The Impact of the Restoration of Invisible Orthodontic Titanium Alloy Implant Without Bracket on Individuals Afflicted with Dental Malocclusion and Arch Deficiency Accompanied by Periodontitis and a Local Periodontal Inflammation.

Objective: To investigate the impact of the restoration of non-bracket invisible orthodontic titanium alloy implant on individuals with dental malocclusion and arch deficiency accompanied by periodontitis and local periodontal Inflammation. Method: A cohort of 120 patients presenting with dental malocclusion and defects compounded by periodontitis, were treated at our institution between January 2021 and January 2022; these patients were enrolled in a randomized controlled trial.. These patients were allocated into two groups. The control group (comprising 60 cases) underwent titanium alloy implant restoration, while the research group (also with 60 cases) received titanium alloy implant restoration following invisible orthodontic treatment without brackets. A one-year post-treatment follow-up was conducted, during which various parameters, including pain levels, aesthetic improvement, inflammatory response, dental function, oral hygiene, and the incidence of adverse events, were evaluated and compared before and after treatment between the two groups. Results: After six months of treatment, the visual analog scale (VAS) in the study group was lower than that in the control group (P < .05). After 6 months of treatment, the research team observed the changes in gingival crevicular interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), Interleuckin-1 (IL-1), plaque index (PLI), and soft dirt index (DI) were all lower than those in the control group (P < .05). After 6 months of treatment, the research group had higher scores for tooth functions such as chewing, swallowing, speech expression, and occlusion than the control group, as well as higher pink and white aesthetics indexes (P < .05). The difference in the incidence rate of adverse outcomes between the research and control group was not distinct (P > .05). Conclusion: In case of dental malocclusion accompanied by periodontal disease, the utilization of titanium implants for rectifying dental arch deformities without the use of orthodontic brackets, devoid of orthodontic brackets, has demonstrated notable efficacy in alleviating patients' periodontal discomfort, their oral hygiene, and dental functionality. This modality is conducive to augmenting dental aesthetics without incurring heightened rates of unfavorable consequences, thereby enhancing treatment outcomes.

[Imaging measurement and analysis of related indexes of variation of femoral head rotation center].

OBJECTIVE: To provide guidance for hip replacement by analyzing the variation of femoral head rotation center in different hip diseases. METHODS: A total of 5 459 patients were collected from March 2016 to June 2021, who took positive and proportional plain films of both hips for various reasons. The relative position between the rotation center of the femoral head and the apex of the greater trochanter was measured. The positive variation is more than 2 mm above the top of the great trochanter, and the negative variation is more than 2 mm below the top of the great trochanter. A total of 831 patients with variation of femoral head rotation center were collected and were divided into 4 groups according to different diseases, and the variation was counted respectively. There were 15 cases in the normal group involving 10 cases of positive variation and 5 cases of negative variation. There were 145 cases of avascular necrosis of femoral head involving 25 cases of positive variation and 120 cases of negative variation. There were 346 cases of congenital hip dysplasia involving 225 cases of positive variation(including 25 cases of typeⅠ, 70 cases of type Ⅱ, 115 cases of type Ⅲ and 15 cases of type Ⅳ), and 121 cases of negative variation(including 50 cases of crowe typeⅠ, 60 cases of typeⅡ, 10 cases of type Ⅲ and 1 case of type Ⅳ). There were 325 cases of hip osteoarthritis group involving 45 cases of positive variation and 280 cases of negative variation. RESULTS: There was significant difference in variation of femoral head rotation center among the four groups(P<0.05). There was significant difference in variation of femoral head rotation center among different types of congenital hip dysplasia(P<0.05). There were significant differences in cervical trunk angle and eccentricity among different variations of femoral head rotation center(P<0.05). CONCLUSION: The variation of femoral head rotation center is related to cervical trunk angle and eccentricity. The variation of femoral head rotation center is an important factor in hip diseases. The variation of femoral head rotation center is different in different hip diseases. Avascular necrosis of the femoral head and osteoarthritis of the hip were mostly negative variations. With the aggravation of congenital hip dysplasia, the variation of femoral head rotation center gradually changed from negative variation to positive variation.The variation of femoral head rotation center should be paid attention to in the preoperative planning of hip arthroplasty. It is of great significance to select the appropriate prosthesis and place the prosthesis accurately.

Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design.

Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors. Generative models that take advantage of deep learning are being increasingly integrated into early drug discovery for hit identification and lead optimization. Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 (23) accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 (23) demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration.

Treatment effects and periodontal status of chronic periodontitis after routine Er:YAG laser-assisted therapy.

BACKGROUND: Routine preclinical interventions for patients with chronic periodontitis such as supragingival cleaning and subgingival curettage, establishing a balanced occlusal relationship, and irrigation with 3% hydrogen peroxide can relieve the symptoms to some extent. However, there is room for improvement in the overall effect. For example, Er:YAG lasers can quickly increase the temperature of the irradiated tissue, effectively eliminate dental plaque and calculus, reduce periodontal pockets, adjust periodontal microecology, and reduce the gingival sulcus. The content of factors in the liquid, and then achieve the purpose of treatment. AIM: The aim was evaluate the effect of Er:YAG laser-assisted routine therapy on the periodontal status in chronic periodontitis. METHODS: Between October 2018 and January 2020, 106 patients with chronic periodontitis in our hospital were randomly assigned to either the study or control group, with 53 patients in each group. The control group underwent routine therapy, and the study group underwent Er:YAG laser therapy in addition to routine therapy. We evaluated the treatment outcome in both groups. Periodontal status was determined by clinical attachment loss (CAL), gingival index (GI), periodontal probing depth (PD), dental plaque index (PLI), and sulcular bleeding index (SBI), inflammatory factors in the gingival crevicular fluid, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8], and colony forming units (CFUs). RESULTS: Total effectiveness in the study group (94.34%) was higher than that in the control group (79.25%, P < 0.05). The clinical parameters in the study group (PD, 5.28 ± 1.08 mm; CAL, 4.81 ± 0.79 mm; SBI, 3.37 ± 0.59; GI, 1.38 ± 0.40; PLI, 2.05 ± 0.65) were not significantly different from those in the control group (PD, 5.51 ± 1.14 mm; CAL, 5.09 ± 0.83 mm; SBI, 3.51 ± 0.62; GI, (1.41 ± 0.37; PLI, 1.98 ± 0.70) before treatment (P > 0.05). However, after treatment, the parameters in the study group (PD, 2.97 ± 0.38 mm; CAL, 2.71 ± 0.64 mm; SBI, 2.07 ± 0.32; GI, 0.51 ± 0.11; PLI, 1.29 ± 0.34) were lower than those in the control group (PD, 3.71 ± 0.42 mm; CAL, 3.60 ± 0.71 mm; SBI, 2.80 ± 0.44; GI, 0.78 ± 0.23; PLI, 1.70 ± 0.51) (P < 0.05). Differences in crevicular TNF-α, IL-6, and IL-8 levels in the study (TNF-α, 7.82 ± 3.43 ng/mL; IL-6, 11.67 ± 2.59 ng/mL; IL-8, 12.12 ± 3.19 pg/mL) and control groups (TNF-α, 9.06 ± 3.89 ng/ml, IL-6, 12.13 ± 2.97 ng/mL, IL-8, 10.99 ± 3.30 pg/mL) before therapy (P > 0.05) were not significant. Following treatment, the parameters were significantly lower in the study group (TNF-α, 2.04 ± 0.89 ng/mL; IL-6, 4.60 ± 1.26 ng/mL; IL-8, 3.15 ± 1.08 pg/mL) than in the control group (TNF-α, 3.11 ± 1.07 ng/mL; IL-6, 6.25 ± 1.41 ng/mL; IL-8, 4.64 ± 1.23 pg/mL, P < 0.05). The difference in the CFU of the study group [(367.91 ± 74.32) × 104/mL and control group (371.09 ± 80.25) × 104/mL] before therapy was not significant (P > 0.05). The CFU decreased in both groups following therapy, however, the CFU values were lower in the study group [(36.09 ± 15.26) × 104/mL] than in the control group [(45.89 ± 18.08) ×104/mL] (P < 0.05). CONCLUSION: Combining Er:YAG lasers with routine measures significantly improved the overall periodontal therapy outcomes by improving periodontal status and reducing oral levels of inflammatory factors and CFUs.

Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT).

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides an indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In the search for structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC50 values as low as 229 nM. The peptides were also found to downregulate MNA production in cellular assays. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.

Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity.

A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.

Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics.

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.

Nicotinamide N-methyl transferase (NNMT): An emerging therapeutic target.

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (NA) to generate 1-methyl nicotinamide. Since its discovery 70 years ago, the appreciation of the role of NNMT in human health has evolved from serving only metabolic functions to also being a driving force in diseases, including a variety of cancers. Despite the increasing evidence indicating NNMT as a viable therapeutic target, the development of cell-active inhibitors against this enzyme is lacking. In this review, we provide an overview of the current status of NNMT inhibitor development, relevant in vitro and in vivo studies, and a discussion of the challenges faced in the development of NNMT inhibitors.

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity.

Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme's active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π-π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 µM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral cancer cell line.