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Ethnopharmacological relevance Radix Paeoniae Alba ( Baishao , BS), one of the most commonly used traditional Chinese medicinal herbs, has many pharmacological effects including analgesic activity. Previous studies found that sulfur-fumigation, a post-harvest handling process developed to prevent mold contamination of medicinal herbs, altered the quality of BS. However, whether sulfur-fumigation affects the pharmacokinetics, safety and efficacy of BS warrants further investigation. Aim of the study To evaluate the feasibility of sulfur-fumigation as a post-harvest handling process of BS from the viewpoints of pharmacokinetics, safety and efficacy. Materials and methods The pharmacokinetic behaviors of four active components of BS and one characteristic component of sulfur-fumigated BS (S-BS) were evaluated by high performance liquid chromatography triple quadrupole mass spectrometry (HPLC-TQ-MS/MS). The safety was investigated using ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS) based metabolomics approach after intragastric (i.g.) administration of non-fumigated BS (N-BS) and S-BS in rats. The analgesic efficacy was compared using hot-plate test in mice, after i.g. administration of N-BS and S-BS, at both high and low dosages. Results Systemic exposures of paeoniflorin and oxypaeoniflorin, two analgesic components of BS, were significantly decreased in the S-BS treated group compared to the N-BS treated group, while paeoniflorin sulfonate, one of the sulfur-containing derivatives of S-BS, was detected in all time-points of S-BS treated group with the area under the plasma concentration–time curve (AUC 0−t ) and the maximum plasma concentration (C max ) as high as 7077.06 ± 2232.97 ng/mL*h and 1641.42 ± 634.79 ng/mL respectively, which indicated that sulfur-fumigation altered the pharmacokinetic behaviors of BS. Besides, paeoniflorin sulfonate and its four metabolites with ambiguous toxicities, as well as one endogenous metabolite p-cresol glucuronide, the biomarker of disordered homeostasis of intestinal bacteria and bile acid, were identified as the characteristic metabolites in S-BS administered rats, suggesting that sulfur-fumigation reduced the safety of BS. Furthermore, the analgesic effects at both low and high dosages were decreased in different extent when compared to N-BS administered groups, indicating that sulfur-fumigation weakened the efficacy of BS. Conclusion Sulfur-fumigation altered the pharmacokinetics, as well as reduced the safety and efficacy of BS, suggesting that sulfur-fumigation is not recommended for post-harvest handling of BS. [ABSTRACT FROM AUTHOR]

• Effects of sulfur fumigation and heating desulfurization on CR's quality were studied. • Untargeted/targeted metabolomics and targeted glycomics were integrated to address the effects. • The two processes changed CR's non-saccharide small-molecule metabolome and glycome. • The two processes significantly affected the quality of CR in different ways. • Researches on heating desulfurization and saccharides should be more conducted. Sulfur fumigation and heating desulfurization are used together in the post-harvest processing of many medicinal herbs. However, little is known about the effects of sulfur fumigation on saccharide components, nor about the effects of heating desulfurization on all herbal constituents. In this study, metabolomics and glycomics were integrated to investigate the effects of these two processes on the chemistry of Codonopsis Radix (CR) as a pilot study. The results showed that both sulfur fumigation and heating desulfurization significantly changed the non-saccharide small-molecule metabolome and the glycome of CR in different ways. Chemical mechanisms, such as esterification, glycosidic hydrolysis, esterolysis, amide bond hydrolysis, oxidation and dehydration, are proposed to be involved. These facts strongly inspire that, in addition to investigations of how sulfur fumigation impacts non-saccharide small-molecule metabolites, researches on heating desulfurization and saccharides should be conducted so as to enable accurate, comprehensive evaluation of the quality of sulfur-fumigated herbs. [ABSTRACT FROM AUTHOR]

Highlights • Processing of plasma and urine metabolite datasets for metabolic pathway recognition. • Independent and integrative processing of the two metabolite datasets are compared. • The two processing approaches generate different impact values of pathways. • The two processing approaches even recognize different significant pathways. • The processing approach potentially affects metabolic pathway recognition. Abstract In metabolomics studies, metabolic pathway recognition (MPR) is performed by software tools to screen out the significant pathways disturbed by diseases or reinstated by drugs. To achieve MPR, the significantly changed metabolites determined in different biospecimens (e.g. plasma and urine) are analyzed either independently (metabolites from each biospecimen as a dataset) or integratively (metabolites from all biospecimens as a dataset). However, whether the choice of these two processing approaches affects the results of MPR remains unknown. In this study, this issue was addressed by selecting evaluation of the effects of the herbal medicine Rehmanniae Radix (RR) on anemia and adrenal fatigue by UPLC-QTOF-MS/MS-based metabolomics as an example. The significant pathways disturbed by the modeling of anemia and adrenal fatigue and those reinstated by treatments with raw and processed RR were recognized using MetPA software tool (MetaboAnalyst 3.0), and compared by independent and integrative processing of the significantly changed metabolites determined in plasma and urine. The results showed that the two processing approaches could yield different impact values of pathways and thereby recognize different significant pathways. The differences appear to happen more easily when metabolites from different biospecimens shared the same metabolic pathway. Such pathway could be recognized as a significant pathway by integrative processing but could be excluded by independent processing due to the converged and dispersed importance contributions of the involved metabolites to MPR in the two processing approaches. This issue should concern researchers because MPR is crucial not only to understanding metabolomics data but also to guiding subsequent mechanistic research. [ABSTRACT FROM AUTHOR]

Exploring processing chemistry, in particular the chemical transformation mechanisms involved, is a key step to elucidate the scientific basis in traditional processing of herbal medicines. Previously, taking Rehmanniae Radix (RR) as a case study, the holistic chemome (secondary metabolome and glycome) difference between raw and processed RR was revealed by integrating hyphenated chromatographic techniques-based targeted glycomics and untargeted metabolomics. Nevertheless, the complex chemical transformation mechanisms underpinning the holistic chemome variation in RR processing remain to be extensively clarified. As a continuous study, here a novel strategy by combining chemomics-based marker compounds mining and mimetic processing is proposed for further exploring the chemical mechanisms involved in herbal processing. First, the differential marker compounds between raw and processed herbs were rapidly discovered by untargeted chemomics-based mining approach through multivariate statistical analysis of the chemome data obtained by integrated metabolomics and glycomics analysis. Second, the marker compounds were mimetically processed under the simulated physicochemical conditions as in the herb processing, and the final reaction products were chemically characterized by targeted chemomics-based mining approach. Third, the main chemical transformation mechanisms involved were clarified by linking up the original marker compounds and their mimetic processing products. Using this strategy, a set of differential marker compounds including saccharides, glycosides and furfurals in raw and processed RR was rapidly found, and the major chemical mechanisms involved in RR processing were elucidated as stepwise transformations of saccharides (polysaccharides, oligosaccharides and monosaccharides) and glycosides (iridoid glycosides and phenethylalcohol glycosides) into furfurals (glycosylated/non-glycosylated hydroxymethylfurfurals) by deglycosylation and/or dehydration. The research deliverables indicated that the proposed strategy could advance the understanding of RR processing chemistry, and therefore may be considered a promising approach for delving into the scientific basis in traditional processing of herbal medicines. [ABSTRACT FROM AUTHOR]

Atractylodis Macrocephalae Rhizoma (AMR) is one of commonly used medicinal and edible herbs in China. It is often sulfur-fumigated during post-harvest processing. Carbohydrates are important active components of AMR. However, it is unknown whether sulfur-fumigation would induce changes on carbohydrates. Here, carbohydrates including polysaccharides, oligosaccharides and free monosaccharides were comprehensively analyzed to characterize the quality changes of sulfur-fumigated AMR. Determination of both homemade sulfur-fumigated AMR samples and commercial samples from market revealed that sulfur-fumigation did not affect molecular weight distribution of polysaccharides, but altered polysaccharides content and its ratios of constituent monosaccharides, especially glucose (Glc) and fructose (Fru), as well as the contents of oligosaccharides DP2–10 and free monosaccharide Fru. Moreover, the variations enhanced with the increasing of residual SO 2 content. The potential transformation mechanisms could be due to the hydrolysis of polysaccharides. The research outcomes could provide a chemical basis for the safety and efficacy evaluations of sulfur-fumigated AMR. [Display omitted] • Multi-chromatographic technology methods were integrated to characterize carbohydrates components of AMR. • Impact of sulfur-fumigation on carbohydrates of AMR was evaluated. • Sulfur-fumigation decreased the content of polysaccharides, whereas increased that of oligosaccharides and free fructose. • The variations of carbohydrates enhanced with the increase of SO 2 residual amounts. • The potential transformation mechanisms might be the hydrolysis of polysaccharides into oligosaccharides and monosaccharides. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Chang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicinal formula, has been clinically used for treatment of irritable bowel syndrome (IBS). The mechanisms of CKF for treating IBS and the components that are responsible for the activities were still unknown. Aim of the study To investigate the chemical profiles and effects of CKF on IBS model. Materials and methods The chemical profiles of CKF were investigated by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS/MS). On colon irritation induced rat neonates IBS model, the influence of CKF on neuropeptides, including substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and 5-hydroxytryptamine (5-HT), were measured by ELISA, and the effect on intestinal sensitivity was assessed based on the abdominal withdrawal reflex (AWR) scores. In addition, the activities of CKF against acetic acid-induced nociceptive responses and prostigmin methylsulfate triggered intestinal propulsion in mice were also evaluated. Results 80 components were identified or tentatively assigned from CKF, including 11 alkaloids, 20 flavanoids, 4 monoterpenoids, 9 iridoid glycoside, 9 phenylethanoid glycosides, 10 chromones, 7 organic acid, 3 coumarins, 2 triterpene and 5 other compounds. On IBS rat model, CKF was observed to reduce AWR scores and levels of SP, CGRP, VIP and 5-HT. Moreover, CKF reduced the acetic acid-induced writhing scores at all dosages and reduced the intestinal propulsion ration at dosage of 7.5 and 15.0 g/kg/d. Conclusions CKF could alleviate the symptoms of IBS by modulating the brain–gut axis through increasing the production of neuropeptides such as CGRP, VIP, 5-HT and SP, releasing pain and reversing disorders of intestinal propulsion. Berberine, paeoniflorin, acteoside, flavonoids and chromones may be responsible for the multi-bioactivities of CKF. [ABSTRACT FROM AUTHOR]

It is well-recognized that multiple components, the majority of which are secondary metabolites and carbohydrates, collectively contribute to the therapeutic effects of herbal medicines. The chemical characterization of herbal medicines has focused extensively on secondary metabolites but has largely overlooked carbohydrates. Here, we proposed an integrated chromatographic technique based targeted glycomics and untargeted metabolomics strategy simultaneously determining carbohydrates and secondary metabolites for the overall chemical profiling of herbal medicines; this strategy was successfully exemplified in an investigation of processing chemistry of Rehmanniae Radix (RR), a Chinese medicinal herb. It was demonstrated that the integrated strategy holistically illuminated the variations in the glycome and metabolome of RR samples processed by the traditionally-adopted nine cycles of steaming and drying, and further elucidated the processing-induced chemical transformation mechanisms of carbohydrates and secondary metabolites, and thereby revealed the inherent chemical connections between carbohydrates and secondary metabolites. The result suggested that the proposed strategy meets the technical demands for the overall chemical characterization of herbal medicines, and therefore could serve as a powerful tool for deciphering the scientific basis of herbal medicines. [ABSTRACT FROM AUTHOR]

Si-Jun-Zi decoction (SJZD) with ginseng as the principal medicinal herb is a traditional Chinese Medicine multi-herb prescription that commonly employed to treat colorectal cancer etc. Previous studies showed that nearly half of the commercial ginseng was sulfur-fumigated, one of the postharvest processing methods that commonly causes sulfur-dioxide (SO 2) residue and chemical composition transformation in medical herbs. In this study, the effect of sulfur-fumigated ginseng on global quality of SJZD was evaluated by UPLC-QTOF-MS/MS based metabolomics and multiple chromatographic techniques based glycomics strategies. For non-saccharides components, sulfur-fumigated ginseng led to the emergence of sulfur-containing derivatives and alteration of saponins and flavonoids in SJZD. For saccharide components, sulfur-fumigated ginseng decreased the total contents and molecular weights of polysaccharides, changed the monosaccharide composition of polysaccharides, and increased the contents of oligosaccharides and free monosaccharides of SJZD. The alterations of SJZD were aggravated with the sulfur-fumigated content of ginseng. Those phenomena might be attributed to 1) sulfur-fumigation caused the generation of sulfur-containing derivatives in ginseng, which further transferred to SJZD, and 2) sulfur-fumigation caused the residue of SO 2 in ginseng, which reduced the pH value and further changed the dissolution of saponins and flavonoids and accelerated the degradation of the polysaccharides to oligosaccharides and/or monosaccharides in SJZD. Furthermore, although storage reduced the SO 2 residue in sulfur-fumigated ginseng, it couldn't recover the alterations of chemical profiles in SJZD. In conclusion, sulfur-fumigated ginseng altered the global quality of SJZD, which promoted that extra attention must be paid during the application of herbal formulas that containing sulfur-fumigated herbs. • Sulfur-fumigated ginseng affected the chemical profiles of Sijunzi decoction (SJZD). • The evaluations were assessed by metabolomics and glycomics strategies. • Non-saccharide and saccharide components in SJZD were altered by fumigated ginseng. • Ginseng in high-extent fumigation showed more serious effect on SJZD. • Storage reduced SO 2 residue but not recovered changes of fumigated ginseng on SJZD. [ABSTRACT FROM AUTHOR]

An improved high performance liquid chromatography–electrospray ionization-mass spectrometry (HPLC–ESI-MS) method was developed to quantitatively evaluate the holistic quality of traditional complex herbal medicines (CHMs). Qiong-Yu-Gao (QYG), a classical CHM consisting of Rehmanniae Radix, Poriae and Ginseng Radix, was used as an example. Thirty-eight major components (including six pairs of epimers/isomers) belonging to five chemical types, i.e., iridoid glycosides, phenethylacohol glycosides, furfural derivatives, ginsenosides and triterpenoid acids, were selected as marker compounds. Programmed ionization mode switching and time segment scanning were designed to improve the sensitivity of the MS detection concerning the diverse chemical features of the analytes. The reference compounds of the analytes were individually injected directly into MS to optimize the ionization cone voltage and to select monitoring ion of each analyte. Nine channels with eight time segments were determined for monitoring the thirty-eight analytes, among which six were detected in positive and thirty-two in negative ion modes respectively. Higher signal-to-noise ratios of the analytes were achieved when compared with full time scanning. In addition, the linearity, precision, accuracy and stability of the method were also validated. The established method was applied for the quantitative evaluation of QYG samples prepared with three different methods. Obvious difference in the contents of thirty-eight components, in particular the original ginsenosides, degraded ginsenosides and furfural derivatives, was found among these QYG samples. All these results demonstrated that the established HPLC–ESI-MS with programmed ionization mode switching and time segment scanning approach is very suitable for the standardization investigation of CHMs. [ABSTRACT FROM AUTHOR]

Sulfur-fumigation undoubtedly alters the chemical and metabolic profiles, but controversially affects the efficacy and safety of medicinal herbs. To comprehensively evaluate the effects of sulfur-fumigation on the efficacy and safety of medicinal herbs using a meta-analysis approach and further investigate the potential contributory factors. Literatures were retrieved on PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Chinese VIP Information and Wanfang, and the outcomes involved activities and toxicities were extracted using standard data extraction forms. The effects of sulfur-fumigation on the efficacy and safety of medicinal herbs were evaluated by meta-analysis approaches. A total of sixteen studies were included in this study. Sulfur-fumigation reduced the efficacies of medicinal herbs with immune activity [thymus index (SMD = −1.81; P < 0.00001); spleen index (SMD = −1.11; P < 0.0001)], anti-oxidative activity [MDA (SMD = 2.60; P = 0.04); SOD (SMD = −2.21; P < 0.00001)], analgesic activity [heat tolerate time (SMD = −2.51; P = 0.001); writhing time (SMD = 0.36; P = 0.006)], anti-platelet aggregation activity (SMD = −1.84; P = 0.001), and anti-inflammatory activity [ear swelling degree (SMD = 0.47; P = 0.006)]. The reductions might be ascribed to sulfur-fumigation significantly reduced the contents of active ingredients in medicinal herbs, leading to dramatic decrease in the absorption of these ingredients and their metabolites in vivo. Furthermore, sulfur-fumigation induced the toxicities of medicinal herbs, mainly on hepatotoxicity, which might due to fumigation-induced residues of sulfur dioxide and heavy metal, and generations of sulfur-containing derivatives and toxic metabolites. Besides, administrated with sulfur-fumigated medicinal herbs with high sulfur ratio and/or higher dosage showed more significant toxicity. Sulfur-fumigation reduced the efficacy and safety of medicinal herbs, indicating sulfur-fumigation might not a feasible approach to process medicinal herbs. However, with obvious limitations, much more rigorous designed-trials are still needed to confirm the conclusion. [Display omitted] [ABSTRACT FROM AUTHOR]

• UPLC-QTOF-MS/MS based chemical profiling was firstly developed for qualitatively characterizing the Impatiens Caulis sample. • A sensitive UPLC-DAD method was firstly developed to quantify eleven compounds in the Impatiens Caulis sample. • The developed method was integrated to compare the quality consistency of commercial Impatiens Caulis samples. In this study, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) and ultra-high performance liquid chromatography coupled with photo-diode array spectrometry (UPLC-DAD) were firstly integrated to qualitatively characterize the chemical profiles and quantitatively determine the major components in Impatiens Caulis (IC), a Chinese medicinal herb derived from the dried stem of Impatiens balsamina. The qualitative analysis revealed that there was no difference in chemical profiles of twenty commercial IC samples. A total of 45 components were characterized, there in 5 naphthoquinones, 3 coumarins, 5 phenolic acids, 12 flavonoids and 3 other compounds were identified definitely. However, the quantitative results showed a significant difference in these IC samples. In particular, the highest content of total quantified compounds was even 9.49 times of the lowest one. Furthermore, the average contents of these quantified compounds in twenty commercial IC samples had high values of relative standard deviation (RSD) ranged from 15.64% to 98.76%, suggesting a poor quality consistency in these commercial IC samples. Therefore, efficacy related chemical markers as well as the cultivation region, harvest time and/or post-harvest handling of IC should be further investigated for ensuring its quality and efficacy consistency. [ABSTRACT FROM AUTHOR]