Calix[4]arene Bridge Mononitration with tert-Butyl Nitrite: Synthesis of Bridging Chiral p-tert-Butylcalix[4]arene with a Mononitro Bridge Substituent.

To explore the reaction universality of bridge nitration, the mononitration of different p-tert-butylcalix[4]arene derivatives was executed with tert-butyl nitrite as a nitration reagent. The effects of calix[4]arene conformations, substituents on the lower rim, and reaction conditions on bridge mononitration are systematically studied. The bridge nitration of p-tert-butylcalix[4]arene derivatives in 1,3-alternate, 1,2-alternate, and partial cone conformations can be smoothly executed while that of p-tert-butylcalix[4]arene derivatives strictly regulated in a cone conformation cannot. The nitration product complexity shows a positive correlation with the bridge-hydrogen types, and the optimal bridge-mononitrated substrate is calix[4]arene with only one bridge-hydrogen type. The electron-withdrawing substituent on the lower rim is apparently beneficial for the bridge mononitration. As a result, a variety of bridging chiral p-tert-butylcalix[4]arenes with a mononitro bridge substituent have been successfully synthesized. The highest bridge-mononitrated yield can reach 27% from 1,3-alternate p-tert-butylcalix[4]arene biscrown-5 under optimal reaction conditions.

Mononitration of a Calix[4]arene Methylene Bridge: Synthesis and Preliminary Catalysis Performances of Bridging Chiral p-tert-Butylcalix[4]arenes with a Monoamino Bridge Substituent in a 1,3-Alternate Conformation.

In order to prepare bridging chiral p-tert-butylcalix[4]crown-5 with a mononitro bridge substituent in a 1,3-alternate conformation, a mononitration method of calix[4]arene bridging methylene has been first developed with tert-butyl nitrite as a nitration reagent. The effects of solvent, reaction temperature, reaction time, and nitration reagent dosage on bridge mononitration have been deeply explored to obtain an optimal nitration condition. The facile nitration presents a new key for calix[4]arene bridge derivatization. After further modification and diastereoisomeric resolution, a pair of bridging chiral p-tert-butylcalix[4]arenes with a monoamino bridge substituent were produced from the bridge-mono-nitrated calix[4]arene. Their preliminary catalysis results in the Henry reaction show good catalytic activities (up to 95% yield) and still low but obviously enhanced enantioselectivities (up to 22.3% ee from 7a, 6% ee from 1), which confirms that the structural transformation indeed improves asymmetric catalysis performances of bridging chiral calix[4]crown-5 amines in a 1,3-alternate conformation.

Retrospective Analysis of Clinicopathological Characteristics of Lacrimal Gland Pleomorphic Adenoma and Mechanism of Tumorigenesis by the Imbalance Between Apoptosis and Proliferation.

BACKGROUND Lacrimal gland pleomorphic adenoma (LGPA) is the most common clinically benign epithelial tumor of the lacrimal gland and is predominantly comprised of epithelial cells and interstitial components. At present, the exact pathogenesis of LGPA remains unclear. Previous research has indicated that the occurrence of LGPA may be related to excessive cell proliferation. MATERIAL AND METHODS This study observed the clinicopathological characteristics of LGPA and investigated the tumorigenesis mechanism of cell over-proliferation caused by the imbalance between apoptosis and proliferation. A total of 27 cases were collected from the Department of Ophthalmology of the Affiliated Hospital of Chengde Medical University and the Third Medical Center of Chinese PLA General Hospital from April 2017 to November 2019. Hematoxylin-eosin (HE) staining and immunohistochemical staining were used to observe the pathological characteristics and analyze the expression of bcl-2 and bax in the lacrimal gland. RESULTS Compared with normal lacrimal gland tissues, LGPA tumor tissues had obvious changes in pathological morphology. The expression of bcl-2 in LGPA lesion tissues was dramatically higher (P<0.001), the expression of bax was not significantly different between groups (P=0.25), but the ratio of bcl-2/bax was significantly higher in tumor tissues (P=0.01). CONCLUSIONS We found that the lacrimal gland tumor tissues had obvious excessive proliferation in pathomorphology, which revealed the necessity of complete surgical removal of the capsule from the perspective of pathological morphology and provided a theoretical basis for the hypothesis that the imbalance between apoptosis and proliferation could lead to cell hyperproliferation.

Identification of protein tyrosine phosphatase 1B (PTP1B) inhibitors through De Novo Evoluton, synthesis, biological evaluation and molecular dynamics simulation.

Protein tyrosine phosphatase 1B (PTP1B) is a widely expressed 50 kDa enzyme and the first intracellular PTP to be purified from human placental tissue. It has been proved that protein tyrosine phosphatase 1B played a significant role in the negative regulation of insulin signaling pathway and overexpression of PTP1B could lead to the decrease of insulin resistance. Therefore PTP1B has emerged as a novel promising therapeutic target for the treatment of type-2 diabetes mellitus. Computer aided drug design (CADD), chemical synthesis and biological activity assay resulted in the identification of a novel potent PTP1B inhibitor, compound 1a, which shared an IC50 value of 4.46 µM. Finally, the analysis of molecular dynamics simulation provided the theoretical basis for favorable activity of compound 1a.

The level of evidence, scientific impact and social impact of clinical studies in periodontology: A methodological study.

AIMS: To analyse the level of evidence (LOE) of clinical studies in the field of periodontology, and to investigate whether LOE is a predictor of scientific impact and social impact. MATERIALS AND METHODS: Clinical studies published in five leading periodontal journals during 2015-2019 were identified. The LOE of included studies were assessed with a modified LOE classification system based on Oxford 2009 LOE, Oxford 2011 LOE and GRADE guidelines. Citation counts were harvested from Web of Science and Scopus. Altmetric Attention Scores (AAS) were obtained from Altmetric Explorer. Multivariable generalized estimation equation (GEE) analyses were used to investigate association between LOE and citation count, as well as between LOE and AAS. RESULTS: Among 768 studies included, the proportion of level-1, level-2, level-3 and level-4 was 10.4%, 44.8%, 13.7% and 31.1%, respectively. In the multivariable GEE analyses, high LOE was a significant predictor of higher average citation count (p = .010) and higher AAS (p < .001). CONCLUSION: The LOE of clinical studies in the periodontal field is relatively high in general, although it varies significantly in different journals. Studies with high LOE tend to have greater scientific impact and social impact than low LOE studies.

Design, synthesis and antifungal activity of threoninamide carbamate derivatives via pharmacophore model.

Thirty-six novel threoninamide carbamate derivatives were designed and synthesised using active fragment-based pharmacophore model. Antifungal activities of these compounds were tested against Oomycete fungi Phytophthora capsici in vitro and in vivo. Interestingly, compound I-1, I-2, I-3, I-6 and I-7 exhibited moderate control effect (>50%) against Pseudoperonospora cubensis in greenhouse at 6.25 µg/mL, which is better than that of control. Meanwhile most of these compounds exhibited significant inhibitory against P. capsici. The other nine fungi were also tested. More importantly, some compounds exhibited remarkably high activities against Sclerotinia sclerotiorum, P. piricola and R. solan in vitro with EC50 values of 3.74-9.76 µg/mL. It is possible that the model is reliabile and this method can be used to discover lead compounds for the development of fungicides.

Facile fabrication of 2D hetero core-satellites patterned Ag nanoparticle arrays with tunable plasmonic bands for SERS detection.

A core-satellites metal nanostructure with high local electromagnetic (EM) intensity and density has shown great potential in ultrasensitive detection technologies, but complexity and uncontrollability of fabrication is a major obstacle for further application. Here, only by controlling the deposited Ag thickness, we facilely achieved 2D hetero core-satellites patterned Ag nanoparticle (NP) arrays for surface-enhanced Raman scattering (SERS) detection. The Ag nanoparticles were assembled by electron beam evaporation of Ag onto the anodized patterned aluminum template (APAlT) at a temperature above 0.24 times the melting point of Ag. The plasmonic bands can be continuously tuned from the visible to near-infrared region. The SERS enhancement factor (EF) and relative standard deviation (RSD) of as-prepared SERS active substrates for R6G molecules reached 107 and about 5%, respectively, and a SERS detection limit down to 10-9 M was obtained. Finite-difference time-domain (FDTD) simulations revealed that the high SERS activity originates mainly from the local electromagnetic (EM) enhancement in the gaps between the core and satellites. The simple and controllable fabrication strategy and superior SERS performance make the 2D hetero core-satellites patterned Ag NPs arrays promising candidates for SERS-based sensor applications and provide a new approach for developing an inexpensive, efficient, and mass-produced SERS active substrate.

Penetration and bactericidal efficacy of two oral care products in an oral biofilm model.

PURPOSE: To investigate the immediate penetration and bactericidal effect of two oral care products marketed in China on an intact natural plaque biofilm model at different time points. METHODS: Eight subjects (aged 20 to 30 years; Turesky Plaque Index Score 2 to 3) were enrolled in the study according to the inclusion criteria. Plaque accumulators were worn by the subjects for 6 and 48 hours for harvesting the dental biofilm. Then the biofilms from different groups were stained with the LIVE/DEAD BacLight fluorescence system to investigate the changes in thickness and fluorescence intensity of living bacteria in biofilm 5 and 15 minutes post-treatment with a mouthrinse containing 0.074% cetylpyridinium chloride (1-minute treatment) or a toothpaste supernatant containing 1.16% stannous chloride (2-minute treatment). In addition, a specific Sn2+ probe was utilized to evaluate the penetration of Sn2+ in the biofilm. Fluorescent images were collected using confocal laser scanning microscopy. Analysis of covariance was used for statistical analyses. All comparisons were two-sided using a 5% level of significance. RESULTS: The thickness of generated plaque biofilm increased gradually from 7.352±4.22 µm at 6 hours to 16.73±7.38 µm at 48 hours (P< 0.05), whereas the thickness and fluorescence intensity of living bacteria stayed unchanged over time. After the treatment of toothpaste supernatant, the ratios of living bacteria thickness and fluorescence intensity of 6- and 48-hour plaque biofilm were significantly decreased (P< 0.05). Treatment of mouthrinse reduced the ratio of living bacteria thickness, but showed no significant impact on overall fluorescence intensity of living bacteria. For 48-hour biofilm, toothpaste supernatant significantly reduced fluorescence intensity of living bacteria from outer layer through inner layer, whereas the mouthrinse showed bactericidal effect only in the outer layer and middle layer. A wide distribution of Sn2+ was shown in the biofilm with the treatment of the tested toothpaste. CLINICAL SIGNIFICANCE: This biofilm model proved to be useful and appropriate for pre-clinical testing of anti-plaque agents. A brief exposure of the biofilm to the tested toothpaste produced significant losses in bacteria viability across outer-middle-inner layers. The tested mouthrinse exerted its bactericidal effect mostly in outer and middle layers of biofilm. The penetration of Sn2+ in the biofilm performed an important function in the bactericidal effect of the toothpaste.

Interactions and effects of a stannous-containing sodium fluoride dentifrice on oral pathogens and the oral microbiome.

Numerous studies have investigated the effects of stannous ions on specific microbes and their efficacy in reducing dental plaque. Nonetheless, our understanding of their impact on the oral microbiome is still a subject of ongoing exploration. Therefore, this study sought to evaluate the effects of a stannous-containing sodium fluoride dentifrice in comparison to a zinc-containing sodium fluoride dentifrice and a control group on intact, healthy oral biofilms. Utilizing the novel 2bRAD-M approach for species-resolved metagenomics, and FISH/CLSM with probes targeting periodontal and caries associated species alongside Sn2+ and Zn2+ ions, we collected and analyzed in situ biofilms from 15 generally healthy individuals with measurable dental plaque and treated the biofilms with dentifrices to elucidate variations in microbial distribution. Although significant shifts in the microbiome upon treatment were not observed, the use of a stannous-containing sodium fluoride dentifrice primarily led to an increase in health-associated commensal species and decrease in pathogenic species. Notably, FISH/CLSM analysis highlighted a marked reduction in representative species associated with periodontitis and caries following treatment with the use of a stannous-containing sodium fluoride dentifrice, as opposed to a zinc-containing sodium fluoride dentifrice and the control group. Additionally, Sn2+ specific intracellular imaging reflected the colocalization of Sn2+ ions with P. gingivalis but not with other species. In contrast, Zn2+ ions exhibited non-specific binding, thus suggesting that Sn2+ could exhibit selective binding toward pathogenic species. Altogether, our results demonstrate that stannous ions could help to maintain a healthy oral microbiome by preferentially targeting certain pathogenic bacteria to reverse dysbiosis and underscores the importance of the continual usage of such products as a preventive measure for oral diseases and the maintenance of health.

Setmelanotide optimization through fragment-growing, molecular docking in-silico method targeting MC4 receptor.

Obesity has emerged as a global issue, but with the complex structures of multiple related important targets and their agonists or antagonists determined, the mechanism of ligand-protein interaction may offer new chances for developing new generation agonists anti-obesity. Based on the molecule surface of the cryo-EM protein structure 7AUE, we tried to replace D-Ala3 with D-Met in setmelanotide as the linker site for fragment-growing with De novo evolution. The simulation results indicate that the derivatives could improve the binding abilities with the melanocortin 4 receptor and the selectivity over the melanocortin 1 receptor. The improved selectivity of the newly designed derivatives is mainly due to the shape difference of the molecular surface at the orthosteric peptide-binding pocket between melanocortin 4 receptor and melanocortin 1 receptor. The new extended fragments could not only enhance the binding affinities but also function as a gripper to seize the pore, making it easier to balance and stabilize the other component of the new derivatives. Although it is challenging to synthesize the compounds designed in silico, this study may perhaps serve as a trigger for additional anti-obesity research.Communicated by Ramaswamy H. Sarma.

3% diquafosol sodium eye drops in Chinese patients with dry eye: a phase IV study.

Introduction: The efficacy and safety of 3% diquafosol sodium eye drops in Chinese patients with dry eye in the real-world setting remains unclear. Methods: 3099 patients with dry eye symptoms were screened according to Asia Dry Eye Society latest recommendation. Among them, 3000 patients were enrolled for a phase IV study. We followed up with multiple clinical characteristics including corneal fluorescein staining, tear break up time, Schirmer's tests, visual acuity, intraocular pressure, and others. The follow ups were performed at baseline, 2 weeks and 4 weeks after treatment. Results: Based on the results of corneal fluorescein staining and tear break up time, all age and gender subgroups exhibited obvious alleviation of the symptoms among the patients with dry eye, and the data in elderly group showed the most significant alleviation. All the adverse drug reactions (ADRs, 6.17%) were recorded, among which 6% local ocular ADRs were included. Meanwhile, mild ADRs (91.8%) accounted for the most. Most of the ADRs (89.75%) got a quick and full recovery, with an average time at 15.6 days. 1.37% of patients dropped out of the study due to ADRs. Discussion: The use of 3% diquafosol sodium eye drop is effective and safe in the treatment of dry eye, with a low incidence of ADRs showing mild symptoms. This trial was registered at Chinese Clinical Trial Registry ID: ChiCTR1900021999 (Registration Date: 19/03/2019).

Synthesis, structure and insecticidal activities of some novel amides containing N-pyridylpyrazole moeities.

In our search for environmentally benign insecticides with high activity, low toxicity and low residue, a novel series of amides containing N- pyridylpyrazole moieties were designed and synthesized. The structures of the title compounds were characterized and confirmed by 1H-NMR and elemental analysis. Furthermore, the structure of compound 7l was determined by single crystal X-ray diffraction. The preliminary bioassay tests showed that some of them exhibited good insecticidal activities against Mythimna separata Walker, Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Hübner.

Association between sleep-disordered breathing and periodontal diseases: A systematic review protocol.

Background: Sleep-disordered breathing (SDB) is a chronic sleep-related breathing disorder, considered associated with increased risk of cardiovascular disorders, metabolic disorders, cognitive dysfunction and behavior changes. Periodontal diseases are chronic infectious diseases that are also believed to be associated with cardiovascular diseases, metabolic syndrome and cognitive dysfunction. Several studies have indicated that SDB may be associated with periodontal diseases through certain mechanisms such as inflammation response, oxidative stress and oral dryness. The aim of this systematic review is to explore the association between SDB and periodontal diseases in an integrated approach. Materials and Methods: This systematic review will include cohort studies, cross-sectional studies and case-control studies that are identified by electronic and manual searches. Electronic searches will be conducted in the following databases: PubMed, Embase, Scopus and Web of Science. Our search will cover articles published from inception of databases to March 2022 without restrictions in language and settings. Pre-determined eligibility criteria include: participants (participants without a history of respiratory diseases, history of periodontal treatment within the past 6 months and history of medication that is known to influence SDB or periodontal diseases); exposure (participants who have been diagnosed with SDB or at high-risk for SDB); comparison (participants without SDB); and outcome (periodontal parameters, such as probing depth, clinical attachment level, bleeding on probing, radiographic bone loss). Two authors will perform study screening and data extraction independently and in duplicate. All discrepancies will be solved by discussion. The methodological quality of included studies will be assessed using the Newcastle-Ottawa Scale. Discussion: This systematic review will summarize the existing evidence on the association between SDB and periodontal diseases, a topic of controversy and clinical significance. Its findings can provide evidence for the development of relevant prevention and treatment strategies. The results will be disseminated through peer-reviewed journals. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022313024. Registered on March 28th 2022.

Ethyl 4-[(4-chloro-phen-oxy)meth-yl]-2-(4-nitro-phen-yl)-1,3-thia-zole-5-carboxyl-ate.

The title compound, C(19)H(15)ClN(2)O(5)S, contains two mol-ecules (A and B) in the asymmetric unit. In mol-ecule A, the dihedral angles between the thia-zole ring and the pendant chloro-benzene and nitro-benzene rings are 72.14 (15) and 3.03 (15)°, respectively. The corresponding angles for mol-ecule B are 45.56 (16) and 1.51 (14)°, respectively. In the crystal, both mol-ecules form inversion dimers linked by pairs of weak C-H⋯O inter-actions.

Synthesis, evaluation, molecular dynamics simulation and targets identification of novel pyrazole-containing imide derivatives.

A new series of novel pyrazole-containing imide derivatives were synthesized and evaluated for their anticancer activities against A-549, Bel7402, and HCT-8 cell lines. Among these compounds A2, A4, A11 and A14 possessed high inhibition activity against A-549 cell lines with IC50 values at 4.91, 3.22, 27.43 and 18.14 µM, respectively, better than that of 5-fluorouracil (IC50=59.27 µM). A2, A4, and A11 also exhibited significant inhibitory activity towards HCT-8 and Bel7402 cell lines. Interestingly, the Heat Shock Protein 90α (Hsp90α, PDB ID: 1UYK) was found to be the potential drug target of these synthesized compounds with the aid of PharmMapper server (http://lilab.ecust.edu.cn/pharmmapper/) and docking module of Schrödinger (Maestro 10.2). Additionally, molecular dynamics simulation was performed out to explore the most likely binding mode of compound A2 with Hsp90α.Communicated by Ramaswamy H. Sarma.

Three new powerful oseltamivir derivatives for inhibiting the neuraminidase of influenza virus.

Owing to its unique function in assisting the release of newly formed virus particles from the surface of an infected cell, neuraminidase, an antigenic glycoprotein enzyme, is a main target for drug design against influenza viruses. The group-1 neuraminidase of influenza virus possesses a 150-cavity, which is adjacent to the active pocket, and which renders conformational change from the 'open' form to the 'closed' form when the enzyme is binding with a ligand. Using AutoGrow evolutionary algorithm, one very unique fragment is screened out from the fragment databases by exploiting additional interactions with the 150-cavity. Subsequently, three derivatives were constructed by linking the unique fragment to oseltamivir at its three different sites. The three derivatives thus formed show much stronger inhibition power than oseltamivir, and hence may become excellent candidates for developing new and more powerful drugs for treating influenza. Or at the very least, the findings may stimulate new strategy or provide useful insights for working on the target vitally important to the health of human beings.

1-(4-Methoxy-phen-yl)imidazolidine-2,4-dione.

In the title compound, C(10)H(10)N(2)O(3), the dihedral angle between the benzene and imidazolidine rings is 6.0 (4)°, consistent with an essentially planar mol-ecule. In the crystal, inter-molecular N-H⋯O hydrogen bonding between centrosymmetrically related mol-ecules leads to loosely associated dimeric aggregates. These are connected into a three-dimensional network by C-H⋯O inter-actions, as well as π-π inter-actions [centroid-centroid distances = 3.705 (3) and 3.622 (3) Å] between the imidazolidine and benzene rings.

3-Hy-droxy-methyl-1-(4-meth-oxy-phen-yl)imidazolidine-2,4-dione.

In the title mol-ecule, C(11)H(12)N(2)O(4), the dihedral angle between the benzene ring and imidazolidine ring is 7.1 (5)°. In the crystal structure, the hy-droxy groups are involved in the formation of inter-molecular O-H⋯O hydrogen bonds, which link the mol-ecules related by translation into C(2) chains along the b axis.

3-Bromo-1-(3-chloro-pyridin-2-yl)-N-(4-eth-oxy-phen-yl)-1H-pyrazole-5-carbox-amide.

In the title compound, C(17)H(14)BrClN(4)O(2), the pyrazole ring is almost coplanar with the benzene ring [dihedral angle = 0.5 (2)°], whereas the pyrazole ring is close to perpendicular to the 3-chloro-pyridine ring [dihedral angle = 73.7 (2)°]. An intra-molecular C-H⋯O hydrogen bond occurs. The dominant inter-action in the crystal packing is an N-H⋯N hydrogen bond, which generates a chain along the c axis. Weak inter-molecular C-H⋯O and C-H⋯N contacts are also observed.

Diagnosis of lacrimal punctum lesions using optical coherence tomography: a preliminary study.

AIM: To study the imaging characteristics of lacrimal punctum lesion with optical coherence tomography (OCT), and provide imaging basis for the diagnosis and treatment of lacrimal punctum diseases. METHODS: A total of 25 patients (28 eyes) with epiphora and lacrimal puncta lesions were enrolled. Lacrimal puncta lesions included: punctum membrane obstruction in 7 cases (9 eyes), punctum agenesis in 1 case (1 eye), a mass protruded from the punctum in 1 case (1 eye), slit puncta in 1 case (1 eye), peri-puncta mass in 2 cases (2 eyes), chronic dacryocystitis in 4 cases (4 eyes), and primary puncta stenosis in 9 cases (10 eyes; 3 eyes mild, 4 eyes moderate and 3 eyes severe). All patients were examined by slit lamp microscopy and OCT to observe the morphological characteristics of abnormal punctum. RESULTS: Two types of complete membrane obstruction and incomplete membrane obstruction of puncta were observed in OCT images of 7 patients. No lacrimal punctum and lacrimal canalicular cavity were found in 1 case with punctum agenesis. OCT images showed that a narrow lumen remained in the lacrimal puncta in 1 patient with a mass protruded from the punctum. OCT of punctum in a patient with slit punctum after stent placement showed stent and abnormal lacrimal structure. No abnormal intraluminal structure was found in 2 cases of peri-puncta mass after OCT scan, and the lacunar space was narrower than that of the contralateral eye. OCT of puncta in 4 patients with chronic dacryocystitis showed that pus floated in tear with lump-like medium-low reflex. In 9 patients with primary lacrimal puncta stenosis, OCT image could clearly show the changes of puncta lumen in different degrees and shapes. CONCLUSION: OCT is feasible for the examination of pathological punctum, and can provide imaging basis for the diagnosis and treatment of punctum disease.