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It is necessary to develop a low temperature process that can deposit and pattern metal on a heat sensitive substrate because most flexible printed electronics use high temperature sensitive materials such as plastic. The most commonly used photolithography process is not suitable for flexible printed electronics because the high temperature thermal treatment process and chemicals are not compatible with plastic. Recently research has been actively conducted on a method of minimizing thermal damage to plastic and high-resolution metal patterning by using selective laser sintering after forming a liquid metal nanoparticle thin film without using existing photolithography and vacuum deposition. In this review paper, we explore flexible printed electronics such as flexible thin film transistors and flexible transparent conductors using selective laser sintering of nanomaterials and discuss future development directions.

Purpose: This narrative review aims to explore the current status of facial scanning technology in the dental field; outlining the history, mechanisms, and current evidence regarding its use and limitations within digital dentistry. Methods: Subtopics within facial scanner technology in dentistry were identified and divided among four reviewers. Electronic searches of the Medline (PubMed) database were performed with the following search terms: facial scanner, dentistry, prosthodontics, virtual patient, sleep apnea, maxillofacial prosthetics, accuracy. For this review only studies or review papers evaluating facial scanning technology for dental or medical applications were included. A total of 44 articles were included. Due to the narrative nature of this review, no formal evidence-based quality assessment was performed and the search was limited to the English language. No further restrictions were applied. Results: The significance, applications, limitations, and future directions of facial scanning technology were reviewed. Specific subtopics include significant history of facial scanner use and development for dentistry, different types and mechanisms used in facial scanning technology, accuracy of scanning technology, use as a diagnostic tool, use in creating a virtual patient, virtual articulation, smile design, diagnosing and treating obstructive sleep apnea, limitations of scanning technology, and future directions with artificial intelligence. Conclusions: Despite limitations in scan quality and software operation, 3D facial scanners are rapid and non-invasive tools that can be utilized in multiple facets of dental care. Facial scanners can serve an invaluable role in the digital workflow by capturing facial records to facilitate interdisciplinary communication, virtual articulation, smile design, and obstructive sleep apnea diagnosis and treatment. Looking into the future, facial scanning technology has promising applications in the fields of craniofacial research, and prosthodontic diagnosis and treatment planning.

The impact of discrepancies between casts produced from digital scans and conventional impressions on the clinical performance of definitive restorations has not been fully investigated.The purpose of this crossover clinical trial was to evaluate the clinical performance of single implant-supported restorations fabricated with the digital scanning technique and computer-aided design and computer-aided manufacturing (CAD-CAM) casts compared with the conventional impression technique and gypsum casts in terms of efficiency, accuracy, and participant preference.Thirty participants underwent conventional impressions and digital scans of a single implant-supported restoration. Two crowns were fabricated for the same implant with each technique. The time taken for each procedure was recorded. After the accuracy and efficiency analysis of both crowns, the better crown was delivered. A questionnaire was used to assess participant preference and comfort with the techniques. The Wilcoxon signed-rank test was used to compare the time measurements, and multiple comparisons were performed using the Bonferroni method. The chi-square test was used to compare the implant locations of delivered crowns (α=.05).The total time for the conventional impression technique was 14.16 minutes, while that for the digital scanning technique was significantly less at 11.28 minutes (P.001). Remake times were 0.56 minutes for conventional impressions and 2.27 for digital scans, also significantly different (P.001). The adjustment time taken in delivering the crowns was 4.35 minutes for conventional impressions and 3.78 minutes for conventional impressions, which was not statistically significant (P=.940). Of the crowns chosen for delivery, 46.7% were from conventional impressions and 53.3% from digital scans. Participants preferred the digital scanning technique (89%) to the conventional impression technique (11%).The digital scanning technique was more efficient than the conventional impression technique for single implant-supported restorations. Digital scans and CAD-CAM implant casts had accuracy comparable with that of conventional impressions and gypsum casts. Most participants preferred digital scans to conventional impressions.

Ceramide-containing phospholipids improve skin hydration and barrier function and are ideal for use in skin care products. In this study, we evaluated the photoprotective effect of milk phospholipids on the skin condition of UVB-irradiated hairless mice. Skin parameters were assessed following oral administration of milk phospholipids. The UVB irradiation induced photoaging in mice. The animals were divided into 5 groups: a control group (oral administration of saline with no UBV irradiation), UVB group (oral administration of saline with UVB irradiation), and 3 UVB irradiation groups receiving the milk phospholipids at 3 different concentrations of oral administration, 50 mg/kg (ML group), 100 mg/kg (MM group), and 150 mg/kg (MH group), for 8 wk. An increase in skin hydration and transepidermal water loss were improved in the 150 mg/kg of milk phospholipid-administered group. Hematoxylin and eosin staining revealed a decrease in epidermal thickness in the milk phospholipid-administered groups (50, 100, and 150 mg/kg of body weight). In particular, the 100 and 150 mg/kg groups showed significant changes in the area, length, and depth of the wrinkles compared with the UVB group. Moreover, the gene expression of matrix metalloproteins was attenuated, and that of proinflammatory cytokines, especially tumor necrosis factor-α, was significantly reduced in the milk phospholipid-administered groups than in the UVB group. The reduced ceramide and increased sphingosine-1-phosphate levels in the skin tissue due to UVB exposure were restored to levels similar to those of the control group following milk phospholipid administration. These results were confirmed to be due to the downregulation of protein expression of nuclear factor kappa-B (NF-κB) and phosphorylated IκB-α (inhibitor of κB α). Collectively, oral administration of milk phospholipids improves skin health through a synergistic effect on photoprotective activity.

Invasive candidiasis has high mortality rates in immunocompromised patients, causing serious health problems. In mouse models, innate immunity protects the host by rapidly mobilizing a variety of resistance and tolerance mechanisms to systemic Candida albicans infection. We have previously demonstrated that exogenous IL-33 regulates multiple steps of innate immunity involving resistance and tolerance processes. In this study, we systematically analyzed the in vivo functions of endogenous IL-33 using Il33−/− mice and in vitro immune cell culture. Tubular epithelial cells mainly secreted IL-33 in response to systemic C. albicans infection. Il33−/− mice showed increased mortality and morbidity, which were due to impaired fungal clearance. IL-33 initiated an innate defense mechanism by costimulating dendritic cells to produce IL-23 after systemic C. albicans infection, which in turn promoted the phagocytosis of neutrophils through secretion of GM-CSF by NK cells. The susceptibility of Il33−/− mice was also associated with increased levels of IL-10, and neutralization of IL-10 resulted in enhanced fungal clearance in Il33−/− mice. However, depletion of IL-10 overrode the effect of IL-33 on fungal clearance. In Il10−/− mouse kidneys, MHC class II+F4/80+ macrophages were massively differentiated after C. albicans infection, and these cells were superior to MHC class II−F4/80+ macrophages that were preferentially differentiated in wild-type mouse kidneys in killing of extracellular hyphal C. albicans. Taken together, our results identify IL-33 as critical early regulator controlling a serial downstream signaling events of innate defense to C. albicans infection.

Uric acid (2,6,8-trihydroxypurine) is a metabolic product of purine, which is one of the important markers of human health. The development of a rapid, facile, highly sensitive, and selective method for uric acid detection is critical for the diagnosis of related diseases and is still a strategic challenge. In this study, we developed a highly sensitive and selective colorimetric assay for the detection of uric acid using biogenic palladium nanoparticles (Pd NPs). The synthesized nanoparticles were shown to acquire peroxidase mimetic activity that oxidized 3,3',5,5'-tetramethylbenzidine and produced a blue colour in an assay. The developed colorimetric assay is instrument-free detection of uric acid with a limit of detection of 0.05 μM and a 1.11 μM limit of quantification (LOQ). This is the first report determining the LOQ for a colorimetric assay that gives the lowest quantity of analyte that can be evaluated with more precision under the specified conditions of the analysis. The developed assay had a linear response at low uric acid concentrations of 0.05 to 1 μM and a 0.99841 linear regression correlation coefficient. This colorimetric detection provides a rapid, cost-effective, and easy-to-use platform for the clinical diagnosis of uric acid biomarkers.

The aim of this clinical study was to investigate the change in occlusal vertical dimension (OVD) with dental casts mounted on a mechanical articulator using an average axis facebow and on a virtual articulator mounted using the Bonwill triangle and the Balkwill angle and compare these groups with OVD change observed clinically in patients. Casts were obtained from each patient (n = 14) and mounted on a semi-adjustable articulator in the facebow preservation group (FPG) and on a virtual articulator using average anatomic values in the average mounting group (AMG). Customized mandibular anterior splints were virtually designed at an OVD increased by 3, 6, and 9 mm. Digital buccal scans were performed with the anterior devices in the participants’ mouths in the intraoral group (IOG), AMG, and FPG at the different OVD increases accordingly. While no statistically significant differences (p > 0.05) were observed in the posterior interocclusal measurements with the incisal guide pin raised by 3 mm and 6 mm among all groups, a 9 mm increase resulted in a significant difference between AMG and IOG. The interocclusal posterior-to-anterior opening ratio observed clinically was 1:1.575. Increases in OVD up to 6 mm on dental casts mounted using average anatomic values performed similarly to the actual intraoral changes.

The restoration of dental implants presents a unique challenge due to the intrinsic biomechanical differences between osseointegrated implants and natural teeth, and their subsequent responses to occlusal loading. However, controversy exists regarding the role that occlusion plays in the physiology of the peri-implant complex.To provide an overview of the scientific literature regarding occlusion as it relates to implant dentistry and peri-implant disease.This article presents a narrative review on occlusal loading and its potential effects on the peri-implant complex, as well as some generally accepted guidelines for occlusion in implant dentistry.Although there is strong evidence linking occlusal factors to mechanical complications of dental implants, the same cannot be said regarding biological complications. There is no clear scientific evidence on the relationship between occlusal overload and peri-implant disease. However, occlusal overload may be an accelerating factor for peri-implant disease in the presence of inflammation. As the biomechanical properties of dental implants differ from that of the natural dentition, modifications to classic concepts of occlusion may be necessary when dental implants are involved. Thus, clinical recommendations are proposed which function to minimize unfavorable occlusal forces on implant restorations and reduce the associated biological and mechanical complications.

Dental fluorosis is a common disorder caused by excessive fluoride intake during tooth development. The esthetic consequences of dental fluorosis can negatively affect oral health-related quality of life and have lasting psychosocial effects. In severe cases, where the fluorosed enamel is prone to chipping, flaking, and developing caries, minimally invasive procedures are ineffectual and a more substantial restorative approach is required to restore optimal function and esthetics. However, no definitive guidelines exist for the management and treatment of severe dental fluorosis due to the limited evidence available in the literature. This case report describes the full-mouth rehabilitation of a patient with severe dental fluorosis utilizing adhesively bonded all-ceramic crowns, veneers, and overlays. The successful follow-up on this case indicates that adhesively bonded restorations may provide a viable option in the functional and esthetic management of severely fluorosed dentition.

The use of digital interocclusal registration scans for virtual articulation and mounting has been studied extensively; however, the accuracy of the cross-mounting procedures in a digital workflow is not well understood.The purpose of this in vitro study was to compare the accuracy of digital and conventional cross-mounting by measuring the 3-dimensional deviation at each step of sequential cross-mounting.A set of reference casts and complete-arch interim restorations was prepared for complete-arch complete-coverage restorations, hand-articulated, and mounted in an articulator. The reference casts were then scanned with and without the interim restorations to generate 4 reference casts for cross-mounting. For the conventional group, 15 sets of the 4 casts were printed. Polyvinyl siloxane interocclusal registration records were made of the reference casts for each set, and casts were sequentially cross-mounted. For the digital workflow, 15 sets of bilateral interocclusal registration scans were made of the mounted reference casts and used to align the cast scans. Three-dimensional deviations at 2 anterior and 2 posterior points were recorded between the experimental mountings and the reference casts on each set of casts. Nonpaired t test and analysis of variance (ANOVA) were used to compare the average discrepancy between the 2 groups, and the pooled anterior versus posterior discrepancies were compared (α=.05).A significant difference was found between conventional and digital cross-mounting procedures (P.001), but no significant difference was found in either group, conventional (P=.116) or digital (P=.987), at each step of the sequential mountings. The mean ±standard deviation at the final set of related casts in the conventional workflow was 201.6 ±137.0 μm and that in the digital group was 50.3 ±47.5 μm, with a significant difference between anterior and posterior deviations in the digital group (P=.028), but not in the conventional group (P=.143). The mean ±standard deviation anterior conventional deviation was 175.6 ±119.2 μm and that in the digital group was 36.9 ±30.9 μm. The mean ±standard deviation posterior conventional deviation was 227.6 ±50.2 μm and that in the digital group was 63.7 ±57.2 μm.Digital cross-mounting was more accurate than conventional cross-mounting, although increased deviation was found in the anterior region compared with the posterior region.

Protein tyrosine phosphatases (PTPs) have an emerging paradigm for the development of antidiabetic drugs. Herein, we provide a comprehensive overview of the relevance of PTPs to type 2 diabetes (T2D) and the therapeutic opportunities thereof, while critically evaluating the potential challenges for PTP inhibitors to be next generation antidiabetics. This review briefly discusses the structure and function of PTPs. An account of importance and relevance of PTPs in various human diseases is presented with special attention to diabetes. The PTPs relevant to T2D have been targeted by small molecule inhibitors such as natural products and synthetic compounds as well as antisense nucleic acids. This review will give better understanding of the important concepts helpful in outlining the strategies for the development of new therapeutic agents with promising antidiabetic activities.

[Image: see text] As the spread of infections caused by hepatitis B virus (HBV) threatens public health worldwide, investigations from multiple perspectives and of various mechanisms of action are urgently required to increase the HBV cure rate. Targeting the encapsidation of the nuclear capsid protein (core protein, HBc) has emerged as an attractive strategy for inhibiting the viral assembly process; however, a drug targeting this mechanism has not yet been approved. We synthesized novel sulfamoylbenzamides (SBAs) as capsid assembly modulators of HBV and found that the effects and safety profiles of compounds 3 and 8 have potential therapeutic applicability against HBV. The formation of tubular particles was time-dependent in the presence of 3, indicating a new mode of protein assembly by SBA compounds. Our findings provide a new entity for developing safe and efficient treatments for HBV infection.

Qualitative analysis of cucurbitane-type triterpenoids of bitter melon (fruit of Momordica charantia L.) using ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry revealed 27 promising cucurbitane-type triterpenoids, and LC/MS-guided chemical analysis of M. charantia fruit extract led to the isolation and structural characterization of 22 cucurbitane-type triterpenoids (1-22), including 8 new cucurbitane-type triterpenoidal saponins, yeojoosides A-H (1-8). The structures of the new compounds (1-8) were elucidated by spectroscopic methods, including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry. Their absolute configurations were assigned by quantum chemical electronic circular dichroism calculations, chemical reactions, and DP4+ analysis using gauge-including atomic orbital NMR chemical shift calculations. All isolated compounds (1-22) were examined for inhibitory activity against protein tyrosine phosphatases relevant to insulin resistance. Nine compounds (7, 8, 9, 11, 14, 15, 19, 20, and 21) showed selective inhibitory effects of over 70% against PTPN2. The present results suggested that these compounds would be potential antidiabetic agents.

The spin Seebeck effect (SSE) refers to a direct energy conversion of heat to electricity that exploits magnon current in a ferromagnet (FM)/normal metal (NM) heterostructure. Since SSE is a transverse thermoelectric effect, it can be employed to realize transverse thermoelectric devices, which could potentially overcome the inherent limitations of conventional Seebeck effect-based devices. Yet, the widespread use of SSE is currently hindered by its low conversion efficiency. The thermoelectric efficiency of SSE can be improved through an optimization of bulk FM as well as FM/NM interface. A bulk FM can enhance the thermoelectric efficiency by introducing a ‘phonon-glass magnon-crystal’ concept, wherein scattering centers selectively scatter the heat-carrying phonons while not affecting the magnons that contribute to SSE. A high-quality FM/NM interface can boost the spin pumping across the interface as well as the electrical transport in NM. Here, by adopting polycrystalline nickel-ferrite (NFO)/Pt as a platform, we demonstrate the successful optimization of bulk FM together with FM/NM interface via a simple heat treatment scheme. The phase separation of NFO via such heat treatment results in a distinctive hierarchical microstructure of nano-sized NFO embedded in micro-sized NiO precipitates; this structure selectively scatters phonons while barely affecting magnons, leading to reduced thermal conductivity without variation of spin Seebeck coefficient. The simultaneous formation of a clean and smooth NFO/Pt interface provides efficient spin pumping at the interface and high electrical conductivity of Pt. As a result, the energy conversion efficiency of SSE in NFO/Pt system can be significantly improved. The proposed facile approach can be applied to design highly efficient oxide-based SSE devices.

Background/purpose There is limited literature on the materials of choice and their properties when repairing 3-D printed resin-based restorations. The objective of this in-vitro study is to determine the shear bond strength of various repair materials to 3D printed SLA (stereolithography) resin. Materials and methods For Group A (control), fifteen cylinders of 3-D printing SLA resin were printed as one unit of a O6.8 × 8 mm (diameter and height) cylindrical block with a O3 × 5 mm cylindrical block at the center. For the test groups, forty-five specimen cylinders of 3-D printing SLA resin (O6.8 × 8 mm) were fabricated and the surfaces were treated with 3 different test materials: Group B: Poly-Methyl Methacrylate (PMMA); Group C: Bis-acrylic composite resin, and Group D: Bis-GMA composite All specimens were tested using an Instron machine at a crosshead speed of 0.5 mm/min. A Shapiro–Wilk test was used to assess normality within the data, then the data was statistically analyzed by a Mann–Whitney test. Results There were no statistically significant differences between testing groups, except Group A. Group B displayed mixed (87%) and adhesive (13%) failure at the fractured surface. Group C showed both mixed (60%) and adhesive failure at the fractured surface (40%). All Group D showed mixed fracture patterns, partly cohesive fractured surface within the base cylinder area and partly adhesive fractured surface at the bonded interface. Conclusion No statistically significant differences in the shear bond strength of the different repair materials to 3D printed cylinders were observed. The 3D printed cylinder repaired with Bis-GMA composite demonstrated the most predictability from the fractography analysis.

The protein p73 acts as a transcription factor, resulting in tumour suppression. MDM2, an oncogenic protein, can negatively influence p73-mediated apoptosis by binding to p73 transactivation domains (TAD). Inhibition of the protein-protein interaction between p73 and oncogenic proteins is an attractive strategy for promoting p73-mediated apoptosis. Herein, we describe the use of a modified p73-TAD peptide for the FRET-based assay of the binding of p73-TAD to MDM2. The FRET probe, equipped with 1-naphthylamine (λex =330 nm, λem =445 nm), serves as a FRET acceptor, and the tryptophan of the protein acts as FRET donor (λex =280 nm, λem =340 nm). Sensitized emission from the FRET probe was observed upon excitation of the protein-FRET-probe complex at the excitation wavelength of Trp. Furthermore, addition of the MDM2 inhibitor Nutiln-3 drastically reduced the FRET signal, thus indicating that the FRET probe competes with Nutiln-3 for MDM2 binding. The developed FRET binding assay might be applicable in high-throughput screening of novel drugs that inhibit interactions between p73 and MDM2.

There has been an increase in utilizing 3D printers in dental restorations. The purpose of the study is to compare mechanical properties of 3D-printed prostheses to those of self-cured and/or computer-aided design-computer-aided manufacturing (CAD-CAM) restorations. A metal master typodont was prepared for the mandibular left sextant with implant analogs embedded at the first premolar and first molar positions with a missing second premolar. Three-unit provisional fixed dental prosthesis (FDP) was designed utilizing the 3Shape tooth library and forty-five uniform specimens were fabricated with different materials: self-cured poly(methyl methacrylate) (PMMA) (N = 15), milled PMMA CAD-CAM blocks (N = 15) and 3D-printed resin (N = 15). All specimens were tested using an Instron machine at a crosshead speed of 0.5 mm/min by an axial load on the occlusal surface of the second premolar pontic site. Statistical analysis was completed with Shapiro-Wilk, ANOVA and Tukey post-hoc tests. Mean fracture force was 300.61 N, 294.64 N and 408.49 N for self-cured PMMA, milled PMMA and 3D-printed resin, respectively. Mean force at FDP fracture of 3D-printed resin was significantly greater than the mean fracture force of either self-cured (p = 0.016, 95% CI [17.86, 197.91]) or milled (p = 0.010, 95% CI [23.83, 203.88]) PMMA.

The accurate diagnosis of individual tooth prognosis has to be determined comprehensively in consideration of the broader treatment plan. The objective of this study was to establish an effective artificial intelligence (AI)-based module for an accurate tooth prognosis decision based on the Harvard School of Dental Medicine (HSDM) comprehensive treatment planning curriculum (CTPC). The tooth prognosis of 2359 teeth from 94 cases was evaluated with 1 to 5 levels (1—Hopeless, 5—Good condition for long term) by two groups (Model-A with 16, and Model-B with 13 examiners) based on 17 clinical determining factors selected from the HSDM-CTPC. Three AI machine-learning methods including gradient boosting classifier, decision tree classifier, and random forest classifier were used to create an algorithm. These three methods were evaluated against the gold standard data determined by consensus of three experienced prosthodontists, and their accuracy was analyzed. The decision tree classifier indicated the highest accuracy at 0.8413 (Model-A) and 0.7523 (Model-B). Accuracy with the gradient boosting classifier and the random forest classifier was 0.6896, 0.6687, and 0.8413, 0.7523, respectively. Overall, the decision tree classifier had the best accuracy among the three methods. The study contributes to the implementation of AI in the decision-making process of tooth prognosis in consideration of the treatment plan.

The emergence of the high correlation between type 2 diabetes and obesity with complicated conditions has led to the coinage of the term “diabesity”. AMP-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPARγ) antagonists have shown therapeutic activity for diabesity, respectively. Hence, the discovery of compounds that activate AMPK as well as antagonize PPARγ may lead to the discovery of novel therapeutic agents for diabesity. In this study, the knockdown of PTPN6 activated AMPK and suppressed adipogenesis in 3T3-L1 cells. By screening a library of 1033 natural products against PTPN6, we found ethyl gallate to be the most selective inhibitor of PTPN6 (Ki = 3.4 μM). Subsequent assay identified ethyl gallate as the best PPARγ antagonist (IC50 = 5.4 μM) among the hit compounds inhibiting PTPN6. Ethyl gallate upregulated glucose uptake and downregulated adipogenesis in 3T3-L1 cells as anticipated. These results strongly suggest that ethyl gallate, which targets both PTPN6 and PPARγ, is a potent therapeutic candidate to combat diabesity.

In Streptococcus mutans, we find that the histidine kinase WalK possesses the longest C-terminal tail (CTT) among all 14 TCSs, and this tail plays a key role in the interaction of WalK with its response regulator WalR. We demonstrate that the intrinsically disordered CTT is characterized by a conserved tryptophan residue surrounded by acidic amino acids. Mutation in the tryptophan not only disrupts the stable interaction, but also impairs the efficient phosphotransferase and phosphatase activities of WalRK. In addition, the tryptophan is important for WalK to compete with DNA containing a WalR binding motif for the WalR interaction. We further show that the tryptophan is important for in vivo transcriptional regulation and bacterial biofilm formation by S. mutans. Moreover, Staphylococcus aureus WalK also has a characteristic CTT, albeit relatively shorter, with a conserved W-acidic motif, that is required for the WalRK interaction in vitro. Together, these data reveal that the W-acidic motif of WalK is indispensable for its interaction with WalR, thereby playing a key role in the WalRK-dependent signal transduction, transcriptional regulation and biofilm formation.

ObjectiveNLRP3 inflammasome regulates T cell responses. This study examined the roles of NLRP3 inflammasome activation in the regulation of T follicular helper (Tfh) cells during humoral response to T dependent antigens and in systemic lupus erythematosus (SLE).MethodsNLRP3 inflammasome activation of Tfh cells was studied in B6, MRL/lpr and NZM2328 mice and in SLE patients and healthy controls using a fluorescence-labelled caspase-1 inhibitor probe. MCC950, a selective inhibitor of NLRP3, was used to investigate the relation between NLRP3 inflammasome activation and germinal centre (GC) reaction, Ab responses to immunisation, and autoantibody production.ResultsNLRP3 inflammasome activation in Tfh cells after immunisation was identified in B6 mice. MCC950 inhibited humoral responses to sheep red blood cell and NP-CGG with reduction of the GC reaction. B6 mice with lymphoid cell-specific deletion ofNLRP3orCasp1mounted suboptimal humoral responses with impaired GC formation and defective affinity maturation. In MRL/lprand NZM2328 mice, inhibition of NLRP3 activation suppressed NLRP3 activated Tfh cell expansion as well as attenuated lupus-like phenotypes. Tfh cells with activated NLRP3 inflammasome exhibited increased expression of molecules for Tfh cell function and differentiation, and had greater ability to activate B cells. In SLE patients, disease activity was positively correlated with an increase in the activated NLRP3+Tfh population and this population was markedly reduced in response to therapy.ConclusionsThe activation of NLRP3 inflammasome in Tfh cells is an integral part of responses to immunisation. The activated NLRP3+Tfh population is essential for optimal humoral responses, GC formation and autoimmunity.

Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure–activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog 1e exhibited improved inhibitory activity against PTPN9 and significantly stimulated glucose uptake via AMPK phosphorylation in differentiated 3T3-L1 adipocytes and C2C12 myotubes; it also induced insulin-dependent AKT activation in C2C12 myotubes in a concentration-dependent manner. Docking simulation results showed that 1e had a better binding affinity through a unique hydrophobic interaction with a PTPN9 hydrophobic groove. Moreover, 1e ameliorated palmitate-induced insulin resistance in C2C12 cells. This study showed that 1e increases glucose uptake and suppresses palmitate-induced insulin resistance in C2C12 myotubes via PTPN9 inhibition; thus, it is a promising therapeutic candidate for treating type 2 diabetes.

Immunoglobulin Gs (IgGs) contain many Lys and Cys residues, which results in an unwanted complex product mixture with conventional drug conjugation methods. We selectively acylated the ε-NH

Background Osteoarthritis (OA) is the most common degenerative joint disease and is characterized by breakdown of joint cartilage. Coenzyme Q10 (CoQ10) exerts diverse biological effects on bone and cartilage; observational studies have suggested that CoQ10 may slow OA progression and inflammation. However, any effect of CoQ10 on OA remains unclear. Here, we investigated the therapeutic utility of CoQ10-micelles. Methods Seven-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. CoQ10-micelles were administered orally to MIA-induced OA rats; celecoxib served as the positive control. Pain, tissue destruction, and inflammation were measured. The expression levels of catabolic and inflammatory cell death markers were assayed in CoQ10-micelle-treated chondrocytes. Results Oral supplementation with CoQ10-micelles attenuated OA symptoms remarkably, including pain, tissue destruction, and inflammation. The expression levels of the inflammatory cytokines IL-1β, IL-6, and MMP-13, and of the inflammatory cell death markers RIP1, RIP3, and pMLKL in synovial tissues were significantly reduced by CoQ10-micelle supplementation, suggesting that CoQ10-micelles might attenuate the synovitis of OA. CoQ10-micelle addition to cultured OA chondrocytes reduced the expression levels of catabolic and inflammatory cell death markers. Conclusions CoQ10-micelles might usefully treat OA.

Urinalysis is a simple and non-invasive approach for the diagnosis and monitoring of organ health and also is often used as a facile technique in assessment of substance abuse. However, quantitative urinalysis is predominantly limited to clinical laboratories. Here, we present an electrical sensing based, reusable, cellular microfluidic device that offers a fast urinalysis through quantitative reading of the electrical signals. The spatial soft porous scaffolds decorated with electrically conductive multiwalled carbon nanotubes that are capable of physically interacting with biomarkers in urine are developed through a cyclic swelling/absorption process of soft materials and are utilized to manufacture the cellular microfluidic device. The sensing capability, sensitivity and reusability (via sunlight exposure) of the device to monitor red blood cells, Escherichia coli, and albumin are systemically demonstrated by programming mechanical deformation of porous scaffolds. Ex vivo experiments in disease mouse models confirm the diagnosis robustness of the device in comparable results with existing biochemical tests. The full integration of electrically conductive nanomaterials into soft scaffolds provides a foundation for devising bioelectronic devices with mechanically programmable microfluidic features in a low-cost manner, with broad applications for rapid disease diagnoses through body fluid.

Background The interscalene nerve block provides analgesia for shoulder surgery. To extend block duration, provide adequate analgesia, and minimize opioid consumption, the use of adjuvants such as dexamethasone as well as the application of perineural liposomal bupivacaine have been proposed. This randomized, double-blinded, noninferiority trial hypothesized that perineural liposomal bupivacaine is noninferior to standard bupivacaine with perineural dexamethasone in respect to average pain scores in the first 72 h after surgery. Methods A total of 112 patients undergoing ambulatory shoulder surgery were randomized into two groups. The liposomal bupivacaine group received a 15-ml premixed admixture of 10 ml of 133 mg liposomal bupivacaine and 5 ml of 0.5% bupivacaine (n = 55), while the bupivacaine with dexamethasone group received an admixture of 15 ml of 0.5% standard bupivacaine with 4 mg dexamethasone (n = 56), respectively. The primary outcome was the average numerical rating scale pain scores at rest over 72 h. The mean difference between the two groups was compared against a noninferiority margin of 1.3. Secondary outcomes were analgesic block duration, motor and sensory resolution, opioid consumption, numerical rating scale pain scores at rest and movement on postoperative days 1 to 4 and again on postoperative day 7, patient satisfaction, readiness for postanesthesia care unit discharge, and adverse events. Results A liposomal bupivacaine group average numerical rating scale pain score over 72 h was not inferior to the bupivacaine with dexamethasone group (mean [SD], 2.4 [1.9] vs. 3.4 [1.9]; mean difference [95% CI], –1.1 [–1.8, –0.4]; P < 0.001 for noninferiority). There was no significant difference in duration of analgesia between the groups (26 [20, 42] h vs. 27 [20, 39] h; P = 0.851). Motor and sensory resolutions were similar in both groups: 27 (21, 48) h versus 27 (19, 40) h (P = 0.436) and 27 [21, 44] h versus 31 (20, 42) h (P = 0.862), respectively. There was no difference in opioid consumption, readiness for postanesthesia care unit discharge, or adverse events. Conclusions Interscalene nerve blocks with perineural liposomal bupivacaine provided effective analgesia similar to the perineural standard bupivacaine with dexamethasone. The results show that bupivacaine with dexamethasone can be used interchangeably with liposomal bupivacaine for analgesia after shoulder surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Objectives. Although digital technology has been widely integrated into dental education, there is limited literature investigating the extent of the integration of computer-aided design and computer-aided manufacturing (CAD-CAM) for removable systems in the dental curriculum. The purpose of this study was to assess the current implementation of CAD-CAM complete and partial dentures in predoctoral (PP) and advanced graduate prosthodontic (AGP) education in US dental schools. The study also aimed to identify potential barriers to its implementation in the dental curriculum. Methods. An online survey with 15 questions was created using online survey software. The survey was distributed to the directors of predoctoral prosthodontics in 56 schools and advanced graduate programs of prosthodontics in 52 schools listed in the 2018–19 American Dental Education Association (ADEA) Directory. Results. The percentage of programs (PP and AGP) implementing CAD-CAM complete dentures (CAD-CAM CDs) and CAD-CAM removable partial dentures (CAD-CAM RPDs) in their didactic, preclinical, and clinical curricula was recorded. CAD-CAM CDs are taught in didactic courses in 54.2% of PP and 65.2% of AGP. However, CAD-CAM RPDs are only taught in 37.5% of PP and 47.8% of AGP. Programs are largely limited by a lack of funds, resources, time, and faculty members. Conclusion. While digital technologies have indeed become more prevalent in dental education, many institutions face barriers to implementation. More research must be conducted in order to support the continued incorporation of digital technologies into dental education.

With the advent of a digital workflow in dentistry, the inter-occlusal articulation of digital models is now possible through various means. The Cadent iTero intraoral scanner uses a buccal scan in maximum intercuspation to record the maxillomandibular relationship. This in-vitro study compares the occlusion derived from conventionally articulated stone casts versus that of digitally articulated quadrant milled models. Thirty sets of stone casts poured from full arch polyvinyl siloxane impressions (Group A) and thirty sets of polyurethane quadrant models milled from digital impressions (Group B) were used for this study. The full arch stone casts were hand-articulated and mounted on semi-adjustable articulators, while the digitally derived models were pre-mounted from the milling center based on the data obtained from the buccal scanning procedure. A T-scan sensor was used to obtain a bite registration from each set of models in both groups. The T-scan data derived from groups A and B were compared to that from the master model to evaluate the reproducibility of the occlusion in the two groups. A statistically significant difference of the contact region surface area was found on #11 of the digitally articulated models compared to the master. An analysis of the force distribution also showed a tendency for a heavier distribution on the more anterior #11 tooth for the digitally articulated models. Within the limitations of this study, the use of a digitally articulated quadrant model system may result in a loss of accuracy, in terms of occlusion, the further anteriorly the tooth to be restored is located. Care must be taken to consider the sources of inaccuracies in the digital workflow to minimize them for a more efficient and effective restorative process.

Although average values and facebow records have been incorporated into prosthetic dentistry with much success, little is known about how using 3D facial scans for mounting compare with traditional mounting methods.The purpose of this pilot clinical study was to determine differences in measurements among casts mounted virtually by using the average values of the Bonwill triangle and the Balkwill angle, casts mounted by using facebow records, and casts mounted from 3D facial scans.Intraoral digital scans were obtained from each participant (n=10) and 3D printed in resin. For the facebow preservation group (FPG), a facebow record was used to mount the resin casts on a semiadjustable articulator. A desktop scanner was used to digitize this mounting while preserving the facebow record. The average mounting group (AMG) consisted of intraoral digital scans that were mounted virtually by using the concepts of the Bonwill triangle and the Balkwill angle. For the facial scan group (FSG), the participants' digitized casts were superimposed on the facial scans by using a target system. The Bergstrom point and the glabella were used to mount these casts and their associated facial scans in the digital environment. This study used the FPG as the group to compare with the other mounting techniques because of its wide acceptance in restorative dentistry. These virtual mountings were completed in a computer-aided design software program, and the distance from right and left condylar elements to the incisal embrasure between mandibular central incisors, distance from left mandibular first molar to left condylar element and from right mandibular first molar to right condylar element, and anterior and posterior recordings at 0 mm, 3 mm, and 5 mm of vertical dimension increase were recorded. A Kruskal-Wallis 1-way analysis of variance was performed (α=.05). The Mann-Whitney U test was performed to evaluate differences in measured values among groups, and multiple comparisons were adjusted by using Bonferroni correction.All anterior and posterior measurements to the condylar elements of the virtual articulator were found to be significantly different (P.05). Both anterior and posterior condylar measurements between the FPG and the AMG were found to be significantly different (P.05), while comparisons between the FPG and the FSG were found not to be significantly different (P.05). All changes in vertical dimension were found not to be significantly different with respect to both anterior and posterior measurements (P.05).When used to virtually mount dental casts, 3D facial scanners performed similarly to traditional facebow records.

Protein tyrosine phosphatases (PTPs) are essential modulators of signal transduction pathways and contribute to a variety of human diseases, including cancer, diabetes, obesity, autoimmune disorders, and neurological diseases, indicating that PTPs are next-generation drug targets. Since PTPN1, PTPN2, and PTPN11 have been reported to be negative regulators of insulin action, the identification of PTP inhibitors may be an effective strategy to develop therapeutic agents for the treatment of type 2 diabetes. In this study, we observed for the first time that nepetin inhibits the catalytic activity of PTPN1, PTPN2, and PTPN11 in vitro , indicating that nepetin acts as a multi-targeting inhibitor of PTPN1, PTPN2, and PTPN11. Furthermore, treatment of mature 3T3-L1 adipocytes with 20 μM nepetin stimulates glucose uptake through AMPK activation. Taken together, our findings provide evidence that nepetin, a multi-targeting inhibitor of PTPN1, PTPN2, and PTPN11, could be a potential therapeutic candidate for the treatment of type 2 diabetes.

Complex prosthodontic treatments frequently require capturing an accurate impression of abutment teeth throughout the dental arch. Intraoral digital scanning has been reported to be accurate within single dental quadrants; however, the positional trueness of complete arch intraoral digital scans is not well understood.The purpose of this in vitro study was to compare the positional trueness of a complete arch digital scan generated by digitally merging portions of a direct digital scan from an intraoral scanner (IOS) with a digitized polyvinyl siloxane (PVS) complete arch impression.A 3D-printed reference cast was scanned with a desktop scanner, and reference standard tessellation language (STL) data sets were obtained. The reference cast was used to generate 4 nonmerged (NM) groups and 2 die-merged (DM) groups. In the NM groups (n=10), a direct digital scan of the reference cast was made with an IOS (NM-IOS), the PVS impression of the reference cast was digitized by using a cone beam computed tomography (CBCT) scanner (NM-PVS-CBCT) or a desktop scanner (NM-PVS-DESK), and the gypsum cast made from the PVS impression was digitized by using a desktop scanner (NM-STONE). In the DM groups (n=10), individual dies were cropped from the complete arch digital scan from the NM-IOS group and merged with the digital scans from the NM-PVS-DESK and NM-PVS-CBCT groups to generate the DM-PVS-DESK and DM-PVS-CBCT groups, respectively. Deviation was measured as the absolute value of the distance from a reference position on the reference cast. The Kruskal-Wallis and Dunn pairwise comparison tests were used to compare the difference in deviation between the groups (α=.05).The NM-STONE and NM-PVS-DESK groups demonstrated the highest positional trueness, with global deviations of 19.6 and 17.7 μm, respectively, with no statistically significant difference (P=1.00). However, both the NM-IOS and NM-PVS-CBCT groups differed significantly from the NM-STONE group (P.001 and P=.003, respectively) and the NM-PVS-DESK group (P.001 and P=.004, respectively). In the DM groups, the DM-PVS-CBCT group presented a higher deviation than the DM-PVS-DESK group.Complete arch digital scans of PVS impressions digitized with a desktop scanner exhibited less positional deviation than those digitized with a CBCT scanner or complete arch digital scans generated with an IOS. Complete arch digital scans generated with an IOS and CBCT scanner result in more deviations in the posterior regions, and their positional trueness may not be sufficient to construct an accurate digital scan. Generating a complete arch digital scan by digitally merging portions of a direct digital scan from an IOS with a digitized PVS complete arch impression is a suitable alternative to the contemporary workflow of digitizing a stone cast with a desktop scanner.

Aims The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs. Methods and results In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs. Conclusion Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.

Despite it being an older, conventional production method, the cast metal post and core is still often considered the best option for the restoration of severely damaged teeth. The direct technique for fabrication of cast post-and-core patterns, however, can pose challenges due to the inefficiencies and guesswork involved in creating an appropriate form and dimension for the core segment. This article presents an enhanced technique for cast post-and-core fabrication in reference to the desired dimensions of the final restoration. As the authors demonstrate, the procedure involves creation of an accurate and passive pattern of each post space. Bis-acrylic composite resin is then injected into a putty impression of the idealized wax-up and seated on the prepared post patterns. A preparation of the abutments is then performed by creating the cores according to the desired dimensions of the final restoration. The major advantages of this technique include a more efficient workflow and a reduction in the number of adjustments needed after insertion.

Hexavalent chromium is extremely toxic and increasingly prevalent owing to industrialisation, thereby posing serious human health and environmental risks. Therefore, new approaches for detoxifying high concentrations of Cr (VI) using an ultralow amount of catalyst with high recyclability are increasingly being considered. The catalytic conversion of Cr (VI) into Cr (III) was previously reported; however, it required a large amount of catalyst to reduce a low concentration of Cr (VI); further, pH adjustment and catalyst separation had to be performed, causing issues with large-scale remediation. In this study, an unprecedented eco-friendly and cost-effective method was developed for the synthesis of Pd nanoparticles (PdNPs) with a significantly narrow size distribution of 3–25 nm. PdNPs demonstrated the presence of elemental Pd with the zero oxidation state when analysed by energy-dispersive X-ray analysis and X-ray photoelectron spectroscopy. The PdNPs could detoxify a high concentration of Cr (VI), without the need to adjust the pH or purify the nanoparticles for reusability. The reusability of the PdNPs for the catalytic conversion of Cr (VI) into Cr (III) was >90% for subsequent cycles without the further addition of formic acid. Thus, the study provides new insights into the catalytic reclamation of Cr (VI) for industrial wastewater treatment.

Background GSTM1 encodes glutathione S-transferase μ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study. Methods We generated a Gstm1 knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and GSTM1 genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic GSTM1 on renal inflammation. Results Gstm1 knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that Gstm1 deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in Gstm1 knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the GSTM1 deletion variant. Conclusions Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.

Yujun Li,1–4,* Jie Liu,5,* Wanglai Hu,6,* Yuliang Zhang,1–4,* Jiangwei Sang,1–4 Huizheng Li,7 Teng Ma,8 Yunfeng Bo,9 Tao Bai,10 Huina Guo,1–4 Yan Lu,11 Xuting Xue,1–4 Min Niu,1–4 Shanshan Ge,12 Shuxin Wen,1–4 Binquan Wang,1–4 Wei Gao,1–4 Yongyan Wu1–4 1Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China; 2Department of Otolaryngology Head & Neck Surgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China; 3Otolaryngology Head & Neck Surgery Research Institute, Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China; 4The Key Scientific and Technological Innovation Platform for Precision Diagnosis and Treatment of Head and Neck Cancer, Shanxi Province, Taiyuan 030001, Shanxi, People’s Republic of China; 5Department of Head and Neck Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 6School of Basic Medical Science, Anhui Medical University, Hefei, Anhui 230027, People’s Republic of China; 7Department of Otolaryngology Head & Neck Surgery, Dalian Municipal Friendship Hospital, Dalian, Liaoning 116001, People’s Republic of China; 8Department of Cellular and Molecular Biology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing 101149, People’s Republic of China; 9Department of Pathology, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, Shanxi 030000, People’s Republic of China; 10Department of Pathology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China; 11Department of Otolaryngology Head & Neck Surgery, The First Hospital, Jinzhou Medical University, Jinzhou 121001, Liaoning, People’s Republic of China; 12Health Management Center, the First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongyan Wu; Wei GaoShanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, The First Hospital of Shanxi Medical University, No. 85, South Jiefang Road, Taiyuan, Shanxi 030001, People’s Republic of ChinaTel +86 351-4867076Fax +86 351-4639218; +86 351-4639218Email wuyongyan@sxent.org; gaoweisxent@sxent.orgBackground: Recent studies revealed that miR-424-5p regulates the malignant behavior of multiple cancer types. However, the expression and function of miR-424-5p in laryngeal squamous cell carcinoma (LSCC) is unclear.Purpose: This study aimed to evaluate the association of miR-424-5p level with clinical features of LSCC and investigate the effect and potential mechanism of miR-424-5p on LSCC progression.Methods: The expression of miR-424-5p in LSCC and paired adjacent normal margin (ANM) tissues from 106 patients with LSCC were analyzed by quantitative PCR (qPCR), and clinical significance was analyzed. Target genes of miR-424-5p were predicted, followed by functional annotation. The functional role of miR-424-5p in LSCC was investigated by molecular and cellular experiments with LSCC cell lines, with flow cytometry used for cell cycle analysis. In addition, miR-424-5p regulation of the predicted target gene cell adhesion molecule 1 (CADM1) was validated by qPCR, Western blot analysis and luciferase reporter assay.Results: miR-424-5p was upregulated in LSCC versus ANM tissues. High miR-424-5p level was significantly associated with poor differentiation, advanced tumor stage and cervical lymph node metastasis. Bioinformatics analysis showed that miR-424-5p target genes are mainly enriched in biological processes of the cell cycle, cell division, and negative regulation of cell migration, and were involved in multiple cancer-related pathways. Overexpression of miR-424-5p promoted proliferation, migration, invasion, and adhesion of LSCC cells and affected the cell cycle progression. Additionally, CADM1 was a direct target of miR-424-5p in LSCC cells.Conclusion: miR-424-5p functions as an oncogene to promote the aggressive progression of LSCC, and CADM1 is a direct downstream target of miR-424-5p in LSCC cells. miR-424-5p may be a potential therapeutic target in LSCC.Keywords: laryngeal squamous cell carcinoma, miR-424-5p, proliferation, migration and invasion, oncogenic miRNA

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5′-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/flmice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/flmice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-β immunoreactivity than CD73fl/flmice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73−/−kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.

The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q10, (CoQ10) a potent antioxidant, can reduce Tac-induced nephrotoxicity via improving mi...

Lupus glomerulonephritis (GN) is an autoimmune disease characterized by immune complex-deposition, complement activation and glomerular inflammation. In lupus-prone NZM2328 mice, the occurrence of lupus GN was accompanied by a decrease in Treg cells and an increase in proinflammatory cytokine-producing T cells. Because IL-33 in addition to IL-2 has been shown to be important for Treg cell proliferation and ST2 (IL-33 receptor) positive Treg cells are more potent in suppressor activity, a hybrid cytokine with active domains of IL-2 and IL-33 was generated to target the ST2+ Treg cells as a therapeutic agent to treat lupus GN. Three mouse models were used: spontaneous and Ad-IFNα- accelerated lupus GN in NZM2328 and the lymphoproliferative autoimmune GN in MRL/lpr mice. Daily injections of IL233 for 5 days prevented Ad-IFNα-induced lupus GN and induced remission of spontaneous lupus GN. The remission was permanent in that no relapses were detected. The remission was accompanied by persistent elevation of Treg cells in the renal lymph nodes. IL233 is more potent than IL-2 and IL-33 either singly or in combination in the treatment of lupus GN. The results of this study support the thesis that IL233 should be considered as a novel agent for treating lupus GN.

Curcuma zedoaria rhizome (Zingiberaceae) is a well-known traditional medicinal plant used in Ayurvedic and traditional Chinese medicine to treat various cancers. This study aimed to identify the cytotoxic components from C. zedoaria rhizomes that act against gastric cancer, which is the third leading cause of death from cancer worldwide because the MeOH extract of C. zedoaria rhizome was found to show a cytotoxic effect against gastric cancer AGS cells. Repeated column chromatography and semi-preparative HPLC purification were used to separate the components from the C. zedoaria MeOH extract. Two new sesquiterpenes, curcumenol-9,10-epoxide (1) and curcuzedoalide B (2), and 12 known related sesquiterpenes (3–14) were isolated from the C. zedoaria MeOH extract. The structures of new compounds were determined by 1D and 2D NMR spectroscopic experiments and HR-ESIMS, and quantum chemical ECD calculations. The cytotoxic effects of the isolated compounds were measured in human gastric cancer AGS cells using an MTT cell viability assay. Compounds 9, 10, and 12 exhibited cytotoxic effects against gastric cancer AGS cells, with IC50 values in the range of 212–392 μM. These findings provide further experimental scientific evidence to support the traditional use of C. zedoaria rhizomes for the treatment of cancer. Curcumenol (9), 4,8-dioxo-6β-methoxy-7α,11-epoxycarabrane (10), and zedoarofuran (12) were identified as the main cytotoxic components in C. zedoaria rhizomes.

Asthma is associated with the overproduction of leukotrienes (LTs), including LTB4. Patients with severe asthma can be highly responsive to 5-lipoxygenase (5-LO) inhibition, which blocks production of both the cysteinyl LTs and LTB4. Production of LTB4 has traditionally been ascribed to neutrophils, mononuclear phagocytes, and epithelial cells, and acts as a chemoattractant for inflammatory cells associated with asthma. The source of LTB4 is unclear, especially in eosinophilic asthma. We speculated that the benefit of 5-LO inhibition could be mediated in part by inhibition of eosinophil-derived LTB4. LTB4 concentrations were assayed in BAL fluid from patients with severe asthma characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4 hydrolase (LTA4H) by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 was quantified by enzyme immunoassay. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR, and IHC. LTB4 concentrations were elevated in BAL fluid from patients with severe asthma, including those with isolated eosinophilic inflammation, and these eosinophils displayed LTA4H via IHC. LTA4H expression by blood eosinophils was confirmed by flow cytometry, IHC, and qPCR. Robust LTB4 production by blood eosinophils was observed in response to some, but not all, stimuli. We demonstrated that eosinophils express LTA4H transcripts and protein, and can be stimulated to secrete LTB4. We speculate that in many patients with asthma, eosinophil-derived LTB4 is increased, and this may contribute to the efficacy of 5-LO inhibition.

Saeng-Ji-Hwang-Ko (SJHK) is a traditional Korean medicine formula derived from Donguibogam, a classic medical textbook, published in 1613. It is described as a general treatment for So-gal (wasting-thirst, ) known as type 2 diabetes mellitus (T2DM) in a modern clinical term. It is necessary to elucidate the potential compounds and targets of SJHK for T2DM treatment by conducting network pharmacology and molecular docking analyses.Information about the chemical constituents of SJHK were collected, and druggable compounds were screened based on oral bioavailability and drug-likeness. Putative target genes of druggable compounds and T2DM-related genes were retrieved from public databases. A compound-target network was constructed to visualize the relationship between the druggable compounds in SJHK and common targets related to T2DM. The constructed network was further investigated through Protein-Protein Interaction, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analyses, and molecular docking.Compound-target network analysis demonstrated that kaempferol, salicylic acid, estrone, and β-sitosterol were key compounds of SJHK with PTGS2, ESR1, PRKAA2, PRKAB1, and CYP19A1 being its key targets. Estrogen signaling, AGE-RAGE signaling, insulin resistance, non-alcoholic fatty liver disease, and TNF signaling pathway were potential pathways involved in the effect of SJHK on T2DM. Molecular docking simulations revealed that estrone and β-sitosterol had the strong binding energies for all the key target proteins.This study demonstrates that network pharmacology and molecular docking analyses help to better understand the potential key compounds and targets of SJHK for treating T2DM as a complementary medicine.Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder caused by genetic and/or environmental factors. There has been a growing attention to new therapeutic approaches to treat T2DM using traditional medicine as a complementary treatment which is expected to have synergistic effects with few side effects. Saeng-Ji-Hwang-Ko (SJHK) is a traditional Korean medicine (TKM) formula derived from Donguibogam, a classic medical textbook, published in 1613. It is described as a general treatment for So-gal (wasting-thirst, ) known as type 2 diabetes mellitus (T2DM) in a modern clinical term. It is necessary to elucidate the potential compounds and targets of SJHK for T2DM treatment by conducting network pharmacology and molecular docking analyses. Compound-target network analysis demonstrated that kaempferol, salicylic acid, estrone, and β-sitosterol were key compounds of SJHK with PTGS2, ESR1, PRKAA2, PRKAB1, and CYP19A1 being its key targets. Estrogen signaling, AGE-RAGE signaling, insulin resistance, non-alcoholic fatty liver disease, and TNF signaling pathway were potential pathways involved in the effect of SJHK on T2DM. Molecular docking evaluation revealed that estrone and β-sitosterol had the highest binding energies for all key target proteins, suggesting potential key compounds of SJHK. Although additional future studies including further experimental and clinical validation are needed, this study demonstrates that SJHK has a great potential for treating T2DM as a complementary medicine.

Background context Macrophages play important roles in the progression of intervertebral disc herniation and radiculopathy. Purpose To better understand the roles of macrophages in this process, we developed a new mouse model that mimics human radiculopathy. Study Design/Setting A preclinical randomized animal study. Methods Three types of surgeries were performed in randomly assigned Balb/c mice. These were spinal nerve exposure, traditional anterior disc puncture, and lateral disc puncture with nerve exposure (n=16/group). For the nerve exposure group, the left L5 spinal nerve was exposed without disc injury. For the traditional anterior puncture, L5/6 disc was punctured by an anterior approach as previously established. For lateral puncture with nerve exposure, the left L5 spinal nerve was exposed by removing the psoas major muscle fibers, and the L5/6 disc was punctured laterally on the left side with a 30G needle, allowing the nucleus to protrude toward the L5 spinal nerve. Mechanical hyperalgesia (pain sensitivity) of hind paws was assessed with electronic von Frey assay on alternative day for up to 2 weeks. MRI, histology, and immunostaining were performed to confirm disc herniation and inflammation. Results Ipsilateral pain in the lateral puncture with nerve exposure group was significantly greater than the other groups. Pro-inflammatory cytokines IL-1β and IL-6 were markedly elevated at the hernia sites of both puncture groups and the spinal nerve of lateral puncture with never exposure group on postoperative day 7. Heterogeneous populations of macrophages were detected in the infiltration tissue of this mouse model and in tissue from patients undergone discectomy. Conclusions We have established a new mouse model that mimics human radiculopathy and demonstrates that a mixed phenotype of macrophages contribute to the pathogenesis of acute discogenic radiculopathy. Clinical significance This study provides a clinically relevant in vivo animal model to elucidate complex interactions of disc herniation and radicular pain, which may present opportunities for the development of macrophage-anchored therapeutics to manage radiculopathy.