Cadmium induced changes in rhizosphere microecology to enhance Cd intake by Ligusticum sinense cv. Chuanxiong.

As the most famous and widely used traditional Chinese medicine (TCM), Ligusticum sinense cv. Chuanxiong (L. Chuaniong) has been affected by cadmium (Cd) exceeding with high ability of Cd accumulation. There is relatively little research on Cd absorption and storage process in L. Chuanxiong, which is an important reason for the poor remediation efficiency. Hence, this study takes L. Chuanxiong as the point of penetration to explore how L. Chuanxiong affects rhizobacteria through root exudates to alter soil Cd intake, as well as to explore the migration and storage of Cd in its body with 0.10 (T0), 5.00 (T5), 10.00 (T10) mg/kg Cd contaminations. The results showed that the relative abundance of amino acids and phospholipids secreted from L. Chuanxiong root noticeably increased with increasing Cd levels, which directly activated soil Cd or extremely significantly (P < 0.01) recruited bacteria such as Bacillus, Arthrobacter to indirectly increase Cd availability. Under the interaction of root exudates and rhizobacteria, Cd bioavailability increased by 80.00% in rhizosphere soil and Cd accumulation in L. Chuanxiong increased 5.44-6.65 mg/kg. Cd subcellular distribution analysis demonstrated that Cd was mainly stored in the root (10-fold more than in the leaf), whose Cd content was cytoderm>cytoplasm>organelle in tissues. The sequential extraction results found that non-soluble phosphate and protein-chelated Cd dominated (85.00-90.00%) in the cell, while Cd cheated with alcohol soluble protein, amino acid salts, water-soluble organic acid in cell was minimal (5.50%). The phenomenon indicated that L. Chuanxiong fixed Cd in root (the medical part) with low translocation ability. This study can provide theoretical support for the high-quality production of L. Chuanxiong and other root medical plant in heavy metal influenced sites.

Hepatoprotective Effect of Medicine Food Homology Flower Saffron against CCl4-Induced Liver Fibrosis in Mice via the Akt/HIF-1α/VEGF Signaling Pathway.

Liver fibrosis refers to a complex inflammatory response caused by multiple factors, which is a known cause of liver cirrhosis and even liver cancer. As a valuable medicine food homology herb, saffron has been widely used in the world. Saffron is commonly used in liver-related diseases and has rich therapeutic and health benefits. The therapeutic effect is satisfactory, but its mechanism is still unclear. In order to clarify these problems, we planned to determine the pharmacological effects and mechanisms of saffron extract in preventing and treating liver fibrosis through network pharmacology analysis combined with in vivo validation experiments. Through UPLC-Q-Exactive-MS analysis, a total of fifty-six nutrients and active ingredients were identified, and nine of them were screened to predict their therapeutic targets for liver fibrosis. Then, network pharmacology analysis was applied to identify 321 targets for saffron extract to alleviate liver fibrosis. Functional and pathway enrichment analysis showed that the putative targets of saffron for the treatment of hepatic fibrosis are mainly involved in the calcium signaling pathway, the HIF-1 signaling pathway, endocrine resistance, the PI3K/Akt signaling pathway, lipid and atherosclerosis, and the cAMP signaling pathway. Based on the CCl4-induced liver fibrosis mice model, we experimentally confirmed that saffron extract can alleviate the severity and pathological changes during the progression of liver fibrosis. RT-PCR and Western blotting analysis confirmed that saffron treatment can prevent the CCl4-induced upregulation of HIF-1α, VEGFA, AKT, and PI3K, suggesting that saffron may regulate AKT/HIF-1α/VEGF and alleviate liver fibrosis.

The synthesis of Paris saponin VII mainly occurs in leaves and is promoted by light intensity.

Unraveling the specific organs and tissues involved in saponin synthesis, as well as the light regulatory mechanisms, is crucial for improving the quality of artificially cultivated medicinal materials of Paris plants. Paris saponin VII (PS VII), a high-value active ingredient, is found in almost all organs of Paris plant species. In this study, we focused on Paris polyphylla var. yunnanensis (Franch.) Hand. - Mzt. (PPY) and found that PS VII synthesis predominantly occurs in leaves and is increased by high light intensity. This intriguing discovery has unveiled the potential for manipulating non-traditional medicinal organ leaves to improve the quality of medicinal organ rhizomes. The analysis of the impact of organ differences on saponin concentration in P. polyphylla var. chinensis (Franch.) Hara (PPC), P. fargesii Franch. (PF), and PPY revealed consistency among the three Paris species and was mainly dominated by PS VII. Notably, the leaves and stems exhibited much higher proportions of PS VII than other organs, accounting for 80-90% of the four main saponins. Among the three Paris species, PPY had the highest concentration of PS VII and was selected for subsequent experiments. Further investigations on saponin subcellular localization, temporal variation, and stem wound fluid composition demonstrated that PS VII is synthesized in mesophyll cells, released into the intercellular space through exocytosis, and then transported to the rhizome via vascular tissue. These findings confirm the significant role of leaves in PS VII synthesis. Additionally, a 13C-glucose feeding to trace PS VII biosynthesis revealed that only PS VII in the leaves exhibited incorporation of the labeled carbon, despite conducting 13C-glucose feeding in leaves, stems, rhizomes, and roots. Thus, the leaves are indeed the primary organ for PS VII synthesis in PPY. Furthermore, compared with plants under 100 µmol m-2 s-1, plants under 400 µmol m-2 s-1 exhibited a higher PS VII concentration, particularly in the upper epidermal cells of the leaves. We propose that high light intensity promotes PS VII synthesis in leaves through three mechanisms: (1) increased availability of substrates for saponin synthesis; (2) protection of leaves from high light damage through enhanced saponin synthesis; and (3) enhanced compartmentalization of saponins within the leaves, which in turn feedback regulates saponin synthesis.

A novel deformable liposomal hydrogel loaded with a SREBP-1-inhibiting polypeptide for reducing sebum synthesis in golden hamster model.

Excessive sebum is the major factor involved in the pathophysiology of seborrheic diseases. Chemical medicines can result in mild to severe side effects. Polypeptides with much less side effects make them ideal for reducing sebum synthesis. Sterol regulatory element-binding proteins-1 (SREBP-1) is necessary for the biosynthesis of sterols. A SREBP-1-inhibiting polypeptide (SREi), which competitively inhibits the ubiquitination of Insig-1 so as to suppress the activation of SREBP-1 was selected as an active ingredient and formulated into skin topical preparations. The SREi anionic deformable liposomes contained sodium deoxycholate (SDCh) at the concentration of 4.4 mg/mL (SREi-ADL3) and SREi-ADL3 in 0.3% (w/v) carbomer hydrogel (SREi-ADL3-GEL) were prepared and characterized. The SREi-ADL3 presented a high entrapment efficiency of 92.62 ± 6.32%, a particle size of 99.54 ± 7.56 nm and a surface charge of -19.18 ± 0.45 mV. SREi-ADL3-GEL exhibited a sustained release behavior, a higher stability, a much more cellular uptake ability and transdermal absorption. In vivo golden hamster model confirmed that SREi-ADL3-GEL presented the strongest inhibitory effect on sebaceous gland growth and sebum synthesis by down-regulating the mRNA and protein expression of SREBP-1, fatty acid synthase (FAS) and acetyl-coenzyme A carboxylase 1 (ACC1). As confirmed by histological analysis, only a small amount of sebaceous gland lobes with the lightest staining intensity and the smallest dyeing area could be observed in the SREi-ADL3-GEL group. Taken together, SREi-ADL3-GEL displayed potential applications in sebum excessive production related diseases.

Influence of chronic diseases on the occurrence of depression: A 13-year follow-up study from the Survey of Health, Ageing and Retirement in Europe.

The causal association between chronic diseases and depression remains unclear. This study aimed to explore the effects of types and number of chronic diseases on the risk of depression using data from the Survey of Health, Ageing and Retirement in Europe (SHARE). A self-admitted questionnaire was used to obtain data on 14 predefined chronic diseases and the European-Depression Scale (EURO-D) was used to assess depression. Among the 16,080 baseline depression-free participants aged 50+, 31.29% (5032) developed depression over 13 years. Multivariate Cox regression models showed that individuals with any chronic diseases were at higher risk of new onset depression compared to disease-free participants. The risk of new onset depression increased with an increasing number of diseases among both younger (50-64) and older (65+) adults. Individuals with heart attack, stroke, diabetes, chronic lung disease, and arthritis were at increased risk of depression across age groups. However, some age-specific associations were observed, with cancer increasing depression risk among younger- and peptic ulcer, Parkinson's disease and cataracts increasing depression risk among older adults. These findings highlight the importance of managing chronic diseases, especially among those with more than two diseases, to prevent the development of depression among middle-aged and older adults.

Perturbations in fatty acid metabolism and collagen production infer pathogenicity of a novel MBTPS2 variant in Osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heritable and chronically debilitating skeletal dysplasia. Patients with OI typically present with reduced bone mass, tendency for recurrent fractures, short stature and bowing deformities of the long bones. Mutations causative of OI have been identified in over 20 genes involved in collagen folding, posttranslational modification and processing, and in bone mineralization and osteoblast development. In 2016, we described the first X-linked recessive form of OI caused by MBTPS2 missense variants in patients with moderate to severe phenotypes. MBTPS2 encodes site-2 protease, a Golgi transmembrane protein that activates membrane-tethered transcription factors. These transcription factors regulate genes involved in lipid metabolism, bone and cartilage development, and ER stress response. The interpretation of genetic variants in MBTPS2 is complicated by the gene's pleiotropic properties; MBTPS2 variants can also cause the dermatological conditions Ichthyosis Follicularis, Atrichia and Photophobia (IFAP), Keratosis Follicularis Spinulosa Decalvans (KFSD) and Olmsted syndrome (OS) without skeletal abnormalities typical of OI. Using control and patient-derived fibroblasts, we previously identified gene expression signatures that distinguish MBTPS2-OI from MBTPS2-IFAP/KFSD and observed stronger suppression of genes involved in fatty acid metabolism in MBTPS2-OI than in MBTPS2-IFAP/KFSD; this was coupled with alterations in the relative abundance of fatty acids in MBTPS2-OI. Furthermore, we observed a reduction in collagen deposition in the extracellular matrix by MBTPS2-OI fibroblasts. Here, we extrapolate our observations in the molecular signature unique to MBTPS2-OI to infer the pathogenicity of a novel MBTPS2 c.516A>C (p.Glu172Asp) variant of unknown significance in a male proband. The pregnancy was terminated at gestational week 21 after ultrasound scans showed bowing of femurs and tibiae and shortening of long bones particularly of the lower extremity; these were further confirmed by autopsy. By performing transcriptional analyses, gas chromatography-tandem mass spectrometry-based quantification of fatty acids and immunocytochemistry on fibroblasts derived from the umbilical cord of the proband, we observed perturbations in fatty acid metabolism and collagen production similar to what we previously described in MBTPS2-OI. These findings support pathogenicity of the MBTPS2 variant p.Glu172Asp as OI-causative and highlights the value of extrapolating molecular signatures identified in multiomics studies to characterize novel genetic variants.

Resveratrol Alleviates Advanced Glycation End-Products-Related Renal Dysfunction in D-Galactose-Induced Aging Mice.

The elderly have higher concentrations of advanced glycation end-products (AGEs). AGEs are considered risk factors that accelerate aging and cause diabetic nephropathy. The effects of AGEs on renal function in the elderly remain to be clarified. This study aimed to explore the role of AGEs in renal function decline in the elderly and the protective effect of resveratrol, a stilbenoid polyphenol, comparing it with aminoguanidine (an AGEs inhibitor). A D-galactose-induced aging mouse model was used to explore the role of AGEs in the process of renal aging. The mice were administered D-galactose subcutaneously for eight weeks in the presence or absence of orally administered aminoguanidine or resveratrol. The results showed that the serum levels of AGEs and renal function markers BUN, creatinine, and cystatin C in the mice significantly increased after the administration of D-galactose, and this outcome could be significantly reversed by treatment with aminoguanidine or resveratrol. The protein expression levels for apoptosis, fibrosis, and aging-related indicators in the kidneys were significantly increased, which could also be reversed by treatment with aminoguanidine or resveratrol. These findings suggest that resveratrol could alleviate AGEs-related renal dysfunction through the improvement of renal cellular senescence, apoptosis, and fibrosis in D-galactose-induced aging in mice.

Genomic, transcriptomic, and epigenomic analysis of a medicinal snake, Bungarus multicinctus, to provides insights into the origin of Elapidae neurotoxins.

The many-banded krait, Bungarus multicinctus, has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia. Characterization of its venoms classified chief phyla of modern animal neurotoxins. However, the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome. Here, we present the 1.58 Gbp genome of B. multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp. Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications. The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins (3FTxs) from membrane tethering before the Colubroidea divergence. Subsequent expansion and mutations diversified and recruited these 3FTxs. After the cobra/krait divergence, the modern unit-B of ß-bungarotoxin emerged with an extra cysteine residue. A subsequent point substitution in unit-A enabled the ß-bungarotoxin covalent linkage. The B. multicinctus gene expression, chromatin topological organization, and histone modification characteristics were featured by transcriptome, proteome, chromatin conformation capture sequencing, and ChIP-seq. The results highlighted that venom production was under a sophisticated regulation. Our findings provide new insights into snake neurotoxin research, meanwhile will facilitate antivenom development, toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.

Identification of phytochemical compounds of Fagopyrum dibotrys and their targets by metabolomics, network pharmacology and molecular docking studies.

Acute lung injury (ALI) is a clinically severe lung illness with high incidence rate and mortality. Especially, coronavirus disease 2019 (COVID-19) poses a serious threat to world wide governmental fitness. It has distributed to almost from corner to corner of the universe, and the situation in the prevention and control of COVID-19 remains grave. Traditional Chinese medicine plays a vital role in the precaution and therapy of sicknesses. At present, there is a lack of drugs for treating these diseases, so it is necessary to develop drugs for treating COVID-19 related ALI. Fagopyrum dibotrys (D. Don) Hara is an annual plant of the Polygonaceae family and one of the long-history used traditional medicine in China. In recent years, its rhizomes (medicinal parts) have attracted the attention of scholars at home and abroad due to their significant anti-inflammatory, antibacterial and anticancer activities. It can work on SARS-COV-2 with numerous components, targets, and pathways, and has a certain effect on coronavirus disease 2019 (COVID-19) related acute lung injury (ALI). However, there are few systematic studies on its aerial parts (including stems and leaves) and its potential therapeutic mechanism has not been studied. The phytochemical constituents of rhizome of F. dibotrys were collected using TCMSP database. And metabolites of F. dibotrys' s aerial parts were detected by metabonomics. The phytochemical targets of F. dibotrys were predicted by the PharmMapper website tool. COVID-19 and ALI-related genes were retrieved from GeneCards. Cross targets and active phytochemicals of COVID-19 and ALI related genes in F. dibotrys were enriched by gene ontology (GO) and KEGG by metscape bioinformatics tools. The interplay network entre active phytochemicals and anti COVID-19 and ALI targets was established and broke down using Cytoscape software. Discovery Studio (version 2019) was used to perform molecular docking of crux active plant chemicals with anti COVID-19 and ALI targets. We identified 1136 chemicals from the aerial parts of F. dibotrys, among which 47 were active flavonoids and phenolic chemicals. A total of 61 chemicals were searched from the rhizome of F. dibotrys, and 15 of them were active chemicals. So there are 6 commonly key active chemicals at the aerial parts and the rhizome of F. dibotrys, 89 these phytochemicals's potential targets, and 211 COVID-19 and ALI related genes. GO enrichment bespoken that F. dibotrys might be involved in influencing gene targets contained numerous biological processes, for instance, negative regulation of megakaryocyte differentiation, regulation of DNA metabolic process, which could be put down to its anti COVID-19 associated ALI effects. KEGG pathway indicated that viral carcinogenesis, spliceosome, salmonella infection, coronavirus disease - COVID-19, legionellosis and human immunodeficiency virus 1 infection pathway are the primary pathways obsessed in the anti COVID-19 associated ALI effects of F. dibotrys. Molecular docking confirmed that the 6 critical active phytochemicals of F. dibotrys, such as luteolin, (+) -epicatechin, quercetin, isorhamnetin, (+) -catechin, and (-) -catechin gallate, can combine with kernel therapeutic targets NEDD8, SRPK1, DCUN1D1, and PARP1. In vitro activity experiments showed that the total antioxidant capacity of the aerial parts and rhizomes of F. dibotrys increased with the increase of concentration in a certain range. In addition, as a whole, the antioxidant capacity of the aerial part of F. dibotrys was stronger than that of the rhizome. Our research afford cues for farther exploration of the anti COVID-19 associated ALI chemical compositions and mechanisms of F. dibotrys and afford scientific foundation for progressing modern anti COVID-19 associated ALI drugs based on phytochemicals in F. dibotrys. We also fully developed the medicinal value of F. dibotrys' s aerial parts, which can effectively avoid the waste of resources. Meanwhile, our work provides a new strategy for integrating metabonomics, network pharmacology, and molecular docking techniques which was an efficient way for recognizing effective constituents and mechanisms valid to the pharmacologic actions of traditional Chinese medicine.

Efficient Delivery of Gemcitabine by Estrogen Receptor-Targeted PEGylated Liposome and Its Anti-Lung Cancer Activity In Vivo and In Vitro.

Lung cancer is one of the main causes of cancer-related deaths. At present, the main treatment method for lung cancer is chemotherapy. Gemcitabine (GEM) is widely applied in lung cancer treatment, but its lack of targeting ability and serious side effects limit its application. In recent years, nanocarriers have become the focus of research to solve the above problems. Here, we prepared estrone (ES)-modified GEM-loaded PEGylated liposomes (ES-SSL-GEM) for enhanced delivery by identifying the overexpressed estrogen receptor (ER) on lung cancer A549 cells. We studied the characterization, stability, release behavior, cytotoxicity, targeting ability, endocytosis mechanism, and antitumor ability to prove the therapeutic effect of ES-SSL-GEM. The results showed that ES-SSL-GEM presented a uniform particle size of 131.20 ± 0.62 nm, a good stability, and a slowly released behavior. Moreover, ES-SSL-GEM enhanced tumor-targeting ability, and the endocytosis mechanism studies confirmed that the ER-mediated endocytosis had the most crucial effect. Furthermore, ES-SSL-GEM had the best inhibitory effect on A549 cell proliferation and significantly suppressed the tumor growth in vivo. These results suggest that ES-SSL-GEM is a promising agent for treating lung cancer.

A novel estrogen-targeted PEGylated liposome co-delivery oxaliplatin and paclitaxel for the treatment of ovarian cancer.

Ovarian cancer is the second cause of death among gynecological malignancies. In this study, we designed a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin and paclitaxel (ES-SSL-OXA/PTX) which could target estrogen receptor (ER) highly expressed on the surface of SKOV-3 cells to enhance therapeutic efficacy and reduce the side effects for SKOV-3 tumor therapy. ES-SSL-OXA/PTX was prepared by thin film hydration method and exhibited a uniform spherical morphology. Encapsulation efficiency (EE) were determined by HPLC method with the results of 44.10% for OXA and 65.85% for PTX. The mean particle size and polydispersity index (PDI) were 168.46 nm and 0.145, respectively. In vivo and in vitro targeting study confirmed that ES-SSL-OXA/PTX has optimum specific targeting ability. Meanwhile, In vitro and in vivo antitumor results of ES-SSL-OXA/PTX exhibited a superior antiproliferative effect on SKOV-3 cells and a stronger anti-tumor efficacy with the tumor inhibition rate of 85.24%. The pharmacokinetics results of ES-SSL-OXA/PTX showed a prolonged half-life time and a slowed clearance rate. The preliminary safety study of acute toxicity and long-term toxicity demonstrated ES-SSL-OXA/PTX exhibited a reduced toxicity profile. Based on the above results, ES-SSL-OXA/PTX could be a promising novel formulation for the treatment of ovarian cancer in future clinic.

AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage.

The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC50 < 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC.

Machine learning and bioinformatics-based insights into the potential targets of saponins in Paris polyphylla smith against non-small cell lung cancer.

Background: Lung cancer has the highest mortality rate among cancers worldwide, and non-small cell lung cancer (NSCLC) is the major lethal factor. Saponins in Paris polyphylla smith exhibit antitumor activity against non-small cell lung cancer, but their targets are not fully understood. Methods: In this study, we used differential gene analysis, lasso regression analysis and support vector machine recursive feature elimination (SVM-RFE) to screen potential key genes for NSCLC by using relevant datasets from the GEO database. The accuracy of the signature genes was verified by using ROC curves and gene expression values. Screening of potential active ingredients for the treatment of NSCLC by molecular docking of the reported active ingredients of saponins in Paris polyphylla Smith with the screened signature genes. The activity of the screened components and their effects on key genes expression were further validated by CCK-8, flow cytometry (apoptosis and cycling) and qPCR. Results: 204 differential genes and two key genes (RHEBL1, RNPC3) stood out in the bioinformatics analysis. Overall survival (OS), First-progression survival (FP) and post-progression survival (PPS) analysis revealed that low expression of RHEBL1 and high expression of RNPC3 indicated good prognosis. In addition, Polyphyllin VI(PPVI) and Protodioscin (Prot) effectively inhibited the proliferation of non-small cell lung cancer cell line with IC50 of 4.46 µM ± 0.69 µM and 8.09 µM ± 0.67µM, respectively. The number of apoptotic cells increased significantly with increasing concentrations of PPVI and Prot. Prot induces G1/G0 phase cell cycle arrest and PPVI induces G2/M phase cell cycle arrest. After PPVI and Prot acted on this cell line for 48 h, the expression of RHEBL1 and RNPC3 was found to be consistent with the results of bioinformatics analysis. Conclusion: This study identified two potential key genes (RHEBL1 and RNPC3) in NSCLC. Additionally, PPVI and Prot may act on RHEBL1 and RNPC3 to affect NSCLC. Our findings provide a reference for clinical treatment of NSCLC.

Ibrutinib Prevents Acute Lung Injury via Multi-Targeting BTK, FLT3 and EGFR in Mice.

Ibrutinib has potential therapeutic or protective effects against viral- and bacterial-induced acute lung injury (ALI), likely by modulating the Bruton tyrosine kinase (BTK) signaling pathway. However, ibrutinib has multi-target effects. Moreover, immunity and inflammation targets in ALI treatment are poorly defined. We investigated whether the BTK-, FLT3-, and EGFR-related signaling pathways mediated the protective effects of ibrutinib on ALI. The intratracheal administration of poly I:C or LPS after ibrutinib administration in mice was performed by gavage. The pathological conditions of the lungs were assessed by micro-CT and HE staining. The levels of neutrophils, lymphocytes, and related inflammatory factors in the lungs were evaluated by ELISA, flow cytometry, immunohistochemistry, and immunofluorescence. Finally, the expression of proteins associated with the BTK-, FLT3-, and EGFR-related signaling pathways were evaluated by Western blotting. Ibrutinib (10 mg/kg) protected against poly I:C-induced (5 mg/kg) and LPS-induced (5 mg/kg) lung inflammation. The wet/dry weight ratio (W/D) and total proteins in the bronchoalveolar lavage fluid (BALF) were markedly reduced after ibrutinib (10 mg/kg) treatment, relative to the poly I:C- and LPS-treated groups. The levels of ALI indicators (NFκB, IL-1ß, IL-6, TNF-α, IFN-γ, neutrophils, and lymphocytes) were significantly reduced after treatment. Accordingly, ibrutinib inhibited the poly I:C- and LPS-induced BTK-, FLT3-, and EGFR-related pathway activations. Ibrutinib inhibited poly I:C- and LPS-induced acute lung injury, and this may be due to its ability to suppress the BTK-, FLT3-, and EGFR-related signaling pathways. Therefore, ibrutinib is a potential protective agent for regulating immunity and inflammation in poly I:C- and LPS-induced ALI.

Comprehensive review of two groups of flavonoids in Carthamus tinctorius L.

Safflower (Carthamus tinctorius L.) is cultivated in various countries for the flavonoid compounds it contains. These flavonoids have been used in many industries as drugs and/or dyes. Over 60 flavonoids have been isolated from safflower. These flavonoids can be divided into two groups: special and common, both of which are active pharmaceutical ingredients efficacious in the treatment of cardiovascular and cerebrovascular diseases. Gene functions have been studied to figure out the biosynthesis of flavonoids in safflower. However, there is no comprehensive summary of the flavonoids in safflower. Research was recognised through systematic searches of ScienceDirect, PubMed, Web of Science, and CNKI databases by searching terms of "Carthamus tinctorius L.", "safflower", "flavonoid", "pharmacology", and "gene". More than 200 research reports were included after eligibility checks. This study summarizes the application of flavonoids in medicine and other industries. Comprehensively collects the chemical structure information of the two groups of flavonoids, and organic acids, alkaloids, spermidine, polyacetylene, and polysaccharides. The mechanism of two groups of flavonoids in treatment of cardiovascular and cerebrovascular diseases was describe in detail, and pharmacological mechanisms of protecting liver, lung and bone, and anti-cancer and anti-inflammatory were also summarised. Besides, the study updated the latest information on the molecular biology of safflower flavonoids. It is found that two groups of flavonoids in safflower have obvious differences in application, chemical structure, pharmacological mechanism, and biosynthetic pathway. It is hoped that this summative research will provide a new insight to flavonoids research in safflower.

In Silico Identification and Validation of Cuproptosis-Related LncRNA Signature as a Novel Prognostic Model and Immune Function Analysis in Colon Adenocarcinoma.

Background: Colon adenocarcinoma (COAD) is the most common subtype of colon cancer, and cuproptosis is a recently newly defined form of cell death that plays an important role in the development of several malignant cancers. However, studies of cuproptosis-related lncRNAs (CRLs) involved in regulating colon adenocarcinoma are limited. The purpose of this study is to develop a new prognostic CRLs signature of colon adenocarcinoma and explore its underlying biological mechanism. Methods: In this study, we downloaded RNA-seq profiles, clinical data and tumor mutational burden (TMB) data from the TCGA database, identified cuproptosis-associated lncRNAs using univariate Cox, lasso regression analysis and multivariate Cox analysis, and constructed a prognostic model with risk score based on these lncRNAs. COAD patients were divided into high- and low-risk subgroups based on the risk score. Cox regression was also used to test whether they were independent prognostic factors. The accuracy of this prognostic model was further validated by receiver operating characteristic curve (ROC), C-index and Nomogram. In addition, the lncRNA/miRNA/mRNA competing endogenous RNA (ceRNA) network and protein−protein interaction (PPI) network were constructed based on the weighted gene co-expression network analysis (WGCNA). Results: We constructed a prognostic model based on 15 cuproptosis-associated lncRNAs. The validation results showed that the risk score of the model (HR = 1.003, 95% CI = 1.001−1.004; p < 0.001) could serve as an independent prognostic factor with accurate and credible predictive power. The risk score had the highest AUC (0.793) among various factors such as risk score, stage, gender and age, also indicating that the model we constructed to predict patient survival was better than other clinical characteristics. Meanwhile, the possible biological mechanisms of colon adenocarcinoma were explored based on the lncRNA/miRNA/mRNA ceRNA network and PPI network constructed by WGCNA. Conclusion: The prognostic model based on 15 cuproptosis-related lncRNAs has accurate and reliable predictive power to effectively predict clinical outcomes in colon adenocarcinoma patients.

Study on the potential mechanism, therapeutic drugs and prescriptions of insomnia based on bioinformatics and molecular docking.

Insomnia is a very common disease worldwide. It seriously affects the quality of human life and even endangers health. Traditional Chinese medicine (TCM) has unique advantages in the intervention and treatment of insomnia. However, its underlying mechanism has yet to be elucidated. This study was performed to explore the potential biomarkers and mechanisms of insomnia, and treatment TCM and classical prescriptions. The gene microarray data of insomnia is downloaded and preprocessed. Differentially expressed genes (DEGs) and GO and KEGG enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed. Small molecule drugs for curing insomnia were identified using cMap and CTD databases. We searched the TCM corresponding to small molecule drugs and the classic prescriptions corresponding to TCM by the TCMSP database. We constructed a network of "ingredient-TCM-classic prescriptions". The molecular docking was performed to validate the screening results. We obtained a total of 124 DEGs, including 78 up-regulated genes, 46 down-regulated genes, 10 Hub genes and 3 key modules. A total of 125 significant GO entries and 15 significant KEGG were enriched (P < 0.05). The main biological processes involve neuronal apoptosis, autophagy, cell growth and apoptosis, etc. These signaling pathways may be involved in molecular regulatory mechanisms of insomnia, such as autophagy regulation, Alzheimer's disease, pathways to neurodegenerative diseases and neurotrophic factor signaling pathways. We identified 10 traditional Chinese medicines and 2 classical prescriptions of potential value. In addition, the molecular docking results indicated that small molecule ligands were nicely bound to the Hub gene, and the binding affinity ranged from -7.6 to -9.7 kcal/mol. This study provides a foundation for the clinical treatment of insomnia, explains the molecular mechanisms, and efficiently develops TCM and classical prescriptions.

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice.

BACKGROUND: Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury. AIM: To elucidate whether clopidogrel is beneficial against DN by using a db/db mouse model. METHODS: db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson's trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1ß mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry. RESULTS: Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1ß and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice (P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice. CONCLUSION: Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

An autophagy-associated lncRNAs model for predicting the survival in non-small cell lung cancer patients.

Long non-coding RNAs (lncRNAs) can influence the proliferation, autophagy, and apoptosis of non-small cell lung cancer (NSCLC). LncRNAs also emerge as valuable prognostic factors for NSCLC patients. Consequently, we set out to discover more autophagy-associated lncRNAs. We acquired autophagy-associated genes and information on lncRNAs from The Cancer Genome Atlas database (TCGA), and the Human Autophagy Database (HADb). Then, the prognostic prediction signature was constructed through using co-expression and Cox regression analysis. The signature was constructed including 7 autophagy-associated lncRNAs (ABALON, NKILA, LINC00941, AL161431.1, AL691432.2, AC020765.2, MMP2-AS1). After that, we used univariate and multivariate Cox regression analysis to calculate the risk score. The survival analysis and ROC curve analysis confirmed good performances of the signature. GSEA indicated that the high-risk group was principally enriched in the adherens junction pathway. In addition, biological experiments showed that ABALON promoted the proliferation, metastasis and autophagy levels of NSCLC cells. These findings demonstrate that the risk signature consisting of 7 autophagy-associated lncRNAs accurately predicts the prognosis of NSCLC patients and should be investigated for potential therapeutic targets in clinic.

Pharmacological and Chemical Potential of Spiranthes sinensis (Orchidaceae): A Narrative Review.

Orchidaceae is one of the largest families of flowering plants with more than 27,000 accepted species, and more than 31,000-35,000 species are estimated to exist in total. The orchid Spiranthes sinensis (Pers.) Ames, having ornamental and medicinal value, is widely distributed throughout Asia and Oceania. S. sinensis (Shou Tsao) is also known as Panlongshen among the common folk herbs. It has a fleshy root similar to ginseng, and the entire plant is widely used in traditional Chinese medicine. Owing to overexploitation and habitat destruction in recent years, the wild population has become scarce. The traits of this species show obvious differences in different countries. In the Taiwanese climate, it flowers during the Ching Ming Festival, also called the ching ming tsao. Previous investigations into S. sinensis have revealed the presence of flavonoids, homocyclotirucallane, dihydrophenanthrenes, ferulic acid, and 3,4-dihydroxybenzaldehyde. Phenolic constituents of structural and biological interest, including phenanthrenes and flavonoids, have been isolated and identified from S. sinensis. This natural product possesses extensive bioactivity, including anti-tumor, anti-inflammatory, and antioxidant effects. In this review, we outline the herbal medicine formulations and plant-derived natural products of S. sinensis.