KRT5 mutation regulate melanin metabolism through notch signalling pathway between keratinocytes and melanocytes.

Dowling-Degos disease (DDD) is an autosomal dominant hereditary skin disease characterized by acquired reticular hyperpigmentation in flexural sites, and one of its causative genes is KRT5 gene. But the effect of KRT5, expressed only in keratinocytes, on melanocytes is unclear. Other pathogenic genes of DDD include POFUT1, POGLUT1 and PSENEN genes, which is involved in posttranslational modification of Notch receptor. In this study, we aim to determine the ablation of keratinocyte KRT5 affect melanogenesis in melanocyte through Notch signalling pathway. Here we found that KRT5 downregulation decreased the expression of the Notch ligand in keratinocytes and Notch1 intracellular domain in melanocytes, by establishing two cell models of ablation of KRT5 in keratinocytes based on CRISPR/Cas9 site-directed mutation and lentivirus-mediated shRNA. Treatment of melanocytes with Notch inhibitors had same effects with ablation of KRT5 on increase of TYR and decrease of Fascin1. Activation of Notch signalling reverses the effect of ablation of KRT5 on melanogenesis. Immunohistochemistry of DDD lesions with KRT5 gene mutation confirmed changes in the expression of relevant molecules in Notch signalling. Our research elucidates molecular mechanism of KRT5-Notch signalling pathway in the regulation of melanocytes by keratinocytes, and preliminary reveal the mechanism of DDD pigment abnormality caused by KRT5 mutation. These findings identify potential therapeutic targets of the Notch signalling pathway for the treatment of skin pigment disorders.

Hordenine improves Parkinsonian-like motor deficits in mice and nematodes by activating dopamine D2 receptor-mediated signaling.

Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the striatum, leading to dopamine (DA) deficiency in the striatum and typical motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine (HOR) is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer, a widely consumed beverage. This study was aimed to identify HOR as a dopamine D2 receptor (DRD2) agonist in living cells, and investigate the alleviative effect and mechanism of HOR on PD-like motor deficits in mice and nematodes. Our results firstly showed that HOR is an agonist of DRD2, but not DRD1, in living cells. Moreover, HOR could improve the locomotor dysfunction, gait, and postural imbalance in MPTP- or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway in C. elegans. Our results suggested that HOR could activate DRD2 to attenuate the PD-like motor deficits, and provide scientific evidence for the safety and reliability of HOR as a dietary supplement.

Multi-Omics Research Strategies for Psoriasis and Atopic Dermatitis.

Psoriasis and atopic dermatitis (AD) are multifactorial and heterogeneous inflammatory skin diseases, while years of research have yielded no cure, and the costs associated with caring for people suffering from psoriasis and AD are a huge burden on society. Integrating several omics datasets will enable coordinate-based simultaneous analysis of hundreds of genes, RNAs, chromatins, proteins, and metabolites in particular cells, revealing networks of links between various molecular levels. In this review, we discuss the latest developments in the fields of genomes, transcriptomics, proteomics, and metabolomics and discuss how they were used to identify biomarkers and understand the main pathogenic mechanisms underlying these diseases. Finally, we outline strategies for achieving multi-omics integration and how integrative omics and systems biology can advance our knowledge of, and ability to treat, psoriasis and AD.

A New Galactoglucomannan from the Mycelium of the Medicinal Parasitic Fungus Cordyceps cicadae and Its Immunomodulatory Activity In Vitro and In Vivo.

A new galactoglucomannan (C-0-1) was purified from the medicinal parasitic fungus of Cordyceps cicadae using an anion-exchange column and gel permeation column. The results of high-performance liquid chromatography and high-performance gel permeation chromatography indicated that C-0-1 consists of galactose, glucose, and mannose in a ratio of 5:1:4 and has a molecular weight of 23.3 kDa. The combined structural elucidation analysis methods including partial acid hydrolysis, methylation analysis, and NMR experiments revealed that C-0-1 was a comb-like polysaccharide with a core structure including (1→2)-α-D-Manp residues in the backbone and branches at O-6 of the main chain. (1→4)-α-D-Glcp, (1→2)-ß-D-Galf, (1→2,6)-ß-D-Galf, and terminal ß-Galf were located at the side chains. An in vitro experiment using RAW 264.7 cells indicated that C-0-1 exhibits good immunomodulatory activity by enhancing inducible nitric oxide synthase secretion and the production of some major inflammatory cytokines. On inhibiting the cytokine production using anti-pattern recognition receptors antibodies, it was revealed that the activation of macrophages is mainly carried out by C-0-1 through the mannose receptor. Toll-like receptor 4 and Toll-like receptor 2 were also involved in this identification process. An in vivo experiment on immunosuppressive mice treated with cyclophosphamide indicated that C-0-1 improves the secretion of serum-related cytokines (IFN-γ, TNF-α, IL-2, IL-4, and IL-10) and affects the balance of T helper cells Th1/Th2. Given the structural and bioactivity similarity between Cordyceps cicadae and Cordyceps sinensis, we can conclude that Cordyceps cicadae could be used as an important medicinal fungus like Cordyceps sinensis.

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors.

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays in vitro. Among them, compounds H34, H42, H48, and H52 displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays in vitro and in vivo proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound H52 exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.HIGHLIGHTSStructural fusion was used to screen brain penetrating PARP-1 inhibitors.55 benzodiazepines were evaluated for their PARP-1 inhibition activity.Four compounds displayed acceptable inhibition effects on breast cancer cells.The benzodiazepine PARP-1 inhibitors were proved to be brain permeable.

LXRα/ß Antagonism Protects against Lipid Accumulation in the Liver but Increases Plasma Cholesterol in Rhesus Macaques.

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver and associates with obesity, hyperlipidemia, and insulin resistance. NAFLD could lead to nonalcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and even cancers. The development of therapy for NAFLD has been proven difficult. Emerging evidence suggests that liver X receptor (LXR) antagonist is a potential treatment for fatty liver disease. However, concerns about the cholesterol-increasing effects make it questionable for the development of LXR antagonists. Here, the overweight monkeys were fed with LXRß-selective antagonist sophoricoside or LXRα/ß dual-antagonist morin for 3 months. The morphology of punctured liver tissues was examined by H&E staining. The liver, heart, and kidney damage indices were analyzed using plasma. The blood index was assayed using complete blood samples. We show that LXRß-selective antagonist sophoricoside and LXRα/ß dual-antagonist morin alleviated lipid accumulation in the liver in overweight monkeys. The compounds resulted in higher plasma TC or LDL-c contents, increased white blood cell and lymphocyte count, and decreased neutrophile granulocyte count in the monkeys. The compounds did not alter plasma glucose, apolipoprotein A (ApoA), ApoB, ApoE, lipoprotein (a) (LPA), nonesterified fatty acid (NEFA), aspartate transaminases (AST), creatinine (CREA), urea nitrogen (UN), and creatine kinase (CK) levels. Our data suggest that LXRß-selective and LXRα/ß dual antagonism may lead to hypercholesterolemia in nonhuman primates, which calls into question the development of LXR antagonist as a therapy for NAFLD.

A piggyBac-based TANGO GFP assay for high throughput screening of GPCR ligands in live cells.

BACKGROUND: GPCRs are considered essential for various physiological processes and have been the most productive drug targets. Therefore, development of the methods of GPCR ligands screening is a high priority for pharmaceutical industries and research institutions. METHODS: We developed a potential method (piggyBac-TANGO) based on the TANGO and PRESTO-TANGO assays. The system was optimized with a piggyBac transposon as a transgene vehicle, and eGFP was used as a reporter instead of luciferase. The assay was validated in the HEK 293T and U87-MG cell lines and antagonist activities of the compounds were assessed. The transgene copy number and long-term stability were evaluated by qPCR. Then, we performed a DRD2-targeted screening for natural products using the piggyBac-TANGO assay. RESULTS: The validation assay showed that using the piggyBac transposon as a transgene vehicle produced high signal-to-background ratio and stable readout confirmed by investigation of the transgene copy number and long-term stability. Use of eGFP instead of luciferase as a reporter enabled to create a high throughput system suitable for live cells. Moreover, the piggyBac-TANGO assay permitted versatile detection of antagonist activity of compounds and was not limited to a particular cell type. With the use of the piggyBac-TANGO assay, we have successfully identified a novel agonist of DRD2. CONCLUSION: Thus, the results indicate that the piggyBac-TANGO method is a user-friendly, robust and imaging-based assay that provides a novel approach to high throughput GPCR-targeted ligand screening and drug development.

Asymmetric expression patterns reveal a strong maternal effect and dosage compensation in polyploid hybrid fish.

BACKGROUND: Hybridization and polyploidization are regarded as the major driving forces in plant speciation, diversification, and ecological adaptation. Our knowledge regarding the mechanisms of duplicated-gene regulation following genomic merging or doubling is primarily derived from plants and is sparse for vertebrates. RESULTS: We successfully obtained an F1 generation (including allodiploid hybrids and triploid hybrids) from female Megalobrama amblycephala Yih (BSB, 2n = 48) × male Xenocypri davidi Bleeker (YB, 2n = 48). The duplicated-gene expression patterns of the two types of hybrids were explored using RNA-Seq data. In total, 5.44 × 108 (69.32 GB) clean reads and 499,631 assembled unigenes were obtained from the testis transcriptomes. The sequence similarity analysis of 4265 orthologs revealed that the merged genomes were dominantly expressed in different ploidy hybrids. The differentially expressed genes in the two types of hybrids were asymmetric compared with those in both parents. Furthermore, the genome-wide expression level dominance (ELD) was biased toward the maternal BSB genome in both the allodiploid and triploid hybrids. In addition, the dosage-compensation mechanisms that reduced the triploid expression levels to the diploid state were determined in the triploid hybrids. CONCLUSIONS: Our results indicate that divergent genomes undergo strong interactions and domination in allopolyploid offspring. Genomic merger has a greater effect on the gene-expression patterns than genomic doubling. The various expression mechanisms (including maternal effect and dosage compensation) in different ploidy hybrids suggest that the initial genomic merger and doubling play important roles in polyploidy adaptation and evolution.

Adsorption of methyl violet onto mesoporous MCM-48 from aqueous solution.

In this study, hexadecyltrimethyl ammonium bromide and triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) were used as co-templates and tetraethoxysilane was used as silica source to synthesize mesoporous MCM-48, which was employed to adsorb methyl violet dye from water. The prepared MCM-48, after calcination at 550 degrees C, was found to have a high surface area of 1072 m2/g and a pore volume of 1.08 cm3/g. The MCM-48 adsorption of methyl violet in aqueous solution was studied using UV-visible spectrophotometry. Experimental conditions, including initial pH of sample solution, initial concentration, MCM-48 amount, adsorption time and temperature, were also investigated. Results showed that the adsorption behavior could well be depicted by Langmuir equations and pseudo-second-order kinetic model. The maximum adsorption capacity of 193.82 mg/g was obtained at 20 degrees C. The values for thermodynamic parameters deltaG0, deltaS0 and deltaH0 were all negative, showing that the MCM-48 adsorption of methyl violet was spontaneous and exothermic.

Advance in Multi-omics Research Strategies on Cholesterol Metabolism in Psoriasis.

The skin is a complex and dynamic organ where homeostasis is maintained through the intricate interplay between the immune system and metabolism, particularly cholesterol metabolism. Various factors such as cytokines, inflammatory mediators, cholesterol metabolites, and metabolic enzymes play crucial roles in facilitating these interactions. Dysregulation of this delicate balance contributes to the pathogenic pathways of inflammatory skin conditions, notably psoriasis. In this article, we provide an overview of omics biomarkers associated with psoriasis in relation to cholesterol metabolism. We explore multi-omics approaches that reveal the communication between immunometabolism and psoriatic inflammation. Additionally, we summarize the use of multi-omics strategies to uncover the complexities of multifactorial and heterogeneous inflammatory diseases. Finally, we highlight potential future perspectives related to targeted drug therapies and research areas that can advance precise medicine. This review aims to serve as a valuable resource for those investigating the role of cholesterol metabolism in psoriasis.

[Retracted] MicroRNA­671­5p inhibits cell proliferation, migration and invasion in non­small cell lung cancer by targeting MFAP3L.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data shown in Fig. 4B and the Transwell cell invasion data shown in Figs. 2D and 4E were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published elsewhere prior to the submission of this paper to Molecular Medicine Reports (one of which has been retracted). Moreover, there appeared to be inappropriately edited western blot bands featured in Figs. 4 and 5. In view of the fact that certain of the abovementioned data had already apparently been published previously, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 25: 30, 2022; DOI: 10.3892/mmr.2021.12546].

Inflammatory loop involving Staphylococcus aureus, IL-36γ, and cathepsin S drives immunity disorders in familial acne inversa keratinocytes.

Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of Staphylococcus aureus on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to S. aureus. By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with S. aureus-induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between S. aureus and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.

Mitophagy and immune infiltration in vitiligo: evidence from bioinformatics analysis.

Background: Vitiligo is an acquired, autoimmune, depigmented skin disease with unclear pathogenesis. Mitochondrial dysfunction contributes significantly to vitiligo, and mitophagy is vital for removing damaged mitochondria. Herein, using bioinformatic analysis, we sought to determine the possible role of mitophagy-associated genes in vitiligo and immune infiltration. Methods: Microarrays GSE53146 and GSE75819 were used to identify differentially expressed genes (DEGs) in vitiligo. By crossing vitiligo DEGs with mitophagy-related genes, the mitophagy-related DEGs were identified. Functional enrichment and protein-protein intersection (PPI) analyses were conducted. Then, the hub genes were identified using two machine algorithms, and receiver operating characteristic (ROC) curves were generated. Next, the immune infiltration and its connection with hub genes in vitiligo were investigated. Finally, the Regnetwork database and NetworkAnalyst were used to predict the upstream transcriptional factors (TFs), microRNAs (miRNAs), and the protein-compound network. Results: A total of 24 mitophagy-related genes were screened. Then, five mitophagy hub genes (GABARAPL2, SP1, USP8, RELA, and TBC1D17) were identified using two machine learning algorithms, and these genes showed high diagnostic specificity for vitiligo. The PPI network showed that hub genes interacted with each other. The mRNA expression levels of five hub genes were validated in vitiligo lesions by qRT-PCR and were compatible with the bioinformatic results. Compared with controls, the abundance of activated CD4+ T cells, CD8+ T cells, immature dendritic cells and B cells, myeloid-derived suppressor cells (MDSCs), gamma delta T cells, mast cells, regulatory T cells (Tregs), and T helper 2 (Th2) cells was higher. However, the abundance of CD56 bright natural killer (NK) cells, monocytes, and NK cells was lower. Correlation analysis revealed a link between hub genes and immune infiltration. Meanwhile, we predicted the upstream TFs and miRNAs and the target compounds of hub genes. Conclusion: Five hub mitophagy-related genes were identified and correlated with immune infiltration in vitiligo. These findings suggested that mitophagy may promote the development of vitiligo by activating immune infiltration. Our study might enhance our comprehension of the pathogenic mechanism of vitiligo and offer a treatment option for vitiligo.

Epidermal Cyst Mimicking Thyroid Cancer Metastasis.

ABSTRACT: A 26-year-old woman with pulmonary metastasis of thyroid cancer underwent a total thyroidectomy and cervical lymph node dissection followed by 2 courses of 131I therapy. The posttherapeutic whole-body scan after the second dose of 131I therapy showed diffuse tracer uptake in both lungs. Besides this, there is a local abnormal radiotracer uptake in the left axillary region. SPECT/CT images localized this abnormal radioactivity in a subcutaneous, oval-shaped, approximately 2.2-cm slightly hyperdense lesion, which was pathologically confirmed as an epidermal cyst.

Crosstalk between cholesterol metabolism and psoriatic inflammation.

Psoriasis is a chronic autoinflammatory skin disease associated with multiple comorbidities, with a prevalence ranging from 2 to 3% in the general population. Decades of preclinical and clinical studies have revealed that alterations in cholesterol and lipid metabolism are strongly associated with psoriasis. Cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-17), which are important in the pathogenesis of psoriasis, have been shown to affect cholesterol and lipid metabolism. Cholesterol metabolites and metabolic enzymes, on the other hand, influence not only the biofunction of keratinocytes (a primary type of cell in the epidermis) in psoriasis, but also the immune response and inflammation. However, the relationship between cholesterol metabolism and psoriasis has not been thoroughly reviewed. This review mainly focuses on cholesterol metabolism disturbances in psoriasis and their crosstalk with psoriatic inflammation.

Proprotein Convertase Furin Regulates Melanogenesis via the Notch Signaling Pathway.

BACKGROUND: Furin is a calcium-dependent serine protease found in almost all mammals. It plays an important role in embryogenesis, tissue homeostasis, tumors pathogenesis, viral infectious diseases, and neurodegenerative diseases. However, whether furin directly regulates melanin synthesis and transport has rarely been evaluated yet. The present study aimed to investigate furin potential function and mechanisms in melanogenesis. METHODS: Short hairpin RNAs targeting furin gene (sh-furin RNAs) were used to inhibit furin gene expression in human melanoma cell line MNT-1 cells. Then, intracellular melanin content was measured using a sodium hydroxide method. Extracellular melanin content was measured determining cell culture medium absorbance at 450 nm. Levodopa (L-DOPA) oxidation rate was measured to assess the tyrosinase activity. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were performed to measure melanogenesis-related genes and Notch pathway-related genes expression levels. Human primary melanocytes (MCs) were extracted from foreskin tissues and were stimulated with a furin inhibitor. Then, the extracellular and intracellular melanin content, tyrosinase activity and molecules related to melanogenesis and the Notch pathway expression were measured in MCs with or without a furin inhibitor. Additionally, morpholino technology was used to inhibit furin in zebrafish. Zebrafish pigmentary phenotypes in the control group and furin inhibition group were observed with a stereo microscope. Then, MCs number in the tail and head of the zebrafish were counted using Image J software (version 1.53t, National Institute of Health, Bethesda, MD, USA). Meanwhile, melanin content, tyrosinase activity, and molecules related to melanogenesis and the Notch pathway expression levels were measured. Subsequently, valproic acid (VPA), a Notch pathway agonist, was used in MNT-1 melanoma cells treated with or without sh-furin lentiviral vectors for rescue experiments. RESULTS: Furin inhibition enhanced intracellular and extracellular melanin content, and cellular tyrosinase activity in MNT-1 cells and MCs. Additionally, furin inhibition increased melanin synthesis-associated and transport-associated proteins expression levels while inhibiting Notch pathway-relevant proteins. After using VPA to activate the Notch pathway in MNT-1 cells transfected with a sh-furin RNA, the biological effects resulting from furin knockdown were reversed. In addition, the results of in vivo experiments using morpholino to knock down furin gene in zebrafish further confirmed that furin knockdown regulated melanogenesis and impaired the Notch pathway. CONCLUSIONS: This study clarified that furin affected the synthesis and transport of melanin via Notch pathway. Notch pathway may be a potential therapeutic target for pigmented skin diseases.

Nomilin and its analogue obacunone alleviate NASH and hepatic fibrosis in mice via enhancing antioxidant and anti-inflammation capacity.

Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis are leading causes of cirrhosis with rising morbidity and mortality worldwide. Currently, there is no appropriate treatment for NASH and hepatic fibrosis. Many studies have shown that oxidative stress is a main factor inducing NASH. Nomilin (NML) and obacunone (OBA) are limonoid compounds naturally occurring in citrus fruits with various biological properties. However, whether OBA and NML have beneficial effects on NASH remains unclear. Here, we demonstrated that OBA and NML inhibited hepatic tissue necrosis, inflammatory infiltration and liver fibrosis progression in methionine and choline-deficient (MCD) diet, carbon tetrachloride (CCl4 )-treated and bile duct ligation (BDL) NASH and hepatic fibrosis mouse models. Mechanistic studies showed that NML and OBA enhanced anti-oxidative effects, including reduction of malondialdehyde (MDA) level, increase of catalase (CAT) activity and the gene expression of glutathione S-transferases (GSTs) and Nrf2-keap1 signaling. Additional, NML and OBA inhibited the expression of inflammatory gene interleukin 6 (Il-6), and regulated the bile acid metabolism genes Cyp3a11, Cyp7a1, multidrug resistance-associated protein 3 (Mrp3). Overall, these findings indicate that NML and OBA may alleviate NASH and liver fibrosis in mice via enhancing antioxidant and anti-inflammation capacity. Our study proposed that NML and OBA may be potential strategies for NASH treatment.

Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions.

Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals' lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.

catena-Poly[[(diaqua-calcium)-bis-(µ-2-fluorobenzoato)-1':1κO:O,O';1:1''κO,O':O] 2,2'-bipyridine hemi-solvate].

In the title compound, {[Ca(C(7)H(4)FO(2))(2)(H(2)O)(2)]·0.5C(10)H(8)N(2)}(n), the Ca(II) atom is coordinated by eigth O atoms from four 2-fluoro-benzoate ligands and two water mol-ecules, resulting in a distorted CaO(8) square-anti-prismatic coordination environment. The 2-fluoro-benzoate ligand bridges two symmetry-related Ca(II) atoms, giving rise to a chain structure extending along [100]. The distances between the Ca atom and its two symmetry-related counterparts are 4.054 (2) and 4.106 (2) Å. The polymeric chains are connected by classical O-H⋯N hydrogen bonds into a layer structure parallel to (010). The layers are connected by non-classical C-H⋯F hydrogen bonds into a three-dimensional supra-molecular structure. O-H⋯O and C-H⋯O inter-actions also occur. The uncoordinated 2,2'-bipyridine mol-ecule is located on a centre of symmetry at the mid-point of the bond between the two heterocycles. One of the two benzene rings is disordered over two sites with occupancy factors of 0.60 and 0.40.

Structures, functions, and inhibitors of LUBAC and its related diseases.

Ubiquitination is a reversible posttranslational modification in which ubiquitin is covalently attached to substrates at catalysis by E1, E2, and E3 enzymes. As the only E3 ligase for assembling linear ubiquitin chains in animals, the LUBAC complex exerts an essential role in the wide variety of cellular activities. Recent advances in the LUBAC complex, including structure, physiology, and correlation with malignant diseases, have enabled the discovery of potent inhibitors to treat immune-related diseases and cancer brought by LUBAC complex dysfunction. In this review, we summarize the current progress on the structures, physiologic functions, inhibitors of LUBAC, and its potential role in immune diseases, tumors, and other diseases, providing the theoretical basis for therapy of related diseases targeting the LUBAC complex.