MITA oligomerization upon viral infection is dependent on its N-glycosylation mediated by DDOST.

The mediator of IRF3 activation (MITA, also named STING) is critical for immune responses to abnormal cytosolic DNA and has been considered an important drug target in the clinical therapy of tumors and autoimmune diseases. In the present study, we report that MITA undergoes DDOST-mediated N-glycosylation in the endoplasmic reticulum (ER) upon DNA viral infection. Selective mutation of DDOST-dependent N-glycosylated residues abolished MITA oligomerization and thereby its immune functions. Moreover, increasing the expression of Ddost in the mouse brain effectively strengthens the local immune response to herpes simplex virus-1 (HSV-1) and prolongs the survival time of mice with HSV encephalitis (HSE). Our findings reveal the dependence of N-glycosylation on MITA activation and provide a new perspective on the pathogenesis of HSE.

Aptamer-functionalized nanomaterials (AFNs) for therapeutic management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents one of the deadliest cancers globally, making the search for more effective diagnostic and therapeutic approaches particularly crucial. Aptamer-functionalized nanomaterials (AFNs), an innovative nanotechnology, have paved new pathways for the targeted diagnosis and treatment of HCC. Initially, we outline the epidemiological background of HCC and the current therapeutic challenges. Subsequently, we explore in detail how AFNs enhance diagnostic and therapeutic efficiency and reduce side effects through the specific targeting of HCC cells and the optimization of drug delivery. Furthermore, we address the challenges faced by AFNs in clinical applications and future research directions, with a particular focus on enhancing their biocompatibility and assessing long-term effects. In summary, AFNs represent an avant-garde therapeutic approach, opening new avenues and possibilities for the diagnosis and treatment of HCC.

Luteinizing hormone signaling restricts hematopoietic stem cell expansion during puberty.

The number and self-renewal capacity of hematopoietic stem cells (HSCs) are tightly regulated at different developmental stages. Many pathways have been implicated in regulating HSC development in cell autonomous manners; however, it remains unclear how HSCs sense and integrate developmental cues. In this study, we identified an extrinsic mechanism by which HSC number and functions are regulated during mouse puberty. We found that the HSC number in postnatal bone marrow reached homeostasis at 4 weeks after birth. Luteinizing hormone, but not downstream sex hormones, was involved in regulating HSC homeostasis during this period. Expression of luteinizing hormone receptor (Lhcgr) is highly restricted in HSCs and multipotent progenitor cells in the hematopoietic hierarchy. When Lhcgr was deleted, HSCs continued to expand even after 4 weeks after birth, leading to abnormally elevated hematopoiesis and leukocytosis. In a murine acute myeloid leukemia model, leukemia development was significantly accelerated upon Lhcgr deletion. Together, our work reveals an extrinsic counting mechanism that restricts HSC expansion during development and is physiologically important for maintaining normal hematopoiesis and inhibiting leukemogenesis.

Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries.

BACKGROUND AND AIMS: Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single-cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 (Tcf21) as a unique marker that restricted its expression to quiescent HSCs. APPROACH AND RESULTS: Tracing Tcf21+ cells by Tcf21-CreER (Cre-Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%-67% of all myofibroblasts in fibrotic livers and ~85% of all cancer-associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 (Tgfbr2) by Tcf21-CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression. CONCLUSIONS: In conclusion, Tcf21-CreER-targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGF-ß signaling links HSC activation to liver fibrosis and tumorigenesis.

Bioactivity-guided synthesis of gramine derivatives as new MT1 and 5-HT1A receptors agonists.

Twenty-four gramine derivatives were synthesized and evaluated on MT1 and 5-HT1A receptors in vitro. Among them, seven derivatives (7, 8, 16, 19, 20, 21, and 24) exhibited higher agonisting activities on MT1 or 5-HT1A receptors. Compared with gramine, derivatives 7, 8, 16, 19, 20, 21, and 24 displayed 1.6-3.5-fold increase in agonistic rates on 5-HT1A receptor. Particularly, derivatives 7, 19, and 21 exhibited significant agonistic activities on MT1 and 5-HT1A receptors with EC50 values of 0.51, 0.39, 0.50 mΜ and 0.28, 0.46, 0.23 mΜ, respectively. The preliminary structure-activity relationships of gramine derivatives were summarized for further investigation on MT1 and 5-HT1A receptors as new potential agonists.

Natural products as antidepressants documented in Chinese patents from 1992 to 2013.

Depressive disorder is a severe psychiatric problem all over the world. Clinical therapeutic agents for the treatment of depression in the market targeting on monoamine neurotransmitters are far from satisfaction due to their adverse effects. Novel classes of antidepressant agents with different mechanisms and low toxicity are needed. Natural products from traditional Chinese medicines have been revealed as new sources to cure the depressive symptoms with various chemical structures and promising activities. This paper reviews natural products as antidepressants documented in Chinese patents so far.

Genome-wide analysis reveals origin of transfer RNA genes from tRNA halves.

Transfer RNAs (tRNAs) play an important role linking mitochondrial RNA and amino acids during protein biogenesis. Four types of tRNA genes have been identified in living organisms. However, the evolutionary origin of tRNAs remains largely unknown. In this article, we conduct a deep sequence analysis of diverse genomes that cover all three domains of life to unveil the evolutionary history of tRNA genes from tRNA halves. tRNA half homologs were detected in diverse organisms, and some of them were expressed in mouse tissues. Continuous tRNA genes have a conserved pattern similar to indels, which is, more closely flanking regions have higher single nucleotide substitution rates, whereas tRNA half homologs do not have this pattern. In addition, tRNAs tend to break into tRNA halves when tissues are incubated in vitro, the tendency of tRNA to break into tRNA halves may be a "side-effect" of tRNA genes evolving from tRNA halves. These results suggest that modern tRNAs originated from tRNA halves through a repeat element-mediated mechanism. These findings provide insight into the evolutionary origin of tRNA genes.

Application of aptamer functionalized nanomaterials in targeting therapeutics of typical tumors.

Cancer is a major cause of human death all over the world. Traditional cancer treatments include surgery, radiotherapy, chemotherapy, immunotherapy, and hormone therapy. Although these conventional treatment methods improve the overall survival rate, there are some problems, such as easy recurrence, poor treatment, and great side effects. Targeted therapy of tumors is a hot research topic at present. Nanomaterials are essential carriers of targeted drug delivery, and nucleic acid aptamers have become one of the most important targets for targeted tumor therapy because of their high stability, high affinity, and high selectivity. At present, aptamer-functionalized nanomaterials (AFNs), which combine the unique selective recognition characteristics of aptamers with the high-loading performance of nanomaterials, have been widely studied in the field of targeted tumor therapy. Based on the reported application of AFNs in the biomedical field, we introduce the characteristics of aptamer and nanomaterials, and the advantages of AFNs first. Then introduce the conventional treatment methods for glioma, oral cancer, lung cancer, breast cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, and prostate cancer, and the application of AFNs in targeted therapy of these tumors. Finally, we discuss the progress and challenges of AFNs in this field.

Antimicrobial Photodynamic Therapy Involving a Novel Photosensitizer Combined With an Antibiotic in the Treatment of Rabbit Tibial Osteomyelitis Caused by Drug-Resistant Bacteria.

Osteomyelitis is deep tissue inflammation caused by bacterial infection. If such an infection persists, it can lead to dissolution and necrosis of the bone tissue. As a result of the extensive use of antibiotics, drug-resistant bacteria are an increasingly common cause of osteomyelitis, limiting the treatment options available to surgeons. Photodynamic antibacterial chemotherapy has attracted increasing attention as a potential alternative treatment. Its advantages are a broad antibacterial spectrum, lack of drug resistance, and lack of toxic side effects. In this study, we explored the impact of the new photosensitizer LD4 in photodynamic antimicrobial chemotherapy (PACT), both alone and in combination with an antibiotic, on osteomyelitis. A rabbit tibial osteomyelitis model was employed and microbiological, histological, and radiological studies were performed. New Zealand white rabbits (n = 36) were randomly divided into a control group, antibiotic group, PACT group and PACT + antibiotic group for treatment. In microbiological analysis, a reduction in bacterial numbers of more than 99.9% was recorded in the PACT group and the PACT + antibiotic group 5 weeks after treatment (p < 0.01). In histological analysis, repair of the damaged bone tissue was observed in the PACT group, and bone repair in the PACT + antibiotic group was even more significant. In radiological analysis, the X-ray Norden score showed that the severity of bone tissue defects or destruction followed the pattern: PACT + antibiotic group < PACT group < antibiotic group < control group.

Identification of Diagnostic Biomarkers and Their Correlation with Immune Infiltration in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of the central retina, with no suitable biomarkers for early diagnosis and treatment. This study aimed to find potential diagnostic biomarker candidates for AMD and investigate their immune-related roles in this pathology. Weight gene correlation analysis was first performed based on data from the Gene Expression Omnibus database and 20 hub genes were identified. The functional enrichment analyses showed that the innate immune response, inflammatory response, and complement activation were key pathways associated with AMD. Complement C1s (C1S), adrenomedullin (ADM), and immediate early response 5 like (IER5L) were identified as the crucial genes with favorable diagnostic values for AMD by using LASSO analysis and multiple logistic regression. Furthermore, a 3-gene model was constructed and proved to be of good diagnostic and predictive performance for AMD (AUC = 0.785, 0.840, and 0.810 in training, test, and validation set, respectively). Finally, CIBERSORT was used to evaluate the infiltration of immune cells in AMD tissues. The results showed that the NK cells, CD4 memory T cell activation, and macrophage polarization may be involved in the AMD process. C1S, ADM, and IER5L were correlated with the infiltration of the above immune cells. In conclusion, our study suggests that C1S, ADM, and IER5L are promising diagnostic biomarker candidates for AMD and may regulate the infiltration of immune cells in the occurrence and progression of AMD.

C-KIT Expression Distinguishes Fetal from Postnatal Skeletal Progenitors.

Hematopoietic stem cells (HSCs) and skeletal stem cells (SSCs) cohabit in the bone marrow. KITL (C-KIT ligand) from LEPR+ adult bone marrow stromal cells is pivotal for HSC maintenance. In contrast, it remains unclear whether KITL/C-KIT signaling also regulates SSCs. Here, we lineage traced C-KIT+ cells and found that C-KIT was expressed by fetal, but not postnatal skeletal progenitors. Fetal C-KIT+ cells gave rise to 20% of LEPR+ stromal cells in adult bone marrow, forming nearly half of all osteoblasts. Disruption of mTOR signaling in fetal C-KIT+ cells impaired bone formation. Notably, conditional deletion of Kitl from PRX1+ fetal bone marrow stromal cells, but not LEPR+ adult bone marrow stromal cells, significantly increased bone formation. Thus, our work identified C-KIT+ skeletal progenitors as an important source of bones formed during development.

N,N-Dimethyl-4-[(E)-phenyl-imino-meth-yl]aniline.

The title compound, C(15)H(16)N(2), contains two aromatic rings linked through an imino group. The mol-ecule exhibits an E configuration with respect to the C=N bond. The dihedral angle between the aromatic rings is 61.96 (1)°.

E-[4-(ß-d-Allopyranos-yloxy)phen-yl]-1-(4-chloro-phen-yl)prop-2-enone ethanol solvate.

The title compound, C(21)H(21)ClO(7)·C(2)H(5)OH was synthesized by the condensation reaction between helicid [systematic name: 4-(ß-d-allopyranos-yloxy)benzaldehyde] and 4-chloro-aceto-phen-one in ethanol. In the mol-ecular structure, the pyran-oside ring adopts a chair conformation. In the crystal structure, the molecules are linked by inter-molecular O-H⋯O hydrogen bonds involving the OH groups from the pyran-oside unit and from the ethanol solvent mol-ecule.

1-[4-(2,3,4,6-Tetra-O-acetyl-ß-d-allo-pyranos-yloxy)benzyl-idene]thio-semi-carbazide.

The title compound, C(22)H(27)N(3)O(10)S, was synthesized by reaction of an ethanol solution of helicid (systematic name: 4-formylphenl-ß-d-allopyranoside), thio-semicarbazide and acetic acid. The mol-ecule exhibits a trans conformation with respect to the C=N double bond. The pyran ring adopts a chair conformation. In the crystal structure, the mol-ecules are linked into chains parallel to the b axis by inter-molecular N-H⋯O hydrogen bonds.

(E)-4-(ß-d-Allopyran-os-yloxy)cinnamyl 4-bromo-phenyl ketone ethanol solvate.

The title compound, C(21)H(21)BrO(7)·C(2)H(6)O, was synthesized by the Claisen-Schimidt reaction of helicid (systematic name: 4-formyl-phenyl-ß-d-allopyran-oside) with 4-bromo-aceto-phenone in ethanol. The pyran ring adopts a chair conformation. In the crystal structure, mol-ecules are linked into a three-dimensional network by inter-molecular O-H⋯O hydrogen bonds.

Identification of potential diagnostic and prognostic biomarkers for prostate cancer.

Prostate cancer (PCa) is one of the most common malignant tumors worldwide. The aim of the present study was to determine potential diagnostic and prognostic biomarkers for PCa. The GSE103512 dataset was downloaded, and the differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) analyses of DEGs were performed. The result of GO analysis suggested that the DEGs were mostly enriched in 'carboxylic acid catabolic process', 'cell apoptosis', 'cell proliferation' and 'cell migration'. KEGG analysis results indicated that the DEGs were mostly concentrated in 'metabolic pathways', 'ECM-receptor interaction', the 'PI3K-Akt pathway' and 'focal adhesion'. The PPI analysis results showed that Golgi membrane protein 1 (GOLM1), melanoma inhibitory activity member 3 (MIA3), ATP citrate lyase (ACLY) and G protein subunit ß2 (GNB2) were the key genes in PCa, and the Module analysis revealed that they were associated with 'ECM-receptor interaction', 'focal adhesion', the 'PI3K-Akt pathway' and the 'metabolic pathway'. Subsequently, the gene expression was confirmed using Gene Expression Profiling Interactive Analysis and the Human Protein Atlas. The results demonstrated that GOLM1 and ACLY expression was significantly upregulated (P<0.05) in PCa compared with that in normal tissues. Receiver operating characteristic and survival analyses were performed. The results showed that area under the curve values of these genes all exceeded 0.85, and high expression of these genes was associated with poor survival in patients with PCa. In conclusion, this study identified GOLM1 and ACLY in PCa, which may be potential diagnostic and prognostic biomarker of PCa.

Cold-induced retrotransposition of fish LINEs.

Classes of retrotransposons constitute a large portion of metazoan genome. There have been cases reported that genomic abundance of retrotransposons is correlated with the severity of low environmental temperatures. However, the molecular mechanisms underlying such correlation are unknown. We show here by cell transfection assays that retrotransposition (RTP) of a long interspersed nuclear element (LINE) from an Antarctic notothenioid fish Dissostichus mawsoni (dmL1) could be activated by low temperature exposure, causing increased dmL1 copies in the host cell genome. The cold-induced dmL1 propagation was demonstrated to be mediated by the mitogen-activated protein kinases (MAPK)/p38 signaling pathway, which is activated by accumulation of reactive oxygen species (ROS) in cold-stressed conditions. Surprisingly, dmL1 transfected cells showed an increase in the number of viable cells after prolonged cold exposures than non-transfected cells. Features of cold inducibility of dmL1 were recapitulated in LINEs of zebrafish origin both in cultured cell lines and tissues, suggesting existence of a common cold-induced LINE amplification in fishes. The findings reveal an important function of LINEs in temperature adaptation and provid insights into the MAPK/p38 stress responsive pathway that shapes LINE composition in fishes facing cold stresses.

Synthesis and Cytotoxicity Evaluation of Tropinone Derivatives.

Sixteen tropinone derivatives were prepared, and their antitumor activities against five human cancer cells (HL-60, A-549, SMMC-7721, MCF-7 and SW480) were evaluated with MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium] assay. Most of the derivatives exhibited better activities compared with tropinone at the concentration of 40 µM. Particularly, derivative 6 showed significant activities with IC50 values of 3.39, 13.59, 6.65, 13.09 and 12.38 µM respectively against HL-60, A-549, SMMC-7721, MCF-7 and SW480 cells, which suggested more potent activities than that of cis-dichlorodiamineplatinum (DDP).

Catalytic Asymmetric Total Synthesis of (+)- and (-)-Paeoveitol via a Hetero-Diels-Alder Reaction.

The first catalytic asymmetric total synthesis of (+)- and (-)-paeoveitol has been accomplished in 42% overall yield via a biomimetic hetero-Diels-Alder reaction. The chiral phosphoric acid catalyzed hetero-Diels-Alder reaction showed excellent diastereo- and enantioselectivity (>99:1 dr and 90% ee); two rings and three stereocenters were constructed in a single step to produce (-)-paeoveitol on a scale of 452 mg. This strategy enabled us to selectively synthesize both paeoveitol enantiomers from the same substrates by simply changing the enantiomer of the catalyst.

Bioassay-guided isolation of saikosaponins with agonistic activity on 5-hydroxytryptamine 2C receptor from Bupleurum chinense and their potential use for the treatment of obesity.

5-Hydroxytryptamine 2C (5-HT2C) receptor is one of the major targets of anti-obesity agents, due to its role in regulation of appetite. In the present study, the 70% EtOH extract of the roots of Bupleurum chinense was revealed to have agonistic activity on 5-HT2C receptor, and the subsequent bioassay-guided isolation led to identification of several saikosaponins as the active constituents with 5-HT2C receptor agonistic activity in vitro and anti-obesity activity in vivo. The new compound, 22-oxosaikosaponin d (1), was determined by extensive spectroscopic analyses (HR-ESI-MS, IR, and 1D and 2D NMR). The primary structure-activity relationship study suggested that the intramolecular ether bond between C-13 and C-28 and the number of sugars at C-3 position were closely related to the 5-HT2C receptor agonistic activity. Saikosaponin a (3), the main saponin in B. chinense, showed obviously agonistic activity on 5-HT2C receptor with an EC50 value of 21.08 ± 0.33 µmol·L-1in vitro and could reduce food intake by 39.1% and 69.2%, and weight gain by 13.6% and 16.4%, respectively, at 3.0 and 6.0 mg·kg-1in vivo. This investigation provided valuable information for the potential use of B. chinense as anti-obesity agent.