Fosfenopril Attenuates Inflammatory Response in Diabetic Dry Eye Models by Inhibiting the TLR4/NF-κB/NLRP3 Signaling Pathway.

Purpose: The purpose of this study was to investigate the involvement of the TLR4/NF-κB/NLRP3 signaling pathway and its underlying mechanism in diabetic dry eye. Methods: Two models of diabetic dry eye were established in high glucose-induced human corneal epithelial (HCE-T) cells and streptozotocin (STZ)-induced C57BL/6 mice, and the TLR4 inhibitor fosfenopril (FOS) was utilized to suppress the TLR4/NF-κB/NLRP3 signaling pathway. The expression changes in TLR4, NF-κB, NLRP3, and IL-1ß, and other factors were detected by Western blot and RT‒qPCR, the wound healing rate was evaluated by cell scratch assay, and the symptoms of diabetic mice were evaluated by corneal sodium fluorescein staining and tear secretion assay. Results: In the diabetic dry eye model, the transcript levels of TLR4, NF-κB, NLRP3, and IL-1ß were raised, and further application of FOS, a TLR4 inhibitor, downregulated the levels of these pathway factors. In addition, FOS was found to be effective in increasing the wound healing rate of high glucose-induced HCE-T cells, increasing tear production, and decreasing corneal fluorescence staining scores in diabetic mice, as measured by cell scratch assay, corneal sodium fluorescein staining assay, and tear production. Conclusions: The current study found that the TLR4/NF-κB/NLRP3 signaling pathway regulates diabetic dry eye in an in vitro and in vivo model, and that FOS reduces the signs of dry eye in diabetic mice, providing a new treatment option for diabetic dry eye.

Oridonin ameliorates ocular surface inflammatory responses by inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway in dry eye.

Chronic inflammation is one of the central drivers in the development of dry eye disease (DED), in which pyroptosis induced by the NLRP3/caspase-1/gasdermin D (GSDMD) pathway plays a key role. This pathway has become a major target for the treatment of a variety of inflammatory disorders. Oridonin (Ori) is a naturally occurring substance with anti-inflammatory properties obtained from Rabdosia rubescens. Whether Ori can exert an anti-inflammatory effect on DED, and its anti-inflammatory mechanism of action, are still unknown. This experiment is intended to investigate the impact of Ori on the hyperosmolarity-induced NLRP3/caspase-1/GSDMD pyroptosis pathway in immortalized human corneal epithelial (HCE-T) cells, as well as its efficacy and mechanism of action on ocular surface injury in DED mice. Our study showed that Ori could inhibit hyperosmotic-induced pyroptosis through the NLRP3/caspase-1/GSDMD pathway in HCE-T cells, and similarly, Ori inhibited the expression of this pathway in DED mice. Moreover, Ori was protective against hyperosmolarity-induced HCE-T cell damage. In addition, we found that the morphology and number of HCE-T cells were altered under culture conditions of various osmolarities. With increasing osmolarity, the proliferation, migration, and healing ability of HCE-T cells decreased significantly, and the expression of N-GSDMD was elevated. In a mouse model of DED, Ori application inhibited the expression of the NLRP3/caspase-1/GSDMD pyroptosis pathway, improved DED signs and injury, decreased corneal sodium fluorescein staining scores, and increased tear volume. Thus, our study suggests that Ori has potential applications for the treatment of DED, provides potential novel therapeutic approaches to treat DED, and provides a theoretical foundation for treating DED using Ori.

Palladium-anchored calix[4]arene-derived porous organic polymer towards efficient hydrolytic cleavage of carbon disulfide.

The release of carbon disulfide can have adverse effects on our environment and human health. The stability of carbon disulfide and the slow kinetics of hydrolysis can make it challenging to achieve efficient and practical cleavage of the CS bonds. Herein, a calix[4]arene-based porous organic polymer (CPOP-1) is innovatively synthesized through an optimized polycondensation reaction using C-Methylcalix[4]resorcinarene and hexafluoro-hexaazatriphenylene as monomers. Subsequently, palladium-induced calix[4]arene-based porous organic polymer was also synthesized via strong Pd-N coordination bonds to construct the metal-induced porous catalyst (CPOP-2). The polymeric catalyst active center [Pd2+(N^N)(NO3-)2] demonstrated outstanding catalytic hydrolysis performance (11.14 µmol g-1 h-1) in 10.5 h which is significantly enhanced by ca.13.2 times as compared to reported mononuclear Bpy-Pd(NO3)2, and 7.07 times than model trinuclear complex catalyst HATN-Pd-1, respectively. The control experiments revealed that POP catalysts showcased robust stability, prolonged effectiveness, and feasible recyclability during the hydrolytic cleavage of carbon disulfide at room temperature in aqueous solutions. Furthermore, the coordination environment of [Pd2+(N^N)] was validated through XPS, EXAFS, and isotope labeling measurements, and the hydrolysis cleavage products were confirmed e. g. CO2, sulfide, and protons. More importantly, a reaction mechanism was formulated coupled with theoretical calculations, and simulations. The proposed mechanism involves sequential OH- nucleophilic attacks on the carbon atoms of insert-coordinated CS2 and COS, leading to the cleavage of double CS bonds and the formation of CO bonds. The concurrent dissociation of the C-S bond and liberation of CO2 result in an intermediate structure characterized by [(N^N)Pd2+](SH-)2. This intermediate motif serves as the source of the thermodynamic driving force for the reaction.

A new genetic diagnosis strategy for paroxysmal kinesigenic dyskinesia: Targeted high-throughput detection of PRRT2 gene c.649 locus.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most prevalent kind type of paroxysmal Dyskinesia, characterized by recurrent and transient episodes of involuntary movements. Most PKD cases were attributed to the proline-rich transmembrane protein 2 (PRRT2) gene, in which the c.649 region is a hotspot for known mutations. Even though some patients with PKD have been genetically diagnosed using whole-exome sequencing (WES) and Sanger sequencing, there are still cases of missed diagnoses due to the limitations of sequencing technology and analytic methods on throughput. METHODS: Patients meeting the diagnosis criteria of PKD with negative results of PRRT2-Sanger sequencing and WES were included in this study. Mutation screening and targeted high-throughput sequencing were performed to analyze and verify the sequencing results of the potential mutations. RESULTS: Six patients with PKD with high mutation ratios of c.649dupC were screened using our targeted high-throughput sequencing from 26 PKD patients with negative results of PRRT2-Sanger sequencing and WES (frequency = 23.1%), which compensated for the comparatively shallow sequencing depth and statistical flaws in this region. Compared with the local normal population and other patients with PKD, the mutation ratios of c.649dupC of these six patients with PKD were much higher and also had truncated protein structures and differentially altered mRNA expression. CONCLUSION: Based on the above studies, we emphasize the routine targeted high-throughput sequencing of the c.649 site in the PRRT2 gene in so-called genetic-testing-negative patients with PKD, and manually calculate the deletion and duplication mutations depth and ratios to lower the rate of clinical misdiagnosis.

Visualizing lateral optical force through surface plasmon-coupled emission.

In this Letter, we report the intrinsic relationship among surface plasmon polaritons, lateral optical force, and surface plasmon-coupled emission. The spin-orbit coupling in the near field through circularly polarized beams would lead to the unidirectional excitation of surface plasmon polaritons, where the symmetry state of the electromagnetic field on the surface is broken. This asymmetric scattering would generate the counter-intuitive lateral optical force due to momentum conservation. As the inverse process of surface plasmon polaritons, surface plasmon-coupled emission enables the guide of the near-field surface plasmon polariton signal to the far field. We found that the lateral optical force produced by the unidirectional excitation of surface plasmon polaritons can be observed in the surface plasmon-coupled emission patterns. The elliptical dipole model was used to demonstrate these coupling processes. The magnitude and direction of lateral optical force can be a dipole, respectively. Moreover, the intensity convergence degree and direction of the surface plasmon-coupled emission distribution can reflect the magnitude and direction of lateral optical force, respectively. This work has great potential in the applications of weak force measurement, dynamic optical sorting, and light-matter interaction research.

The Material Basis and Mechanism of Xuefu Zhuyu Decoction in Treating Stable Angina Pectoris and Unstable Angina Pectoris.

METHODS: Firstly, we used a network proximity approach to calculate and compare the effectiveness of the formula with that of Western drugs for each type of angina, including all targets and intersecting targets, from a topological perspective. Secondly, we compared the mechanisms of action of the two angina pectoris at three levels and five aspects, including conventional and modular analysis approaches. Thirdly, based on the unique functions of each angina in the complex heterogeneous network, we designed a reverse process for finding the material basis using dynamic, static, and enriched items as well as a total item. Finally, the designed inverse process, material basis, and mechanism of action were validated. RESULTS: The target network of Xuefu Zhuyu decoction is closer to the target network of each type of angina than that of Western drugs, and the intersection targets have a closer proximity. Comparison of the mechanisms of action showed that stable angina and unstable angina had 158 common targets, while the unique targets were 34 and 1, respectively. Modularity analysis showed that the GO similarity of target modules was highly correlated with KEGG similarity. We ended up with 67 compounds upregulated for stable angina and 47 compounds upregulated for unstable angina. Our results were validated by literature mining, high-volume molecular docking, and miRNA enrichment analysis. CONCLUSIONS: For both types of angina pectoris, Xuefu Zhuyu decoction is superior to Western drugs. A comparison of various aspects led to the unique mechanisms of action, from which the material basis of each type of angina was deduced.

The Biological Fate of Pharmaceutical Excipient ß-Cyclodextrin: Pharmacokinetics, Tissue Distribution, Excretion, and Metabolism of ß-Cyclodextrin in Rats.

ß-cyclodextrin has a unique annular hollow ultrastructure that allows encapsulation of various poorly water-soluble drugs in the resulting cavity, thereby increasing drug stability. As a bioactive molecule, the metabolism of ß-cyclodextrin is mainly completed by the flora in the colon, which can interact with API. In this study, understanding the in vivo fate of ß-cyclodextrin, a LC-MS/MS method was developed to facilitate simultaneous quantitative analysis of pharmaceutical excipient ß-cyclodextrin and API dextromethorphan hydrobromide. The established method had been effectively used to study the pharmacokinetics, tissue distribution, excretion, and metabolism of ß-cyclodextrin after oral administration in rats. Results showed that ß-cyclodextrin was almost wholly removed from rat plasma within 36 h, and high concentrations of ß-cyclodextrin distributed hastily to organs with increased blood flow velocities such as the spleen, liver, and kidney after administration. The excretion of intact ß-cyclodextrin to urine and feces was lower than the administration dose. It can be speculated that ß-cyclodextrin metabolized to maltodextrin, which was further metabolized, absorbed, and eventually discharged in the form of CO2 and H2O. Results proved that ß-cyclodextrin, with relative low accumulation in the body, had good safety. The results will assist further study of the design and safety evaluation of adjuvant ß-cyclodextrin and promote its clinical development.

Reinstatement of Ticanto (Leguminosae-Caesalpinioideae) - the final piece in the Caesalpinia group puzzle.

A recent molecular phylogenetic analysis of the Caesalpinia group demonstrated that it comprises 26 genera, but the recognition of a putative 27th genus, Ticanto, remained in doubt. This study presents a phylogenetic analysis of ITS and five plastid loci revealing a robustly supported monophyletic group representing the Ticanto clade, sister to the morphologically distinct genus Pterolobium. Based upon this evidence, along with a morphological evaluation, the genus Ticanto is here reinstated. Descriptions are provided for all nine species of Ticanto, together with a key to the species, maps, and colour photographs. Nine new combinations are made: Ticantocaesia (Hand.-Mazz.) R. Clark & Gagnon, T.crista (L.) R. Clark & Gagnon, T.elliptifolia (S. J. Li, Z. Y. Chen & D. X. Zhang) R. Clark & Gagnon, T.magnifoliolata (Metcalf) R. Clark & Gagnon, T.rhombifolia R. Clark & Gagnon, T.sinensis (Hemsl.) R. Clark & Gagnon, T.szechuenensis (Craib) R. Clark & Gagnon, T.vernalis (Champion ex Benth.) R. Clark & Gagnon and T.yunnanensis (S. J. Li, D. X. Zhang & Z.Y. Chen) R. Clark & Gagnon. The final major question in the delimitation of segregate genera from within Caesalpinia sensu lato and the Caesalpinia group is thus resolved.

Lespedezadanxiaensis (Fabaceae), a new species from Guangdong, China, based on molecular and morphological data.

Lespedezadanxiaensis (Fabaceae), a new species from Danxiashan National Nature Reserve in Guangdong Province, is described and illustrated. The new species is morphologically similar to Lespedezapilosa, but it can be easily distinguished by its thin leathery leaflets and long peduncles. Phylogenetic analysis based on ITS confirmed that the new species belongs to Lespedezasubg.Macrolespedeza. The new species is the first known species of Lespedeza endemic to Danxia landform and is currently only known from Mount Danxia, Guangdong.

Nephrotoxicity of Immune Checkpoint Inhibitors: A Disproportionality Analysis from 2013 to 2020.

Nephrotoxicity occasionally occurs during treatment with immune checkpoint inhibitors (ICIs). Few related studies compare the differences between these drugs. This study aimed to systematically characterize nephrotoxicity after ICI initiation. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis, including information components (ICs) and reporting odds ratios (RORs), was performed to determine the potential renal toxicity of ICIs. A total of 7,204 reports of renal adverse events (AEs) were identified in the FAERS database. Renal AEs were most commonly reported for nivolumab (46.84%). Strong signals were detected in male patients combined with ICIs. In the clinical application of ICIs, attention should be paid to patients, especially male patients, with acute kidney injury, nephritis, autoimmune nephritis and other nephrotoxic AEs. The use of ICIs is likely to aggravate their condition.

Trajectory Simulation and Prediction of COVID-19 via Compound Natural Factor (CNF) Model in EDBF Algorithm.

Natural and non-natural factors have combined effects on the trajectory of COVID-19 pandemic, but it is difficult to make them separate. To address this problem, a two-stepped methodology is proposed. First, a compound natural factor (CNF) model is developed via assigning weight to each of seven investigated natural factors, that is temperature, humidity, visibility, wind speed, barometric pressure, aerosol, and vegetation in order to show their coupling relationship with the COVID-19 trajectory. Onward, the empirical distribution based framework (EDBF) is employed to iteratively optimize the coupling relationship between trajectory and CNF to express the real interaction. In addition, the collected data is considered from the backdate, that is about 23 days-which contains 14-days incubation period and 9-days invalid human response time-due to the nonavailability of prior information about the natural spreading of virus without any human intervention(s), and also lag effects of the weather change and social interventions on the observed trajectory due to the COVID-19 incubation period; Second, the optimized CNF-plus-polynomial model is used to predict the future trajectory of COVID-19. Results revealed that aerosol and visibility show the higher contribution to transmission, wind speed to death, and humidity followed by barometric pressure dominate the recovery rates, respectively. Consequently, the average effect of environmental change to COVID-19 trajectory in China is minor in all variables, that is about -0.3%, +0.3%, and +0.1%, respectively. In this research, the response analysis of COVID-19 trajectory to the compound natural interactions presents a new prospect on the part of global pandemic trajectory to environmental changes.

Nuclear phylotranscriptomics and phylogenomics support numerous polyploidization events and hypotheses for the evolution of rhizobial nitrogen-fixing symbiosis in Fabaceae.

Fabaceae are the third largest angiosperm family, with 765 genera and ∼19 500 species. They are important both economically and ecologically, and global Fabaceae crops are intensively studied in part for their nitrogen-fixing ability. However, resolution of the intrasubfamilial Fabaceae phylogeny and divergence times has remained elusive, precluding a reconstruction of the evolutionary history of symbiotic nitrogen fixation in Fabaceae. Here, we report a highly resolved phylogeny using >1500 nuclear genes from newly sequenced transcriptomes and genomes of 391 species, along with other datasets, for a total of 463 legumes spanning all 6 subfamilies and 333 of 765 genera. The subfamilies are maximally supported as monophyletic. The clade comprising subfamilies Cercidoideae and Detarioideae is sister to the remaining legumes, and Duparquetioideae and Dialioideae are successive sisters to the clade of Papilionoideae and Caesalpinioideae. Molecular clock estimation revealed an early radiation of subfamilies near the K/Pg boundary, marked by mass extinction, and subsequent divergence of most tribe-level clades within ∼15 million years. Phylogenomic analyses of thousands of gene families support 28 proposed putative whole-genome duplication/whole-genome triplication events across Fabaceae, including those at the ancestors of Fabaceae and five of the subfamilies, and further analyses supported the Fabaceae ancestral polyploidy. The evolution of rhizobial nitrogen-fixing nodulation in Fabaceae was probed by ancestral character reconstruction and phylogenetic analyses of related gene families and the results support the hypotheses of one or two switch(es) to rhizobial nodulation followed by multiple losses. Collectively, these results provide a foundation for further morphological and functional evolutionary analyses across Fabaceae.

DNA barcoding and molecular phylogeny of Dumasia (Fabaceae: Phaseoleae) reveals a cryptic lineage.

Dumasia taxonomy and classification have long been problematic. Species within this genus have few morphological differences and plants without flowers or fruits are difficult to accurately identify. In this study, we evaluated the ability of six DNA barcoding sequences, one nuclear (ITS) and five chloroplast regions (trnH-psbA, matK, rbcL, trnL-trnF, psbB-psbF), to efficiently identify Dumasia species. Most single markers or their combinations identify obvious barcoding gaps between intraspecific and interspecific genetic variation. Most combined analyses including ITS showed good species resolution and identification efficiency. We therefore suggest that ITS alone or a combination of ITS with any cpDNA marker are most suitable for DNA barcoding of Dumasia. The phylogenetic analyses clearly indicated that Dumasia yunnanensis is not monophyletic and is separated as two independent branches, which may result from cryptic differentiation. Our results demonstrate that molecular data can deepen the comprehension of taxonomy of Dumasia and provide an efficient approach for identification of the species.