The role of sialidase Neu1 in respiratory diseases.

Neu1 is a sialidase enzyme that plays a crucial role in the regulation of glycosylation in a variety of cellular processes, including cellular signaling and inflammation. In recent years, numerous evidence has suggested that human NEU1 is also involved in the pathogenesis of various respiratory diseases, including lung infection, chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. This review paper aims to provide an overview of the current research on human NEU1 and respiratory diseases.

Echinacoside: A promising active natural products and pharmacological agents.

Echinacoside, a natural phenylethanoid glycoside, was discovered and isolated from the garden plant Echinacea angustifolia DC., belonging to the Compositae family, approximately sixty years ago. Extensive investigations have revealed that it possesses a wide array of pharmacologically beneficial activities for human health, particularly notable for its neuroprotective and anticancer activity. Several crucial concerns surfaced, encompassing the recognition of active metabolites that exhibited inadequate bioavailability in their prototype form, the establishment of precise molecular signal pathways or targets associated with the aforementioned effects of echinacoside, and the scarcity of dependable clinical trials. Hence, the question remains unanswered as to whether scientific research can effectively utilize this natural compound. To support future studies on this natural product, it is imperative to provide a systematic overview and insights into potential future prospects. The current review provides a comprehensive analysis of the existing knowledge on echinacoside, encompassing its wide distribution, structural diversity and metabolism, diverse therapeutic applications, and improvement of echinacoside bioavailability for its potential utilization.

Evaluation of raw and processed Phellodendri Chinensis Cortex using the quality marker analysis strategy by UHPLC-Q-Orbitrap MS and multivariate statistical analysis.

Introduction: Phellodendri Chinensis Cortex is a necessary part of healthcare for its significant clinical efficacy. Raw and processed Phellodendri Chinensis Cortex is both documented in the Chinese Pharmacopoeia (2015). After processing, the therapeutic effects are believed to differ according to traditional Chinese medicine theories. However, the chemical mechanism responsible for this processing, according to traditional Chinese medicine theories, is still not clear. Methods: In this study, the therapeutic effects of various ions were examined based on traditional Chinese medicine theories by ultra-high performance liquid chromatography-hybrid quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap MS) coupled with multivariate statistical analysis, such as principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), to comprehensively compare the differences between raw and processed Phellodendri Chinensis Cortex for the first time. Results: A total of 48 compounds were screened, out and 10 of them simultaneously transformed with significant variation in processed products compared with raw materials. It was illustrated that the contents of berberine, palmatine, jatrorrhizine, magnoflorine, menisperine, phellodendrine, tetrahydrojatrorrhizine, and tetrahydropalmatine decreased, while the compounds of berberrubine and fernloylquinic acid methyl ester newly appeared in processed herbs. This is likely to be related to the conversion of ingredients during processing. Discussion: Altogether, the fact that quality markers have been successfully identified to differentiate processed Phellodendri Chinensis Cortex from raw materials suggests that this approach could be used for the investigation of chemical transformation mechanisms involved in the processing of herbal medicine.

The role of sphingosine-1-phosphate in the development and progression of Parkinson's disease.

Parkinson's disease (PD) could be viewed as a proteinopathy caused by changes in lipids, whereby modifications in lipid metabolism may lead to protein alterations, such as the accumulation of alpha-synuclein (α-syn), ultimately resulting in neurodegeneration. Although the loss of dopaminergic neurons in the substantia nigra is the major clinical manifestation of PD, the etiology of it is largely unknown. Increasing evidence has highlighted the important role of lipids in the pathophysiology of PD. Sphingosine-1-phosphate (S1P), a signaling lipid, has been suggested to have a potential association with the advancement and worsening of PD. Therefore, better understanding the mechanisms and regulatory proteins is of high interest. Most interestingly, S1P appears to be an important target to offers a new strategy for the diagnosis and treatment of PD. In this review, we first introduce the basic situation of S1P structure, function and regulation, with a special focus on the several pathways. We then briefly describe the regulation of S1P signaling pathway on cells and make a special focused on the cell growth, proliferation and apoptosis, etc. Finally, we discuss the function of S1P as potential therapeutic target to improve the clinical symptoms of PD, and even prevent the progression of the PD. In the context of PD, the functions of S1P modulators have been extensively elucidated. In conclusion, S1P modulators represent a novel and promising therapeutic principle and therapeutic method for PD. However, more research is required before these drugs can be considered as a standard treatment option for PD.

Transcriptome and Gut Microbiota Profiling Analysis of ANIT-Induced Cholestasis and the Effects of Da-Huang-Xiao-Shi Decoction Intervention.

Cholestasis is characterized by bile acid (BA) circulation disorders, which is usually related to damage of hepatocyte barrier function. Currently, patients with cholestasis face several obstacles in seeking diagnosis and therapy. Da-Huang-Xiao-Shi decoction (DHXSD) is an ancient classic formula that has been used clinically for cholestasis treatment. Nevertheless, the underlying biological activities and therapeutic mechanisms remain unclear. In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis rat model was established to examine the anticholestatic effects of DHXSD using histopathological and molecular analyses. Transcriptomic analysis combined with 16S rRNA gene sequencing analysis was systematically applied to study the mechanism of action of DHXSD. Simultaneously, the effect of DHXSD on gut microbiota, short-chain fatty acids (SCFAs), and intestinal barrier function were evaluated based on the ANIT-induced cholestasis model in rats. The results showed that DHXSD effectively attenuated ANIT-induced cholestasis by reducing liver function indicators (alanine transaminase [ALT], P < 0.05; alkaline phosphatase [ALP], P < 0.05; total bile acid [TBA], P < 0.01; γ-glutamyl transpeptidase [GGT], P < 0.001) and levels of hepatotoxicity-related enzymes (P < 0.05), thus improving the recovery of histopathological injuries, and regulating levels of inflammatory cytokines (P < 0.05). In addition, 16S rRNA gene sequencing analysis combined with intestinal barrier function analysis revealed that the DHXSD significantly ameliorated ANIT-induced gut microbiota dysbiosis. Significantly altered genes in the model and treatment groups were screened using transcriptomic analysis. Sixty-eight genes and four microbial genera were simultaneously altered with opposing trends in variation after ANIT and DHXSD treatments. We built a framework for predicting targets and host-microbe interaction mechanisms, as well as identifying alternative treatment for cholestasis, which should be validated further for clinical application. In conclusion, DHXSD appears to be a promising agent for protection against liver injury. IMPORTANCE Cholestasis is a serious manifestation of liver diseases resulting in liver injury, fibrosis, and liver failure with limited therapies. To date, only ursodeoxycholic acid (UDCA) has been approved by the U.S. Food and Drug Administration for the treatment of cholestasis. However, approximately one-third of patients with cholestasis are unresponsive to UDCA. Therefore, it is urgent to search for appropriate therapeutic agents for restoring stoppage status of the bile components to treat cholestasis. In this study, we investigated how the microbiome and transcriptome data sets correlated with each other to clarify the role of microbiome alterations in host metabolism. In combination, this research offers potential molecular biomarkers that should be validated for more accurate diagnosis of cholestasis and the clinical utilisation of gut microbiota as a target for treatment.

Interactions between gut microbiota and Parkinson's disease: The role of microbiota-derived amino acid metabolism.

Non-motor symptoms (NMS) of Parkinson's disease (PD), such as constipation, sleep disorders, and olfactory deficits, may emerge up to 20 years earlier than motor symptoms. A series of evidence indicates that the pathology of PD may occur from the gastrointestinal tract to the brain. Numerous studies support that the gut microbiota communicates with the brain through the immune system, special amino acid metabolism, and the nervous system in PD. Recently, there is growing recognition that the gut microbiota plays a vital role in the modulation of multiple neurochemical pathways via the "gut microbiota-brain axis" (GMBA). Many gut microbiota metabolites, such as fatty acids, amino acids, and bile acids, convey signaling functions as they mediate the crosstalk between gut microbiota and host physiology. Amino acids' abundance and species alteration, including glutamate and tryptophan, may disturb the signaling transmission between nerve cells and disrupt the normal basal ganglia function in PD. Specific amino acids and their receptors are considered new potential targets for ameliorating PD. The present study aimed to systematically summarize all available evidence on the gut microbiota-derived amino acid metabolism alterations associated with PD.

The application of omics techniques to evaluate the effects of Tanshinone IIA on dextran sodium sulfate induced ulcerative colitis.

Ulcerative colitis (UC) is the most frequent disease classified under the umbrella term inflammatory bowel disease (IBD) with potentially serious symptoms and devastating consequences for the affected patients. In clinical research, Salvia miltiorrhiza Radix et Rhizoma, which includes the active ingredient of Tanshinone IIA, has been proven to have an anti-inflammatory effect. However, Tan IIA anti-inflammatory effect and mechanism are not clear. In this study, the pharmacodynamic index was used to evaluate the effects of Tan IIA on UC mice, such as general conditions, disease activity index (DAI), pathological morphology of the colon and pharmacodynamic indices were taken into account. The UPLC-Q-Exactive Orbitrap/MS technology was further utilized to conduct a metabolomic analysis of mice's colon tissue to explore the intervention approaches. The results demonstrated that Tan IIA could significantly improve the general condition of UC mice, decrease DAI score and histopathological score, reduce the concentrations of TNF-α, IL-1ß, IL-6 and increase IL-10 in the serum. Twenty endogenous components, such as taurine, L-glutamine were recognized as underlying biomarkers of the curative effect of Tan IIA. According to the system network analysis of the corresponding ways, the effect of Tan IIA on UC in mice is mainly through the regulation of taurine and hypotaurine metabolism. Tan IIA has been shown to possess definite pharmacological activities on the pharmacodynamic indexes and pathological observations on UC mice by partially regulating the destabilized network. Moreover, the findings acquired from the present study may provide a better understanding of the mechanisms of UC disease and potential therapies.

Multi-Omics Integration in Mice With Parkinson's Disease and the Intervention Effect of Cyanidin-3-O-Glucoside.

Background: Parkinson's disease (PD) is a multifactorial degenerative disease of the central nervous system, which affects mostly older adults. To date, research has focused on the progression of PD. Simultaneously, it was confirmed that the imbalances in gut microbiota are associated with the onset and progression of PD. Accurate diagnosis and precise treatment of PD are currently deficient due to the absence of effective biomarkers. Methods: In this study, the pharmacodynamic study of cyanidin-3-O-glucoside in PD mice was used. It intends to use the "imbalance" and "balance" of intestinal microecology as the starting point to investigate the "gut-to-brain" hypothesis using metabolomic-combined 16S rRNA gene sequencing methods. Simultaneously, metabolomic analysis was implemented to acquire differential metabolites, and microbiome analysis was performed to analyze the composition and filter the remarkably altered gut microbiota at the phylum/genera level. Afterward, metabolic pathway and functional prediction analysis of the screened differential metabolites and gut microbiota were applied using the MetaboAnalyst database. In addition, Pearson's correlation analysis was used for the differential metabolites and gut microbiota. We found that cyanidin-3-O-glucoside could protect 1-methyl-4-phenyl-1,2,3,6- tetrahydropy ridine (MPTP)-induced PD mice. Results: Metabolomic analysis showed that MPTP-induced dysbiosis of the gut microbiota significantly altered sixty-seven metabolites. The present studies have also shown that MPTP-induced PD is related to lipid metabolism, amino acid metabolism, and so on. The 16S rRNA sequencing analysis indicated that 5 phyla and 22 genera were significantly altered. Furthermore, the differential gut microbiota was interrelated with amino acid metabolism, and so on. The metabolites and gut microbiota network diagram revealed significant correlations between 11 genera and 8 differential metabolites. Conclusion: In combination, this study offers potential molecular biomarkers that should be validated for future translation into clinical applications for more accurately diagnosing PD. Simultaneously, the results of this study lay a basis for further study of the association between host metabolisms, gut microbiota, and PD.

Celastrol: An Update on Its Hepatoprotective Properties and the Linked Molecular Mechanisms.

The liver plays an important role in glucose and lipid homeostasis, drug metabolism, and bile synthesis. Metabolic disorder and inflammation synergistically contribute to the pathogenesis of numerous liver diseases, such as metabolic-associated fatty liver disease (MAFLD), liver injury, and liver cancer. Celastrol, a triterpene derived from Tripterygium wilfordii Hook.f., has been extensively studied in metabolic and inflammatory diseases during the last several decades. Here we comprehensively review the pharmacological activities and the underlying mechanisms of celastrol in the prevention and treatment of liver diseases including MAFLD, liver injury, and liver cancer. In addition, we also discuss the importance of novel methodologies and perspectives for the drug development of celastrol. Although celastrol has been claimed as a promising agent against several metabolic diseases, both preclinical and clinical studies are highly required to accelerate the clinical transformation of celastrol in treating different liver illness. It is foreseeable that celastrol-derived therapeutics is evolving in the field of liver ailments.

Untargeted GC-MS-Based Metabolomics for Early Detection of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers in the world with a 5-year survival rate of approximately 68%. Although researchers accumulated many scientific studies, its pathogenesis remains unclear yet. Detecting and removing these malignant polyps promptly is the most effective method in CRC prevention. Therefore, the analysis and disposal of malignant polyps is conducive to preventing CRC. METHODS: In the study, metabolic profiling as well as diagnostic biomarkers for CRC was investigated using untargeted GC-MS-based metabolomics methods to explore the intervention approaches. In order to better characterize the variations of tissue and serum metabolic profiles, orthogonal partial least-square discriminant analysis was carried out to further identify significant features. The key differences in tR-m/z pairs were screened by the S-plot and VIP value from OPLS-DA. Identified potential biomarkers were leading in the KEGG in finding interactions, which show the relationships among these signal pathways. RESULTS: Finally, 17 tissue and 13 serum candidate ions were selected based on their corresponding retention time, p-value, m/z, and VIP value. Simultaneously, the most influential pathways contributing to CRC were inositol phosphate metabolism, primary bile acid biosynthesis, phosphatidylinositol signaling system, and linoleic acid metabolism. CONCLUSIONS: The preliminary results suggest that the GC-MS-based method coupled with the pattern recognition method and understanding these cancer-specific alterations could make it possible to detect CRC early and aid in the development of additional treatments for the disease, leading to improvements in CRC patients' quality of life.

UHPLC-MS-based metabolomics and chemoinformatics study reveals the neuroprotective effect and chemical characteristic in Parkinson's disease mice after oral administration of Wen-Shen-Yang-Gan decoction.

Parkinson's disease (PD), the typical neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, no therapeutic agent used currently could slow down neuronal cell loss so as to decelerate or halt the progression of PD. Traditional Chinese medicine (TCM) has been utilized to treat the dysfunction of the autonomic nervous system. Wen-Shen-Yang-Gan decoction (WSYGD) has a good effect on the clinical treatment of PD with constipation. However, it is not clear which ingredients and what mechanism are responsible for the therapeutic effect. In this study, the pharmacodynamic study of WSYGD in PD mice was applied. Concurrently, a novel method for the identification of metabolic profiles of WSYGD has been developed. Finally, we found that WSYGD could protect the PD mice induced by rotenone. The underlying mechanism of the protective effect may be related to the reduction of the DA neurons apoptosis via reducing inflammatory reaction. By virtue of UPLC-MS and chemoinformatics method, 35 prototype compounds and 27 metabolites were filtered out and tentatively characterized. In conclusion, this study provides an insight into the metabolism of WSYGD in vivo to enable understanding of the metabolic process and therapeutic mechanism of PD.

Effect of Wenshen-Yanggan Decoction on Movement Disorder and Substantia Nigra Dopaminergic Neurons in Mice with Chronic Parkinson's Disease.

This study aimed to explore the protective effects of Wenshen-Yanggan decoction on dopaminergic (DA) neuron injury in a rotenone-induced mouse model with chronic Parkinson's disease (PD) and explore its mechanism of action. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to measure the content of six main components in the Wenshen-Yanggan decoction. The chronic PD mouse model was established by treating 10-month-old healthy wild C57BL/6 male mice with rotenone 30 mg/kg/day for 28 days in succession. The pole test and rotarod test were applied to detect the rescue effect of Wenshen-Yanggan decoction in high, medium, and low dosages, respectively, on PD-like behaviors in mice with chronic PD. The protective effect of Wenshen-Yanggan decoction on the mesencephalic nigrostriatal DA neuron injury was determined employing tyrosine hydroxylase (TH) immunofluorescence staining. Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the inflammatory cytokines in serum, including TNF-α (tumor necrosis factor-alpha), IFN-γ (interferon gamma), NF-κB (nuclear factor kappa-B), and IL-1ß (interleukin-1 beta). Western blotting was performed to quantify the expression of phosphorylated c-Jun N-terminal kinase (p-JNK), cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), and NF-κB in the brain. Our results showed that the Wenshen-Yanggan decoction in high, medium, and low dosages reduced the turning time of mice (P < 0.01, P < 0.01, and P < 0.05). The high and medium dosages shortened the total climbing time of PD mice in the pole test (P < 0.01 and P < 0.05). Meanwhile, the high, medium, and low dosages increased the rod-standing time of PD mice in the rotarod test (P < 0.01, P < 0.05, and P < 0.05). Besides, the decoction reversed the decrease in TH-positive neurons induced by rotenone, upregulated TH protein expression, and downregulated the α-syn expression in the PD model. Moreover, the decoction in high dosage significantly inhibited the expression of p-JNK, cleaved caspase-3, and NF-κB in the midbrain of PD mice (P < 0.05, P < 0.05, and P < 0.01), upregulated the expression of Bcl-2 (P < 0.05), and decreased the content of TNF-α, IFN-γ, NF-κB, and IL-1ß in the serum (P < 0.001, P < 0.001, P < 0.001, and P < 0.001). Taken together, the Wenshen-Yanggan decoction could protect mice from rotenone-induced chronic PD, which might be related to the reduction of the DA neuron apoptosis via suppressing the inflammatory reaction and the neuronal apoptosis pathway.

UPLC-MS-based metabonomic analysis of intervention effects of Da-Huang-Xiao-Shi decoction on ANIT-induced cholestasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis, caused by hepatic accumulation of bile acids, is a serious manifestation of liver diseases resulting in liver injury, fibrosis, and liver failure with limited therapies. Da-Huang-Xiao-Shi decoction (DHXSD) is a representative formula for treating jaundice and displays bright prospects in liver protective effect. AIM OF THE STUDY: This study was designed to assess the effects and possible mechanisms of DHXSD against alpha-naphthylisothiocyanate-induced liver injury based on ultra-high performance liquid chromatography-hybrid quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap MS) metabonomic approach. MATERIALS AND METHODS: The effects of DHXSD on serum indices (TBIL, DBIL, AST, ALT, ALP, TBA, and γ-GT) and the histopathology of the liver were analyzed. Moreover, UHPLC-Q-Orbitrap MS was performed to identify the possible effect of DHXSD on metabolites. The pathway analysis was conducted to illustrate the pathways and network by which DHXSD treats cholestasis. RESULTS: The results demonstrated that DHXSD could significantly regulate serum biochemical indices and alleviate histological damage to the liver. Twelve endogenous components, such as glycocholic acid, taurocholic acid and indoleacetaldehyde, were identified as potential biomarkers of the therapeutic effect of DHXSD. A systematic network analysis of their corresponding pathways indicates that the anti-cholestatic effect of DHXSD on alpha-naphthylisothiocyanate-induced cholestasis rats occurs mainly through regulating primary bile acid biosynthesis, arginine and proline metabolism, and arachidonic acid metabolism. CONCLUSIONS: DHXSD has exhibited favorable pharmacological effect on serum biochemical indices and pathological observation on cholestatic model by partially regulating the perturbed pathways. Moreover, these findings may help better understand the mechanisms of disease and provide a potential therapy for cholestasis.

Non-targeted metabolite profiling and specific targeted discrimination strategy for quality evaluation of Cortex Phellodendri from different varieties.

Cortex Phellodendri is derived from two species of Phellodendron amurense Rupr. and Phellodendron chinense Schneid. Traditionally, the two species are utilized interchangeably under the name of "huangbo" in the clinic because they are believed to share the same clinical efficacy. However, the chemical analysis in vitro couldn't directly reflect the pharmacological effects. Therefore, whether the constituents could be absorbed into the blood becomes the uppermost problem to account for the clinical efficacy differences of the two species. Therefore, a rapid and sensitive approach to differentiate the two species of Cortex Phellodendri based on non-targeted metabolite profiling and the specific targeted discrimination strategy was first established. Samples from different cultivars were clearly discriminated by principal component analysis and orthogonal partial least squares discriminant analysis. 17 prototype compounds and 22 metabolites contributing to the group separation were identified and tentatively characterized, three of which were found for the first time. Moreover, six of them were screened out as the chemical markers which contribute most to the differences between the two species. Taken together, the application of the non-targeted metabolite profiling and specific targeted discrimination strategy is suitable for the assessment of Cortex Phellodendri.

The pharmacokinetic screening of multiple components of the Nao Mai Tong formula in rat plasma by liquid chromatography tandem mass spectrometry combined with pattern recognition method and its application to comparative pharmacokinetics.

The Nao Mai Tong formula (NMT) is composed of Rhubarb, Ginseng, Ligusticum wallichii and Pueraria in a ratio of 3:3:2:2 (w/w) and is a well-known traditional Chinese prescription that has been clinically employed for treating ischemia cerebrovascular disease. The goal of this study was to investigate the pharmacokinetics of multiple components (chryohol-8-O-ß-D-glucoyroide, physcion-8-O-ß-D-glucopyranoside, aloe-emodin, rhein, emodin, chrysophanol, ginsenoside Rg1, ginsenoside Rb1, ginsenoside Rb3, ginsenoside Rc, senkyunolide I, ligustilide puerarin, daidzein, 3'-methoxy puerarin) after the oral administration of the NMT formula in rats. A rapid and sensitive UHPLC-Quadrupole-Orbitrap-MS with a sequential positive and negative ionization mode was developed to determine the 15 absorbed ingredients. After extraction from blood, the analytes and internal standards were subjected to ultra-high performance liquid chromatography with Agela Venusil MPC18 (2.1mm×100mm, 3µm, Agela, USA). The mobile phase consisted of methanol and ammonium acetate (3mmolL-1) under gradient elution conditions. This validated method was successfully applied to a comparative pharmacokinetic study of fifteen components in rat plasma after oral administration of the NMT formula or single herb extracts to normal and stroke-afflicted rats. A principal component analysis (PCA) was utilized to evaluate the differences in the pharmacokinetic behavior (time-course) of the absorbed components of NMT, and the absorbed components were assigned to 3 separate clusters. A comparison of the body dynamics of each group indicated that cluster B (ginsenoside Rg1, ginsenoside Rb1, ginsenoside Rb3, ginsenoside Rc) might be the most important constituents controlling the pharmacological effects of NMT. The comparative pharmacokinetic study showed that the different groups had different pharmacokinetic characteristics. The pharmacokinetics-based UHPLC Quadrupole-Orbitrap-MS using a full-scan mode combined with a pattern recognition approach can provide a reliable and suitable means of screening and identifying potentially bioactive components that contribute to the pharmacological effects of Traditional Chinese Medicine (TCM).