Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.

Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function, and molecular pathways between mammalian podocytes and Drosophila nephrocytes are highly conserved, therefore we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes of high-sucrose diet flies showed significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocytes filtration structure known as the slit diaphragm was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunction. Regulating mitochondrial dynamics by either genetic modification of the Pink1/Park (mammalian PINK1/PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1/Park-mediated mitophagy and associated control of mitochondrial dynamics, essential for function, in diabetic nephropathy; and demonstrate that targeting this pathway might provide therapeutic benefits in type 2 diabetic nephropathy.

HIV-1 Nef acts in synergy with APOL1-G1 to induce nephrocyte cell death in a new Drosophila model of HIV-related kidney diseases.

Background: People carrying two APOL1 risk alleles (RA) G1 or G2 are at greater risk of developing HIV-associated nephropathy (HIVAN). Studies in transgenic mice showed that the expression of HIV-1 genes in podocytes, and nef in particular, led to HIVAN. However, it remains unclear whether APOL1-RA and HIV-1 Nef interact to induce podocyte cell death. Method: We generated transgenic (Tg) flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. Results: We found that HIV-1 Nef acts in synergy with APOL1-G1 resulting in nephrocyte structural and functional defects. Specifically, HIV-1 Nef itself can induce endoplasmic reticulum (ER) stress (without affecting autophagy). Through a different pathway, Nef exacerbates the organelle acidification defects and reduced autophagy induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating ER stress, triggering nephrocyte dysfunction and ultimately cell death. Conclusions: A new Drosophila model of HIV-1-related kidney diseases identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high relevance between Drosophila nephrocytes and human podocytes, this finding suggests ER stress as a new therapeutic target for HIV-1 and APOL1-associated nephropathies.

Three-Component Reaction for the Synthesis of Spiro-Heterocycles from Isatins, Substituted Ureas, and Cyclic Ketones.

We reported an efficient three-component reaction to access new spiro heterocycles through the annulation reactions of isatins, substituted ureas, and cyclic ketones under normal laboratory conditions, which is another example of isatins being used to build spiro compounds by the ring-opening and recyclization processes. The wide range of substrates, simple operation, normal experimental conditions, and high yields make the approach of high practical value.

Parameter-Free and Electron Counting Satisfied Material Representation for Machine Learning Potential Energy and Force Fields.

We proposed a parameter-free volume element representation that satisfies the electron counting model and obtains accurate machine learning potential energy and direct force fitting of randomly perturbed hexagonal BN. Our method preserves permutational, translational, and rotational invariance and can be extended to three-dimensional systems, verified by a system of bulk Si. As a result, we obtained 0.57 meV/atom potential energy root mean squared error (RMSE) and 59 meV/Å force RMSE for perturbed bulk BN systems and 0.43 meV/atom potential energy RMSE and 36 meV/Å force RMSE for perturbed Si systems. In addition, an unbiased perturbation-based data set construction scheme is introduced and a continuous population distribution is obtained with a training data set of 4500, which is about 1 order of magnitude smaller than standard methods based on first-principles molecular dynamics simulations and saves a large amount of computing resources. General validity of our model is verified by structure optimization, molecular dynamics simulations, and extrapolations.

Multidirectional insights into the phytochemical, biological, and multivariate analysis of extracts from the aerial part of Swertia perennis Linnaeus.

Swertia perennis Linnaeus (SP) has been utilised to treat gastritis. We report the qualitative and quantitative phytochemical analysis, antioxidant and enzyme inhibitory activities of SP. The correlation between the biological activities and total bioactive contents of the extracts was also studied via multivariate analysis. Methanol extract contained many active compounds and exhibited good antioxidant activity. Therefore, this was selected for further phytochemical profiling and stability studies. Fourteen compounds were identified by ultra-performance liquid chromatography-electrospray ionisation-orbitrap-mass spectrometry for the first time from this plant. Iridoids, xanthones, and flavonoids were the main components. Methanol extract exhibited good stability and antioxidant capacity in stability studies, with low toxicity, and showed a protective effect on the oxidation of olive and sunflower oils. SP has the potential to be developed and used as an antioxidant, or as urease and XO inhibitors, and its methanol extract could be used as a natural oil stabiliser.

Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development.

Highly evolutionarily conserved multiprotein complexes termed Complex of Proteins Associated with Set1 (COMPASS) are required for histone 3 lysine 4 (H3K4) methylation. Drosophila Set1, Trx, and Trr form the core subunits of these complexes. We show that flies deficient in any of these three subunits demonstrated high lethality at eclosion (emergence of adult flies from their pupal cases) and significantly shortened lifespans for the adults that did emerge. Silencing Set1, trx, or trr in the heart led to a reduction in H3K4 monomethylation (H3K4me1) and dimethylation (H3K4me2), reflecting their distinct roles in H3K4 methylation. Furthermore, we studied the gene expression patterns regulated by Set1, Trx, and Trr. Each of the COMPASS core subunits controls the methylation of different sets of genes, with many metabolic pathways active early in development and throughout, while muscle and heart differentiation processes were methylated during later stages of development. Taken together, our findings demonstrate the roles of COMPASS series complex core subunits Set1, Trx, and Trr in regulating histone methylation during heart development and, given their implication in congenital heart diseases, inform research on heart disease.

APOL1-G2 accelerates nephrocyte cell death by inhibiting the autophagy pathway.

People of African ancestry who carry the APOL1 risk alleles G1 or G2 are at high risk of developing kidney diseases through not fully understood mechanisms that impair the function of podocytes. It is also not clear whether the APOL1-G1 and APOL1-G2 risk alleles affect these cells through similar mechanisms. Previously, we have developed transgenic Drosophila melanogaster lines expressing either the human APOL1 reference allele (G0) or APOL1-G1 specifically in nephrocytes, the cells homologous to mammalian podocytes. We have found that nephrocytes that expressed the APOL1-G1 risk allele display accelerated cell death, in a manner similar to that of cultured human podocytes and APOL1 transgenic mouse models. Here, to compare how the APOL1-G1 and APOL1-G2 risk alleles affect the structure and function of nephrocytes in vivo, we generated nephrocyte-specific transgenic flies that either expressed the APOL1-G2 or both G1 and G2 (G1G2) risk alleles on the same allele. We found that APOL1-G2- and APOL1-G1G2-expressing nephrocytes developed more severe changes in autophagic pathways, acidification of organelles and the structure of the slit diaphragm, compared to G1-expressing nephrocytes, leading to their premature death. We conclude that both risk alleles affect similar key cell trafficking pathways, leading to reduced autophagy and suggesting new therapeutic targets to prevent APOL1 kidney diseases.

Chemical composition and biological evaluation of the essential oil of the flowering aerial parts of Aegopodium alpestre Ledeb.

Aegopodium alpestre Ledeb (A. alpestre) is a plant known for its fragrant smell and has been traditionally used to treat influenza. However, despite its widespread use, there is no research on its flowering aerial parts. This study aims to contribute to the understanding the flowering aerial parts by investigating its volatile oil. The essential oil was extracted through hydrodistillation and analysed using GC-MS. The analysis identified 54 compounds, which accounted for 95.16% of the oil composition. The major components are germacrene D (31.68%), ß-caryophyllene (16.07%), and (E)-ß-farnesene (7.99%). To evaluate the antioxidant activity of volatile oil, six antioxidant experiments were conducted. The results indicated that volatile oil exhibited significant 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt and hydroxyl radical scavenging abilities. Furthermore, the antibacterial activity of volatile oil was assessed against four common pathogenic bacteria. The findings demonstrated that volatile oil displayed potent antibacterial activity against Escherichia coli and Aerogenic bacterium.

Mesencephalic trigeminal nucleus neurons with collaterals to both eyelid and masseter muscles shown by fluorescent double-labeling, revealing a potential mechanism for Marcus Gunn Syndrome.

Poking palpebral conjunctiva evoked upper-eyelid retraction during ophthalmic surgery. Iatrogenic eyelid ptosis occurred if eyelid branch of lachrymal nerve was sectioned. Mesencephalic trigeminal nucleus (Vme) neurons were labeled when tracer injected into lachrymal nerve innervating eyelid Mueller's muscle. Masseter afferent Vme neurons projecting to oculomotor nucleus (III) was observed in toad and rat, which helps amphibians to stare prey when they open mouth widely to prey. We hypothesized single Vme neurons may have peripheral collaterals to both eyelid and masseter muscles. WGA-594 was injected into upper eyelid, and WGA-488 was simultaneously delivered into ipsilateral masseter muscle in the same rat. Then, double labeled Vme neurons were found under both conventional and confocal microscope. Meanwhile, contact of WGA-594 positive eyelid afferent Vme neurons with WGA-488 labeled masseter afferent ones were observed sometimes. Combined with our previous observation of oculomotor projection Vme neurons, we thought WGA-594/488 double labeled Vme cells, at least some of them, are oculomotor projecting ones. Contact between eyelid and masseter afferent Vme neurons are supposed to be electrotonically coupled, based on a line of previous studies. If exogenous or genetic factors make these Vme neurons misinterpret masseter input as eyelid afferent signals, these Vme neurons might feedforward massages to eyelid retractor motoneurons in the III. Besides, oculomotor projecting Vme neurons might be co-fired by adjacent masseter afferent Vme neurons through electrotonic coupling once the masseter muscle is activated. In these cases, Marcus Gunn Syndrome might occur. This finding leads to a new hypothesis for the Syndrome.

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes.

BACKGROUND: People of Sub-Saharan African ancestry are at higher risk of developing chronic kidney disease (CKD), attributed to the Apolipoprotein L1 (APOL1) gene risk alleles (RA) G1 and G2. The underlying mechanisms by which the APOL1-RA precipitate CKD remain elusive, hindering the development of potential treatments. RESULTS: Using a Drosophila genetic modifier screen, we found that SNARE proteins (Syx7, Ykt6, and Syb) play an important role in preventing APOL1 cytotoxicity. Reducing the expression of these SNARE proteins significantly increased APOL1 cytotoxicity in fly nephrocytes, the equivalent of mammalian podocytes, whereas overexpression of Syx7, Ykt6, or Syb attenuated their toxicity in nephrocytes. These SNARE proteins bound to APOL1-G0 with higher affinity than APOL1-G1/G2, and attenuated APOL1-G0 cytotoxicity to a greater extent than either APOL1-RA. CONCLUSIONS: Using a Drosophila screen, we identified SNARE proteins (Syx7, Ykt6, and Syb) as antagonists of APOL1-induced cytotoxicity by directly binding APOL1. These data uncovered a new potential protective role for certain SNARE proteins in the pathogenesis of APOL1-CKD and provide novel therapeutic targets for APOL1-associated nephropathies.

Screening the Extract of Laportea bulbifera (Sieb. et Zucc.) Wedd. Based on Active Component Content, Its Antioxidant Capacity and Exploration of Hepatoprotective Activity in Rats.

Laportea bulbifera (Sieb. et Zucc.) Wedd., a plant with a long history of medicinal use, possesses uncertainly defined medicament portions while its antioxidant capacity remains largely unexplored. To gain a better understanding of its medicinal value, this study focused on investigating the Laportea bulbifera aboveground part (LBAP) and the Laportea bulbifera root (LBR). Through an assessment of the bioactive compound content, a significant finding emerged: the LBR exhibited notably higher levels of these bioactive phytochemicals compared to the LBAP. This observation was further reinforced by the antioxidant assays, which demonstrated the superiority of the LBR's antioxidant capacity. The experimental results unequivocally indicate that the root is the optimal medicament portion for Laportea bulbifera. Furthermore, it was discovered that the presence of alcohol in the extraction solvent significantly enhanced the extraction of active ingredients, with the methanol extract of LBR performing the best among the extracts tested. Consequently, this extract was selected for further research. Leveraging cutting-edge UHPLC-ESI-Q-TOF-MS technology, the methanol extract of LBR was meticulously analyzed, revealing the presence of 41 compounds, primarily belonging to the phenolics and fatty acids. Remarkably, stability experiments demonstrated that the phenolics in the methanol extract maintained their stability across various pH values and during in vitro simulations of the human digestive system, albeit showing gradual degradation under high temperatures. Furthermore, the oxidative stability tests conducted on oils revealed the potential of the methanol extract as a stabilizer for olive oil and sunflower oil. Moreover, oral acute toxicity studies confirmed the low toxicity of the methanol extract, further supporting its safe use for medicinal purposes. Of particular note, histopathological examination and biochemical analysis affirmed the remarkable protective effects of the methanol extract against d-galactosamine-induced liver damage. These findings underscore the therapeutic potential of the methanol extract from the LBR in the treatment of diseases associated with oxidative imbalance.

Complete chloroplast genome of Adonis pseudoamurensis W.T.Wang (Ranunculaceae).

Adonis pseudoamurensis W.T. Wang 1980 is an important traditional medicinal plant used for the treatment of cardiac diseases. The complete chloroplast (cp) genome of Adonis pseudoamurensis is reported for the first time in this study. The circular cp genome is 156,917 bp in length, consisting of a large single-copy region (86,262 bp), a small single-copy region (18,067 bp), and two inverted repeat regions (26,294 bp). The genome encodes 129 genes, comprising 84 protein-coding genes, 37 transfer RNA (tRNA) genes, and 8 ribosomal RNA (rRNA) genes. Phylogenetic analysis showed that A. pseudoamurensis is closely related to A. amurensis.

Phytochemistry and Pharmacology of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu: A Review.

Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu (E. sessiliflorus), a member of the Araliaceae family, is a valuable plant widely used for medicinal and dietary purposes. The tender shoots of E. sessiliflorus are commonly consumed as a staple wild vegetable. The fruits of E. sessiliflorus, known for their rich flavor, play a crucial role in the production of beverages and fruit wines. The root barks of E. sessiliflorus are renowned for their therapeutic effects, including dispelling wind and dampness, strengthening tendons and bones, promoting blood circulation, and removing stasis. To compile a comprehensive collection of information on E. sessiliflorus, extensive searches were conducted in databases such as Web of Science, PubMed, ProQuest, and CNKI. This review aims to provide a detailed exposition of E. sessiliflorus from various perspectives, including phytochemistry and pharmacological effects, to lay a solid foundation for further investigations into its potential uses. Moreover, this review aims to introduce innovative ideas for the rational utilization of E. sessiliflorus resources and the efficient development of related products. To date, a total of 314 compounds have been isolated and identified from E. sessiliflorus, encompassing terpenoids, phenylpropanoids, flavonoids, volatile oils, organic acids and their esters, nitrogenous compounds, quinones, phenolics, and carbohydrates. Among these, triterpenoids and phenylpropanoids are the primary bioactive components, with E. sessiliflorus containing unique 3,4-seco-lupane triterpenoids. These compounds have demonstrated promising properties such as anti-oxidative stress, anti-aging, antiplatelet aggregation, and antitumor effects. Additionally, they show potential in improving glucose metabolism, cardiovascular systems, and immune systems. Despite some existing basic research on E. sessiliflorus, further investigations are required to enhance our understanding of its mechanisms of action, quality assessment, and formulation studies. A more comprehensive investigation into E. sessiliflorus is warranted to delve deeper into its mechanisms of action and potentially expand its pharmaceutical resources, thus facilitating its development and utilization.

Tuning Band Alignment at Grain Boundaries for Efficiency Enhancement in Cu2ZnSnS4 Solar Cells.

Conducting atomic force microscopy has been performed for a fundamental understanding of the mechanism responsible for the lower power conversion efficiency (PCE) of Cu2ZnSnS4 (CZTS) solar cells than that of CuIn1-xGaxSe2 (CIGS) solar cells. The difference in efficiency is partly attributed to the distinctly different band alignment between the grain boundaries (GBs) and grain interior (GI) for the two materials. While CIGS shows type-II band alignment, CZTS was discovered to demonstrate type-I band alignment with the conduction band shifting downward while the valence band shifting upward at the GBs. The type-I band alignment in CZTS leads to both electron and hole trapping, enhancing their recombination, and lowers the PEC. Band engineering was realized by moderate oxidative annealing of CZTS. The preferential GB oxidation changes the band alignment into inverse type-I (i.e., the conduction band upward bending and valence band downward bending at GBs). The blocking of carrier recombination at GBs leads to 30% enhancement in PCE. Our work reveals the critical role that band alignment between the grain boundary and interior plays in polycrystalline thin film solar cells and suggests band alignment engineering as a practical approach to enhance PCE. Furthermore, conducting AFM has been shown to be a powerful tool for qualitative and semiquantitative characterization of band alignment in polycrystalline films.

Phytochemical Analysis, Antioxidant Activities In Vitro and In Vivo, and Theoretical Calculation of Different Extracts of Euphorbia fischeriana.

Euphorbia fischeriana has a long-standing history of use in traditional medicine for the treatment of tuberculosis diseases. However, the plant's therapeutic potential extends beyond this specific ailment. The present study aimed to investigate the antioxidant properties of Euphorbia fischeriana and lay the groundwork for further research on its potential therapeutic applications. Phytochemical tests were performed on the plant, and 11 types of phytochemicals were identified. Ultraviolet-visible spectrophotometry was used to evaluate the active components and antioxidant properties of eight different solvent extracts, ultimately selecting acetone extract for further research. UHPLC-ESI-Q-TOF-MS identified 43 compounds in the acetone extract, and chemical calculations were used to isolate those with high content and antioxidant activity. Three stability experiments confirmed the extract's stability, while cell viability and oral acute toxicity studies demonstrated its relatively low toxicity. In rats, the acetone extract showed significant protective effects against D-galactosamine-induced liver damage through histopathological examination and biochemical analysis. These results suggest that Euphorbia fischeriana's acetone extract has potential in treating diseases related to oxidative imbalances. Therefore, this study highlights the plant's potential therapeutic applications while providing insight into its antioxidant properties.

The Roles of Histone Lysine Methyltransferases in Heart Development and Disease.

Epigenetic marks regulate the transcriptomic landscape by facilitating the structural packing and unwinding of the genome, which is tightly folded inside the nucleus. Lysine-specific histone methylation is one such mark. It plays crucial roles during development, including in cell fate decisions, in tissue patterning, and in regulating cellular metabolic processes. It has also been associated with varying human developmental disorders. Heart disease has been linked to deregulated histone lysine methylation, and lysine-specific methyltransferases (KMTs) are overrepresented, i.e., more numerous than expected by chance, among the genes with variants associated with congenital heart disease. This review outlines the available evidence to support a role for individual KMTs in heart development and/or disease, including genetic associations in patients and supporting cell culture and animal model studies. It concludes with new advances in the field and new opportunities for treatment.

H3K36 Di-Methylation Marks, Mediated by Ash1 in Complex with Caf1-55 and MRG15, Are Required during Drosophila Heart Development.

Methyltransferases regulate transcriptome dynamics during development and aging, as well as in disease. Various methyltransferases have been linked to heart disease, through disrupted expression and activity, and genetic variants associated with congenital heart disease. However, in vivo functional data for many of the methyltransferases in the context of the heart are limited. Here, we used the Drosophila model system to investigate different histone 3 lysine 36 (H3K36) methyltransferases for their role in heart development. The data show that Drosophila Ash1 is the functional homolog of human ASH1L in the heart. Both Ash1 and Set2 H3K36 methyltransferases are required for heart structure and function during development. Furthermore, Ash1-mediated H3K36 methylation (H3K36me2) is essential for healthy heart function, which depends on both Ash1-complex components, Caf1-55 and MRG15, together. These findings provide in vivo functional data for Ash1 and its complex, and Set2, in the context of H3K36 methylation in the heart, and support a role for their mammalian homologs, ASH1L with RBBP4 and MORF4L1, and SETD2, during heart development and disease.

Artificially controlled nanoscale chemical reduction in VO2 through electron beam illumination.

Chemical reduction in oxides plays a crucial role in engineering the material properties through structural transformation and electron filling. Controlling the reduction at nanoscale forms a promising pathway to harvest functionalities, which however is of great challenge for conventional methods (e.g., thermal treatment and chemical reaction). Here, we demonstrate a convenient pathway to achieve nanoscale chemical reduction for vanadium dioxide through the electron-beam illumination. The electron beam induces both surface oxygen desorption through radiolytic process and positively charged background through secondary electrons, which contribute cooperatively to facilitate the vacancy migration from the surface toward the sample bulk. Consequently, the VO2 transforms into a reduced V2O3 phase, which is associated with a distinct insulator to metal transition at room temperature. Furthermore, this process shows an interesting facet-dependence with the pronounced transformation observed for the c-facet VO2 as compared with the a-facet, which is attributed to the intrinsically different oxygen vacancy formation energy between these facets. Remarkably, we readily achieve a lateral resolution of tens nanometer for the controlled structural transformation with a commercial scanning electron microscope. This work provides a feasible strategy to manipulate the nanoscale chemical reduction in complex oxides for exploiting functionalities.

Transcriptome analysis provides insights into the cell wall and aluminum toxicity related to rusty root syndrome of Panax ginseng.

Rusty root syndrome is a common and serious disease in the process of Panax ginseng cultivation. This disease greatly decreases the production and quality of P. ginseng and causes a severe threat to the healthy development of the ginseng industry. However, its pathogenic mechanism remains unclear. In this study, Illumina high-throughput sequencing (RNA-seq) technology was used for comparative transcriptome analysis of healthy and rusty root-affected ginseng. The roots of rusty ginseng showed 672 upregulated genes and 526 downregulated genes compared with the healthy ginseng roots. There were significant differences in the expression of genes involved in the biosynthesis of secondary metabolites, plant hormone signal transduction, and plant-pathogen interaction. Further analysis showed that the cell wall synthesis and modification of ginseng has a strong response to rusty root syndrome. Furthermore, the rusty ginseng increased aluminum tolerance by inhibiting Al entering cells through external chelating Al and cell wall-binding Al. The present study establishes a molecular model of the ginseng response to rusty roots. Our findings provide new insights into the occurrence of rusty root syndrome, which will reveal the underlying molecular mechanisms of ginseng response to this disease.

The complete chloroplast genome sequence of Aconitum tschangbaischanense (Ranunculaceae).

The perennial herbal medicine species Aconitum tschangbaischanense, is endemic to Changhai Mountain, Jilin province. In this study, we attempted to uncover the complete chloroplast (cp) genome of A. tschangbaischanense based on sequencing data using the Illumina sequencing technology. As per the results: (1) the length of its complete cp genome is 155,881 bp with a typical tetrad structure; (2) the structure of its cp genome contains large single-copy and small single-copy (LSC and SSC) regions of 86,351 and 16,9444 bp, respectively, isolated by two inverted repeat regions (IRs) of 26,293 bp; (3) we annotated a total 131 genes, consisting of 86 protein-coding genes, eight rRNA genes, and 37 tRNA genes. According to the maximum-likelihood phylogenetic tree based on complete cp genomes, A. tschangbaischanense, showed close association with A. carmichaelii, which belongs to clade I. Finally, this study provides the characteristics of the cp genome of A. tschangbaischanense, and its phylogenetic position.