Mesenteric adipose-derived exosomal TINAGL1 enhances intestinal fibrosis in Crohn's Disease via SMAD4.

INTRODUCTION: Crohn's Disease (CD) is a chronic inflammatory condition characterized by intestinal fibrosis, severely impacting patient quality of life. The molecular mechanisms driving this fibrosis remain inadequately understood. Recent evidence implicates mesenteric adipose tissue (MAT) in CD pathogenesis, particularly through its exosome secretion, which may influence fibrogenic pathways. Understanding the role of MAT-derived exosomes is crucial for unraveling these molecular processes. OBJECTIVES: This study aims to elucidate the role of MAT-derived exosomes in CD-related intestinal fibrosis. We focus on investigating their molecular composition and the potential impact on fibrosis progression, with an emphasis on identifying novel therapeutic targets. METHODS: We induced chronic intestinal inflammation in mice using dinitrobenzene sulfonic acid (DNBS), simulating CD-like fibrosis. Exosomes were isolated from DNBS-treated mice (MG) and normal controls (NG) for characterization using electron microscopy and proteomic analysis. Additionally, human colonic fibroblasts were exposed to exosomes from CD patients and healthy individuals, with subsequent assessment of fibrogenesis through proteomic and RNA sequencing analyses. RESULTS: Proteomic analyses revealed a significant activation of the TGF-ß signaling pathway in MG-treated mice compared to controls, correlating with enhanced intestinal fibrosis. In vitro experiments demonstrated that colonic fibroblasts exposed to CD patient-derived exosomes exhibited increased fibrogenic activity. Protein docking and co-immunoprecipitation studies suggested a critical interaction between TINAGL1 and SMAD4, enhancing fibrosis. Importantly, in vivo experiments corroborated that recombinant TINAGL1 protein exacerbated DNBS-induced intestinal fibrosis. CONCLUSION: Our findings highlight the pivotal role of MAT-derived exosomes, particularly those carrying TINAGL1, in the progression of intestinal fibrosis in CD. The involvement of the TGF-ß signaling pathway, especially the SMAD4 protein, offers new insights into the molecular mechanisms of CD-related fibrosis and presents potential targets for therapeutic intervention.

Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. METHODS: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1's role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1's regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. RESULTS: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. CONCLUSIONS: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.

An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management.

PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.

Oat beta-glucan reduces colitis by promoting autophagy flux in intestinal epithelial cells via EPHB6-TFEB axis.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract, mainly including Crohn's disease and ulcerative colitis. Epidemiological findings suggest that inadequate dietary fibers intake may be a risk factor for IBD. Oat beta-glucan is a type of fermentable dietary fiber and has been proved to reduce experimental colitis. However, the mechanism remains unclear. The aim of this study was to explore the role and possible mechanism of oat beta-glucan in reducing experimental colitis. We used a dextran sulfate sodium (DSS)-induced mice acute colitis model to explore the potential mechanism of oat beta-glucan in reducing experimental colitis. As a result, oat beta-glucan upregulated the expressions of Erythropoietin-producing hepatocyte receptor B6 (EPHB6) and transcription factor EB (TFEB), promoted autophagy flux and downregulated the expressions of interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in intestinal epithelial cells (IECs). The role of the EPHB6-TFEB axis was explored using a lipopolysaccharide-induced HT-29 cells inflammation model. The results revealed that EPHB6 regulated the expression of TFEB, and knockdown of EPHB6 decreased the protein level of TFEB. When EPHB6 or TFEB was knocked down, autophagy flux was inhibited, and the anti-inflammatory effect of sodium butyrate, a main metabolite of oat beta-glucan in the gut, was blocked. In summary, our findings demonstrated that oat beta-glucan reduced DSS-induced acute colitis in mice, promoted autophagy flux via EPHB6-TFEB axis and downregulated the expressions of IL-1ß, IL-6 and TNF-α in IECs, and this effect may be mediated by butyrate.

Clinical value of fecal calprotectin for evaluating disease activity in patients with Crohn's disease.

Objective: To explore the clinical value of fecal calprotectin (FC) for evaluating disease activity in patients with Crohn's disease (CD) and its relationship with disease location. Methods: Patients with CD were enrolled retrospectively, and clinical data, including FC levels, were collected. Clinical activity was assessed using the Crohn's disease activity index (CDAI). Endoscopic activity was assessed using a simple endoscopic score for Crohn's disease (SES-CD). The partial SES-CD (pSES-CD) was scored for the size of ulcers in each segment as defined by the SES-CD and was calculated as the sum of segmental ulcer scores. Results: This study included 273 CD patients. The FC level was significantly positively correlated with the CDAI and SES-CD, with correlation coefficients of 0.666 and 0.674, respectively. The median FC levels in patients with clinical remission and mildly active and moderately-severely active disease were 41.01, 164.20, and 444.45 µg/g. These values were 26.94, 66.77, and 327.22 µg/g during endoscopic remission and mildly and moderately-severely active stages, respectively. Compared with c-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and other biomarker parameters, FC was better at predicting disease activity for CD patients. For an FC <74.52 µg/g, the area under the curve (AUC) for predicting clinical remission was 0.86, with a sensitivity of 89.47% and a specificity of 71.70%. Moreover, endoscopic remission was predicted with a sensitivity of 68.02% and a specificity of 85.53%. The AUC was 0.83, and the cutoff value was 80.84 µg/g. In patients with ileal and (ileo) colonic CD, FC was significantly correlated with the CDAI, SES-CD, and pSES-CD. The correlation coefficients were 0.711 (CDAI), 0.473 (SES-CD), and 0.369 (pSES-CD) in patients with ileal CD and 0.687, 0.745, and 0.714 in patients with (ileo) colonic CD, respectively. For patients in remission, those in the active stage, and those with large or very large ulcers, differences in FC levels were not significant between patients with ileal and (ileo) colonic CD. Conclusion: FC is a reliable predictor of disease activity in patients with CD, including those with ileal CD. FC is thus recommended for the routine follow-up of patients with CD.

Multimodal Identification by Transcriptomics and Multiscale Bioassays of Active Components in Xuanfeibaidu Formula to Suppress Macrophage-Mediated Immune Response.

Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 104 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide I, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.

Xuanfei Baidu formula alleviates impaired mitochondrial dynamics and activated NLRP3 inflammasome by repressing NF-κB and MAPK pathways in LPS-induced ALI and inflammation models.

BACKGROUND: Xuanfei Baidu Formula (XBF) is an effective traditional Chinese medicine (TCM) remedy for treating coronavirus disease 2019 (COVID-19) in China. This herbal medicine has shown effects in reducing clinical symptoms and shortening the average length of hospital stay for COVID-19 patients. Previous studies have demonstrated that XBF alleviates acute lung injury (ALI) by regulating macrophage-mediated immune inflammation, but the mechanisms of action remain elusive. PURPOSE: This study aimed to evaluate the lung-protective and anti-inflammatory effects of XBF and its underlying mechanisms. METHODS: Here, XBF's effects were investigated in an ALI mouse model induced by inhalation of atomized lipopolysaccharide (LPS). Besides, the LPS-induced inflammation model in RAW264.7 cells was used to clarify the underlying mechanisms of XBF against ALI. RESULTS: Our results showed that XBF treatment alleviated LPS-induced lung injury, as evidenced by reduced histopathological changes, pulmonary alveoli permeability, fibrosis, and apoptosis in the lung tissues. In addition, inflammation was alleviated as shown by decreased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß in serum and bronchoalveolar lavage fluid (BALF), and reduced white blood cell (WBC) count in BALF. Furthermore, consistent with the in vivo assay, XBF inhibited LPS-induced inflammatory cytokines release and pro-inflammatory polarization in RAW264.7 cells. Mechanistically, XBF increased mitochondrial fusion by upregulating Mfn1 and attenuated NLRP3 inflammasome activation by repressing Casp11, respectively, to inhibit NF-κB and MAPK pathways, thus repressing pro-inflammatory macrophage polarization. CONCLUSION: In this study, we demonstrate that XBF exerts anti-ALI and -inflammatory effects by recovering mitochondrial dynamics and reducing inflammasome activation, providing a biological illustration of the clinical efficacy of XBF in treating COVID-19 patients.

[Theoretical innovation of component-based Chinese medicine and its exemplary practice: the study on creating Guanxinning Tablets].

Upholding the wisdom of traditional Chinese medicine that the therapeutic principle, method, formula and medicine are coherent with each other, we propose the technical methodology for intelligent creation of component-based Chinese medicine by integrating multidisciplinary knowledge such as artificial intelligence, pharmaceutical informatics, system pharmacology and phytochemistry. Taking the creation of Guanxinning Tablets as an example, we expound the technical principle for creating component-based Chinese medicine and briefly describe the design method for optimizing the entity of Chinese medicine efficacy by rational combination of active components. Our research sought to "clarify and explain" the mechanism of its clinical treatment action through multi-modal and multi-scale systematic pharmacology studies. This work emphatically demonstrates the pilot workshop and engineering validation platform based on the intelligent simulation of whole production process, and outlines the design principles of the intelligent production line for innovative Chinese medicine. The results of industrial research show that the ourself established method for evaluating the process quality controllability and intelligent production line can be applied to manufacturing Guanxining Tablets with high quality. Through the innovative research of multidisciplinary cross-border integration, the present work explored a new way for the creation of modern Chinese medicine.

Network pharmacology study to reveal active compounds of Qinggan Yin formula against pulmonary inflammation by inhibiting MAPK activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Pneumonia is common and frequently-occurred disease caused by pathogens which predisposes to lung parenchymal inflammation leading pulmonary dysfunction. To prevent and alleviate the symptoms of pneumonia, Qinggan Yin formula (QGY) was composed based on clinical experience and four classical traditional Chinese medicine prescriptions which frequently applied to treat infectious diseases. AIM OF THE STUDY: Traditional Chinese medicine is a complex mixture and it is difficult to distinguish the effective component molecules. The aim of this study is to identify the compounds of QGY with anti-inflammatory effects and investigate the molecular mechanism. MATERIALS AND METHODS: The high-resolution mass spectrometry and molecular networking were performed for comprehensive chemical profiling of QGY. Network pharmacology was used to generate "herbal-target-pathway" network for target predictions. The anti-inflammation effects of QGY were evaluated in mice model of lipopolysaccharide (LPS) induced acute inflammation. Tail transected zebrafish was also employed to validate macrophage migration reversed effect of QGY. Based on the molecular enrichment analysis, the active substances of QGY with anti-inflammatory effects were further identified in cellular model of macrophage activation. The mechanisms of active substances were investigated by testing their effects on the expression of correlated proteins by Western blot. RESULTS: In total, 71 compounds are identified as major substances of QGY. According to the results of network pharmacology, QGY shows moderate anti-inflammatory effects and inhibit pulmonary injury. MAPK signaling pathway was predicted as the most related pathway regulated by QGY. Moreover, QGY significantly inhibit LPS-induced pulmonary inflammation in mice, and reversed macrophage migration toward the injury site in zebrafish. We also validate that some major compounds in QGY significantly attenuated the release of IL-1ß, IL-6 and TNF-α in LPS-stimulated macrophage. Those active substances including acacetin and arctiin can inhibit the phosphorylation of ERK/JNK and down-regulated the protein expression of BCL-2. CONCLUSION: Collectively, QGY possessed pronounced anti-inflammation effects. The integration of network pharmacology and experimental results indicated arctiin, iridin, acacetin, liquiritin, and arctigenin are major active substances of QGY with anti-inflammatory effects. The underlying mechanism of QGY involves MAPK signaling pathway and oxidative stress pathway.

LA-ICP-MS bioimaging demonstrated disturbance of metal ions in the brain of Parkinson's disease model mouse undergoing manganese-enhanced MRI.

Manganese-enhanced MRI (MEMRI) is a powerful tool to study neuronal activity and microarchitecture in vivo. Yet the influence of exogenous manganese on the brain of the Parkinson's disease (PD) model mouse is poorly understood. Laser ablation connected to inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging for tissue section is an ideal tool to simultaneously analyze the metabolism of endogenous metal ions. In this study, DJ-1 knockout PD model mice were subjected to an MnCl2 saline treatment and the distribution of Mn and several other endogenous metal ions in brain regions was assessed by MEMRI and LA-ICP-MS imaging. The results demonstrated that Mn mainly deposited in subcortical regions, such as ventricles, hippocampus (HC), medial preoptic nucleus (MPO), lateral septal nucleus (LS), and ventromedial hypothalamic nucleus (VMH). The enhanced signal-to-noise ratio (S/N) determined by MEMRI for Mn is closely related to the signal in LA-ICP-MS imaging. Significantly, the treatment of MnCl2 disturbs the homeostasis of iron, zinc, copper, and calcium in the DJ-1 mouse, which could result in more severe symptoms of PD. Therefore, the application of MEMRI in the study of neurological disease must be made with caution.

An online, non-destructive method for simultaneously detecting chemical, biological, and physical properties of herbal injections using hyperspectral imaging with artificial intelligence.

Botanical drugs hold great potential to prevent and treat complex diseases. Quality control is essential in ensuring the safety, efficacy, and therapeutic consistency of these drug products. The quality of a botanical drug product can be assessed using a variety of analytical methods based on criteria that judge the identity, strength, purity, and potency. However, most of these methods are developed on separate analytical platforms, and few approaches are available for in-process monitoring of multiple quality properties in a non-destructive manner. Here, we present a hyperspectral imaging-based strategy for online measurement of physical, chemical, and biological properties of botanical drugs using artificial intelligence algorithms. An end-to-end convolutional neural network (CNN) model was established to accurately determine phytochemicals and bioactivities based on the spectra. Besides, a new dual-scale anomaly (DSA) detection algorithm was proposed for visible particle inspection based on the images. The strategy was exemplified on Shuxuening Injection, a Ginkgo biloba-derived drug used in the treatment of cerebrovascular and cardiovascular diseases. Four quality metrics of the injection, including total flavonol, total ginkgolides, antioxidant activity, and anticoagulant activity, were successfully predicted by the CNN model with validation R2 of 0.922, 0.921, 0.880, and 0.913 respectively, showing better performance than the other models. Unqualified samples with visible particles could be detected by DSA with a low false alarm rate of 9.38 %. Chromaticity results indicated that the inter-company variations of color were significant, while intra-company variations were relatively small. This demonstrates a real application of integrating hyperspectral imaging with artificial intelligence to provide a rapid, accurate, and non-destructive approach for process analysis of botanical drugs.

A rapid and facile analytical approach to detecting Salmonella Enteritidis with aptamer-based surface-enhanced Raman spectroscopy.

Salmonella should be absence in pharmaceutical preparations and foods according to regulations in many countries. Up to now, rapidly detecting Salmonella at 1 CFU·[10 g (mL) ]-1 in pharmaceutical preparation or 1 CFU·[25 g (mL) ]-1 in food samples is still a challenge. Herein, we present an aptamer-based surface-enhanced Raman spectroscopy (SERS) method for rapidly detecting Salmonella Enteritidis by using a handheld Raman instrument. The aptamer could specifically recognize S. Enteritidis, and 4-MBA self-assembled on the surface of Au@Ag NPs was used as a Raman reporter molecule. The method was validated to be high specific with no interference from other five pathogenic bacteria. It could identify S. Enteritidis contaminant at âˆ¼ 1 CFU·(10 g)-1 spiked level in a real sample (Wenxin granule, a botanical drug) after 6 h of enrichment. The detection time was much shorter than that of the methods (more than 54 âˆ¼ 96 h) in the standards of pharmaceutical preparations and foods. In addition, the method could quantitatively determinate S. Enteritidis with satisfactory results. The SERS peak intensities of 4-MBA at 1072 cm-1 showed a good linear correlation (R2 = 0.9873) with the logarithms of S. Enteritidis concentrations ranging from 4.17 × 102 to 1.39 × 107 CFU·mL-1. T-test result (P = 0.425) revealed that there was no significant difference between the determination results obtained by the SERS method and the plate counting method. Therefore, the study indicated that the method was practical and reliable, and it could be a promising alternative for the on-site detection of S. Enteritidis.

Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance.

In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.

An ultra-robust fingerprinting method for quality assessment of traditional Chinese medicine using multiple reaction monitoring mass spectrometry.

Chromatographic fingerprinting has been perceived as an essential tool for assessing quality and chemical equivalence of traditional Chinese medicine. However, this pattern-oriented approach still has some weak points in terms of chemical coverage and robustness. In this work, we proposed a multiple reaction monitoring (MRM)-based fingerprinting method in which approximately 100 constituents were simultaneously detected for quality assessment. The derivative MRM approach was employed to rapidly design MRM transitions independent of chemical standards, based on which the large-scale fingerprinting method was efficiently established. This approach was exemplified on QiShenYiQi Pill (QSYQ), a traditional Chinese medicine-derived drug product, and its robustness was systematically evaluated by four indices: clustering analysis by principal component analysis, similarity analysis by the congruence coefficient, the number of separated peaks, and the peak area proportion of separated peaks. Compared with conventional ultraviolet-based fingerprints, the MRM fingerprints provided not only better discriminatory capacity for the tested normal/abnormal QSYQ samples, but also higher robustness under different chromatographic conditions (i.e., flow rate, apparent pH, column temperature, and column). The result also showed for such large-scale fingerprints including a large number of peaks, the angle cosine measure after min-max normalization was more suitable for setting a decision criterion than the unnormalized algorithm. This proof-of-concept application gives evidence that combining MRM technique with proper similarity analysis metrices can provide a highly sensitive, robust and comprehensive analytical approach for quality assessment of traditional Chinese medicine.

A Comprehensive Review of the Therapeutic Value of Urine-Derived Stem Cells.

Stem cells possess regenerative powers and multidirectional differentiation potential and play an important role in disease treatment and basic medical research. Urine-derived stem cells (USCs) represent a newly discovered type of stem cell with biological characteristics similar to those of mesenchymal stromal cells (MSCs), including their doubling time and immunophenotype. USCs are noninvasive and can be readily obtained from voided urine and steadily cultured. Based on advances in this field, USCs and their secretions have increasingly emerged as ideal sources. USCs may play regulatory roles in the cellular immune system, oxidative stress, revascularization, apoptosis and autophagy. This review summarizes the applications of USCs in tissue regeneration and various disease treatments. Furthermore, by analysing their limitations, we anticipate the development of more feasible therapeutic strategies to promote USC-based individualized treatment.

A strategy for identifying effective and risk compounds of botanical drugs with LC-QTOF-MS and network analysis: A case study of Ginkgo biloba preparation.

Botanical drugs have unique advantages in the treatment of complex diseases. In order to ensure the efficacy and safety of botanical drugs, ascertaining the effective and risk compounds is quite necessary. However, the conventional identification method is laborious, time-consuming, and inefficient. In this work, a 3-steps strategy was presented to rapidly identify the effective and risk compounds of botanical drugs, and a Ginkgo biloba preparation, Shu-Xue-Ning injection (SXNI), was taken as a case study. Firstly, mass spectral molecular networking was used to rapidly identify the compounds of SXNI. Secondly, three networks (i.e. the compound-target network, the indication-related biomolecule network, and the adverse drug reaction-related biomolecule network) are constructed. Finally, a novel network analysis algorithm was used to predict the effective and risk compounds in SXNI. By this strategy, a total of 138 compounds were identified including the firstly reported terpenoid glycosides and lignan glycosides. Among them 71 compounds were predicted as effective ones, and 42 compounds as risk ones. Especially, 31 compounds relevant to both efficacy and safety should be scientifically controlled during manufacturing. In addition, ten pathways were enriched to preliminarily explain the action mechanism of SXNI. This strategy for MS data analysis can be applied to provide important basis for the manufacturing and quality control, as well as valuable points for research on the pharmacological mechanisms of botanical drugs.

Photoactivatable diazido Pt(IV) anticancer complex can bind to and oxidize all four nucleosides.

Photoactivatable diazidodihydroxido Pt(iv) complex trans,trans,trans-[Pt(N3)2(OH)2(py)2] (1; py = pyridine) is a promising anticancer agent which can be activated by visible light to induce cancer cell death. DNA has been thought to be involved in the mechanism of action of this kind of Pt(iv) prodrug. However, the detailed photodecomposition pathways of complex 1 and its interaction modes with DNA are complex. Herein we report that upon light irradiation complex 1 can bind to all four nucleosides covalently with the reduced Pt(ii) species. Moreover, apart from the covalent coordination, various oxidation adducts of these four nucleosides induced by the reactive oxidative species (ROS) generated during the photoactivation of the complex 1 have also been identified, especially the induced oxidation of adenosine and cytidine which was firstly reported for this kind of photoactivatable Pt(iv) prodrug. Such dual-action may contribute to the highly potent photo-antiproliferativity of complex 1 towards cancer cells, which may account for the unique mechanism of action of the photoactivatable diazido Pt(iv) anticancer complexes.

Implication of Gut Microbiota in Cardiovascular Diseases.

Emerging evidence has identified the association between gut microbiota and various diseases, including cardiovascular diseases (CVDs). Altered intestinal flora composition has been described in detail in CVDs, such as hypertension, atherosclerosis, myocardial infarction, heart failure, and arrhythmia. In contrast, the importance of fermentation metabolites, such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acid (BA), has also been implicated in CVD development, prevention, treatment, and prognosis. The potential mechanisms are conventionally thought to involve immune regulation, host energy metabolism, and oxidative stress. However, numerous types of programmed cell death, including apoptosis, autophagy, pyroptosis, ferroptosis, and clockophagy, also serve as a key link in microbiome-host cross talk. In this review, we introduced and summarized the results from recent studies dealing with the relationship between gut microbiota and cardiac disorders, highlighting the role of programmed cell death. We hope to shed light on microbiota-targeted therapeutic strategies in CVD management.

Reactions of a photoactivatable diazido Pt(iv) anticancer complex with a single-stranded oligodeoxynucleotide.

Platinum based anticancer agents are widely applied in clinic and their major target is believed to be DNA. Herein, the interaction of a photoactivatable diazido Pt(iv) anticancer prodrug trans,trans,trans-[Pt(N3)2(OH)2(py)2] (py = pyridine; 1) with a 15-mer single-G-containing oligodeoxynucleotide (ODN I: 5'-CT2CTCTTG8T9CT11TCTC-3') was investigated by mass spectrometric methods. Up to penta-platinated ODN I adducts were identified from primary mass spectra while the mono- and di-platinated adducts had the highest intensity. Fragmentation of mono-, di- and tri-platinated I adducts in tandem MS revealed that T2, G8, T11 and T9 are binding sites. No cytosine sites were identified which may be due to the facile loss of Pt adducts from cytosine during CID. The intensity of {Pt(py)2}-bound adducts was comparable to that of {Pt(N3)(py)2}-bound adducts, indicating that the photo-reduction pathway of complex 1 from Pt(iv) to Pt(ii) through two one-electron donations from two azides was substantial. Moreover, no transformation of N3 to NH3 on the {Pt(N3)(py)2}-bound adducts was observed, whereas it is very popular during the reactions of complexes with short ODNs or mono-nucleotides. The oxidation on I induced by the reactive oxygen species (ROS) formed by the photodecomposition of complex 1 was significant, and the oxidation of G8 to 8-hydroxyguanine (8-OH-G), spiroiminodihydantoin (Sp) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) was discovered. These results unambiguously revealed a sequence-length-dependent photochemical reactivity of complex 1 when it interacted with different ODNs, providing deeper understanding in the reactivity of photoactivatable diazido anticancer Pt(iv) prodrugs to DNA.

The Effect of Chinese Traditional Medicine Huaiqihuang (HQH) on the Protection of Nephropathy.

Kidney disease is one of the common diseases with high morbidity and high mortality, which brings a huge burden to the society and the patient's family. The pathogenesis, treatment, and prognosis of kidney diseases are related to oxidative stress, inflammation, mitochondrial damage, and immune dysfunction. However, existing treatments always cause some damage to the kidneys. Kidney disease and immunosuppressant used together often lead to drug toxicity, patients with weakened immunity, organic rupture of the normal structure of the kidney, damage to the physiological function of the kidney, etc. Huaiqihuang is a kind of traditional Chinese medicine with a history of more than one thousand years. According to research, Robinia pseudoacacia can regulate the immune function by regulating oxidative stress, calcium inflow, and mitochondrial ATP. At the same time, it is also involved in regulating the ways of cell death, such as apoptosis, autophagy, ferroptosis, pyroptosis, and clockophagy, to reduce kidney damage, which has important clinical value. This article reviews the exact mechanism and clinical application of Huaiqihuang in different types of nephropathy. The aim is to provide new ideas for the treatment of clinical nephropathy.