679 patients were included in the study. The primary outcome was long-term mortality. Secondary endpoints were mainly major adverse cardiovascular and cerebrovascular events (MACCEs), defined as a combination of stroke, cardiac death, stent thrombosis, recurrent myocardial infarction, and target vessel revascularization. The mean follow-up time of this study was 35.9 ± 22.5 months. We defined the best cutoff value of MHR according to the receiver operating curve (ROC), and then patients were divided into high and low WHR groups according to the cutoff value. We analyzed the data in both an acute coronary syndrome group (ACS) and a stable CAD subgroup, respectively. Results: Overall, there were 293 cases of long-term mortality during the follow-up period. According to the cutoff value (WHR = 8.25), 1,901 ACS patients were divided into high WHR group (n = 724) and low WHR group (n = 1,177). Compared to low WHR group, the incidence of all-cause mortality (ACM, 5.5 vs. 3.6%, p = 0.048) and cardiac death (4.7vs. 2.9%, p = 0.042) were significantly higher in the high WHR group. In stable CAD group, we also found the incidence of ACM and cardiac death were significantly higher in the high group compared to that in the low group. We did not find significant difference between the high and the low WHR group in the incidence of MACCEs. The multivariate Cox proportional hazards model showed that increased WHR level was independently correlated with the mortality. In the high WHR group, the risk of ACM increased two times in ACS [adjusted HR = 2.036 (1.258-3.296), p = 0.004] and 1.5 times in stable CAD [adjusted HR = 1.586 (1.178-2.136), p = 0.002]. Conclusion: The present study indicated that an increased WBC count to HDL-C ratio was independently associated with long-term mortality in CAD patients who underwent PCI.

Conditional deletion of Adrb2 in mesenchymal stem cells attenuates osteoarthritis-like defects in temporomandibular joint.

ß2-adrenergic signal transduction in mesenchymal stem cells (MSCs) induces subchondral bone loss in osteoarthritis (OA) of temporomandibular joints (TMJs). However, whether conditional deletion of ß2-adrenergic receptor (Adrb2) in nestin+ MSCs can alleviate TMJ-OA development remains unknown. In this study, nestin-Cre mice were crossed with Adrb2 flox mice to generate mice lacking Adrb2 expression specifically in the nestin+ MSCs (Adrb2-/-), and TMJ-OA development in such mice was investigated. Adrb2 flox mice (Adrb2+/+) and Adrb2-/- mice were subjected to unilateral anterior crossbite (UAC), while mice in the control group were subjected to sham operation. Adrb2+/+ and Adrb2-/- mice in the control group showed no distinguishable phenotypic changes in body weight and length, mandibular condylar size, and other histomorphological parameters of the condylar subchondral bone. A significant increase in subchondral bone loss and cartilage degradation was observed in Adrb2+/+ UAC mice; the former was characterized by decreased bone mineral density, bone volume fraction, and trabecular plate thickness, and increased trabecular separation, osteoclast number and osteoclast surface, and pro-osteoclastic factor expression; the latter was characterized by decreased cartilage thickness, chondrocyte density, proteoglycan area, and collagen II and aggrecan expression, but increased matrix metalloproteinase and alkaline phosphatase expression and percentage area of calcified cartilage. Adrb2 deletion in nestin+ MSCs largely attenuated UAC-induced increase in condylar subchondral bone loss, cartilage degradation, and aberrant calcification at the osteochondral interface. Thus, Adrb2-expressing MSCs in the condylar subchondral bone play an important role in TMJ-OA progression and may serve as novel therapeutic targets for TMJ-OA.

Gut Microbiome-Based Diagnostic Model to Predict Coronary Artery Disease.

In the present study, we aimed to characterize gut microbiome and develop a gut microbiome-based diagnostic model in patients with coronary artery disease (CAD). Prospectively, we collected 309 fecal samples from Central China and Northwest China and carried out the sequencing of the V3-V4 regions of the 16S rRNA gene. The gut microbiome was characterized, and microbial biomarkers were identified in 152 CAD patients and 105 healthy controls (Xinjiang cohort, n = 257). Using the biomarkers, we constructed a diagnostic model and validated it externally in 34 CAD patients and 18 healthy controls (Zhengzhou cohort, n = 52). Fecal microbial diversity was increased in CAD patients compared to that in healthy controls (P = 0.021). Phylum Bacteroidetes was increased in CAD patients versus healthy controls (P = 0.001). Correspondingly, 48 microbial markers were identified through a 10-fold cross-validation on a random forest model, and an area under the curve (AUC) of 87.7% (95% CI: 0.832 to 0.916, P < 0.001) was achieved in the Xinjiang cohort (development cohort, n = 257). Notably, an AUC of 90.4% (95% CI: 0.848 to 0.928, P < 0.001) was achieved using combined analysis of gut microbial markers and clinical variables. This model provided a robust tool for the prediction of CAD. It could be widely employed to complement the clinical assessment and prevention of CAD.

[Methods of removing failed implants].

Implant restoration has become one of the most regular methods of restoring dentition defect or edentulous. Implant placement and osseointegration are partly unreserved (fracture, implant is not in the correct three-dimensional position and cannot be repaired, peri-implantitis-affected nonmobile implants) need to be removed. This article reviews the different methods of removing implants and discusses the limitations of each method, as well as the complications that may occur during the procedure.